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Home , Coacervate, Emil Frei, Giardiavirus, Mycoplasma laboratorium, Vinther

Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia

*) in Support of the Text with Literature Citations. Referrals to illustrations in Appendix 2.

Cancer in the Plant. The insertion of the Agrobacterium tumefaciens circular plasmid T (transferred) DNA into the genome of its new host, the plant (Gelvin BS. Microbiol Molecular Biol Rev 2003;67:16–37). The plant cancer “crown gall” (agrocallus; Agrobacterial crown gall) consists of malignantly transformed cells replicating the agrobacterial T DNA plasmid (reviewed in postscript Table XXXV). For reference: Koncz C Mayerhofer R Koncz-Kálmán Zs et al EMBO J 1990;9:1337–1346. Transfer of potentially oncogenic bacterial genes and proteins to patients: Septicemic Bacteroides enterotoxigenic (Sinkovics J G & Smith JP Cancer 1970;25:663–671; Viljoen KS et al PLoS One 2015;10(3):e0119462); Bartonella bacilliformis etc (Guy L et al PLoS Genet 2013;9(3):e1003393; Harms A & Dehio C Clin Microbiol Rev 2012;25:42–78; Llosa M et al Trends Microbiol 2012;20:355–9; Minnick MF et al PLoS Negl Trop Dis 2014;6(7):e2919); Helicobacter pylori (Bonsor DA et al J Biol Chem 2015;pii:jbc.M115.641829; Su YL et al J Immunol 2015;194:3997–4007; Vaziri F et al Pathog Dis 2015;73(3). pii.ftu021); Porphyromonas gingivalis (Katz J et al Int J Oral Sci 2011;3:209–215); Tuberculous infections with A. tumefaciens in patients (Ramirez FC et al Clin Infect Dis 1992;15:938–940).

DNA-binding Antibodies. DNA- (or RNA-) binding proteins use zink ﬁnger motifs, leucine zippers and winged (beta-sheet loops) helix-turn helix motifs (HTH, two helices separated by the loop, RNA/DNA-binding domains) in recognition of RNA/DNA receptors for attachment. Pro-apoptotic protein p53 is commonly attached to DNA (vide infra). Advanced multicellular organism established a fundamental relationship between DNA genes and circulating antibodies, which overlapped the pre-existing miR activity for posttranslational gene expression. One of the best examples is played out in the pathogenesis of the T cell lymphoma mycosis fungoides and Sézary syndrome (that may also hide the underlying retroviral pathogen/passenger presumed to be there by Dorothea Zucker Franklin) (Proc Natl Adad Sci 1991;88:7630–7634; 1997;94:6403–6407). One of the inducer oncogenes of mycosis fungoides is TOX (thymocyte selection-associated high mobility group protein box gene), which normally regulates T cell differentiation.

© Springer International Publishing Switzerland 2016 559 J.G. Sinkovics, RNA/DNA and Cancer, DOI 10.1007/978-3-319-22279-0 560 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia

Overexpressed TOX induces mycosis fungoides tumor cell proliferation and migration. The TOX protein mRNA is under the control of miR-223 through speciﬁc domain alignment to its 3′ UTR (untranslated region) in the AGO complex. High blood levels of miR-223 bring about the cessation of mycosis fungoides tumor cell growth. The production of tumor initiator high mobility group (HMG) DNA-binding protein is targeting its own DNA genes of T cell dediffer- entiation and homing; it is switched off by a speciﬁc miR (Huang Y et al Oncotarget 2014;5:4418–4425; McGirt L et al J Invest Dermatol 2014; 134:1101–1107; O’Flaherty E & Kaye J BMC Genomics 2003;4:13).

Continuous Replication of the Trypanosoma in liquid media. Not in the insect’sgut, but in the blood stream of its mammalian host, the slender Trypanosoma cell is fed primarily on sugar. This protozoan is also capable to synthesize glucose-6-phosphate. Growing in vitro in suspension, its speed of replication is dependent on the concentration of sugar in the liquid media. The stress responsive heat shock proteins (Hsp90) work in cell survival pathways in the protozoa, but became oncoproteins in multicellular, incl. human, hosts. Questions still incompletely answered: In the rapidly growing T. brucei, sugar metabolism is warburgian? Insulin-like growth factor receptor (IGFR) is overexpressed? Hsp90 promotes growth; is there growth dependence on Hsp90? Intranuclear Ki-67 is overexpressed? Telomers are capped after each cell division? Hsp90 inhibitors (geldanamycin analogs) induced trypanosomal death due to heat shock. Positive answers would mean that the unicellular protozoan’s rapid growth is comparable to that of a cancer cell. Cooperative studies of Ludwig Maximilian University (LMU); Institut National des Sciences Appliqueés (INSA), Université Toulouse; Centre National de la Recherche Scientiﬁque (CNRS), Université Bordeaux. Allmann S et al Biol Chem 2013;288:18494–18505. Van Reet N et al Exp Parasitol 2011;128:285–290. Meyer KJ & Shapiro TA J Infect Dis 2013;208:489–499 http:// www.pasteur.fr/ip/easysite/pasteur/en/research/scientiﬁc-department/parasitology; http:/ phys.org/news/2013-07-parasite-sugar.html; http://www.ncbi.nlm.nih.gov/pubmed/? term=trypanosoma+liquid++culture Faculty Biology, Ludwig-Maximilians- UniversitätMünchen; Biozentrum, Grosshadernerstrasse 2–4, D82152 Martinsried, Germany. The Johns Hopkins University School of Medicine, Baltimore, USA.

Stem Cells Ascend from the bottom of the Lieberkühn crypt to renew themselves and release somatic cells to function as epithelial cells of the mucous membrane (reviewed in Table I).

S. Yamanaka Lentivirally Transferred four stem cell genes (oct4; sox2; klf4; c-myc) for reprogramming human differentiated cells into pluripotential stem cells; re-differentiation of pluripotential stem cells into differentiated cell could be induced. http://syntheticdaisies.blogspot.com/2012/10/the-spawn-of-gurdons-frogs.html.

Dictyostelia amoebae. The Amoebozoan Dictyostelium discoideum exists in many life forms: in sexual cycle, in vegetative cycle, and in social cycle. Its discoidin is a ﬁbronectin; its tiger genes encode histocompatibility complexes; it uses Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 561

ERK/MAPKK signaling “cell survival pathways” (extracellular signal regulated kinase; mitogen-activated protein kinase kinase). MAPKK becomes a proto-oncogene in vertebrate mammalian (human) cells: in ras- (rat sarcoma) transformed cancer cells. Members of the D. discoideum clade (D. purpureum, D. fasciculatum) are comparable in their genomics and proteomics. Evolutionarily they separated from their common ancestor 600–800 mya and in comparison to the yeast, doubled their number of protein-coding genes up to 12,000 (Loomis WE Methods Mol Biol 2013;983:39–58). The other social amoeba, Acytostelium subglobosum emerges as a different species, which increased its chromosome number up to 18, but not because it has become diploid. The starving D. discoideum forms a conditionally multicellular fruiting body with spore ball on a stalk. It is the migratory slug cells that either form the fruiting body or the stalk. The fruiting body represents the germ cells and the stalk consists of the terminally differentiated somatic cells. The A. subglobosum does not differentiate its stem cells to a stalk; its stalk is a-cellular. The cellulose synthase gene builds the cell-free stalk. If “The differentiation of mortal or sacriﬁced somatic cells from reproductive germ cells was the key event for the establishment and diversiﬁcation of multicellular systems” (Urushihara H et al BMC Genomics 2015;16(1):80), then D. subglobosum should be regarded evolutionarily more ancient than D. discoideum. A. subglobosum and D. discoideum are casting light to the beginning of a decisive process in the development of multicellularity. The Dd-MRP4 mitochondrial ribosomal protein is able to induce in human cancer cells the process of programmed cell death (apoptosis). Mitochondrial ribosomes are of ancient bacterial derivation. The Dd-mrp4 gene product protein in D. discoideum is the major initiator of cell differentiation (induced by starvation). Differentiation induction is achieved by the Dd-MRP4 protein through its entry into the nucleus for activation of its target genes (miR genes?). Another unrelated and different D. discoideum ribosomal protein is S4 (Dd-RPS4). It is homologous to the human chromosome X-linked cytoplasmic ribosomal protein S4 (Hs-RPS4X) in 66% identity and 92% similarity in their aa sequence (Maeda Y Biomolecules 2015;5:113–120).

Amphioxus I, prominent among them is Branchiostoma ﬂoridae. Possesses notochord and primordial nervous system consisting of intraabdominal sensory cells and notochord nerve cells connected with axons and synapses. An advanced neuro- chemical network releases and circulates cholinergic and GABAergic/glycinergic (gamma aminobutyric acid) molecular mediators. The amphioxus’ achaete scute homologues (Ash) exist conserved up to Homo (Lu TM et al Development 2012;139:2020–2030). The Ash genes may act as proto-oncogenes subject to malignant transformation. The achaete scute homolog basic helix loop helix gene (ash) and the delta ligand Notch pathway evolved at this site. The adult amphioxus preserves its notochord, whereas tunicate larvae of Ciona lose their cordate characteristics through metamorphosis into adulthood. The amphioxus frontal eye spot reveals photoreceptor Joseph cells with many homologies to camera-type lens eyes of jawless (lamprey) to jawed (sharks) vertebrates (Candiani S et al BMC Neurosci 2012;13:59; Lu TM et al Development 2012;139:2020–2030; Vopalensky P et al 562 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia

Proc Natl Acad Sci 2012;109:15383–15388). The amphioxus and the sponge Amphimedon qeenslandica share an ancestral TGFβ gene (Song X et al Genomics 2014;103:147–153). An advanced miR system controls amphioxus gene expression (Zhou X et al Gene 2012;508:110–116). The amphioxus genome preserved inserted six clades of non-LTR retrotransposons named among a long list of non-LTR elements of other sources including those from Ciona intestinalis (Permanyer J et al Int J Biol Sci 2006;2:48–53). The Lu TM team worked with B. ﬂoridae specimens collected in the Tampa Bay, Florida (W.P. Hall http://forums.about.com/ab-christianity/ messages?msg=10917.2462). As oncogenes, Ash induce esthesioneuroblastoma*), medullary carcinoma of the thyroid, small cell undifferentiated carcinoma of the lung, or transforms pre-existing adenocarcinoma cells into chemo-radiotherapy-resistant neuroectodermal malignant cells (Wang XY et al Lab Invest 2007;87:527–539) Single nucleotide polymorphism in the 3′ untranslated region of miRNAs (hsa-miR-1827) occur in small cell lung cancers, in which the L-myc1 (1p34) and achaete scute human homolog genes (11p15.1; 12q22-q23) are involved (Xiong F et al Cancer Res 2011;71:5175–5181).

*) Esthesioneuroblastoma. The orbits and sinuses contain a large, enhancing, and expansile mass occupying the ethmoid air cells. The cribriform plate is invaded. The left anterior cranial fossa is broken into. Preoperative platinum-based chemotherapy, surgical resection, and postoperative radiotherapy is the standard treatment of Hyams’ high grade and Kadish advancing stage tumors. From Mayo Clinics: USA, McElroy EA Jr et al Neurosurgery 1998;42:1023–1027; from Institut Gustave Roussy, Villejuif, France, Modesto A et al Oral Oncol 2013;49:830–834; from Children Hospital, Rabat, Morocco, El Kababri M et al Pediatr Hematol Oncol 2014;36:91–95. Comment: Treated high grade tumors lie dormant and relapse.

Choanoflagellates (Monosiga brevicollis; ovata). Choanoflagellate genomic segments containing cell survival pathway Pak (p21 activated kinase); when transfected into somatic cells of metazoan multicellular vertebrate hosts (mice; rats; human), pak/Pak induces “malignant transformation” (Watari A et al Oncogene 2010;29:3815–3826). The merlin-encoding tumor suppressor gene neurofibro- matosis NF2, the suppressor of cyclin D1 (or Bcl-1) promoter, is regulated by the pak/Pak pathway. PAK1 stimulates the cyclin D1 promoter; cyclin D1 mRNAs rise. Merlin inhibits the cell cycle in G1 by suppressing cyclin D1 and CDK4 (cyclin-dependent kinase) and dephosphorylating the retinoblastoma RB protein. The Rac/Pak axis is an oncogene (Xiao G-H et al Mol Cell Biol 2005;25:2384–2394).

Blooming Dinoflagellate Symbiodinium (zooxanthella) cells survive self-generated toxins that are highly lethal to multicellular life forms up to fishes and Florida manatees. ATP-cassette ABC transporter protein pumps expel the toxins by mechanisms similar to those of tumor cells gaining resistance to chemotherapy (Table I). Symbiodinium cells parasitize the cytoplasm of cnidaria corals, where they are replicating very rapidly. There is a mass exodus of flagellated mastigote Symbiodinium cells from the parasitized host cells. “Bleached” (whitened) coral Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 563 colonies are left behind. The motile mastigotes discard they flagellae and assume non-motile metabolically quiescent coccoid morphology ranging in size of 6–13 μm. Both mastigotes and coccoid cells undergo mitosis generating two mastigotes. Dinoflagellates carry reticulated chloroplasts. The light-harvesting center is in the thylakoid membrane; it contains a chlorophyll-protein complex. Symbiodinium cells carry also mitochondria retaining some of their original genes. The intranuclear DNA is kept supercoiled within the chromosomes. In the S-phase of the cell cycle, the uncoiled DNA duplicates. Symbiodinium cells rapidly replicate in cultures in the laboratory. The rapidly replicating genomes are of interest: what genes are constitutively activated? Are intranuclear Ki67 proteins overproduced? The Symbiodinium genome operates over 42,000 protein-coding genes; duplicated genes; basic eukaryotic and horizontally acquired bacterial genes. It is spliceosomal intron-rich: 18.6 introns / gene; its spliceosomal snRNA genes (U1-U6) are clustered (Jeong HJ et al J Eukaryot Microbiol 2014;61:75–94; Shinzato C et al PLoS One 2014;9(1):e85182; Shoguchi E Curr Biol 2013;23:1399–1408). In Summary, some cnidarians carry virally infected endosymbiotic algae and respond with an active NFκB/STAT pathway (in Sinkovics JG Int J Oncology 2015;47:1211–1229).

Tibor Gánti’s Chemoton. The chemoton is a self-reproducing automatic machinery; it operates autocatalytic cycles of chemicals in a liquid base surrounded by a bilipid membrane. Chemotons grow by metabolism and reproduce by biological fission, but as non-genetic entities. Osmotic pressure within the microsphere (the chemoton) induces invagination of the membrane leading to fission. The chemical reactions within the chemoton are not dependent on enzymes. Divided chemoton units are identical without hereditary variation. Cycle stochiometry characterizes math- ematically and expresses quanitatively the chemical reactions occurring within the chemoton. Incorporation of a new external molecule (molecule T) into the system occurs through small gaps of the membrane. The amphipathic dynamic molecule advances the internal metabolism of the chemoton toward the acquisition of heri- table enzymes (ribozymes being the first). Chemotrons are the primordial first cells of the living matter (Gánti T: “The Principles of Life”. Oxford University Press, 2003; Chemoton Theory. I. Theoretical foundation of fluid machineries. II. Theory of living systems. Kluwer Academic/Plenum Publishers 2003. Csendes T. A simulation study of the chemotron. Kybernetes 1984;13:79–85).

An Advanced Oparin’s Coacervate (кoaцepвaт,Oпapин) would be an imaginary protobiont, which would engulf either proteobacteria for mitochondrial symbionts (in animal cells), or cyanobacteria for plastids with eye spot for photosynthesis (in plant cells). Visiting lecturer Nasif Nahle, at Aguascalientes, Monterrey, Mexico in 2004, at the Conference of Astrobiology http://biocab.org/Astrobiology.html.

Reverse Transcriptase (D. Baltimore/H.Temin) transforms RNA into complementary cDNA. mRNA is used as template. The ssDNA strand is made into a dsDNA strand on a primer by DNA polymerase. Taq (Thermus aquaticus) heat stable 564 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia polymerase (K. Mullins) synthesizes complementary DNA strands from primer in the polymerase chain reaction.

The Extant DNA/RNA Complex Reverts back to the Primordial RNA/DNA Complex. Predecessor cytogeneticist Barbara McClintock laid down the morphological foundations of chromosome science: deletions, inversions, translocations of mobile elements, ring formation, broken ends and fusions, that restructure the genome. Resurrection from ‘genome shock’. Insertion of related elements at distinct loci and remaining under coordinated regulation (McClintock B. Significance of response of the genome to challenge. Science 1964;226:792–800). Re-emerges the primordial dependence of DNA on RNA, and on protein enzymes. SINE (short interspersed nucleotide elements) releasing mRNAs. Retrotransductions of LINEs (long interspersed nucleotide element) consisting of RNA and cDNA molecules. A combination of exons and introns in inverted terminal repeats. MITE DNA transposons (miniature inverted-repeat transposable elements). Inter-prokaryotic, intereukaryotic, including inter-kingdom, horizontal gene transfers. Symbiotic cellular unisons (cyanobacterial plastids in plant cells; alpha-proteobacterial mitochondria in animal cells). Tertiary symbioses in dinoflagellates, thus earning energy from photosynthesis. Evolution of genomes by whole genome doublings (WGD, repeatedly so) (Shapiro JA. Mobile DNA and evolution in the 21st century. Mob DNA 2019;1.4). The human genome is interspersed by transposable elements (TE), which are either DNA transposons, or RNA retrotransposons. The retrotransposons are SINEs, LINEs, LTRs (long terminal repeats), and Alus. TEs dictate the long term evolution of the genome. Satellite S (micro-, or macroS) DNAs are high copy number tandem repeats. The snoRNAs (small nucleolar) are the ancestors of the α-Satellate RNAs. Some ncRNAs are expressed from repetitive repRNAs. Noncoding ncRNAs of highly repetitive regions form a large reservoir capable to evolve into novel functional RNAs. The 300 bp Alu repeats (Arthrobacter luteus Alu enzyme that cuts DNA) are SINE family member ncRNAs. SINEs derive from tRNAs. SINE’s RNA polymerase III transcribes Alus. Alu sequences remain embedded in protein-coding genes. Small nuclear snRNAs act like TEs and end up as pseudogenes (Matylla-Kulinska K et al Functional repeat-derived RNAs often originate from retrotransposon-propagated ncRNAs. Wiley Interdiscip Rev RNA 2014;5:591–600). MicroRNAs (miR-661; miR-885-3p) balance p53 and MDM protein expressions by controlling their mRNAs. In another level, Alus embedded in the 3’UTR (untranslated region) of mRNAs, as co-recipients of the aligning microRNAs, may accept or reject alignment (Hoffman Y et al microRNAs and Alu elements J Mol Cell Biol 2014;6:192–197). The primate-related SINE-Alu sequences appeared first in the Branchiostoma amphioxus (Holland LZ A SINE in the genome of the cephalochordate Int J Biol Sci 2006;2:61–65). In the Argonaute (AGO) protein family, PIWI proteins bind PIWI-interacting piRNAs (P element-induced wimpy testis, drosophila); it is one of the three small RNAs (micro miRNA; small interfering siRNA). AGO proteins also bind miRNAs and siRNAs. PIWI proteins are primarily expressed in the germline, but somatic tissues are not exempt of their presence either; that includes stem cells. The PIWI/piRNA pathway Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 565 suppresses transposons, thus saving the integrity, and the regulation with chromatin, of the protein-coding genes (Mani SR & Juliano CE Untangling the web Mol Reprod Dev 2013;80:632–654).

Acholeplasma (Mycoplasma) laidlawii was grown in culture and its fusogenic phage particles were purified and concentrated (www.lookfordiagnosis.com). Author’s first encounter with A. laidlawii occurred in the early 1970s at M.D. Anderson Hospital, where A. laidlawii was found to have contaminated a human sarcoma established cell line. The contaminated fluid was transferred to Ferenc Györkey of the Pathology Department at the Veterans Administration Hospital, Houston, TX for further studies in cell fusion experiments (unpublished). Similar contaminated human cancer cell cultures were reported from Russia (Polinskaia GG et al Tsitologiia 2000;42:190–195; 794–801). A swine pathogenic Acholeplasma exists in Hungary (Stipkovits L et al Acta Vet Acad Sci Hung 1973;23:307–313; 361–368; J Hyg (London) 1974;72:289–296). Cells of the pathogenic PG8 strain of Acholeplasma laidlawii (the causative agent of phytomycoplasmosis in Oryza sativa L plants infected through their roots) release extracellular membranous vesicles. These vesicles contained virulence proteins, RNA nucleotide sequences, including rRNAs (Chernov VM, Chernova O A et al Scientific World J 2011;11:1120–1130; 2012;3154–3174; J Proteomics 2014;110:117–128). The presence of rRNAs indicates to this author that the extracellular membranous vesicles are ribosome-like exosomes. The phenomenon of exosome release is universal in the cellular world. Observations without actual precise counts indicate that virulent pathogenic or malignantly transformed cells release excessive numbers of exosomes. This author suggested that DNA-free but RNA-loaded exosomes (including rRNA) represent a retrograde evolutionary descent of the cell to the precellular era of the living matter. In the RNA World exosome-like units might have populated the Earth. Precellular ribozyme-armed and readily mutable rRNA-containing ribosome-like units might have existed with simple ribonucleoproteins (RNP) within (Sinkovics JG Europ J Microbiol Immunol 2015;5:25–43). Metabolomic analysis shows some unique differences between A. laidlawii (strain PG-8A) and Mycoplasma pneumoniae in that, three amino acids (alanine, asparagine, valine) present in M. pneumoniae are missing from A. laidlawii. It is possible that alanin is very rapidly incorporated into proteins through aminoacyl-tRNA synthetase, thus apparently disappearing from the metabolome. A. laidlawii operates a unique lysine decarboxylase not possessed by any other Mycoplasmataceae. In riboflavin biosynthesis, in addition to the customary bifunctional riboflavin kinase, only A. laidlawii possessed enzymes for the conversion of diamino-hydroxyphosphoribosyl-aminopyrimidines (Vanyushkina AA et al PLoS One 2014;9(3):e89312). Virally infected (phage-carrier) JA1 strains of A. laidlawii reveal acute infections with cell lysis, and chronic non-lytic non-cytocidal infection with rapid growth of infected cells. A. laidlawii has no bacterial cell wall; it is surrounded by a single lipoprotein cell membrane, similarly to spheroplasts, or to eukaryotic cells of uni- or multicellular hosts (Liss A & Ritter BE J Gen Microbiol 1985;131:1713–1718). After lysis of the membrane with antibody and complement, the remaining cytoplasms were referred to as ghosts 566 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia

(Brunner H et al Infect Immun 1976; 13:1671–1677), but without stating if the membrane-free cytoplasms could metabolize and to what extent. The membrane-free E. coli cytoplasms observed by this author were presented as examples of “cell-free living matter”, “plasma” (even though they were lost for further studies in 1956) (Sinkovics J Biol Közlem (Hungary) 1954;2:69–81; 1957;5:19–27; Acta Microbiol Hung 1957;4;59–75; Die Grundlagen der Virusforschung, Hung Acad Sci, 1956). However, extracellular E. coli ribosomes remained functional in vitro in the M W Nirenberg and J H Matthaei experiments (Proc Natl Acad Sci USA 1961;47:1580– 1586; 1588–1602). Now, A. laidlawii exosomes emerge; however, they are membrane-bound cytoplasmic units (vide supra).The extant Mollicute A. laidlawii strains exhibit a high degree of genomic and proteomic deviation among themselves; the deepest branching member of the clade remains A. laidlawii (Stepens EB et al Yale J Biol Med 1983;56:729–735; Kube M et al J Mol Microbiol Biotechnol 2014;24:19–35). The ancestors of the unique Mollicute mycoplasma A. laidlawii and its fusogenic virus coexisted with archaea (crenarchaea) spheroplasts, a scenario that readily offers itself for theories of primordial cell fusions that might have created the ﬁrst eukaryotic cells; a situation possibly amenable to reproduction in the laboratory (Sinkovics JG Acta Microbiol Immunol Hung 2001;48:115–127).

Fusogenic Viruses. Not all phages are lysogenic. An Acholeplasma phage (see Text) might have been the ancestor of eukaryotic fusogenic viruses, which induce coalescence of their host cells’ membranes. Of numerous eukaryotic fusogenic viruses, stand out the Mus cervicolor leukemia retrovirus M813 fusing T lymphoma cells; the EnvV syncytin-producer retroviruses fusing syncytiotrophoblasts of the placenta; HIV-1 fusion protein fusing infected lymphocytes; inﬂuenza viral fusion peptides fusing lipid bilayer vesicles; parainﬂuenza and paramyxoviral cell fusion proteins; corona virus-induced syncytia; measles virus producing multinucleated giant cells; Sendai virus-fused cells; herpes simplex viral cell-fusogenic glycoprotein M; env gene/protein-acquiring endogenous retroviruses budding from human tumor cells (lymphoma, Reed-Sternberg cells, Kaposi sarcoma, adenocarcinoma, melanoma) and inducing cell fusions. Virus-producer fused tumor cells may gain growth advantages; may express new antigenic targets to immune defenses or to immunotherapy (see Text). Upon cellular encounters, the identity or chemical relatedness of cell membrane or viral capsid/envelope structures leads to cell fusions (Ogle BM et al Nature Reviews Molecular Cell Biology 2005;6:567– 575). A candidate fusion partner is the ancestral mycoplasma Acholeplasma, and the primordial mediator is its fusogenic virus (phage) (see in Text).

The much Debated Tree of Life was set into three domains by Ernst Haeckel: “Monophyletischer Stammbaum der Organismen” consisting of Protista, Plantae and Animalia. Extraordinary acquisition of genes through horizontal (lateral) routes invalidates the evolutionary pathways that were constructed by true vertical inheritance. Among Bacteria, Mycoplasmataceae vie with Aquifex aeolicus for the basic position; regression of Mycoplasmataceae from Bacteroides is unacceptable Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 567

(Klenk H-P et al J Mol Evol 1999;48;528–541; Woese CR Maniloff J Zablen LB Proc Natl Acad Sci USA 1980;77:494–498).

After long debates, it has been fully accepted that cyanobacteria entered as endoplasmic symbionts of the eukaryotic algae-to-plants lineage; and that ancestral purple proteobacteria have become the eukaryotic cytoplasmic endosymbiont mitochondria of animalia.

Archaea are more accurately divided as phyla Crenarchaeota, Euryarchaeota, Korarchaeota, and Nanoarchaeota. In evolutionary order, for the position of the ﬁrst domain, vie the prokaryotes Mycoplasmataceae or Aquifex, with Nanoarchaea. Recent isolates include the Lokiarchaeota loaded with genes, whose signatures later become dominant in the eukaryotic proteomic repertoire (Spang A et al Nature 2015;521;173–179). The TACK archaeal superphylum consists of Thaumarchaeota/ Aigarchaeota/Crenarchaeota/Korarchaeota existing in sister relationship with Euryarchaeota, both being ancient carriers of genomes/proteomes that reappear in eukaryota (Raymann K et al Proc Natl Acad Sci USA 2015;12:6670–6675). A hyperthermophilic extremophile archaea isolated from the hot springs of the Yellowstone National Park carries a virus with a circular dsDNA genome, which encodes elaborate turret-like structures in its capsid. These structures of the Sulfolobus turreted icosahedral virus re-appear throughout evolution in bacteriophages, algal viruses and adenoviruses. Its gene might have originated in a common ancestor that existed before the division of the three domains of life (Rice G et al Proc Natl Acad Sci USA 2004;101:7716–20).

Joseph, Rhawn: Genetics and evolution of the life from other planets. J Cosmology 2009;1:150–200). In contrast, the present author prefers to envision the origin of life on the ancient planet Earth. Between the first protocells, virally-mediated fusion of two equal partners: a spheroplast of an archaeon (a crenarchaeota) and a spheroplast of a prokaryota (a mycoplasma), followed by the later engulfment of the α-proteobacterium to become the mitochondrium, or a cyanobacterium to become a photosynthetic unit (plastid). Phage-mediated fusions of cell wall-free mycoplasma-like cells (the Acholeplasma) do occur. The equal fusion partner of the prokaryota would be a crenarchaeota (both in the form of spheroplasts), but would they yield to the same fusogenic phage? These basic fundamental experiments of nature could possibly be reproduced in a laboratory. The candidate fusion partner archaea might have been thermophilic. Thermophilic archaea populated (still do) hot submarine vents. Light energy from the Sun does not penetrate the depths of the seas. There, geothermal radiation provides the energy to anaerobic photosynthetic pigments (Beatty JT et al Proc Natl Acad Sci USA 2005;102:9306– 10). Some nanoarchaea (N. equitans and Ignicoccus hospitalis) form unisons without fusion. Such unisons are expected to have been formed among the deepest branch-offs (Stetter KO: A brief history of the discovery of hyperthermophilic life. Biochem Soc Trans 2013;41:416–429. Jahn U et al Nanoarchaeum equitans and Ignicoccus hospitalis: New insights into a unique, intimate association of two 568 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia archaea. J Bacteriol 208;190:1743–1750. Podar M et al A genomic analysis of the archaeal system Ignicoccus hospitalis-Nanoarchaeum equitans. Genome Biol 2008;9(11):R158). Fused cells of equal ranks created the first eukaryote; the united large cell was able to engulf single-celled bacteria, which surrendered to endosymbiosis in a subservient position as mitochondria and plastids. The mitochondria transferred most of their genes to the host cell nucleus, but retained the faculty of the endogenous apoptosis induction in their host cells. The widely practiced lateral (horizontal) gene transfers between archaea and bacteria (uni- directional; bidirectional?) resulted in species diversification, but transfer-resistant macromolecular genes preserved the dominant vertical routes of evolution (Abby SS et al Proc Natl Acad Sci USA 2012;109:4962–4967).

The Unicellular Ciliate Protozoon, Paramecium tetraurelia, possesses nuclear dimorphism: a germline genome in its micronucleus (MIC) and a somatic genome in its macronucleus (MAC). Its cytochrome b5 genes carry out the ubiquitous electron transports. Upon its three or four rounds of whole genome duplications, the largest numbers of reduplicated and retained, and the smallest numbers of lost, genes are the cytochrome b5 genes (of the whole macronuclear and mitochondrial genomes consisting of some 40,000 genes). Among others, sequenced were the tRNA trp and tRNA tyr (tryptophan; tyrosine) genes. The paramecium germ line nucleus is transcriptionally silent, and the somatic macronucleus is transcriptionally active. Germ line-speciﬁc sequences (internal eliminated sequences, IESs) are excised by the thousands, but with great precision (as in other ciliates). One IES is located in an intron. Gene expressions are carried out with extraordinary replication ﬁdelity, especially in their DNA polymerases, resulting in nucleotides conserving amino acid sites (Sung W et al Proc Natl Acad Sci USA 2012;109;19339–19344; Vayssié l et al Nucleic Acids Res 1997;25:1036–1041; Wu KJ et al Genet Mol Res 2013;12:1882–1896).

Conjugating Paramecia. After the sexual event, the new somatic MAC submits the germline MIC to a series of rearrangements. The rearrangements consist of the precise excision from the diploid germline genome of inserted parasitic DNA elements. Unique-copy Internal Eliminated Sequences (IESs) are excised by certain long ago inserted, but by now domesticated transposases, such as from the piggyBack (from cabbage looper moth Trichoplusia ni) to the PiggyMac element. Targeted are the Tc1/mariner, sardine and anchois transposons. All IESs are remnants of these, or other pre-inserted transposons. Some IES inserts shorten (<159 bp) and decay. Epigenetic ncRNAs locate the targets; ncRNAs remain on board to purify eukaryotic genomes of RNA-to-DNA inserts. Two dinucleotide TA sequences flank the IES to be excised. Mutated flanking TA dinucleotides with cis-acting Mendelian mutations prevent their excision; otherwise mutation in one of the two flanking TA dinucleotides pose an absolute requirement for IES excision. The Oxytricha genome is heavily infested by inserted transposons. The endonuclease required for the cleavage of the Oxytricha genome is a transposase derived from its germline TBE (telomere-bearing elements) transposons. The piggyback Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 569 domain5 (PGBD) element was domesticated in the amphioxus 500 mya. It remains conserved in all vertebrates, but in the human genome it lost its catalytic motif and acquired restrictive-silencer factors, thus it is non-functional (Arnaiz O et al PLoS Genet20112;8(10):e1002984; Pavelitz T et al Mob DNA 2013;4(1):23).

The Vegetative Giardia Trophozoites are binucleated. The mitosomes of the Giardia and the hydrogenosomes of the trichomonads are remnants of pre-existing mitochondria (Dolezal P et al Proc Natl Acad Sci USA 2005; 102;10924–9). The giardial genome operates 6470 ORFs. They encode ubiquitin-activating enzymes. During the process of encystation, many proteins are eliminated by ubiquitination. Polo-like kinases, initiators of mitosis, are also degraded (Nino CA et al Microbiology 2013;2:525–539). The low branching unicellular eukaryotic diplomonads, Giardia, operate noncoding ncRNAs, small nucleolar snoRNAs, spliceosomal small nuclear snRNAs, and inhibitory micro miRNAs. Giardias preserved the key ribozymes/RNPs for pre-rRNA processing (mitochondrial RNA processing in an amitochondriate). The H/ACA box snoRNAs (adenine cytosine adenine) are for pseudouridylation (posttranscriptional isomerization of uridine to pseudouridine ψ) of mRNA/rRNA/snRNA. The ψ synthases are guided to their targets by the small snRNAs already in the archaea. The location of pseudouridine nucleotides has been conserved throughout evolution. H/ACA-like RNAs, the ﬁrst stem-loop, are shown (Chen XS et al BMC Genomics 2011;12:550; Kiss-László Z et al Cell 1996;85:1077–1088). The nucleolar localization elements, the single-stranded domain H box stands for ANANNA, N for any nucleotide; a 3’ hairpin is followed by the adenine cytosine adenine ACA box (Fourmann J-B et al PLoS One 2013;8(7):e70313). The three PI3K genes encode the kinases for the cell survival pathways. Giardia PI3Ks disable host dendritic cells rendering them from immunogenic to tolerogenic entities (Cox SS et al BMC Microbiol 2006;6:45; Hernandez Y et al J Eukaryot Microbiol 2007;54:29–32; Kamda JD & Singer SM Infect Immunol 2009;77:685–693). Giardia lamblia is expressing its cell surface antigens upon inhibition of iRNA (rendering inhibitory RNA machinery defective). Hugo D. Luján, Catholic University, Córdoba, Argentina. http://medgadger.com/ 2008/12/ is studying_the_chameleonlike_properties_of_giardia_parasites

Chlamydomonas reinhardtii single-celled-green-alga. The bi-ﬂagellated photosynthetic green alga C. reinhardtii operates some 15.000 genes, cyclic AMP and GMP prominent among them, and generates oxygen in its chloroplasts. The ancestors of some genes of ﬂowering plants and vertebrate mammalians (humans) are operational in its genome, including those of the trichomonads, and mammalian vertebrate cells’ myb proto-oncogene. AlgaePath home page (Zheng H-Q et al BMC Genomics 2014;15:196 pp 1–11. doi:10.1186/1471-2164-15-196,http://AlgaePath. itps.ncku.edu.tw

The Colony of Volvox Cells swimming in accord toward light consists of the large (1 millimeter) gelatinous body surrounded by hundreds of non-reproductive cells. Inside the gelatinous body are the reproductive cells (gonidia) practicing isogamy. 570 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia

The related and more advanced Pleodorina gametes distinguish sperm-producing male individuals from ovum-holding female individuals, and thus practice aniso- gamy. The male Pleodorina gametes possess the active intranuclear otokogi (chi- valry) gene. The chlamydomonas mid/MID (minus dominance) gene, the forerunner of the otokogi gene, is operational in the otherwise indistinguishable plus female individuals; the males are recognized as the the minus individuals; plus-females rendered MID-negative minus males (but not vice versa) (Hisayoshi Nozaki, Biological Sciences Graduate School of Science, University of Tokyo, Japan. Nikon Corporation, 2011).

Of Retroviruses, the reticuloendotheliosis viruses (REV) excel as the most prominent collectors of cellular proto-oncogenes (c-onc → v-onc). None of this was known when Vilhelm Ellermann and Oluf Bang isolated the first chicken leukosis retrovirus in the first years of the last century, and when J.W. Beard, Dorothy Beard and Ursula Heine collected and maintained by passages all new isolates of leukemia-and sarcomagenic reticuloendotheliosis viruses at Dukes’ in Durham N.C. Hidesaburo Hanafusa in New York (beginning with the Rous sarcoma virus), and Peter K. Vogt and associates in Los Angeles CA, identified the oncoproteins encoded by the avian reticuloendotheliosis viral isolates. J.M. Bishop and H.E. Varmus and associates (D. Stehelin, P.K. Vogt), and H. Hanafusa established the cellular origin of these oncoproteins. Phylogenetic studies of the REVs reveal that they are of mammalian retroviral origin; their ancestral genomic sequences are conserved in the mammalian genomes. A REV- infected plasmodium (P. lophurae) was distributed in various laboratories in the 1930s for the study of anti-malaria vaccination. This plasmodium infected first laboratory birds with REV. From REV-infected birds a wide array of wild bird population picked up REV, which rapidly spread world-wide. The most mutagenic and promiscuous REV genomes inserted themselves within coinfected cells first into the Marek’s herpesvirus of turkeys (gallid herpesvirus type 2), and more recently into the avian fowlpox virus (Niewiadomska AM & Gifford RJ PLoS Biol 2013;11(8):e1001642). The Bittner mouse mammary tumor (MMTV) retrovirus may spread horizontally with the milk, or may insert its gene into its host’s genome for vertical spread. A MMTV-relative is detectable in human breast cancer tissue. MMTV encodes transmembrane glycoprotein superantigens (Sag). Sag-expressor infected B lymphocytes spread the virus within their host. TCR Vβ CD 4+ lymphocytes respond to the horizontally spread MMTV infection. In lack of its own oncogene, the MMTV genome inserts itself into cellular proto-oncogenes, targeting the int, wnt and fgf/FGF, or Notch genes. An avian REV erythroblastosis virus-incorporated the EGFR gene which is expressed in some human breast cancer cells (Her2/neu). The amplified HER protein induces an antibody and T-lymphocyte-mediated immune reaction (Punkosdy GA et al Proc Natl Acad Sci USA 2011;108:3677–3682 george.pun- [email protected]; Holt MP et al Front Oncol 2013;3:287; Szakacs JG & Livingston SK Ann Clin Lab Sci 1994;24:324–338). Human endogenous retroviral gene-encoded proteins and fully mature enveloped retroviral particles are frequently expressed in human leukemia and solid tumor cancer cells. The endogenous Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 571 retroviral particles often induce the fusion of the malignant cell with a non-transformed host cell (monocyte-Mϕ) (Januszkieweicz-Lewandowska D et al Acta Haematol 2013;1229:232–237; Mullins CS & Linnebacher M World Gastroenterol 2012;18:6027- 6035; Wang-Johanning F et al J Natl Cancer Inst 2012;104:189–210).

Exogenous viruses force neoplastic transformation upon their host, usually overcoming host resistance. Exogenous virally induced neoplastic transformation for a cell is an attack, not a “rescue mission”, and as such, it is responded to immunologically. In contrast, domesticated ancient retroviral inserts (endogenous retroviruses or retrotransposons) may internally (endogenously) induce cell transformations, that may be considered as an attempt at regressing the cell into a state of primordial immortality, and as such, it may be supported by the host. Not all endogenous retroviruses are reticuloendotheliosis viruses. Soft-shell clams (Mya arenaria) harbor the leukemogenic retrotransposon Steamer of the gypsy family. One clone of leukemic cells has been spreading among the clams. The leukemic cells express high levels of Steamer retrotransposon mRNAs. Steamer DNA is inserted in the cells’ genomic DNA, and reaches high copy numbers in leukemic haemocytes. The Steamer ORF encodes a large Gag-Pol protein, but not an env protein. Thus, Steamer does not spread as an infectious retrovirus. The leukemic cells show increased RT expression. Disabled p53 levels are high, and no apoptotic haemocytes are reported. Leukemic haemocytes spread the disease as they are able to travel in sea water. Similar leukemias exist in mussels (Mytilus) (see in text), and oysters (Crassostrea) (Arriagada G et al Proc Natl Acad Sci USA 2014;111:14175– 14180; Metzger MJ et al Cell 2015;161:255–263).

Ancestral Unicellular and Early Multicellular Eukaryotes Utilized an Array of Transposable Elements (TE), LINE-1 (L1) Being Prominent, in Their Cell Survival Pathways, as Shown Conserved in the Extant Descendants. Malignantly Transformed (Cancer) Cells Also Utilize High LINE-1 Activity and HSP. The amoeba Dictyostelium discoideum operates a long list of repeated transposable elements (Glöckner G et al Genome Res 2001;11:685–694). The yeast Saccharomyces cerevisiae harbors the non- LTR retrotransposons LINE-1 (Dong C et al Genetics 2009;181:301–311). All ancient sexually developed phyla harbor LINE-1 and gypsy-like reverse transcriptases (RT) and mariner transposases. Listed in Table 1 of the cited article, these are the Cnidarian Hydra, ctenophores, and Spongiae. Only the asexually evolved bdelloid rotifers miss LINE and gypsy retrotransposons and their encoded RTases (but harbor mariners), indicating that in all other taxa LINE-and gypsy transposons are sexually transmitted. In absence of env/Env, these sequences are are not readily transmitted horizontally. Higher up on the evolutionary scale (Branchiostoma floridae; Danio rerio; Xenopus; Mus mus- culus), the genomic copy numbers of the LINE and gypsy sequences rise (Arkhipova I & Meselson M Proc Natl Acad Sci USA 2000;97:14473–14477). The gypsy family LINE-1 retrotransposons remained active in, and form cca 17% of the human genome. These elements express ORF 1 and 2 and are either 572 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia non-coding, or are able to encode endonucleases, RTases, and RNA-binding proteins, most of which are truncated and immobile. However, rapidly proliferating cells overexpress RT induction of LINE-1-derivation. Transposable elements often appear as non-coding ncRNAs. and miRNAs. Within them embedded are the TE sequences at their transcription starting sites, whereas protein-coding exons are free of the TE sequences. RNAi (inhibitory RNA) by downregulating LINE-1, exerted anti-proliferative effect to human melanoma xenografts by inducing their differentiation. Upon cessation of RNAi administration, the tumor cells regained their aggressive undifferentiated phenotype and re-expressed L1 and RNA:DNA hybrids. The role of L1-encoded RT in the maintenance of the malignantly transformed state of the cell is essential (Spadafora C Ann N Y Acad Sci 2015;1341:164–171; Sciamanna I et al Oncotarget 2014;5:8039–8051). An example of extraordinary LINE-1 retrotransposon activity in cancer cells is the human colorectal carcinoma. L1 retrotransposition is carried by the process of target-primed reverse transcription (TPRT) with the help of ORF1/2-encoded endonuclease and RTase. The L1 elements practice insertional mutagenesis in genes protein tyrosine phosphatase receptor type M (PTPRM), odd Oz/ten-m homolog 3 (ODZ3), roundabout axon guidance receptor homolog 2 (ROBO2), pericentriolar material 1 (PCM1) and cadherin -11 (CDH11), or ICDH12. The genes mutagenized by the human L1H (human) elements fulfill driver function for the transformed cell. Due to attempted DNA repair mechanisms, the inserted L1 elements suffer truncation, nevertheless sustain rapid cell cycle turnovers (elevated cell division) rates (Solyom S et al Genome Res 2012;22:2328–2338). L1 retrotransposition are prelude to pseudogene generation. In that, the Trichomomas cells and the malignantly transformed (cancer) cells imitate each other (vide infra). In comparison to differentiated resting cells, de-differentiated active cells overexpress these retroelements. Both low branching unicellular, or early multicellular eukaryotes, ancestral and extant, and selected single cells of advanced multicellular hosts, in the process of malignant transformation, utilize alike L1 sequences for survival. Termed ‘malignant’ only, because transformed single cells of advanced multicellular hosts inadvertently consume and kill their host. Questions arise: where is the origin of endogenous LINE-encoded RT overproduction? It was in the first unicellular and early multicellular eukaryotes, where it was in use in the cell survival pathways in support of survival in distress LINE-1 together with the ancient heat shock proteins (HSP) (Nicosia A et al PLoS One 2014;9(9):e 105908), were utilized in response to exogenous physicochemical environmental inflicts. In a form of retrograde phylogenesis, selected cells of multicellular extant hosts may return to that stage of evolution by reactivating genomic faculties conserved from the ancestors, and thus resume their phenotype of rapid replication and resistance to physicochemical inflictions. Is the cancer-free longevity of the blind or naked mole rats (Spalax; Heterocephalus) consequential to the absence of viable transposable elements (no LINE-1) in their genomes? (Manov I et al BMC Biology 2013;11:91. doi:10.1186/1741-7007-11-91).

Gene Methylators-Demethylators; Acetylators-Deacetylators. Early discovered histone lysine (K) methyltransferase protein domains are those from Paramecium Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 573 bursaria chlorella virus, and trithorax from drosophila’s suppressor of variegation Su (var), and enhancer of zeste (SET); further, the myeloid translocation protein, nervy, and deformed epidermal autoregulatory factor (DEAF; MYND; SMYD*). *) The two transcript variant human SMYD (SET and MYND domains) gene maps on 1q44 (Luo XG et al J Biosci Bioeng 2007;103:444–450). Highly overexpressed in cancer cells (Hamamoto R et al Cancer Sci 2006;97:113–118). SET and SMYD transactivate the promoter of telomerase reverse transcriptase (hTERT) by di- or trimethylating its H3K4. This process is highly and constitutively upregulated in malignantly transformed human cells. It is targeted for inhibition by small iRNA. The hTERT promoter is subject to demethylation and repression; and acetylation and phosphorylation (Liu C et al Cancer Res 2007;67:2626–31). Hypermethylation of the CpG island of the cycline-dependent kinase inhibitor p16/CDKN3A tumor suppressor gene at 9p21 (or deletion of this gene) is a pre-disposing event for the development of sporadic malignant melanoma (Gonzalgo ML et al Cancer Res 1997;57:5336–47). These are early recognized examples of epigenetic proto-oncogene transactivation and tumor suppressor gene de-activation by gene silencer/promoter methylation/demethylation (Dillon SC et al Genome Biol 2005;6(8):227).

Histone deacetylases are upregulated in malignantly transformed cells. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) induced differentiation of murine erythroleukemia cells (Richon VM et al Proc Natl Acad Sci USA 1998;95:3003–7). Histone deacetylase 1 is an activator of the translocated fusion oncogene/oncoprotein TMPRSS2/ERG in prostate cancer (androgene-dependent transmembrane serine protease; E26 ETS-related gene ERG) (Iljin K et al Cancer Res 2006;66:10242–6). The deacetylated constitutively expressed testosterone- driven androgen receptor genome drives prostate cancers. Histone deacetylase inhibitors re-acetylate and silence the androgen gene. Prostate cancer cells so treated undergo apoptotic death. Of numerous histone deacetylase inhibitors (depsipeptide, Na-butyrate, trichostatin, valproic acid), SAHA appears to be the most efﬁcient (Marroco DL et al Mol Cancer Ther 2007;651–60). In black C57 mice, SAHA subdued allogeneic graft-vs-host disease with preservation of the graft-vs-leukemia effect (Reddy P et al Proc Natl Acad Sci USA 2004;101:3921–6).

Missense Mutations. Mismatch Repair. Rare missense point mutations (non-synonymous substitutions in a single nucleotide of a codon) may not be cau- sally cancer-associated; recurrent missense mutations are frequently cancer-related. In a nonsense mutation, the stop codon encodes a truncated protein. The encoded serine/threonine protein kinase of B-raf (rat ﬁbrosarcoma) gene residing at 7q34 is BRAF, activator of the ancient MAP/ERK pathway. In the V600E mutation in codon 600 valine is replaced by glutamic acid (E). Somatic mutations prevalently associated with the cause of cancers, while germ line mutations rather spell predisposition. For distinction, computational algorithms have been designed (Kaminker et al Cancer Res 2007;67:465–73). Frameshift mutations consist of deletions and insertions of several nucleotides resulting in the sequential position of codons, thus 574 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia altering the triplets, and thus translation of the genetic code. Frameshift indel mutations in the tumor necrosis factor superfamily gene 10 in prostate cancer cells disrupt its open reading frame disabling it to induce apoptosis (Xu X et al Gene 2013;519:343–7). The common single nucleotide polymorphisms (snips) consist of single nucleotide replacements (thymine for cytosine). In the two parental copies of the genome, single nucleotide polymorphic regions with different bases coexist in heterozygosity. Loss of one parental region leaves one copy remaining: hemizy- gosity for that region, due to loss of heterozygosity. Tumor suppressor genes losing one parental copy remain functional; loss of the second allele (Knudson’s second hit for the retinoblastoma gene) opens up unopposed oncogenic pathways. Microsatellites are repetitious up to six DNA base-pair sequences (simple sequence repeats, SSR). Instability of microsatellites occurs during faulty mismatch repair, leading to hypermutability of the genes involved (as in xeroderma pigmentosum; prominently in colorectal adenocarcinomata, etc). The evolutionarily conserved mismatch repair mechanism excises the faulty DNA segment and replaces it with the correct sequence (that can be over 1000 base pair long). The mismatch repair enzymes MutS, MutH, MutL recruit other enzymes (methyl transferase, helicase, exo- and endonuclease) to jointly carry out the nicking, separating and replacing the involved segments. The process of mismatch repair may fail due to point mutations of the enzymes: mismatch repair deﬁciency. The familial non-polyposis colon cancer Lynch syndrome is characterized by germ line mutations of the mismatch repair enzymes (Boland CR Gastroenterology 2013;144:868–70).

The ‘driver mutations’ conferring selective growth advantages of the tumor cell usually appear in a set sequential order of tumor suppressor gene eliminations and proto-oncogene point mutations (the Vogelstein sequence in colon cancer). Thereafter, very large numbers of haphazard somatic gene mutations occur. Mismatch repair deﬁcient tumors excel in the pursuit of this latter pattern. In this phase of host-tumor relationship, the tumor loses the support of its host, and is subjected to excessive lymphocyte-mediated immune reactions. Innumerable new protein mutations induce the attacker lymphocytes. In response, the tumor cell overproduces PD-1 ligands for the induction of apoptotic death in the attacker lymphocytes, and thus it prevails. External help with monoclonal antibodies nivolumab and pembrolizumab protect PD-1 from contact with its ligands; the intact lymphocytes attack and destroy the tumor. Thus is the extraordinary susceptibility of mismatch repair deﬁcient tumors to antibodies that protect PD-1 from contact with its apoptosis-inducer ligands (Le DT et al New England J Med 2015;372:2509–20).

The First Encounter with NK Cells. The NCI project site visitors arbitrarily transferred the healthy control investigator’s (JGS) research funds from M.D. Anderson Hospital to the NCI intramural Herberman laboratory for the “clarification of the in vitro artifact reactions”. In the clarification efforts, the Herberman laboratory used the modern and accurate “radioactivity-release assay”, instead of the “out-moded and clumsy” chamber-slide assay. However the radioactivity-release assay did not distinguish between different types of cytolytic lymphocytes. Neither the Hellström, nor Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 575 the Herberman laboratories visualized the morphological differences that attacking lymphocytes clearly exhibited in the most meticulous and reliable chamber-slide assay (in use in the Sinkovics Lab). Several years later the Herberman Lab declared their discovery of “natural killer cells”, a subclass of lymphocytes, that killed autologous virally-infected or malignantly transformed cells without pre-immunization. The NK cells appeared as large granular lymphocytes (as shown earlier in the chamber-slide cultures in the Sinkovics Lab). Both healthy donors and patients with cancer possessed NK cells, but only the patients generated the small compact immune T lineage lymphocytes lytic to autologous (and related allogeneic) tumor cells (Lichtman MA: Historical landmarks in the understanding of the lymphocytes. In P.H. Wiernik et al (eds) “Neoplastic Diseases of the Blood”. Springer Science, New York, 2013; Pp 789–83. Sinkovics JG & Horvath JC. Internat J Oncol 2005;27:5–47; Sinkovics JG: “Cytolytic Immune Lymphocytes…” Schenk Buchverlag, Passau & Budapest, 2008). From the late 1960s on, at the Section of Human Tumor Virology & Immunology of M.D. Anderson Hospital, this author (JGS) observed lymphocyte-mediated cytotoxicity expressed to various target cells, prominent among them human sarcoma, melanoma and kidney carcinoma cells. Lymphocytes killed human tumor cells by cytoplasmic lysis or by nuclear clumping (later recognized as apoptosis) illustrated in photographs and graphs. Patients with metastatic melanoma or sarcoma circulated small compact lymphocytes (later: immune T cells) and large granular lymphocytes (later: NK cells), that killed autologous (and related allogeneic) tumor cells in vitro (Sinkovics JG: “Cytolytic Immune Lymphocytes…” Schenk Buchverlag Passau/Budapest 2008). While the patients’ lymphocytes killed tumor cells in vitro, in vivo the tumors could advance. Treatment of disseminated rhabdomyosarcoma-afflicted twin with buffy coat lymphocytes of the healthy twin sister was attempted in 1968. The healthy twin yielded large granular lymphocytes attacking the afflicted twin’s rhabdomyosarcoma cells. Remission was induced; that was lost later to relapse (Sinkovics JG Expert Rev Anticancer Ther 2007;7:31–56; 183–210). The failure of immune T cells to eradicate a tumor in vivo was attributed (in other laboratories) to the induction of Treg cells that were directed to eliminate immune T cells. The chemokine stromal cell-derived factor-1 as ligand-to-receptor CXCL→R, acted in a network to direct Treg cells. Depleting the host’s resident lymphocyte population allowed autologous immune T cells (and NK cells) to attack tumor cells in vivo and to induce remissions. S.A. Rosenberg & associates (Patrick Hwu now M.D. Anderson professor) at the NIH/NCI established the efficacy of immune T (and NK) cell infusions into lymphocyte-depleted hosts by inducing durable remissions of metastatic tumors (especially melanomas) (Rosenberg SA Cancer Immunology: Building on Success, NIH/NCI Sept 22–23 2011). Consideration was given to low dose intraabdominal radiotherapy for the induction of innate immunity in lymph nodes in response to gut flora invasion of the lymph nodes (explained in Sinkovics JG “Cytolytic Immune Lymphocytes…” Schenk Buchverlag, Passau/Budapest pp 264–5, 2008). Recently discovered autologous immune T cells with genetically engineered TCRs (the CAR chimeric antigen receptors), and replicating in their tumor-bearing hosts in vivo, are able to 576 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia completely eradicate metastatic tumors (lymphocytic leukemia-lymphoma cells; solid tumor cells). Massive tumor cell lysis occurs so rapidly that patients suffer, and are to be protected from, acute tumor lysis syndromes (Morgan A et al Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006;314:126–129; Robbins PF et al Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 2011;29:917–924; Frigault MJ et al including Carl H June. Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells. Cancer Immunol Res 2015;3:356–367), that is tumor-specific immune T cells. Resting continuously (as long as residual tumors exist; or even after the eradication of all tumors), the immune T cells survive. Their renewed attacks on relapsed tumor cells sustain complete remissions for years: a result tantamount to cure (earliest results reviewed in Science Dec 20 2013).

Some Misconceptions. In 1968, the landmark paper of Hellström & Hellström appeared to have set the basic rules of cancer immunology. In the case of pediatric neuroblastoma, granulocyte-cleared peripheral blood “lymphocyte suspensions” of patients (and their mothers) specifically inhibited the growth of autologous (“au- tochthonous”) tumor cells (but not fibroblasts). The sera of the donors, who yielded ‘colony inhibitory lymphocytes’, contained antibodies, which were specifically inhibitory to tumor cell colonies in a strictly complement-dependent manner. “In no case did lymphocyte from healthy controls, from patients with non-neoplastic disease or from patients with other kinds of tumor selectively inhibit the growth of neuroblastoma cells.” Patients’ sera and complement acted similarly to the lymphocytes in tumor cell colony inhibition assays. Both the text and the summary contains the fateful statement: “In no case were tumor cells selectively inhibited by lymphocytes from the controls, which included children with other tumors, children with non- neoplastic diseases, or mothers of healthy children…” (Hellström IE, Hellström KE, Pierce GE, Bill AE: Demonstration of cell-bound and humoral immunity against neuroblastoma cells. Proc Natl Acad Sci USA 1968;60:1231–1238). The work was supported by USA NIH and American Cancer Society grants. The manuscript was sponsored for publication by USA National Academy of Sciences member Frank L. Horsfall Jr. The paper failed to explain that if the control lymphocytes never killed tumors selectively, could they kill tumors ‘non-selectively’? In the late 1960s, at the Section of Clinical Tumor Virology and Immunology in the M.D. Anderson Hospital, this author (JGS) was engaged in the establishment of human tumor cell lines (lymphoblasts-lymphocytes in suspension cultures; solid tumors, especially sarcoma, melanoma and kidney carcinoma) (Sinkovics JG et al Methods Cancer Res 1978;14: 243–323). Against these cultured tumor cells, the patients’ and healthy controls’ ficoll-hypaque purified lymphocytes (prepared by Cameron Tebbi and Jerry Cabiness) and sera were tested for non-specific and specific immune reactions. The chamber-slide assay was used; stained slides were viewed to actually visualize the lymphocytes’ interactions with tumor cells (Sinkovics JG & Horvath JC. Internat J Oncol 2005;27;5–47). It has become immediately evident that healthy individuals, first this author (and patients with tumors) circulate a class of lymphocytes (large Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 577 granular lymphocytes) that attached to allogeneic tumor cells and killed them. Under the effect of the Hellström paper (and on the recommendation of the first author of that paper, who actually rendered a NCI-appointed project site visit in this author’s (JGS) laboratory), it was declared that this author’s chamber-slide assay was out- moded, unreliable, and thus yielding “laboratory artifacts”. The author’s NCI grant was transferred to Ron Herberman’s in-house NCI laboratory in order to clarify what the “in vitro artifacts” meant. To the NCI project site visitors, it was unacceptable that lymphocytes would render an immune reaction without their specific pre-immunization. Even though, in reply, this author showed that his lymphocytes killed female breast and ovarian carcinoma cells, and that the lymphocytes responsible for this reaction were not the compact small T cells, but the large granular cells (referred to as ‘Burnet’s immune surveillance cells’ in the author’s laboratory). View convincing original photographs in Sinkovics JG Cytolytic Immune Lymphocytes. Schenk Buchverlag, Passau/Budapest, 2008. However, the incorrect “Hellström doctrine” prevailed until after Herberman’s and other laboratories proved the existence of “natural killer cells” (same as the allogeneic large granular lymphocytes of this author). Marshall Lichtman credited this author (JGS) for the first observation of tumor cell-killer human large granular lymphocytes (later: NK cells) (Lichtman M A in P.H. Wiernik et al Neoplastic Diseases of the Blood. Springer Science New York, 2013. doi:10.1007/978-1-4614-3764-2_39.

HMG Proteins Drive the Amoeba Nucleus. High mobility group helix-turn-helix DNA-binding proteins are shared by the amoeba and its parasite mimiviruses. Prokaryotes, archaea and unicellular eukaryotes share HMG proteins. LUCA, the last universal common (cellular) ancestor, presumably operated HTH HMG proteins for carbamoyl phosphate synthetase. In the precellular RNA World the ancestors of these proteins functioned in ribonucleoproteins, ribozymes and riboswitches. The amoeba expresses intranuclear HMG14/17 proteins (Anantharaman V Koonin EV Aravind. Nucl Acids Res 2002;30:1427–1464). The HMGB1/2/3 transcription proteins of higher multicellular eukaryotes derive from the amphioxus’ single HMGB gene. Tumor cells of the highest eukaryotes utilize HTH HMGB proteins as auxiliary oncoproteins (Tables XI/I and XI/II). For amoeboid movement of invading tumor cells, see text.

Ribozymes Appeared. Tetrahymena thermophila revealed its group I intron ribozymes in Thomas Czeh’s laboratory. Ribozymes catalyze their substrates (“like protein enzymes”) intra- and intermolecularly. The tetrahymena ribozyme’s intramolecular catalysis consists of self-splicing (Golden BL et al Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO. Science 1998;282:259–264). Alu ribonucleoproteins consists of polymerase III-transcribed Alu sequences and signal recognition proteins (SRP9/14) united. In the ribosome, these units inhibit IRES-mediated (internal ribosome entry site) translation initiation (Ivanova E et al Nucleic Acids Res 2015;43:2874–2887). 578 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia

Spliceosomes. Spliceosome, the intranuclear organ of eukaryotes, consists of five small nuclear snRNAs and their associated proteins, the small nuclear ribonucleic proteins (snRNP). Each pre-mRNA/hnRNA (heterogeneous RNA) can generate the assemblage of its own spliceosome. Each spliceosome will contain five snRNAs marked as U1, U2, U4, U5, U6. In the spliceosome, ribozymal catalytic reactions remove (excise) the introns from nuclear pre-mRNAs and reconnect (ligate) the flanking exons: the splicing reaction of Philip Sharp. The assembly of snRNP particles occurs stepwise on hnRNA substrate. The first transesterification takes place in the bulging duplex of the U2 snRNP and the branch region of the hnRNA. The U2 snRNA auxiliary factor recruits U2 snRNP to the branch region. An altered conformation of RNA-RNA duplex is shaped by the peudouridine residue of the U2 snRNA. Splicing begins in the 2' OH of the bulging adenosine. U4/U5/U6 snRNPs form a triplet. U2 snRNA binds to the branch point sequence and RNA-RNA interactions displace protein-RNA interactions. The stem loops U4/U6 dissociate with the elimination of U4. Stem loop U6 base pairs with U2 snNA, and appears as the U2/U6 helix. Alternative splicing is performed when two different exons are recombined. BS = branch site ISL = internal stem loop http://www.cityofhope.org/ the-catalytic-core-of-the-spliceosome Excision of intron in the spliceosome (SM). Copyright McGraw-Hill Companies. McGraw-Hill Higher EducationMcGraw-Hill Online Learning Center Test mhh.co, Spliceosome abbreviations: LSm protein: like SM spliceosomal; Prp genes: precursor RNA processing (not “platelet-rich plasma”); Brr: balanced repeated replication (not “bad response to refrigeration”; not “bean root rot fusarium”); Snu: snRNP “snurp” proteins, snurps). The supras- pliceosomes remove the introns and ligate the exons. They are composed of four united active native spliceosomes equipped with components for processing intronic microRNAs and changing the 5’-end and the 3’-end pri- into pre-miRNAs. All five-spliceosomal U1, U2, U4, U5, U6 snRNPs are present. The RNA-editing enzymes ADAR1,2 are actively involved (dsRNA adenosine deaminase). The enzymes Drosha/DGCR8 are the major microprocessors (DiGeorge chromosomal region). Stop codon-mediated suppression of splicing (SOS) is installed. Latent splicing initiated by a mutated translation initiation codon (AUG) is suppressed by an initiator tRNA construct (Shefer K, Sperling J, Sperling K Comput Struct Biotechnol J 2014;11:113–122). Some degenerative diseases due to RNA/DNA processing errors occur (retinitis pigmentosa; spinal muscular atrophy) due to misregulation of splicing. Mutation of U2 snRNP results in defective snRNP assembly in CCL and myelodysplasia (Matera AG & Wang Z Nat Rev Mol Cell Biol 2914;15:108–121). Indeed, these malignant transformations are due to functional error of the RNA/DNA complex.

Drosophila Brain Tumors and Leukemia. The drosophila genome encodes the ontogenesis of the larva to adulthood with precision, but not without occasional lapses. Carcinogenesis appears to be included into the physiology of the genome: anlage lay down, differentiation, organ formation and polarity, stem cell maintenance with asymmetric release of somatic cells, provisions for progeny, cell senescence and death. Not in the case of every individual, but in selected (gain-of-function mutated) Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 579 hosts, regression of a part of the soma to germline level, or evolutionarily deeper down below, to the independent life style of immortalized single cells, takes its place. “Carcinogenesis” is recognized. Most commonly involved in this latter event are the hedgehog, notch, runt, polycomb, trithorax and wingless genes. Gene expressions are regulated by mono-dimethylases at H3K4me3 (trimethylated by the cara mitad enzyme); a demethylase acts also at H3K27. The polycomb repressive complex 2 (PRC) is the chromatin modifying enzyme of H3K27. The SET domain methyltransferases (Su-var9/ enhancer of zeste/ trithorax) are the most prominent. Most drosophila genes have their orthologs downward and upward on the evolutionary scale. The drosophila trithorax (histone lysine methyl-transferase) and trithorax-related genes are orthologous to the mll1-mll2/MLL1-MLL2 (mixed lineage leukemia, lymphocytic, myelocytic) genes and gene product proteins. In human lymphomas and lymphocytic blastic leukemias the overproduced MLL proteins derive from a promiscuously fused mll gene (Chauhan C et al Development 2012;139:1997–2008; Geissler K & Zach O Ann Haematol 2012;91:645–669; Kanda H et al Mol Cell Biol 2013;33:1702–1710; Patel A et al J Biol Chem 2014;289:868–884; Rain AN et al Mol Cell Biol 2013;33:4844–4856; Xie J et al OncoTargets Ther 2013;6:1425–1435). The increased ectopic expression of meiosis-related gene-product proteins (cancer-testis, CT; synaptonemal complexes, SYCP; PIWI) in cancers, both in drosophila and human, indicates a soma-to-germline transitional shift in cancer (Feichtinger J et al Int J Cancer 2014;134:2359–2365). Receptor tyrosine kinase RTK (one of them EGFR), and the PI3K/Akt pathways, are the initiators of glioma induction in the drosophila brain. Right open ORF serine/threonine kinases 1/2 (RIOK) respond and form complexes with mTOR. Forced reduced expression of RIOK1/2 (immune iRNA) allowed p53-induced cessation of cell cycle and apoptosis to take place. The inhibitor of neuroblast differentiation (symmetrical cell divisions) is the early growth response EGR transcriptional regulator klu/Klumpfuss protein. Transplantable neuroblast (NB) tumor cells overexpress Klu. Drosophila larval type I NB cells divide into a large stem cell and a smaller ganglion mother cell, which symmetrically divides into two postmitotic ganglion cells. Type II NB cells divide asymmetrically into a stem cell and a smaller intermediate neural progenitor (INP) cell. Deadpan (Dpn) and Asense (Ase) proteins differentiate INP cells; without Ase and Dpn expression, INP cells remain stem cells. Gain-of-function mutated drosophila brain tumor gene (brat) and drosophila lethal(3) malignant brain tumor (l3mbt) gene induce malignantly transformed cell clones. Differentiation inducers are the Notch inhibitor Numb, and the cell cycle inhibitor Pro (prospero). Loss-of-function mutated numb and pro genes fail to induce neuroblast cell differentiation (Berger C et al Cell Rep 2010;2:407–418; Read RD et al PLoS Genet 2013;9(2):e1003253; springer com.article/10.1186% 2F1471-21645-24). The neurotrophin receptor p75NTR reacts to early growth response (EGR) transcriptional regulators. Klu is an EGR agent. EGR proteins contain three Zn ﬁnger motifs allowing them to positively or negatively regulate cell proliferation (apoptosis versus cell proliferation). In mammalian cells, EGR-1 is an inhibitor of TNF-related apoptosis-inducing ligand (TRAIL) expression in NK cells. The extracellular signal-regulated oncogenic ERK pathway in lung adenocarcinoma 580 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia cells induces the egr-1/EGR-1 gene/protein. EGR-1 acting as a DNA-binding protein, activates the VEGF-A promoter. Both the mutually exclusive K-RAS and EGFR mutated proteins also activate EGR-1. Activated EGR-1 overrules its inhibitor NAB (nerve growth factor binding) protein, when it is epigenetically silenced (unless NABs are constitutively expressed) (Balzarolo M et al Immunol Lett 2013;151:61– 67; Gao X et al Mol Cell Neurosci 2007;36:501–514; Shimoyamada H et al Am J Pathol 2010;177:70–83; Thiel G & Cibelli G J Cell Physiol 202;193:287–292). Terminal differentiation of blast stage myeloid leukemia cells is blocked by c-Myb or by C-Myc. EGR-1 could abrogate the c-Myc, but not the c-Myb blockade (Gibbs JD Cell Cycle 2007;6:1205–1209; Leukemia 2008;22:1909–1916). EGRs are evolutionarily conserved. A recent new discussion from another angle (Sinkovics JG Europ J Microbiol Immunol 2015;5:25–43). The ancestral oncogene / oncoprotein of human carcinoma of the thyroid, RET (rearranged in transformation) suffers gain-of-function mutation in the drosophila. Abnormal neural epithelium restored to normal by the administration of small molecular Ret inhibitor ZD6474, which is in human clinical trials as Zactima (Marcos Vidal & Ross Cagan, Mount Sinai School of Medicine) http://www.cancer.gov/NCIcancerbulletin/archive/2009/012709/page6

Reversed Ontogenesis. Hydractinia echinata and H. symbiolongicarpus colonies consist epithelial cells, stem cells or interstitial I cells (originally called Urkeimzellen, Stammzellen by August Weismann in 1883), and defensive stinging cells (microbasic mastigophores). The epithelial cells form the mass of the colony; these cells may de-differentiate into stem cells, or tumor stem cells. The genuine stem cells are in the interstitium in between epithelial cells in the epidermal com- partment. The stem cells provide germ cells. Silenced and activated stem cell genes include ancestral Wnt elements (from frizzled to β-catenin); Pin, encoding POU proteins and possible predecessors of Oct4; Myc; Nanog; Piwi. The stinging cells protect the integrity of the colony (practice allorecognition) and kill invader cells upon attempt at fusion by another, but incompatible, colony. POU proteins are pituitary/Oct-octamer/undifferentiated or uncontrolled (see text). Cnidaria consisting of anthozoa (the “flower animals”, sea anemones, the Nematostella; Hydra and Hydractinia); and Medusozoa (medusa, the jelly fish) practice bidirectional regeneration, transdifferentiation, and reverse development, or reversal of ontogenesis. In transdifferentiation, a differentiated cell assumes the appearance and functioning of another differentiated cell. In the reversal of ontogenesis, a mature cell assumes the appearance and functioning of one of its embryonic ancestors. Reverse development may be viewed as a physiological process of rejuvenation: senescence post- poned, life span extended (Carla EC et al Tissue & Cell 2003;35:213–222; Khalturin K et al Dev Biol 2007;309:32–44; Plickert G et al Int J Dev Biol Sci 2012;56:519–534; Schmich J et al Int J Dev Biol 2007;51:45–56). Induced de-differentiation (reprogramming) of somatic cells in a vertebrate multicellular host (a mammal) to pluripotent stem cells is a form of reverse evolution encoded by the classical stem cell product proteins (Oct4, Kfl4, Myc, Sox2: the OKMS). Dox (doxycycline) is an inducer of stem cells (breast cancer stem cells, BCSC). In the background, BMP/SMAD (bone morphogenetic protein; signaling mothers against Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 581 decapentaplegic, drosophila), and miR-200 induce mesenchymal-to-epithelial transition (MET), including the activation of stage-specific embryonic antigen 1 (SSEA) and pluripotency regulators Nanog and Sall4 (spalt-like transcription factor). The induction and the maintenance of the state of pluripotency is encoded by two different arrangements of the stem cell genes (Golipour A et al Cell Stem Cell 2012;11:769–783). The cell rejuvenation process is an inherent ancient faculty of the RNA/DNA complex; mature somatic cells of a multicellular host are able to resort to it. If the promoters are constitutively amplified without a gain-of-function mutation, is the process excessive but still physiological? If the inhibitors (suppressors) suffer a loss-of-function mutation, is the process pathological? Certain “rejuvenating mutations” in the RNA/DNA complex may be viewed inherent and physiological, inasmuch as distant ancestors of cellular life (the medusa) practice it. The overgrowth of rejuvenated cell colonies may be lethal to their host. Further discussed (Sinkovics JG Europ J Microbiol Immunol 2015;5:25–43).

Nematostella vectensis, is the early branching metazoan cnidarian without mesoderm. The sea anemone, anthozoan cnidaria, N. vectensis, is among the first to operate the venus kinase receptor (vkr) gene, which characterized the first bilaterian phyla (Annelida, Mollusca, Echinodermata, Platyhelminthes). The receptor captured extracellular amino acids and eventually formed the venus fly trap module of the larvae in invertebrate hosts up to the the metazoan cnidaria. Its possible role in cell-to-cell communication in higher ranking metazoan is unknown, however, the vkr gene was lost at the caenorhabditis and drosophila level (Vanderstraete M et al BMC Genomics 2013;14:361). The Wnt signaling pathway is very active in Nematostella larvae; its activity extends to TCF (T cell factor) signaling by intranuclear β-catenin. The hedgehog Hh pathway is active as well. The faultless physiological pathways establish the correct anterior-posterior axis and the dorsal-ventral polarity of the embryo (Marlow H et al Dev Biol 2013;380:324–334; Matus DQ et al Dev Biol 2008;313:501–518; Röttinger E et al PLoS Genet 2012;8 (12):e10031164). The Wnt/Hh/Tcf signaling pathways may malignantly transform human cells into adenocarcinomas. LIM homeobox Lhx transcription factors (lineage, caenorhabditis; isl, insulin-like rat gene enhancer binding protein; med-3, mechanosensory, cnidaria) of the cnidaria with proteins Rho and ROCK (rhom- botin; Rho-associated kinase) form fusion oncoproteins in human T cells. The hydra (H. magnipapillata) genome operates six Lhx genes (Boehm T et al Proc Natl Acad Sci USAc 1991;88:4367–4371; Srivastava M et al BMC Biol 2010;8:4). The achaete scute (ash) gene product proteins regulate the early neurogenesis in the cnidaria Nematostella (and in the early chordate Branchiostoma amphioxus); four such genes in Nematostella (Layden MJ et al Development 2012;139:1013–1022). Human ash genes encode transformation of adenocarcinoma cells into neuroectodermal cancer cells, or induce primary esthesioneuroblastomas (Linnoila RI et al Exp Lung Res 2005;31:37–55; Wang XY et al Lab Invest 2007;87:527–539). Cnidarian “small silencing” microRNAs (87 identified, including PIWI-interacting piRNAs) are extremely active in cleavage (post-transcriptional regulation / translational inhibition) of mRNAs, thus regulating gene expression. Cnidaria 582 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia miRNAs/siRNAs are ancestral to those of both animalia (Bilateria) and plantae. Plant miRNAs are methylated (CH3) at their 3′ ends; animal miRNAs are not. The HOXD (homeobox) gene/protein cluster harbors its regulator, the intron-embedded miR-2026. The cnidarian miR-156 shows sequence homology with moss and Arabidopsis miRs reflecting back to a common ancestor of animalia and plantae (rule out horizontal transfers). The cnidarian miRs slice their mRNA targets directly, that is different from the mRNA slicing of Bilaterian miRs. The cnidarian ur-bilaterian miRNA miR-100 remains conserved in all vertebrates up to Homo (Moran Y et al Genome Res 2014;24:651–663). The human miR-100 often expresses tumor suppressive activity (hepatocellular carcinoma; osteogenic and chondrosarcoma; malignant lymphoma (Chen P et al Mol Cell Biochem 2013;383:49–58; Huang J et al Tumour Biol 2014;35:1095–1100; Li XJ et al Br J Cancer 2012;109:189–198). In non-small cell lung cancer, tumor suppressor miR-100 targets polo-like kinase (Liu J et al BMC Cancer 2012;12:519). Dihydroxyvitamin D and miR-100 suppress prostate cancer (Giangreco AA et al Cancer Prev Res 2013;6:483–494). miR-100 suppresses growth of transitional cancer cells of urinary bladder (Oliveira JC et al Asian Pac J Cancer Prev 2011;12:3001–3004). In small cell lung cancer, HOXA gene expressions favored the host by inducing tumor cell growth arrest and increased chemotherapy sensitivity and apoptosis. High expression levels of miR-100 reduced HOXA expression. miR-100 targeted the 3’UTR region of the HOXA protein mRNA (Xiao F et al Eur J Cancer 2014;50:1541–1554). Devious expressions of “involved”“regulated” without specifying up or down characterize the contradictory results reported on miR-100 and polo-like kinase interactions in human cancers. This ancestral interaction was established in the cnidaria. In cnidarian cells, the existence and physiological functioning of human disease-associated genes, including those of cancer, is remarkable. Prominent are 11 of the 12 human Wnt genes, and close to human-identical numbers and repeats of the BRCA2 and RAD51 genes (Sullivan JC & Finnerty JR Genome 2007;50:689–692). Add bone morphogenetic protein (BMP2/4 and TGFβ drosophila decapentaplegic orthologs with the mammalian counterparts) and the BMP antagonist chordin (Technau T & Steele RE Development 2011;138:1447–1456). Fully mature cnidarian cells practice bidirectional regeneration and reverse development, a form of transdifferentiation (TD). In TD, a fully differentiated cell functioning with a limited number of active genes, silences these genes, and activates a number of previously silenced genes, thus assuming the appearance and functioning of another mature cell (Graf T & Enver T Nature 2009;462:587–594). A reversal of ontogenesis consists of the de-differentiation of a fully matured cell. Cnidaria cells practice reverse development. De-differentiation of a mature somatic cell of set limited functioning in a vertebrate mammalian host is tantamount to a descent on the evolutionary scale to far distant ancestors? Cnidarians accept each-others plasmid DNA and laboratory-made transgenic cnidarians (Hydra; Hydractinia) exist (reviewed in Technau T & Steele RE Development 2011;138:1447–1458). Recently, a comparison is being made between the cnidarian (N. vectensis) NFкB/STAT combined pathway and its more advanced derivative operational in human cells. The cnidarian Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 583 cell survival NFкB/STAT pathway’s human derivative is highly oncogenic especially in certain malignant lymphoma cells. Extensively so in Reed-Sternberg cells of Hodgkin lymphoma, and mediastinal diffuse large B cell lymphoma with constitutive expression of these oncoproteins, and to a lesser degree in other B cell lymphomas and in the T cell lymphoma mycosis fungoides. A correlation with viral initiation in both case was suggested, inasmuch that cnidaria are often infected with herpes-like viruses that may be predecessors of the Epstein-Barr HHV4. The cnidarian endosymbiont algae carry these viruses. The cnidarian genomes carry predecessors of the human proto-oncogenes/oncoproteins, the runt-related Runx, Hedgehog and Wnt (wingless, drosophila; integrated, mouse); Sox (sex determination region Y, SRY box); and the achaete scute predecessors, that will encode the first nervous system in the amphioxus, and become a proto-oncogene in the human genome, as inducers of esthesioneuroblastoma, small cell undifferentiated lung carcinoma and others (Sinkovics JG Europ J Mirobiol Immunol 2015;5:25–43; Abstracts, Second NorHGT & LUCA Conference, Sohan Jheeta, University Leeds, England; M D Anderson Hospital Symposium on Cancer Research, Oct 9–10 2014. Referenced manuscript in print Internat J Oncology 2015;47:1211–1229). In advanced eukaryocytes of multicellular (human) hosts, the Janus kinase-related STAT is activated by phosphorylation of its tyrosine residue Tyr705, dimerizes and translocates intranuclearly. There, it activates genes involved in cell survival, self-renewal, neo-angiogenesis, locomotion, and immune evasion. Constitutively activated STATs induce the malignant transformation of the cell. In human T lymphoma cells, Jak3 activates STAT3/5 DNA-binding proteins, that suppress the promoter gene of tumor suppressor miR-22, thus inducing constitutive replication of the involved T lymphocytes in absence of miR-22. Anti-Jak3 histone deacetylase inhibitors, or anti-Jak3 curcumin, reverse the process (Sibbesen NA et al Oncotarget 2015;6:20555–69).

The ancestral mena proteins appeared first in the cnidarians (Hydra; Nematostella), and in the yeast (Saccharomyces); and are fully operational in the Spemann-Mangold gastrula organizer blastomeres of the Xenopus. This is the site where the LIM homeobox gene lhx1/lim1, noggin and chordin (nog, chd) interact (Figure 38; Table XVI) (Krogan NJ et al Nature 2006;440:637–43; Insenser MR et al J Proteomics 2010;73:1183–95; Pham TK & Wright PC Expert Rev Proteomics 2007;4:793–813; Rentzsch F et al Proc Natl Acad Sci USA 2007;104: 3249–54; Yasuoka Y et al Development 2009;136:2005–14). View Internet/Google images of ‘mena proteins in Spemann blastomeres’. The vertebrate mammalian (including Homo) menaINV proteins (mammalian enabled; mammalian invasive; actin microfilament regulatory) remodel the cytoskeleton, regulate cellular apical orientation, determine cell polarity, and direct lamelli- and filopodial cell migration. The human ortholog is encoded from locus 1q42.12. When the gene is amplified, or is gain-of-function mutated in malignantly transformed cells (adenocarcinoma cells), the gene-product proteins appear in multiple isoforms, are excessively produced, and dictate accelerated multicellular streaming locomotion, thus, invasiveness and metastatic spread. Mena protein overproducing cancer cells exhibit highly 584 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia malignant behavior, express vasodilator phosphoproteins, create the microanatomic Tumor Microenvironment of Metastasis environment, and significantly shorten patients’ survival (Forse CL et al BMC Cancer 2015;15:483. doi:10.1186/s12885- 015-1468-6; Rohan TE J Natl Cancer Inst 2014;106:135. doi:10.1093/jnci/dju136). Macrophages support mena protein-expressor tumor cells, which withstand humoral and immune CD8 T cell-mediated host immune reactions (Di Modungo F et al Int J Cancer 2004;109:909–18; Roussos ET et al J Cell Sci 2011;124:2120–31; Wychoff JB et al Cancer Res 2007;67:2649–56). Comment. Here, a fundamentally basic physiological embryonic event is turned into a constitutively expressed cell survival pathway, for the rescue of some individual cells, while the host of these cells succumbs in the process.

Ciona intestinalis. The ascidian urochordate sea squirt, vase tunicate, C. intestinalis (Chordata/Tunicata) demonstrates extraordinary genomic versatility, as it transforms from swimming tadpoles into tubular organisms fixed to the floor in the bottom of the sea (Satou Y et al BMC Genomics 2012;13:208). The embryonic ciona swims with appropriate musculature. The mature ciona colony lives attached to the sea floor. In the swimming ciona larva or tadpole, the notochord and its pigment cell sensory organs, the photoreceptive ocellus and the melanin granule-containing otolith receive their activation by fibroblast growth factor FGF3 and its receptor, and the MAPK pathway. The MAPK proteins activate the ets1/2 transcription factor (named after the avian erythroblastosis retrovirus E26 E-twentysix, that originally incorporated the host cell proto-oncogene ets). The ETS protein activates the T cell factor gene (tcf/TCF) and the lymphocyte enhancer factor gene (lef/LEF). The tcf/lef genes are proto-oncogenes in the human genome, serving as targets to β-catenin. TCF/LEF are downstream members of the Wnt pathway through the intranuclear transfer of β-catenin. Another activator of the Wnt pathway is the downregulation of GSK3β (glycogen synthase kinase) gene product protein. Ciona operates TGFβ and its antagonist Smad (signaling mothers against decapentaplegic, drosophila); and hedgehog and JAK/STAT genes, active in a switched on and off mechanism in the metamorphosis of the tadpole into adult organisms (Hino K et al Dev Genes Evol 2003;213:264–272; Shi W et al Development 2009;136:23–28; Squarzoni P et al Development 2011;138:1421– 1432). The Ciona cell survival Wnt pathway is correlated with the human oncogenic Wnt pathway (Sinkovics JG Europ J Microbiol Immunol 2015;5:25–43). All the ancient pathways named are conserved in vertebrate mammalian cells in switched on and off sequences in embryonic ontogenesis. All the ancient pathways named become oncogenes/oncoproteins, when either amplified or constitutively expressed with or without gain-of-function mutations in vertebrate mammalian hosts (Sinkovics JG Europ J Microbiol Immunol 2015;5:25–43). FGF-R overexpression with or without mutations or fusion acts as an oncoprotein in diverse (adenocarcinomas, including thyroid tumors) human cancers. FGF-induced lym- phangiogenesis promotes tumor cell invasiveness and metastasis (Larrieu-Lahargue F et al PLoS One 2012;7(6):e39540; Redler A et al PLoS One 2013;8(8):e72224). Otherwise, the LIM (Table XVI) and Hox homeodomain genes were lost from the Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 585

Ciona genome. Gene product proteins in Ciona are ancestral to thyroid hormones and their receptors (ciona nuclear receptor-1 as thyroid hormone receptor-associated protein) in vertebrate mammalian (human) hosts. The ciona nkx/Nkx gene/protein is referred to as TTF-1 (thyroid transcription factor, or natural killer homeobox protein, Nkx). The ortholog of mammalian vertebrate thyroid stimulating hormone activator of the NIS system (natrium-iodine symporter) and its mRNA in the ciona is Nkx/TTF-1. The amphioxus harbors ancestors of the vertebrate mammalian thyroid transcription factor-1. In ascidian larvae (Ciona), thyroid hormone precursors regulate larval metamorphosis in selecting cells to be retained, or to be eliminated by apoptosis (Carosa E et al Poc Natl Acad Sci USA 1998;95:1152–1157. Di Fiore et al Life Sci 1997;61:623–629. Krishnan A et al Gene 2013;526:122–133. Ogasawara M et al J Exp Zool 199;285:158–169. Patricolo E et al J Exp Zool 2001;290:426–430. Tóth G & Noszál B Acta Pharm Hung 2013;83:35–45). In distress (heat; endoplasmic reticulum stress) ciona mobilizes cell survival pathways. It releases heat shock proteins (Hsp) as chaperones, and the BAG (Bcl-2-associated athanogene 3) co-chaperone proteins. Observe ciona cell responses to brefeldin, thapsigargin and tunicamycin (FujikawaT et al Cell Stress Chaperons 2010; 15: 193–204). The stressed ciona cell metabolizes like a tumor (colon cancer) cell (Yang X et al Histol Histopathol 2013;28:1147–1156). For the differentiating notochord-ephrins, Ciona cells establish the proper FGF/MAPK balance (Shi W & Levine M Development 2008;135:931–940). This overexpressed pathway is frequently operational in human cancer cells. Germ layer segregation in the ciona embryo is directed by β-catenin (Hudson et al Curr Biol 2013;23:491–495), a tcf/lef proto-oncogene-activator in human cells. Reviewed with historical details (Sinkovics JG European J Microbiol Immunol 2015;5:25–43). Are some thyroxin-related proteins physiological in the Ciona, become oncoproteins in human thyroid carcinoma? The other tunicate, Oikopleura dioica, compacted its genome even more, and reduced the numbers and sizes of its introns (down to 70 Mb with 18,000 genes with short introns of <50 nt, in comparison to the amphioxus 520 Mb genome operating 22,000 genes). Most lost O. dioica introns (spliced out in spliceosomes) are being recently replaced in different new positions. Of many retrotransposons, the O. dioica genome retained two prominent ones, Odin and Tor, and eliminated many others. O. dioica cells exposed to natural UV light at the surface of the oceans evolve fast due to an accelerated rate of point-mutations and to limited faculties of DNA repair. Is the O. dioica genome a representative of the mutator geno-phenotypes? So is the genome of C. savignyi, that split from C. intestinalis some 180 mya (Berná L & Alvarez-Valin F Genome Biol Evol 2014;6: 1724–1738).

Botryllus. The tunicate urochordates Botryllus live in colonies, and operate a 580 Mbp genome consisting of some 14,000 intron-containing, and some 13,500 intron-less genes. The Botryllus genomics has not as yet been correlated with those of the highly evolved multicellular eukaryotes (Homo included). Calling for “Botryllus Wnt, Hedgehog, NFkappaB/STAT “ etc etc etc, the answer is “no item found”. Cursory mention is available to correlation of Botryllus genes with mutated 586 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia counterparts in human diseases (cataracts; deafness; myopathy; pregnancy-speciﬁc glycoproteins), but not cancer. Native immunity and hematopoiesis (an NK-like cell in the common haemolymph of each zooid cluster) are accurately addressed (Khalturin K et al Proc Natl Acad Sci USA 2003;100:622–627. Voskoboynik A et al Elife 2:e00569). The origin of NK cells in the Botryllus; the correlation of the human maternal NK cells with the placenta and the fetus; and the imitation of the fetus by cancer cells were the subject matters of one of the discussions this author initiated in the early 2000s (Sinkovics JG & Horvath JC Int J Oncol 2005;27:5–47; Sinkovics JG, Horvath JC Kay HD Book of Abstracts, The 56th Annual Symposium Fundamental Cancer Research, The University of Texas M.D. Anderson Cancer Center, Houston TX 2003 p 117 #1–33). A more sophisticated presentation followed (Lightner A et al Clin Dev Immunol 2008:631920. doi:10. 1155/2008/631920).

Amphioxus II. Integrated in the amphioxus genome resides an ancient herpesviral genomic sequence related to oyster, and more distantly, to the gastropod abalone herpesvirus (Savin KW et al Virol J 2010;7:308. doi:10.1186/1743-422X-7-308). One of the genes in the amphioxus waiting to be recruited by the forthcoming adaptive immune system is the rag/RAG sequence. The protein expresses a retroviral type II nuclease motif, localizes in the nucleus, and performs V(D)J-like recombination if brought together with a mouse RAG2 protein (Yu C et al J Immunol 2005;174:3493–3500; Zhang Y et al Proc Natl Acad Sci USA 2014;111: 397–402). A newly isolated bat betaherpesvirus encodes proteins homologous with human herpesvirus’ 6 U94, the incorporated parvoviral sequence; MHC class II homologous proteins; NK cell receptor-like lectins; and immunoglobulin beta-sandwich domains (Zhang H et al J Virol 2012;86:8014–8030). Herpesviruses ancestral to EBV were claimed to have incorporated V(D)J-like genomic elements (Dreyfus DH PLoS One 2009;4:e5778; Nillen et al Acta Microbiol Immunol Hung 2004:51:469–484), and thus initiated adaptive immunity in their hosts, which were living at the innate immunity level. Could the amphioxus herpesviral genome be the ﬁrst possessor of primordial genes of adaptive immunity? It is also possible that herpesviruses incorporated the genes of adaptive immunity from hosts, which already possessed these genes ﬁrmly in use; this could be the case for some bat herpesviruses and EBV (see text).

Viral Oncolysates. In an interview, Sinkovics stated (in replying the question: “VOs cure sarcomas or melanomas?”) that metastatic tumors were not cured with VO treatment alone (however lives were prolonged). Unfortunately, the interviewer published the interview under the title: “Viral oncolysates are ineffective”. Most recent references avoid mentioning “viral oncolysates” by name; instead re-name them as “oncolytic vaccines”, and thus entirely omit referrals to their predecessors (Elsedawy NB & Russell SJ Expert Rev Vaccines 2013;12:1155–1172); however, claim and illustrate their rationality for high immunogenicity. The original theory in Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 587 support of VOs as cancer vaccines rested on the expectation that the immunized tumor-bearing host will recognize antigens of cytoplasm and cell membranes and viral capsids or other structural proteins fused at viral egress, as non-self. Therefore vaccinated subjects should respond to their altered self-antigens immunologically. Such immune responses by antibodies and immune T cells to autologous tumor cells (sarcoma, melanoma, adenocarcinoma) were documented in the chamber slide cultures in vitro in patients immunized with autologous VOs (Sinkovics JG Cytolytic Immune Lymphocytes. Schenk Buchverlag Budapest/Passau 2008), but the formation of such fused antigens was not experimentally documented at that time. The cancer cell surface antigens against which the host directed its immune reactions were not identified. For that reason, the NIH/NCI denied grant support for VO cancer immunotherapy. However, later elsewhere it has been well documented that such fused antigens are formed. Influenza viral structural proteins fuse not only with cell surface sialic acid proteins, but also with the host cells’ endosomal CD81 proteins (He J et al PLoS Pathog 2013; 9(10):e1003701). Thus, the influenza virus particles emerging from cancer cells expresses immunogenic cancer cell antigens fused with viral structural proteins. Properly prepared VOs (re-named “oncolytic vaccines”) may remain in use for cancer immunotherapy.

Lamprey lymphocytes. Leucine-rich repeat cassettes and variable lymphocyte receptors provide adaptive immune reactions without immunoglobulins. Release chemokines and interleukins and their receptors; express TCR (Mayer WE Proc Natl Acad Sci USA 2002;99:14350–14355; Pancer Z et al Proc Natl Acad Sci USA 2004;101:13273–13278; Uinuk-Ool T et al Proc Natl Acad Sci USA 2002;99:14356–14361;

Gnathostomata Collected and United the Genomics of the Adaptive Immune System. The by now extinct armored fish Placoderms predated the cartilagenous sharks and their followers, the bony fishes. While they preserved the innate immune system (Toll-like receptors with a chemokine, microRNA and some lympho- and cytokine network; phagocytic leukocytes, monocytes and macrophages, dendritic cells; invariable NK cells; but no immunoglobulins), the followers of the placoderms, the chondrichtyes gnathostomata sharks, possess and practice a full adaptive immune system consisting of MHC cell-presented antigens, B and T lymphocytes with variable receptors and an extensive immunoglobulin network. Some of the genes of the complex adaptive immune system (V and RAG) appear singly “in the waiting” in the amphioxus and sea urchin, but assigned to tasks other than those of the forthcoming adaptive immune system. The adaptive immune system worked in unison for the first time at the placoderm/shark level. Vertically inherited and horizontally transferred genes generated the adaptive immune system. Either one or both, retrotransposons (harbingers, helitrons, politrons, transibs), and/or elements inserted into ancient herpesviral genomes (vdj, rag) and thus passed from host-to-host, encountered for the first time in united activity in the lymphoid tissues encircling the intestinal tracts of ancient sharks. Phylogenetic vertical inheritance interrupted by episodes of horizontal gene transfers secured the existence and 588 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia reinforced the performance of the system up to the highest level of vertebrate mammalian hosts (Dreyfus DH et al Virol J 2011;8:422. doi:10.1186/1743-422X-8- 422; Fugmann SD Semin Immunol 2010;22:10–16; Kapitonov VV & Jurka J PLoS Biol 2005;3(6):e181; Litman GW et al Nat Rev Immunol 2010;10:543–553; Niller HH et al Acta Microbiol Immunol Hung 2004;51:469–484). The adaptive immune system had to reconcile with the placenta of the vertebrate mammalian hosts. The placenta acts as a “pseudomalignant organ” inducing tolerance in its host (the mother) (Sinkovics JG Horvath JC International J Oncol 1999;14:615–646).

Ferroplasma acidarmanus. Tetraether-linked membranes enable the hyper-acidophil Ferroplasma acidarmanus to live and metabolize in hyperacidic (pH 0–1) environments. Zinc reaches extremely high concentrations in heavy metal-polluted environments inhabited by the arsenic-hypertolerant, iron-oxidizing extremophil archaeon and its relatives. These microorganisms suffer oxidative stress and produce methanethiol and volatile sulfur. In response, heavy metal exporter and zinc homeostasis genes and gene product proteins are constitutively expressed and upregulated in order to keep intracellular zinc levels low constant. The DNA strand separations in F. acidarmanus are performed by DNA helicases, which are recognized to be ancestral Rad3 xeroderma pigmentosum (F. Hebra & M. Kaposi, 1874) group D (FacXPD) proteins (related to the human enzymes in the pathological entity XP). These helicases possess unique iron-sulfur cluster (FeS) for their insertion to perform NER (DNA unwinding in nucleotide excision repair) and to initiate transcription. The FeS cluster recognizes the enzyme’s substrate, the ssDNA-dsDNA junction; thus, ssDNA-dependent ATP hydrolysis and ssDNA translocation are performed. The FacRd3 enzyme is a ssDNA translocase (Mangold S et al Extremophiles 2013;17:75–85. Pugh RA et al J Biol Chem 2008;283:1732– 1743; J Mol Biol 2008;383:982–998). The FeS clusters of the human XPD enzymes are subject to point mutations. A common XPD point mutations consists of the substitution of serine to cysteine. In the recessive human disorder XP: a common XPD point mutation is R683W (arginine; tryptophan) at 19q13, inhibiting NER. Other consequences of this mutation are trichothiodystropy and Cockayne syndrome. The risk for melanoma is increased. Megakaryoblastic leukemia may occur. Risk for breast cancer in Egyptian women is increased (Hussein YM et al Mol Biol Rep 2012;39:1895–1901; Janjetovic S et al Acta Haematol 2013;129:121–125; Paszkowszka-Szczur K et al Int J Cancer 2013;133:1094–1100; Ueda T et al J Exp Med 2009;206:3031–3046). Triplex DNA formations (H-DNA) develop dsDNA breaks with the formation of γH2AX (histone variant; ataxia telangiectasia) foci, which recruit XPD. The phosphorylated serine 139 and tyrosine 142 residues of H2AX induce p53-mediated apoptosis (Tiwari MK & Rogers FA Nucleic Acids Res 2013;41:8979–8994), thus preventing transformation. Mutations of helicases other than XPD (RecQ4; BLM; WRN) lead to Fanconi anemia; Bloom syndrome; Werner syndrome (see text). The descendant of the archaean enzyme in the human genome suffers point mutations; the mis-repaired DNA either translocates (c-myc in Burkitt’s lymphoma in the H-DNA triplex, cited by Tiwari & Rogers), or encodes an oncoprotein. Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 589 p53/MDM. The pro-apoptotic p53 gene product protein is neutralized by the anti-apoptotic MDM oncoprotein. The gene and gene-product protein mdm/MDM (murine double minute; human counterpart) exerts ancient opposition to the p53 family members: the MDM proteins fused with the p53/p73 proteins direct the complex to ubiquitination. The MDM protein is a ubiquitin ligase. Thus the MDM protein can transform cells (rat embryo fibroblasts) into focus-forming entities, which grow into tumors in nude mice. The human mdm gene from its locus 12q13-15 encodes its MDM protein. Human sarcoma cells amplify the mdm gene and overproduce the MDM protein. In human malignant tumors the MDM4 protein is the most active suppressor of p53/p73. In the MDM/p53 protein complex, the p53 transactivator pro-apoptotic protein is inactivated (Barak Y & Oren M EMBO J 1992;11:2115–2121; Momand J et al Cell 1992;69:1237–1245; Oliner JD et al Nature 1992;358:80–83. Bert Vogelstein, Clayton Professor of Oncology; Johns Hopkins University Medical Institutions; Ludwig Center at Johns Hopkins; Sidney Kimmel Comprehensive Cancer Center; Baltimore, MD). The sea squirt (Ciona intestinalis) and the amphioxus operate the first mdm/MDM1 genes/proteins (only one mdm gene, which also encodes a p53 family member). Choanoflagellates did not as yet reveal a mdm/MDM system; they may be devoid of it. However a genome-protector p53 family ancestor exists in choanoflagellates. A substitute different from mdm/MDM suppresses p53 in the caenorhabditis. The drosophila is devoid of the classical MDM proteins, yet both drosophila and caenorhabditis experience constitutively replicating cells tantamount to malignant transformations. The mdm genes underwent duplications in cartilaginous fishes (chondrichtyes); since then, MDM2/4 remain conserved. The p53 proteins were DNA-binding, whereas the MDM proteins do not target the p53 gene; the MDM proteins form complexes with the p53 proteins (Momand J et al Gene 2011;486:23–30). The mussel (mollusk) Mytilus trossulus expresses the ancestor of the MDM2/4 molecule (before its divergence) and the p53 ancestor p63. The mussel MDM molecule forms complexes with its p63/63 proteins. The N-terminal deleted p63 (ΔNp63) isoform was up-, and the transactivation domain p63 (TAp63) isoform was down-regulated. Not quantitatively, but by its codon 13 mutation, the mussel haemocytes’ ancestral ras gene dictates uncontrolled cell divisions (Muttray AF et al Comp Biochem Physiol B Biochem Mol Biol 2010;156:298–308). In plants (maize; rice), the MDM1/2 genomic elements reveal long terminal inverted repeats (LTIR), possible functional transposase-binding sites, as if they were originally Mutator Elements; their 8–9 bp termini are those of mutator-like elements (Yang G & Hall TC J Mol Evol 2003;56:255–264).

G 4 Quadruplex DNA. All eukaryotic G-quadruplexes assemble from G-rich single-stranded (ss) DNA sequences when dsDNA is unwound. The human telomeres contain TTAGGG repeats in dsDNA 2–15 kb strands ending in a G-rich single-stranded 3′ overhang consisting of 50–400 nucleotides. Intramolecular G-qadruplexes in the template inhibit DNA polymerases; DNA synthesis is stalled. Translesion DNA polymerases are recruited to the sites of replication blockade. Thus, misincorporation of nucleotides occurs: mutagenesis ensues. Single strand gaps lead 590 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia to ds breaks, the hallmark of pre-cancerous state. Some helicases may succeed or fail to resolve G-quadruplex structures (Fanconi, Bloom, Werner syndrome helicases) (Edwards DN et al PLoS One 2014;9(1):e80664). Proto-oncogenes/oncogenes often assume constitutive G-quadruplex formations and encode oncoproteins (KIT, BCL2, VEGF, KRAS, MYC, SRC). Recruitment of the DNA damage marker γH2AX (ataxia) reveals the site involved. G-quadruplex-stabilizing ligands exist in human cancer cells (breast adenocarcinoma) (Lam EY et al Nat Commun 2013;4:1796). In unicellular eukaryotes (oxytricha), G-4 DNA structures function as a cell survival pathway. In the differentiated somatic cells of multicellular hosts, G-quadruplexes maintain telomeres and induce dsDNA mutations: they act as oncogenes. G-4 quadruplexes are targeted for cancer therapy. Natural and synthesized G-quadruplex-intercalating agent telomestatin (S2T1-6OTD) disables c-Myc in medulloblastoma and rhabdoid tumor cells (Shalaby T et al Mol Cancer Ther 2010 9;167. doi:10.1158/1535-7163.MTC-09-0586). An acridinium methosulfate derivative (RHPS4) brings primitive neuroectodermal tumor, glioblastoma and medulloblastoma cells to standstill at G1 by anti-proliferative effect (Lagah S et al PLoS One 2014;9(1):e86187). Enantiomer NiP (nickel; a non-superposable stereoisomer) induced telomere uncapping and G-overhang degradation in tumor (but not in normal human ﬁbroblast or umbilical vein endothelial) cells. The lesions attracted γH2AX. Some of the 3′ overhang-protective shelterin proteins were removed. The tyr707-phosphorylated hTERT protein translocated from nucleus to cytoplasm and was reduced in amount. Cell cycle inhibitors (p16; p21) rose. G-quadruplex remained stable; it could not protect the tumor cells against apoptosis: apoptosis may overrule the G-quadruplex (Wang J et al Nucleic Acids Res 2014;42: 3792–3802). After their discovery (Gellert M et al Proc Natl Acad Sci USA 1962;48: 2013–2016), DNA G-quadruplex formations were recognized to have occurred within human proto-oncogenes (bcl-2; K-ras; myb; c-myc; hTERT) (Ambrus A et al Biochemistry 2005;44:2048–2058; Dai J et al Nucleic Acids Res 2006;34:5133– 5144; J Am Chem Soc 2006;128:1096–1098; Cogoi S & Xodo LE Nucleic Acids Res 2006:34:2536–2549; Palumbo SL et al J Am Chem Soc 2009:131:10878–10891). These structures ﬁrst downregulate transcription. However, mutations occur within the quadruplex DNAs, which abrogate the negative effects, and induce increased gene expressions: loss of quadruplex stability abolishes the gene silencing effect of the quadruplex formation. The promoter gene of the human telomerase is a subject of DNA G-quadruplex mutations in glioblastoma and melanoma cells. The central quadruplex of the structure is affected. For example, guanine-to-adenine mutations produce new binding sites for the ETS oncoprotein (product of the E26 retroviral c-onc→v-onc proto-oncogene). Such mutations in a G4 DNA-quadruplex within the hTERT (human telomeric reverse transcriptase) promoters in glioblastoma and melanoma cells increases those gene expression (Chaires JB et al PLOS 2014;9(12): e115580). Telomeric overexpressions in malignantly transformed cells are the major contributors to the cells’ immortality. However, G-quadruplex-forming G-rich oligodeoxynucleotides (GQ-ODNs), and the telomeric G-tail oligodeoxynucleotides (TG-ODNs) may exert antiproliferative activity in tumor cells, leading to apoptosis, Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 591 mediated by ataxia telangiectasia mutated ATM-dependent c-Jun NH2-terminal kinase (JNK) (Qi H et al Cancer Res 2006;66:11808-16).

Theileria-Infested Bovine Lymphocytes support the parasite by assuming “malignant transformation”. The tick-transmitted protozoan T. parva undergoes a major transitional life cycle in the lymphoid cells of the infected ruminants. The gametes transform in the guts of the tick into into zygotes, the fused male and female gamonts. Kinetes derive from gamonts and occupy cellular elements of the tick’s salivary glands. There, the infectious sporoblasts and sporozoites are formed. In the mammalian (bovine, ovine) lymphocytes sporozite-derived schizonts undergo merogony and emerge as merozoites. The schizonts-containing lymphocytes de-differentiate into lymphoblasts and multiply rapidly by clonal expansion expressing constitutively certain proto-oncogenes . The lymphoblasts and the schizonts divide synchronously. The lymphoblasts exert cytotoxicity to parenchymal host cells. Immune T cells of the host recognize the infected lymphoblasts and try to kill them. The killed lymphoblasts release the pathogen in its piroplasma stage. The piroplasmas enter red blood cells and upon tick bites of the host enter the ticks’ gut, where the piroplasmas convert into sporozoites; the sporozoites will infect the mammalian hosts. The African East Coast fever endemic in cattle (Faculty of Veterinary Science, University of Zimbabwe, Harare. Assistance to Veterinary Service of Zambia. Control of East Coast Fever in Zambia. Control Strategy for theileriosis in Rwanda. Centre for Ticks and Tick-borne Diseases in Malawi. ITM Antwerp Annual Report 2002 D. Geysen http://www.itg.be/internet/ jaarverslag02/en/animalhealth.html.

Life Cycle of Malaria Plasmodium. The analysis of plasmodia mitochondrial genomes indicates that human ancestors were infected with plasmodia of gorilla origin in median estimate 365,000 years ago; human-adapted plasmodia radiated thereafter. P. malariae might have been the ﬁrst human malaria pathogen, and P. falciparum is the last most recent acquisition, while human infestation with P. vivax might have originated even more recently from Southeast Asian macaques (Baron JM et al J Mol Evol 2011;75:297–304; Escalante AA et al Proc Natl Acad Sci USA 2005;102:1980–5; Sabbatini et al Infez Med 2010;18:56–74). The P. falciparum genome harbors a phage integrase-like domain referred to as Pf-Int atv locus Mal13P1.42. Pf-Int is a tyrosine recombinase; the mRNA encoded enzyme is a 490 aa polypeptide. The enzyme is not essential for the life cycle of the plasmodium, but it contributes to its genetic diversity and virulence (Ghorbal M et al PLoS One 2012;7(10):e46507). Targeting the ubiquitin/proteasome system kills the plasmodia (Chung DW & Le Roch KG Infect Disord Drug Targets 2010;10:158–164). The proteasome inhibitors bortezomib and carﬁlzomib kill the human myeloma cell (Jurczyszyn A et al Contemp Oncol (Poznan) 2014;18:17–21).

Pinealoma. The circadian rhythms of the pineal gland and their ancient beginnings, and their oncologic connotations, are present in the pinealoma. This neuroendocrine organ receives its adrenergic innervations from the hypothalamic suprachiasmatic 592 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia nucleus. Peripheral photosensitive cells (some of them in the retina) provide input to the suprachiasmatic nucleus (Hafner et al PLoS Comput Biol 2012;8(3): e1002419. Parenchymal cells of the gland produce from serotonin the nocturnal hormone melatonin. Other constituents are germ cells and neuroectodermal cells. All cellular elements are synchronized by the circadian rhythm. Pineal gland tumors are of parenchymal, germ cell, and neuroectodermal histopathology. Tumors may de-differentiate into pineoblastomas, anaplastic xanthoastrocytomas or papillary cancers. All pinealomas are interconnected with the clock genes of the circadian rhythm. Long noncoding RNAs are metabolically and transcriptionally extremely active. Leading genes are for proteins BMAL (brain and muscle Arnt-like), Clock, Cry and PER (circadian molecular clocks; cryptochromes; period), CREB/ETS (cAMP-response element-bindig protein; E-twentysix retroviral proto-oncogene), c-Myc at 17q (myelocytosis), CaMP/CaKM (calcium/calmodulin-dependent protein kinase), Wee (small), cyclin D cell circle genes (Coon SL et al Proc Natl Acad Sci USA 2012;109:13319–13324; Kees UR et al Cancer Cytogenet 1998;100:159– 164; Kelleher FC et al Cancer Lett 2014;342:9–18; Tovin A et al PLoS Genet 2012;8(12):e1003116.

Neurospora crassa, operates active CREB proteins (vide supra). Superoxide anions through protein phosphatase 2 activate the positive elements of the circadian clock (Gyöngyösi N et al Free Radic Biol Med 2013;58:134–143).The signalosome integrity is essential for hyphal growth. The circadian clock activates the MAPK/ERK (MAK) pathway; it induces robust activation of genes ccg (clock-controlled genes) and mitochondrial gene U07465 (Bennett LD et al Eukaryot Cell 2013;12:59–69; Zhou Z et al PLoS 2012;8(5):e1002712). The protein arginine methyl transferase PRMT in a cell survival pathway protects against oxidative stress (Feldman D et al PLoS One 2013;8(11):e80756). The CaMK proteins phosphorylate frq (frequency), thus accelerating cell growth (Gooch VD et al J Biol Rhythms 2014;29:38–48; Yang Y et al J Biol Chem 2001;276:41064– 41072).The Δcamk-2 mutant CaKM protein remained active in oxidative stress and exhibited thermotolerance. The Δcamk-1,3,4 mutant genes reduced growth rate and hyphal growth and failed to protect against oxidative stress (Kumar R & Tamuli R Arch Mikrobiol 2014;196:295–305; Yang Y et al J Biol Chem 2001;276:41064– 41072). A genome-wide characterization of blue-light-regulated genes of N. crassa is available (Wu C et al G3 Bethesda 2914;4:1731–1745). The N. crassa genes encode kinases for the phosphorylation of amino acids serine, threonine, tyrosin in order to activate proteins; and phosphatases to deactivate proteins by removal of the phosphate groups (dephosphorylation). The class 2 phosphatases (PP2A) dephos- phorylate, thus inactivate MAPK. Loss-of function-mutated PP2A phosphatases allow MAPK overactivity to its constitutive expression. Hyphal overgrowth and hyphal cell fusions follow. The proliferating hyphae fail to respond with cessation of growth to the inhibitory chemical butyl-hydroxy-peroxide (t-BuOOH, Sigma) (Bennett LD et al Eukaryot Cell 2013;12:59–69; Ghosh A et al G3 Bethesda 2014;4:349–365). Response to the light-induced circadian rhythm activates MAPK. Recently reviewed (Sinkovics JG Europ J Microbiol Immunol 2015; 5:25–43). Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 593

Comment. The human CaKMs promote cancer cell (breast, endometrium) growth and are targeted for therapy (Bitschgi A et al Proc Natl Acad Sci USA 2013;110: E1026–1034; Takai N et al Cancer Lett 2009;277:235–243).The Neurospora genome contains the elements antecedent to protooncogenes (Creb; MAPK) and tumor cell promoter (frq; PRMT; CaKM; Δcamk-2) and tumor suppressor genes (Δcamk-1,3,4). In some human cancers cells (colon cancer; neuroblastoma; myeloid leukemia) some of the CaKM pathways were apoptosis/necroptosis- or differentiation-inducers (Jutong S et al J Clin Invest 2007;117:1412–1421; Kim do Y et al J Agric Food Chem 2009;57:10573–10578; Nomura M et al Cancer Res 2014;74:1056–1066). Pineal region masses: differential diagnosis (Smirniotopoulos JG et al RadioGraphics 1992; 12: 577). Correlate with circadian rhythm of Neurospora crassa (in Appendix 2 Explanations to the Figures, Figure 63).

Trichomonas. The parabasalian trichomonads enriched their genomes through receptions by horizontal transfers and insertion of prokaryotic genes, prominent among them the GTPase signaling system (Anantharaman V et al Gene 2011;475:63–78). The eukaryotic GTP-binding signal transductions are conducted by ancient monomeric proteins of the Ras superfamily. The enzymes catalyzing GTP to GDP emerged in prokaryota and archaea, and are conserved in eukaryota. The ribbon plots and crystal structures of the GTPases are very well known. The ancestral GTPase MnmE (methylaminomethyl E) was acquired in eukaryotes from a protomitochondrial endosymbiont. The ancestral E. coli Ras-like protein (Era) is present in the Aquifex aeolicus. An ancestral Era might have existed in precellular ribosomes? Chlamydia, Mycobacteria and fungi lost Mnm and Era. In plants and fungi, the Era-related GTPase (Erg) is operational. The human Era homolog ERAL (Era-like) remains located in the mitochondrial matrix. Overexpressed ERAL induces mitochondrial apoptotic death of HeLa cells. Related and conserved GTPases conduct ribosome assembly, cell cycle regulation and stress response. The vast majority of bacteria (over 75% of the species) share 13 GTPases. Many of these GTPases remain conserved in eukaryotes functioning as translation factors, or signal recognition associates. Of translation factors, IF (initiation factors) expand from archaea to human cells. Some of the signal recognition associates remained in chloroplasts, where they mutually activate each other (Verstraeten N et al Microbiol Mol Biol Rev 2011;75:507–542). The prokaryotic MgLA (CH3-galactoside transport, L-arabinose) proteins are considered to be the ancestors of their eukaryotic descendants (Notley-McRobb L & Ferenci T Genetics 2000;156:1493–1501; Dong JH et al Gene 2007;396:116–124). N-ras appears to be a derivative of prokaryotic cold-shock domain proteins (Doniger J et al New Biol 1992;4:389–395). Early multicellular eukaryotes with two ecto/endodermal cell layers without mesoderm (N. vectensis, C. intestinalis) operate ancestral GTPase ras genes. Ras family genes are absent in plants and alveolates (P. falciparum). Rho family genes replace them. Rab family genes operate in amebozoans and ciliates. The ras gene-coded monomeric GTP-binding proteins of 181 aa appear in the T. vaginalis (Xu MY et al Biochem Cell Biol 2007;85:239–245). In the human genome 167 ras superfamily sequences are operational. Some basic science reviewers omitted all oncogenic 594 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia connotations. For the phylogenetic tree of human Ras superfamily, see Figure 3 of the article (Rojas AM et al J Cell Biol 2012;196;189–205). The Harvey (H) and Kirsten (K) ras sarcoma genes were found in the Moloney murine leukemia/sarcoma retrovirus strains passaged in rats: ras rat sarcoma. The low branching unicellular eukaryote Trichomonas in its very large 160 mb genome operates ancestral Ras subfamily protein-encoding intronless genes (Rsp) (Xu MY et al Biochem Cell Biol 2007;85:239–245). Transfer from its ancient free-living entity to being a parasitic microorganism has come with major genomic changes in the trichomonads: replacement of lost genes by horizontally acquired novel genes. Indeed, trichomonads share numerous genes with bacteria, yeast fungi, Entamoeba, Giardia, and the human host. The ras genes are not named in the list of laterally acquired genes (Singh S et al, Bioinformation 2012;8:189–195). The Trichomonas genome harbors three myb (myeloblastosis, avian) transcription factor genes, whose gene-product proteins attach to Myb protein recognition sites (MRE) in its genome. The iron-responsive promoter region of the ap65-1 gene (adhesion protein, adhesin) is the target of the Myb proteins. Cytoadherence is essential for the pathogenicity and virulence of trichomonas cells. The adhesion DBD (DNA-binding domain) protein is a pyruvate:ferredoxin oxidoreductase homologous to a similar gene of Entamoeba histolytica (Moreno-Brito V Cell Microbiol 2005;7:245–58). The trichomonas Myb3 protein displays 83% aa identity with the human c-Myb. Its binding to DNA is similar to that of the FOXO (forkhead box) protein (Wei S-Y et al Nucleic Acids Res 2012;40:449–460). The most widely spread ras proto-oncogenes/oncoproteins served in cell survival pathways of bacteria and archaea before moving into eukaryotes. In multicellular hosts, the cell survival pathways have become proto-oncogenic transformators. In unicellular eukaryotes (amoeba; ciliates; trichomonas) appear the ancestral myb/Myb pathways not known to be constitutively expressed, but essential for virulence. Trichomonas may coexist with pathogenic viruses (HPV, BK polyoma virus, XMRV, the xenotropic murine leukemia virus-related virus, HIV-1), in the human female and male genitourinary tract (including the prostate), and remains a suspect for the initiation of malignant transformation.

The Trichomonas genome is large, constantly active due to multiple gene acquisitions; readily trans-speciates the cell (amoeboid to flagellar, to and from); carries the ancestors of several human proto-oncogenes, primarily myb/Myb; and is loaded with pseudogenes (1354 annotated pseudogenes). The total gene numbers are between 46,000 to 60,000 in six chromosomes. Transposable elements make up 45%, pseudogenes 5% of the genome. There are 668 ribosomal rRNAs and 468 transfer tRNAs; snRNAs, snoRNAs, miRNAs, long non-coding lncRNAs are all operational in the nuclear spliceosome and the cytoplasmic AGO/Dicer complex. Many lncRNAs reveal significant sequence similarities to genomic loci annotated as protein-coding genes. Thus, these lncRNAs are descendant pseudogenes. The fact that prokaryotes and archaea do not possess spliceosomes indicates that these organs appeared first in eukaryotes. Yet the Trichomonas introns appear to support the “introns first” hypothesis. In opposition, eukaryotic introns derive from the Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 595 presumably intron-rich LECA (last eukaryotic common ancestor) (Rogozin IB et al Biol Direct 2012;7:11; Vaňáčková S et al Proc Natl Acad Sci USA 2005;102:4430– 4435; Woehle C et al BMC Genomics 2014;15:906). Pseudogenes persist as copies of ancestral protein-coding genes deriving from gene duplications or retrotrans- positions of mRNA sequences. Thus, pseudogenes may yield endogenous miRNAs to inhibit the mRNA of a related fully operational gene; they may be transcribed into dominant-negative polypeptides. All in these, the trichomonas genome is similar to an oncogenome. In this last aspect, human cancer cells accumulate and utilize pseudogenes for their own promotion. Prominent example is the stem cell proto-oncogene oct/Oct4 encoded from gene POU5F1 (Pit-1, pituitary; Oct1,2; Caenorhabditis unc, uncoordinated) at chromosome 6p21.3, and its numerous pseudogenes in glioblastoma and hepatocellular carcinoma, where they upregulate the PI3K/Akt pathway (Zhao QW et al Oncol Rep 2015;33:1521–1529). In prostate cancer, both ETS-positive and ETS-negative cells express the gene CXADR, but only ETS-negative cancer cells express its pseudogene CXADR-Ψ (retrovirus Ets/E26; coxsackie virus adenovirus receptor, CAR). In breast cancer, the ATP8A2 (adenosinetriphosphate) gene and its pseudogene ATP8A2Ψ compete. The pseudogene-expressor tumor cells gain replication and migration advantage (Kalyanja-Subaram S et al Cell 2012;149:1622–1634). Thus, the Trichomonas pseudogenes may also serve (not yet documented) as factors of increased virulence. lllustrations can be found at Science Photo Library Trichomonas vaginalis_para- sites_computer_artwork_z100202.jp. The avian retrovirus myeloblastosis E26 (Ets E twentysix) incorporated its host’s c-myb gene. The human c-myb oncogene/Myb oncoprotein is expressed in HeLa cells, as shown by staining with fluorescent polyclonal IgG antibody ab167537 of ABCAM 888-7722226.

Epithelial-to-Mesenchymal Transition. Tumor cells may recruit ﬁbroblast-, or monocyte-Mϕ-like cells to fuse with them and thus assume a highly mobile slick elongated shape. Accordingly, the cytoskeleton is transformed. The cytoplasm is vimentin-positive. These tumor cells locally invade tissues, or enter into lymph vessel or vascular endothelial cells, into the lumen of lymphatic and blood vessels, in order to be able to travel by the lymph or blood stream and settle at, and colonize, distant sites (Dittmar T & Zänker KS “Cell Fusion in Health and Disease. II. Cell Fusion in Disease”, 2011. Advances in Experimental Medicine and Biology, 2010; 714. Springer Dordrecht Heidelberg London New York. Sinkovics JG Int J Oncol 2009;35:441–465). The biological meaning (metastasis formation), early and reliable recognition and the value of immediate treatment for circulating tumor cells (CTC) are under extensive investigation Epithelioid breast cancer cells leave the tumor mass, convert into elongated mesenchymal-like cells to enter blood vessels (Karabacak NM et al Nat Protoc 2014;9:694–710; Ma X et al Tumour Biol 2014;35:5551–5560; Shao C et al PLoS One 2014;9(2):e88967). 596 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia

Oxytricha fallax and trifallax. These large (1 mm) unicellular ciliates ingest nutri- ents in food vacuoles (a “digestive tract”; osmoregulate their cytoplasm with con- tractile vacuoles (a kidney-like “urinary tract”), and evacuate waste through their “cytoproct”. In their macronucleus they carry over 25 million minichromosomes (fragmented chromosomes) and over 30,000 genes. Massive apoptosis occurs when post-conjugation the germline micronucleus (Mic) transforms (“differentiates”) into the somatic macronucleus (Mac): transposons and non-coding DNA sequences are eliminated. Transposases excise and do not reinsert the transposons. The fragmented genome is precisely reconstructed based on ssRNA copies of each minichromosome gene. The oxytricha genomes, cap their chromosomes’ ends after each binary fission of vegetative clones (karyonides), or conjugation. Prior fission, the Mac chromosomes end-reduplicate. Telomeres are re-caped. Thus, they experience no double break repair, or breakage-fusion-bridge catastrophes (first described by Barbara Mc McClintock in 1938). The tandem repeat G-rich 20 bp sequence telomeres are de novo polymerized, templated by an RNA component, and primed by a 3'OH end. Telomeres maintained in full length prevent senescence of the cell (Nowacki M et al Nature 2007;451:153–158; Science 2009;324:935–938; Williams KR et al BMC Genet 2002;3:16). The oxytricha mitochondrial genes are arranged in two transcriptional directions (in contrast to paramecia mitochondrial genes arranged in just one transcriptional direction). The oxytricha mt genome contains a large linear plasmid. These mitochondria have recently acquired this plasmid, because its ORFs have not as yet engage in the tryptophan codon usage (the tryptophan bias). The mt genome encodes 11 tRNA genes, more than other ciliates’. It operates both RNA and DNA polymerases; one RNA polymerase is of bacteriophage-derivation. Thus, the ancient proteobacteria before became mitochondria harbored phages. Others are distantly related to DNA polymerases of the amoebozoan D. discoideum, or of the oomycete Phytophthora (Table XXX). The mitochondrial genes are capped by 35 bp telomeres (Swart EC et al Genome Biol Evol 2012;4:136–154).

Pluricellular Advancement of a Cancer Cell Armada. By morphological appearance, the crawling locomotion of cancer cells imitates that of the amoeba. A pseudopod protrudes first and attaches to the ground; the body elongates; the rear of the cell is retracted. The malleable cytoplasm can negotiate narrow spaces between fibers, but the nucleus retains its firm substance, except for some limited elongation. The cancer cell nuclei are usually larger (7 μm2 cross section) than that of normal cells (T lymphocyte, 4 μm2; neutrophil leukocyte, 2 μm2). Extracellular collagen matrix can be dissolved by metalloproteinases. The sedentary cuboid cancer cell restructures its cytoskeleton, becomes sarcomatoid and mobile and activates the descendants of the native amoebal genes, that were in use for cell locomotion since ancient times (see text). What is not available for the solitary amoeba, the colonies of cancer cell have acquired: multicellular mechanocoupling moving cell sheets forward in a coordi- nation arranged between leader and follower cells, in which the leader cell applies a traction force to the follower cells. The Rho GTPase-driven leader cell is able to drag follower cells by peripheral pluricellular actin-myosin cables. Multicellular migration follows and results in collective cancer cell invasion (Alexander S et al Curr Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 597

Opin Cell Biol 2013;25:659–671; Friedl P et al Nat Cell Biol 2014;16:208–210; Reffay M et al Nat Cell Biol 2014;16:217–223; Wolf K et al J Cell Biol 2013;201:1069–1084). The pseudopods of Amoeba proteus: one pseudopod forms two arches and three points of contact with the substratum (Cameron I, Rinaldi RA, Kirby G, Davidson D. University Texas Health Science Center, Department Cellular Structural Biology; Southwest Research Institute, San Antonio, TX; University Colima, Colima, Mexico; Tulane University School Medicine, Department Structural Cellular Biology, New Orleans Louisiana. Cell Biology International 2007;31:759–776). Invasive human breast cancer cell driven by protein tTG (tissue transglutaminase, vide infra) chaperoned by Hsp70 protrudes its leading edge. The tTG protein protect cells from serum-starvation-induced apoptosis, and activates c-Scr and PI3K/mTOR complex proto-oncogenes (Boroughs LK, Antonyak MA, Cerione RA. Johnson JL Cornell University, Department Molecular Medicine, Ithaca, NY. J Biol Chemistry 2014;289:10115–10125).

Tissue Transglutaminase (tTG). tTGs form cross-linking isopeptide bonds between two proteins in embryogenesis, apoptosis, angiogenesis, and cancer. tTGs evolved through unicellular eukaryotes, crustaceans to vertebrate mammalians, incl Homo. Increased levels occur in malignantly transformed mammalian vertebrate cells: adenocarcinomas of esophagus, pancreas, kidney, prostate; melanoma (Ashour AA et al J Cell Mol Med 2014;18:2235–2251; Erdem S et al World J Urology 2014 Dec 17 SpringerLink PMID 25515319; Han AL et al Eur J Cancer 2014;50:1685–1696; Kim HJ et al Biomol Ther 2014;22:207–212; Leicht DT et al J Thorac Oncol 2014;9:872–881). In clear cell carcinoma of the kidney, strong TG2 expression correlated with metastatic disease and increased mortality (Park MJ et al J Pathol Transl Med 2015;49:37–43). tTG is a cell survival promoter, as it acts as an anti-apoptotic agent and PI3K/mTOR complex activator (Boroughs KL et al J Biol Chem 2014;289:10115–10125). tTG inhibitors suppress cancer cell growth (Ku BM et al J Cancer Res Clin Oncol 2014;140:757–767; Yakubov B PLoS One 2014;90 (2):e89285). The slime mold Physarum polycephalum pertains the life style of unicellular eukaryotes, such as amoeba and plasmodia. It possesses mammalian type tTGs, also related to the tTGs of Ciona, crustaceans, Drosophila, Caenorhabditis, ﬁshes, and mammals, including Homo (Wada F et al Eur J Biochem 2002;269:3451– 3460). Comment: Another example of a life survival pathway operational in a unicellular eukaryote, that has become a human proto-oncogene.

Neuroblastoma (NB). Tumor suppressor gene and immunotherapy for NB. There is an extensive discussion in the text on biological measures that are able to induce differentiation in neuroblastoma cells. Toward tumor antigen ganglioside GD2-redirected, chimeric antigen receptor-armed (CAR) (vide supra), immune T cells, synergized with oncolytic adenovirus Ad5Δ24 expressing chemokine RANTES (regulated on activation normal T cells expressed and secreted; CCL5 from chromosome 17q1) in solid tumor immunotherapy (Nishio N et al Cancer Res 2014;74:5195–5205). Vα24 anti-GD2-expressor CAR-armed invariant natural killer cells (NKT) attacked NB tumors, thus extending patients’ survival without 598 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia inducing GvH disease (Heczey A et al Discov Med 2013;16:287–294; Blood 2014;124:2824–2833). Advancing NB in patients was due to the elimination of the FOXP1 (forkhead box) tumor suppressor gene in chromosome 3p14.1. The loss was not due to potentially reversible CpG gene hypermethylation. In tumor cell lines, doxycycline could induce re-expression of FOXP1 gene. These, and FOXP1-transgenic NB cells, ceased their growth and underwent either apoptosis or a neuronal differentiation pathways (Ackerman S et al BMC Cancer 2014;14(1):840. doi:10.1186/1471-2407-14-840). New monoclonal antibodies, new vaccines and adoptive transfer of immune T cells or NK cells (even allogeneic from parents or siblings) are in the investigational use (Croce M et al Immunotherapy 2015;7:285– 300; Seidel D et al Department Pediatric Hematology Oncology, University Medicine Greifswald, Germany. Cancer Immunol Immunother 2015; Epub PMID 25711293 SpringerLink). The NK cell line NK-92-scFV(ch14.18)-zeta carries the genetically engineered chimeric antigen receptor (CAR) speciﬁc to GD2 (disialo- ganglioside). It attacks and lyses GD2-expressor drug-resistant NB-cells. MYCN-ampliﬁed tumor-bearing patients should receive immunotherapy in addition to standard surgery, radio-chemotherapy (Csanády M et al Int Pediatr Otorhinolaryngol 2014;78:2103–2106). Neuroblastoma cells may be induced to re-differentiate. Comment. Gene therapy aimed at the oncogene, and immunotherapy aimed at the oncoprotein are to be combined. Some malignantly transformed tumor cells (acute promyelocytic leukemia, PML cells) carrying fusion oncoprotein with retinoic acid receptor (RAR) at t(15;17, or losing tumor suppressor genes (in NB, FOXP1), may recover from the stages of “malignant transformation” and resume their service as members of organized cell communities. Unexplained re-differentiation of chondrosarcoma cells in vitro in co-existence with lymphocytes of a healthy donor was observed (Sinkovics JG Pathol Oncol Res 2004;10:174– 187). Recently reviewed (Sinkovics JG Europ J Microbiol Immunol 2015;5:25–43).

Accelerated Life Style of the Ctenophores. Prior to the bilaterians, there existed four clades of metazoans: 1 Cnidaria corals, sea anemones (the Nematostella; Hydra/Hydractinia), Medusozoa jellyﬁsh). 2 Porifera sponges, (Amphimedon; Suberites). 3 Placozoans (Trichoplax). 4 Ctenophores represented by the predatory omnivore Mnemiopsis leidyi (warty sea walnut) and Pleurobrachia pileus, the comb jelly. The ctenophores’ outer epidermal layer is separated by mesoglea from the inner gastrodermal layer. Mesenchymal smooth muscles are operational in the body wall, tentacles (the specialized colloblasts for capturing prey), and the pharynx. For swimming, there are eight longitudinal rows of cilia alongside the body. The ctenophore cydippid larva is a free-swimming entity. The mature adult is a hermaphrodite harboring both ova and sperms for self-fertilization. Freshly shed eggs are immediately fertilized. The ctenophores possess photocells with opsins mediating light detection, operate TGFβ, homeodomain Hox and Frizzled Wnt pathways, and a neurosensory system (Feuda R et al Genome Biol Evol 2014;6:1954– 1971; Moroz LL et al Nature 2014;510:109–114; Pang K et al EvoDevo 2010;1:10; Ryan JF et al Science 2013;342(6164):1342592; EvoDevo 2010;1:9; Biol Direct 2007;2:37), but operate a much premature microRNA system (Maxwell EK et al Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 599

BMC Genomics 2012;13:714; Moran Y et al Mol Biol Evol 2013;30:2541–2552). The ctenophores’ nervous system functions without serotonin (in contrast to that of the cnidarians). It consists of a subepithelial net, neurons in the mesoglea and innervation of the tentacles (Moroz LL et al Nature 2014;519:109–114). Ctenophores are usually captured in the Eel Pond of Woods Hole MA for genomic, metabolic, and innate immunological studies to be conducted at Whitney Lab for Marine Bioscience, University of Florida, St. Augustine, FL; Rice University, Houston, TX, and at many other sites worldwide. From the western Atlantic Ocean, this extremely vigorous predator species is rapidly invading the Black, Caspian and North Seas (Ryan JF et al Science 2013;342/6164. doi:10.1126/1242592).

The ctenophore genome acquired several of its mitochondrial genes; especially tRNAs had been depleted; thus the M. leidyi mitochondria are small (10 kb, 10,326 bp, 33 ORF). Some (34) mt ribosomal proteins of M.leidyi are homologous to human MRPs, what is half of what A. queenslandica (61) and N. vectensis (62) possess. Just like the alga, Chlamydomonas reinhardtii, M.leidyi also transferred its mitochondrial gene atp (adenosine triphosphate) to its nucleus. This continued to be like this in Cnidaria, Placozoa, Bilateria, and all Eumetazoa (including Homo). The mitochondrial atp genes were retained in the mitochondria in fungi, choanoﬂagellates and poriferan spongi (Pett W et al Mitochondrial DNA 2011;22:130–142).

M. leidyi operates some 16,545 protein-coding genes. Among the encoded proteins, there are glycoprotein hormones of the cystine knot growth factor protein superfamily .These are the TGFβ; nerve growth factor, platelet-derived growth factor (without platelets), bone morphogenetic protein antagonists, which are the predecessors of the bursicons of insects, gremlin, neuroblastoma suppressor of tumorigenicity, and the Wnt-activator and BMP/TGFβ-inhibitor norrin (without bones). Norrin is one of the ligands to the LGR (leucine-rich repeat-containing G protein-coupled receptor) (Deng C et al J Cell Sci 2013;126:20602–20608. Roch GJ & Sherwood NM Genome Biol Evol 2014;6:1466–1479. Xu S et al PLoS Biol 2012;10(30;E10011286). The ctenophore M. leidyi expresses the LIM homeobox proteins (Table XVI) (Simmons DK et al EvoDevo 2012;3:2. doi:10. 1186/2014-9139-3-2). Cnidarians (N. vectensis; H. magnipapillata), ctenophores, and the placozoan Trichoplax adhaerens possess the ribonuclease family III Dicers operating in the RISC (RNA-induced silencing complex), but choanoﬂagellates (Monosiga brevicollis) are devoid of the system (Gao Z et al PLoS One 2014;9(4): e95350). The presence of mesenchymal genes (ﬁbroblast growth factor, notch, hedgehog, nodal) is expected on account of the smooth muscles, but these are not detectable; the gli gene is present, but not the mesenchymal cells, rather the nerve cells express it. The hedgehog Hh and JAK/STAT pathways are not operational (Ryan JF Science 2013;342:1242502). Instead, the Wnt pathway with Frizzled proteins is highly upregulated, as it is acting without its customary inhibitors. Some introns of the Wnt genes are conserved in number, size and location up to the mammalian Wnt genes. Wnt ligands are accepted by the Frizzled (Fz) and LRP5/6 600 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia

(lipoprotein receptor-related protein), and Dishevelled (Dvl/Dsh) receptors. Thus GSK-3 (glycogen synthase kinase) could be inhibited through phosphorylation by Dvl/Dsh. Failure of GSK-3 to phosphorylate β-catenin allows for the accumulation of the latter in the cytoplasm and for its eventual transfer into the nucleus, there, for the activation of the targeted tcfTCF/lefLEF gene complex, whose gene product proteins activate promoter DNAs of numerous other genes. The descendants of the tcfTCF/lefLEF genes and their protein products will often form oncogenic pathways in vertebrate mammalian (human) cells. This very same cascade is that of a constitutive oncogenic pathway in many human cancers (especially adenocarcinomas). The ctenophores’“β-catenin-destructive complex” is deficient, in that it lacks axin, and its suppressor gene APC (adenomatous polyposis coli) is defective in expressing all its domains. The “destructive complex” in malignantly transformed human cells is notoriously rendered inactive due to loss-of-function mutations or deletions of its components (axin, APC, GSK). This is naturally so in ctenophores (M. leidyi). Further, the physiological inhibitors of the canonical Wnt pathway working in mammalian cells, are absent in ctenophore cells. These are primarily the dickkopf (drosophila) gene product proteins, Wnt inhibitory factor WIF (and Cerberus/CER, present only in vertebrates). The secreted frizzle-related protein MlSfrp lacks the netrin domain (Jager M et al PLoS One 2013;8(12): e84363, Pang K et al EvoDevo 2010;1:10. doi:10.1186/2014-9130-1-10; Schenkelaars Q et al Evol Dev 2015;17:160–169). In addition to its naturally overactive Wnt pathway, the ctenophore genome expresses several sox/Sox genes and high mobility group gene-product proteins, from the larval cydippid stage on. The Sox proteins are encoded by the regular mRNA pathway and are subject to miRNA/siRBA control. The mammalian sox genes form five groups (BCDEF). The ancestors of the BCEF sox genes are present in the ctenophore genome (M. leidyi; P. pileus). Some of these sox genes are shared with the Hydra and the Choanoflagellata (Schnitzler CE et al EvoDevo 2014;5:15). Comment: Genomic and protein pathways (wnt/Wnt; sox/Sox HMGP), that will become mammalian vertebrate proto-oncogenes/oncoproteins, are physiologically hyperactive (“upregulated”) in the ctenophore genomes. Their suppressors are non-functional, as they are eliminated alike in the “malignantly transformed” cells of mammalian vertebrate (human) hosts. The ctenophore cells are physiologically driven by the predecessors of the proto-oncogenes Wnt/β-catenin (Sinkovics JG Europ J Microbiol Immunol 2015;5:25–43; Sinkovics JG Int J Oncology 2015;47:1211–1229).

The Evolution of Ribosomes. This author would like to further promote the idea that precellular ribozyme-armed, functional rRNA-containing precellular ribosomes existed on, and populated the ancient Earth. Thus, ribonucleoproteins (RNP) were synthesized with substantial genetic errors. If so, these structures might have synthesized the successors of the viroids, and provided the platform on which precellular viruses could have existed and grow by fusion. JH Matthaei and MW Nirenberg worked well with extracellular E. coli ribosomes in the late 1950s, early 1960s (Proc Natl Acad Sci USA 1961;47:1580–1586; 1588–1602). However, the ribosome assembly in bacteria (E. coli) requires RNA helicases (Peil L et al FEBS J Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 601

2008;275:3772–3782). Nevertheless, ribosomal assembly in vitro is slow, but possible (Shajani Z et al Annu Rev Biochem 2011;80:501–526). The in vitro 30S ribosome assembly cofactors are recognized (20 cofactors in bacteria), including rRNA-binding proteins, such as essential GTPases. Figure 1 of the cited article shows the Nomura assembly map. In the 30S biogenesis, the role of Rims (RimM, RimP, ribosome maturation factor) has been clariﬁed. The kinetic interactions of the Era (E. coli ras-like protein, see Trichomonas) with 16S rRNA and nucleotide cofactor GTP could be determined. The ﬁnal ribosome biogenesis is depicted in Figure 4 of the article (Brunner AE et al J Mol Biol 2010;398:1–7). When singled out cells of multicellular hosts undergoing the process of the so-called malignant transformation in the form of de-differentiation to their ancestral life forms, could the excessive release of RNA-loaded exosomes be a manifestation of that process? Could the exosomes be viewed as the extant replicas of their predecessors, the precellular ribosomes? (Sinkovics JG Europ J Microbiol Immunol 2015;5:25–43). In ribosomal 60S subunits stalled translation recruits a ribosome quality control complex (RQC). In turn, RQC enlists alanine- and threonine- charged tRNAs. Consequentially, tRNAs elongate the nascent chain independently from mRNA. The incompletely synthesized nascent chains are degraded by ubiquitylation (Shen PS et al Science 2015;347:75–78). Comment: Are the natural ribosomes punctilious?

Problems with unexplained abbreviations. Lenghty complicated nomenclature is commonly cited in abbreviated form; the abbreviations often remain unexplained and not spelled out. In this Text, Legends, Tables and Appendix the abbreviations received extraordinary attention: they are often spelled out repeatedly. An exem- plary article deserves to be cited here for its clarity of style and for its elaborate listing of spelled out abbreviations: Futosi K, Fodor Sz, Mócsai A: Neutrophil cell surface receptors and their intracellular signal transduction pathways (Int Immunopharmacol 2013;17:638–650). An extensive alphabetical list of abbrevia- tion for oncology terminology is printed in Weinberg RA: The Biology of Cancer. 2nd Ed Garland Science, New York & London, 2014. The volume publishes a very large number of superb illustrations in color.

A Contrast. Cancer chemotherapy. In the years 1960–70s combination chemotherapy has become the officially accepted, established, and firmly imple- mented standard treatment of leukemias and metastatic cancers. Non-specific immunization primarily with BCG was accepted (by now discontinued), but tumor-specific immunotherapy received practically no support. The concepts and aim of high dose combination chemotherapy were that the higher the dosage was raised, the better the chances will be to kill the last cancer cell, thus resulting in cure of the disease. Without recognized specific cancer antigens, attempts at immunizing against cancer were considered to be futile (but the general immune state of the patients stimulated by coryne-, or mycobacterial vaccines was allowed). This concept was developed by Georges Mathé at Gustave Roussy’s in Villejuif, France (le nécrologie; décédé 2010; in Acta Microbiol Immunol Hung 2010;57:322) and promoted at the National Institutes of Health / National Cancer Institute in Bethesda MD. 602 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia

It was most prominently practiced at the Department of Developmental Therapeutics (DDT) at M.D. Anderson Hospital. The DDT was a detachment of the NIH/NCI, and as such received the highest support from the NCI and from the Pharmaceutical Industry. Truly, partial and complete remissions for the first time were induced by combination chemotherapy in patients with leukemias and solid tumors. However, not all patients receiving the same treatment responded. The actual cure rate remained low, due to frequent relapses. Toxic side effects (severe protracted nausea; leuko- penic septic infections, often fatal septic shock; hemorrhagic events; neurological and endocrine side effects; retarded mentation) were slowly and steadily diminished by new antibiotic combinations, platelet transfusions and anti-nausea medications. Intensified general medical and nursing care, and specialized attendance allowed the administration of full dosage chemotherapy as calculated in the protocols. Exceptional patients in durable complete remission with minimal residual side effects were prominently publicized. Private practice medical oncology clinics flourished on the high profits of combination chemotherapy. The efforts to cure leukemia and metastatic cancers culminated in the STAMP program initiated by the former head of the DDT, Emil Frei III. The STAMP regimen consisted of very large (triple) dosages of combination chemotherapy followed by “stem cell rescue” (autotransplants of stem cells collected from the circulating blood, or the bone marrow). Various aspects of the natural biology of the cancer cell were either unknown or ignored. The unusual natural biological features of the cancer cell consisted of its extraordinary radiation- and chemotherapy-resistance, manifesting in the form of recurrences after periods of “tumor dormancy” (now autophagy); the ability to circulate in the blood or lymph; to emit exosomes; to circulate its DNA; to recruit-supporting mesenchymal cells from the bone marrow or in its microenvironment; and to overcome immune reactions of the host, if any. The fact that the cancer-bearing patient generated some immune reactions against the autologous tumor was recognized. Some immunizations with irradiated tumor cells could be conducted, but were abandoned as ineffective. Vaccinations with viral oncolysates, in which a non-self viral antigen fused with a self cell surface oncoprotein, could have immunized the patient, but these projects received no grant support (because the targeted tumor antigen was not specifically identified). Instead, the highly upheld curative aim of combination chemotherapy was persuasively promoted (because it was known how it damaged the DNA in general, but without knowing exactly which oncogenes were targeted). The possi- bility that treatment-acquired endocrine or central and peripheral neurological defi- ciencies (especially in children and adolescents) may remain permanent, was listed among collateral damages acceptable for the cure. However, the end results of the STAMP program revealed that it was much more toxic, but not more effective than the previous standard dosage chemotherapy. The STAMP program was discontinued (Berry DA et al J Clin Oncol 2011; 29:3214–3223). In addition to its failure to improve treatment results (overall survival), a faked STAMP-like program was subjected to major falsifications of its results for the better: a most dismal event in the history of medical oncology (Bezwoda WR Eur J Cancer Care 1997;6:10–15; Bezwoda W et al Oncology 1990;47:4–8. Vickers A & Christos P. Bezwoda: “evidence of fabrication” in original article (J Clin Oncol 2000;15:2933). Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 603

Cancer Immunotherapy. Clifton Dexter Howe, the Head of the Department of Medicine (DM) at M.D. Anderson Hospital, was an open opponent of high dose combination chemotherapy (in the era when supportive measures were non-existent); eventually, he was demoted into an administrative position. This author (JGS) serving as a medical oncologist at the DM of M.D. Anderson Hospital (1959; 1962–1980) received no NCI support for human cancer immunotherapy, or virotherapy; he treated his patients at the Melanoma-Sarcoma Clinics and In-patient Service with standard full dose combination chemotherapy by approved institutional protocols. His proposal of immunotherapy with viral oncolysates was based on the idea, that viral structural, capsid or membrane proteins fuse with tumor cell membrane proteins at the egress of the viral particle, and that these fused proteins are “non-self” to the host, thus are immunogenic. In the treated subjects, viral oncolysis would be followed by anti-cancer immunization. Viral oncolysates induced strong anti-cancer immunity in mice. Influenza virus particles replicating in, and thus lysing cancer cells, would construct such fused, and thus immunogenic antigens. However, such fused and thus immunogenic proteins were not actually produced in the author’s laboratory. Their existence was documented elsewhere (in the literature). It remains a solid fact; so is the fusion of the influenza viral hemagglutinin with cellular sialic acid receptors expressed in the cell membrane (Hamilton BS et al Viruses 2012;4:1144–1168). The viral oncolysate immunotherapy protocol was approved by the M.D. Anderson Hospital Institutional Surveillance Committee in 1967; it was funded from private donations (not by the NCI); and its course was reported in the biannual M.D. Anderson Hospital’s Research Reports (as summarized in Sinkovics JG & Horvath JC Archives Immunologiae Therapiae Experimentalis Birkhäuser Verlag, Poland/Switzerland 2008;56:3–59). This author recognized that large granular non-specific (later NK cells), and small compact specific (later immune T cells) lymphocytes are naturally generated against autologous tumor cells in tumor-bearing patients, and that these reactions quantitatively increased in patients receiving viral oncolysate vaccine. In the pre-IL-2 era, large live populations of these lymphocytes for treatment could not be produced and provided. Later in the 1990s in academic medicine-affiliated private practice of medical oncology at St. Joseph’s Hospital in Tampa, FL, this author with Joseph C. Horvath could apply viral oncolysate immunotherapy with standard combination chemotherapy given in full dosage, and use autologous immune lymphocyte infusions prepared in IL-2-containing liquid media for the treatment of metastatic melanoma. This author declined participation in any STAMP-like high dose chemotherapy programs, which were installed also in Tampa by private practitioners of medical oncology, and was carried out at St. Joseph’s Hospital under the egis of a nationally approved private company (discontinued in total failure after a few years).

After many decades of trials and errors, the faculties of virotherapy and immunotherapy of cancer have by now succeeded in proving their extraordinary value in the treatment of lymphomas,-leukemias and certain metastatic cancers (especially melanoma). The basic elementary knowledge that the host recognizes and 604 Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia attempts the rejection of incipient cancers by antibody- and lymphocyte-mediated reactions has been well recognized and elaborated on, but without the practical means of effective therapeutic translation of this knowledge into practice (Harris JE & Sinkovics JG. The Immunology of Malignant Disease, 2nd ed Mosby, St. Louis, 1976; Sinkovics JG Cytolytic Immune Lymphocytes. Schenk Buchverlag, Passau-Budapest, 2008; Sinkovics JG Acta Microbiol Immunol Hung 2010;57:253– 347; Sinkovics JG & Horvath JC Acta Microbiol Immunol Hung 2006;53:367–419; Arch Immunol Ther Exper 2008;56:S1–59). Monoclonal antibodies were the first agents which could suppress oncoproteins. Rituximab and trastuzumab were the flagships followed by even more effective new agents. They combine well with standard dosage chemotherapy. The CHOP-R regimen is highly effective (probably curative) in diffuse B cell and other malignant lymphomas. Pertuzumab and trastuzumab attack the breast cancer oncoprotein Her2/neu synergistically. Natural oncoprotein-reactive immune T lymphocytes without or with genuinely tumor cell-reactive NK cells extracted from the patient and grown to billion-size populations in IL-2-containing media, upon re-infusion attack and lyse large tumors (primarily melanomas). The National Cancer Institute program of Steven A Rosenberg proved that effectively oncoprotein-reactive immune T cells are mobilized in limited numbers in patients with cancer. Retrieved from the patient, expanded by lymphokines in vitro, and re-infused, these autologous immune T cells lyse large tumors (but not without failures or relapses). Further, oncoprotein-reactive autologous immune T cells with the genetically engineered T cell receptors CAR induce complete remissions of curative effect in patients with lymphomatous malignant tumors (Frigault M et al Cancer Immunol Res 2015;3:356–367). Tumor cell destruction is so extensive and rapid that clinically it manifests in a tumor lysis syndrome with a lymphokine storm ensuing. Tumor lysis syndrome is treatable with rasburicase. IL-6 is the leader of the lymphokine storm. Major participants in the lymphokine storm are IL-2, IL-6, IL-10, TNFα and IFNγ. Monoclonal antibodies tocilizumab or siltuximab promptly neutralize IL-6 with life-saving efficacy. Ipilimumab protects from apoptotic death the CTLA-4+ T lymphocytes: they are ready to attack malignantly transformed melanoma cells. Potentially autoimmune T cells are further withheld by their natural inhibitor PD1 (programmed death). When the PD1 ligand activates receptor PD1, the PD1+ T lymphocyte kills itself in apoptosis. Malignant tumor cells masquerading as self, produce the PD1 ligands excessively, and thus eliminate PD1-expressor, autoimmune-active, T cells from their environment. The mcab pembrolizumab neutralizes the ligand and the PD1+ cell is free to attack the transformed cell; another mcab neutralizing the receptor PD1 (nivolumab), also rescues the T cell from its apoptotic death. At the potential price of some autoimmune reactions (thyroiditis; hypophysitis), a massive destruction of tumor (melanoma; bronchogenic carcinoma) cells ensues (Luke JJ & Ott PA Oncotarget 2015;6:3479–3492; Mahoney KM et al Clin Ther 2015. doi:10.1016/jclinthera.2015.02.018). Intratumoral Newcastle disease virus inoculations (oncolytic viral therapy that was denied research funding at the NIH/NCI in the 1960–70s) combined with CTLA-4 checkpoint blockade mutually intensify the efficacy of each other reactions (Zamarin D et al Sci Transl Med 2014;6(226):2264ra32). Many times what worked in the rodent host, like this Appendix 1*) For Essential Information Very Well Illustrated in Google and Wikipedia 605 experiment, failed in the human host. Nevertheless, clinical trials on human patients with ipilimumab and oncolytic herpesvirus talimogene laherparepvec are ready to go (Clinical Trials.gov; NCT01740297). In metastatic prostate cancer, docetaxel chemotherapy added to androgen-depriving hormonal therapy may be additively effective. The Bavarian Nordic avian poxvirus-based prostate cancer vaccine ril- imogene galvacirepvec glafolivec increased the survival of chemotherapy-naïve patients with metastatic prostate cancer from 18 months to 31 months; and combined with ipilimumab, to 37 months (Report from the 2015 Genitourinary Cancers Symposium, The ASCO POST 2015;6:1, 3–4). A new generation of oncologists rises to catch up with decades of delays that the practice of cancer immunotherapy suffered, a replica of a natural faculty, undeservedly; while high dose combination chemotherapy (utterly alien to the treated host) was favored. Accept, that combination chemotherapy saved and prolonged many lives. It will have to be kept in use as long as it contributes to survival with acceptable and reversible side effects. Targeted chemotherapy, with especially oncoprotein-targeted therapies (small kinase enzyme inhibitor molecules aiming at a special domain of oncoproteins); and monoclonal antibodies prominently remain in use. Therapeutic cancer vaccines based on live oncolytic viruses will emerge. Genetically engineered oncolytic viruses may surpass in efficacy naturally oncolytic viruses; some of them may replace lost tumor suppressor genes.

The initial natural defense of an organized cell community against malignantly transformed cells within, led by the NK cells and tumor suppressor gene-product proteins of the host, seldom eliminates a tumor without outside help. Tumor biology reveals that the multicellular host may promote the co-existence of internally induced proliferation of transformed cells. In contrast, the host is opposed to the proliferation of externally induced transformed cells. These host immune reactions can be augmented to curative strength. The number of spontaneously regressed tumors, if any, is unknown. The malignantly transformed cells in multicellular, especially vertebrate mammalian, hosts acquired placenta-like defensive reactions, that induce Th2-type tolerance in their host. Further, when the malignant transformation occurs in cells living in a multicellular community, those cells, in addition to their ancient inherited cell survival pathways, have evolved new faculties, that neutralize or eliminate the tumor suppressor proteins of the host. These cells mobilize mesenchymal and vasculo-endothelial cells of their host to render full support to them, while they are undergoing a reversal into the life forms of their primordial ancestors. The genes which frequently undergo fusion in extant malignantly transformed cells are well conserved from their primordial ancestors and frequently function in stem cells (Narsing S et al Department Molecular Medicine, The University South Florida Morsani College of Medicine, Tampa, Fl. Cancer Genetics Cytogenetics 2009;191:78–84). Just practicing an inherent and conserved faculty of the primordial RNA/DNA complex, serving blindly and determinedly for the sustenance of living matter in the Universe. Appendix 2 Explanations to the Figures*)

*) In elaborated legends, the author is trying to render service to the readers.

Figure 1. The A and B X-ray diffraction spatial (3-dimensional) configurations of the double helix deoxyribose DNA molecule are from Rosalind Franklin’s lab (1951). The A-DNA B-DNA photographs are from Baianu IC et al. Maurice Wilkins’ lab yielded the C configuration in 1958. DNA A and B are natural (derive from living cells); DNA C configuration is an artifact formed in the drying process of a lithium-DNA salt. RNA the predecessor of DNA, is equipped with the 2’OH group on each of its ribose molecules; it frequently functions single-stranded (ss), but in certain circumstances (ds RNA viruses) it can assume a double-stranded (ds) helical structure (A-RNA to Z-RNA). The interferon-induced enzyme dsRNA adenosine deaminase acting on RNA (ADAR) promotes the A-to-Z left-handed helical dsRNA transition; ADAR specifically with high affinity binds to ds Z-RNA/Z-DNA.

RNA molecular constituents adenine, guanine, cytosine, uracil form from for- mamide under the impacts of high energy laser imitating extraterrestrial bom- bardments of the ancient Earth over four billion years ago (Ferus M et al J Phys Chem 2014;118:719–736; Proc Natl Acad Sci USA 2015;112:657–662).

Figure 2. Reverse transcriptases encode in Neurospora crassa the ancient mitochondrial Mauriceville plasmid (Chen B & Lambowitz AM J Mol Biol 1997;271:311–332; Baidyaroy D et al Fungal Biol 2012;116:919–931) and the telomeres (Wu C et al Genetics 2009;181:1129–45). The chromosome harbors the Pogo transposable elements. Distinct subtelomeric elements and the TLH telomere-linked helicase are uniquely absent. The biological clock is circadian rhythm-dependent. Longevity versus senescence is determined in the T-loop structure of the TTAGGG duplex region. The ancestral proto-oncogene ras is known in N. crassa as the band (bd) gene; it is re-enforced by the longevity assurance gene lag/LAG. Macroconidia with gain-of-function mutated ras and lag genes live 120 days, versus 24 days median life span physiologically (Case ME et al Ecol Evol 2014;4:3494–3507). More in Figure 63.

Figure 3. Sex determining region Y-box 2 (SRY) pluripotent transcription factors are active in embryonic stem cells. SOX high mobility group (HMG) proteins express evolutionarily conserved DNA-binding domain (Tables XI/I and XI/II). The human gene sox2 maps to chromosome 3q26.33. The so-called LIF (leukemia inhibitory factor) protein activates sox2 (and Krüppel-like factor 4, Klf4) genes. Proteins Oct4, Nanog and Sox2 maintain pluripotency for their stem cells. These gene product proteins form complexes with protein NPM1 (nucleophosmin; protein B23), a regulator of NFκB. The Sox2 protein inhibits mesenchymal, and promotes neuroectodermal, germ layer differentiation. Stem cells with active Sox2 protein renew themselves and release differentiated neural cell by asymmetric divisions. Hypermethylation of the sox2 gene (or its promoter) deprives the gene of its pluripotent faculty. Ampliﬁed (or constitutively expressed) Sox2 protein drives cancers (squamous cell carcinoma lung; high Gleason grade prostate adenocarcinoma; undifferentiated colorectal adenocarcinoma). More in Ctenophores: The cell survival pathways of the comb jelly ctenophores are driven by ancient sox/SOX genes/proteins (see more in the Appendix 1).

Figure 4. Deinococcus radiodurans. Withstanding high dose radiation of canned food, there it was discovered alive and replicating. Its radioresistance is effective against 1.5 million rads. Survives 5000 Gray (500,000 rads) ionizing radiation; upon an exposure of 15000 Gy, it retains 37% of its viability. For comparison, 2.5– 5 Gy (250–500 rads) whole body exposure to the human subject is considered to be lethal. D. radiodurans metabolizes nuclear waste. Its ring-shaped DNA does not fall apart upon radiation exposure and retains high sensitivity to its extremely effective DNA repair enzymes. Carries two circular chromosomes 2.65 million base pairs long consisting of 3195 genes; and two plasmids 117000 and 46000 base pairs in size. Presented here in its tetrad form. Its DNA can migrate within the tetrads. The Mycoplasma laboratorium artiﬁcially constructed utilizes some D. radiodurans DNA repair enzymes.

Figure 5. The Coelacanth’s fins evolving toward hind legs, its gills transforming into lungs and its brain enlarging were postulates read out of its fossils. When the extant coelacanth re-appeared, those postulates had to be seriously doubted and eventually discarded. The transitional pathway from fish to amphibians is characterized by missing links. The maximum parsimony, neighbor-joining and maximum likelihood of the nuclear ribosomal genes 28S of coelacanths and lungfishes indicate that they are monophyletic and are related to the first land vertebrates. The mitochondrial cytochrome oxidase subunit genes’ nucleotide to amino acid sequences indicate coelacanth/lungfish and lungfish/tetrapod clades (overruling an immediate coelacanth/tetrapod clade) (Zardoya R & Meter A Proc Natl Acad Sci USA 1996;93:5449–5454; Yokobori S et al J Mol Evol 1994;38:602–609). Intron-containing Interferon gene type I in fish and amphibians, and intron-less IFN gene type III in amphibians (Xenopus) diverged during a transitional period of their hosts migrating from their aquatic environment to land. Intron-less type I IFN genes of reptiles, birds and mammals lost the intron-containing type I IFN genes due to an Appendix 2 Explanations to the Figures*) 609 retroposition event. The receptors of the Xenopus type III IFN are distinct from those of type I IFNs (Qi Z et al J Immunol 2010;184:5038–5046). The ancestors of the amphibians were the sarcopterygii lobe-finned bony fishes (osteichtyes: Latimeria coelacanths; Dipnoi lungfishes), whose pectoral and pelvic paired fins articulate with their pectoral and pelvic girdles using a single bone, that was the ancestor of the humerus in descendent tetrapod amphibians. Their shared 28S rRNA genes make coelacanths and lungfishes sister groups. Of the recombination activation genes rag1/2, one amino acid is deleted from the aminoterminal region of the Rag2 protein in lungfishes, chondrichtyes and amphibians, but not in the coelacanths. This deletion makes lungfishes and amphibians sister groups. The entire rag gene sequences suggest lungfishes to be the ancestors the amphibians, and all tetrapods, in the monophyly of sarcopterygii (Brinkmann H et al Proc Natl Acad Sci USA 2004;101:4900–4905). Illustrations: West Indian coelancant (Latimeria chalumnae) caught in 1974, Comoro Island.

Figure 6. The Amoebozoan, Dictyostelium discoideum exists in many life forms: in sexual cycle, in vegetative cycle, and in social cycle. Its discoidin is a ﬁbronectin; its tiger genes encode histocompatibilty complexes; it uses an ERK/MAPKK signaling “cell survival pathway” (extracellular signal regulated kinase; mitogen-activated protein kinase kinase). MAPKK becomes a proto-oncogene in vertebrate mammalian cells: in ras- (rat sarcoma-) transformed cancer cells. For vital functions of D. discoideum cells, the expression of the ancestral PTEN phosphatase gene is essential; it suppresses phosphatidyl inositol by dephosphorylation, like its ortholog human gene. D. discoideum’s cell cycle passes through G1 as if it were non-existent (the Rb protein fails to stabilize it); the protein-product of the retinoblastoma gene ortholog inhibits the S-phase of the cell cycle by interacting with transcription factor E2F (cyclin kinase E2 phosphorylator of the retinoblastoma protein); it also dictates the differentiation of spores (Lusche DF et al PLoS One 2014;9(9):e108498; Strasser K et al PLoS One 2012;7(6):e39914). See more in Appendix 1. Illustration: The Amoebozoan life cycle of Dictyostelium discoideum. Schaap, Pauline, College Life Sciences University Dundee. Evolutionary crossroads in developmental biology: Dictyostelium discoideum. Development 2011; 138: 387–396. doi:10.1242/ dev.048934, [email protected]

Figure 7. The Wnt (wingless; integration site, drosophila; mouse) pathway. DSH = disheveled; FRZ = frizzled; LPR = low density lipoprotein receptor-related protein; APC = adenomatosis polyposis coli; CK = cell cycle; GSK = glycogen synthase kinase; LEF = lymphoid enhancer-binding factor (associated with TCF = T cell factor, proto-oncogenes) The Wnt signaling pathway is ancient. It was and it is operational in the ancestral and in the extant Ciona and Nematostella. It is vital for the developing embryo in regulating cell proliferation and differentiation. In healthy cells, the Axin, APC, GSF proteins regulate β-catenin in the cytoplasm by marking it to ubiquitynation. In malignantly transformed cells (colon cancer cells with deleted APC gene, or otherwise defective “destruction complex”), β-catenin escapes demolition in the proteasome, and transfers from cytoplasm to nucleus. 610 Appendix 2 Explanations to the Figures*)

Being a DNA-binding protein, β-catenin activates proto-oncogenes TCF/LEF. In the genome of comb jelly ctenophores, the “destruction complex” is physiologically defective (lacks Axin), thus β-catenin readily enters the nucleus to activate its target genes (which are predecessors of vertebrate mammalians’ proto-oncogenes, tcf/lef); dickkopf, a major inhibitor of the Wnt pathway, is missing. The ctenophore cells physiologically function like Wnt-transformed entities (in the Appendix 1). Jörg Huesken, Walter Birchmeier, Max Delbrück Centrum, Berlin-Buch, Germany.

Figure 8. Staging of colon cancer. Educational videos. Tony Talebi & Caio Rocha Lima at The University of Miami Sylvester Comprehensive Cancer Center, Miami FL http://www.hemonc101.com/colon-cancer. With permission of copyright owner Terese Winslow. All rights reserved.

Figure 9. Warburg glycolysis (Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science 2009;324(5930):1029–1033). In osseous metastases of hormone-resistant prostate cancer cells enhanced aerobic Warburg glycolysis is the main source of energy. The process is inhibited by simvastatin (mevalonate pathway inhibitor) and metformin (adenosine monophosphate-activated protein kinase activator) combined, resulting in cell cycle arrest in G1, and leading to the autophagy-apoptosis-necrosis pathway of the tumor cells (Babcock MA et al Cell Death Dis 2014;5(11):e1536).

Figure 10. Neuron with axons and synapses in their surroundings. (Boundless Textbook chapter 62.3 open contents http://en.wikipedia.org/wiki/Neuron).

Figure 11. Biomolecules. Lower left column from bottom up shows the synthesis of amino acids from simple organic molecules. These natural processes were reproduced in the laboratory by Stanley Miller and their occurrence was documented further very recently (Parker ET et al PNAS 2011;108;5526–5531; Orig Life Evol Biosph 2012;41:569–574). The self-replicating and hypercycling polypeptides and the chiroselective peptide replicator are cited from work carried out at the Ghadiri Laboratory, Scripps Research Institute (Lee DH et al Nature 1996;382:525–528; 1997;390:591–594; Saghatelian A et al Nature 2001;409:797–801). The right lower column from bottom up shows the formation of nucleotides (example: cytosine) from simple cyanide molecules. RNA, ribozymes, ribonucleoproteins (RNP), ribosomes and riboswitches naturally existed in the pre-cellular/protocellular world. RNA and polypeptide molecules hypercycled; carbohydrates and lipids formed a-new, but without hypercycling. Vesicle-forming lipids arrived via meteorites (Murchison). RNA strands self-replicated in hypercycles in hydrothermal vents (Eigen M & Schuster P The Hypercycle. Springer Verlag). Arguments are presented for the coexistence of RNA and DNA and the complex formations thereof already in the precellular era. The ingredients of life started to interact in unison in double lipid-walled vesicles (Figure 12). There tRNAs captured amino acids and lined them up in chains. In spheroplast-like protocells, DNA has taken over from RNPs the initiation of protein synthesis. The genomes enriched themselves by capturing new Appendix 2 Explanations to the Figures*) 611 laterally entering genes and then propagated them vertically. Genomes increasing in size were condensed into individual chromosomes, which were separated from, but biochemically interacted with, compartments (especially spliceosomes and ribosomes) formed in the nuclei and cytoplasm. The fusion of crenarchaeal and prokaryotic (mycoplama-like) spheroplasts as equal partners was very likely mediated by a fusogenic virus (phage, marked with red arrow). The ancestor of the Acholeplasma laidlawii phage is the fusogenic suspect (Figures 15–18). The complex large cells phagocytosed proteo- and/or cyanobacteria for ever-lasting intracellular symbiosis in the ancestral animal and plant cells. Viral particles synthesized in the precellular ribosomes invaded the newly formed cells. A mutual exchange of host cell and viral genes had taken place. In phase one, viral particles lost the majority of their genes in favor of the host cell genome, and thus viruses became totally dependent for replication on their host cells. Viruses retained their “virus hallmark genes” not shared with their host cells (Koonin VE, Senkevich O, Dolja VV Biol Direct 2006;1:29). In phase two, viruses are retrieving host cell genes in order to inhibit host cell death (apoptosis) prior to the full maturation of the viral progeny; and present themselves to the host as “self” in order to alleviate host immune reactions. This illustration was presented ﬁrst in Sinkovics J. Studia Physiologica Scientia, Budapest, 2001. Text ref 2.

Figure 12. Protocells. It is not known how protocells were formed. Gánti’s biochemical machine is the chemoton without a genome. Biological units were envi- sioned as Oparin’s coacervats; advanced coacervats became protobionts. Self-replicating and hypercycling RNA/RNPs and polypeptides interacted. Advanced biological units might have formed a conglomerate of adherent spheroplasts. Within the double lipid membrane of the spheroplasts, RNPs catal- ysed the generation and fusion of nucleotides and polypeptides. Short sequences existing in long non-coding RNA strands were to be transformed enzymatically into cDNAs (creating a natural cDNA library). Ribonucleotide reductase-like proteins converted RNA into deoxyribonucleotides (DNA), either in precellular, or in protocellular ribosomes. If DNA existed in the precellular environment, it managed to enter the protocells together with RNA ribozymes. RNA/DNA complexes with their supportive proteins condensed into chromosomes. Cytoplasmic compartments (precellular ribosomes might have existed) were formed internally, or acquired horizontally from the outside. Horizontal acquisitions and exchanges of genes, even operons, were extensive. The first eukaryotes were fused cells with nuclei. Eukaryotes acquired mitochondria and/or chloroplasts. These organelles engaged in a workable unison with their host cells’ nuclei and cytoplasm. Nucleocentrists and cytoplasmists debate the priority of a genome, or a metabolizing cytoplasm with ribosomes in the origin of life pre-cellularly, or in the first protocells. Could any one of these units exist without the other? Figure was first introduced in Sinkovics J, Studia Physiologica Scientia, Budapest, 2001. Text ref 2.

Further developments: Szostak et al generating multi-lamellar vesicles; dividing long threadlike vesicles; protocells with native and synthesized ribozymes. Mann S 612 Appendix 2 Explanations to the Figures*)

Acc Chem Res 2012;45:21231–31241. Jia TZ et al Orig Life Evol Biosph 2014;44:1–12. Schrum JP et al Cold Spring Harb Perspect Biol 2010;(9):a002212. Teresawa H et al Proc Natl Acad Sci USA 2012;109:5942–5947. Sohan Jheeta: Emergence of cellular life from LUCA (Last Universal Cellular Ancestor). Sohan Jheeta: Life (Basel) 2013;2:518-523; 2015;5:1446-1453.

Figure 13. Alpha-Helical Peptides in autocatalytic reactions chiroselectively templated and propagated their own synthesis in hyper- or supercycles. Template-directed condensation of peptide fragments occurs. In the presence of carboyl sulﬁde (as in volcanic fumes) in aqueous solution amino acids are condensed into peptides. Thioester peptid nucleic acids (tPNA) cross-pair with RNA and DNA strands, and as such interact with side chain functionalities of the molecules. tRNA do not assume self-replicatory reactions (unless a catalyser for such a reaction is found) (Lee DH et al Nature 1997;390:591–594; Saghatelian A et al Nature 2001;409;797–801)

Figure 14. Plasma Alive. Sealed aged bouillon-cultures of E. coli yielded pleuropneumonia-like units (“Pleuropneumonie-ähnliche Eigenheiten”) that could regenerate vegetative cells. Through ruptured cell walls, aged E. coli cells released plasma with electron-dense units (bacterial chromosome fragments vs phage particles). Some larger units (>350 mμ) measured by filtration (Ferenc Fornosi’s membranes) regenerated only after fusion, as visualized in light, dark field and electron microscopy technology (Iván Hollós). Large (>350 mμ) cytoplasmic units passed through collodion membrane filters of 600 mμ pore size (Ferenc Fornosi’s membranes) and regenerated into vegetative E. coli cultures. In dark field- and electron-microscopy, units passing the filter were seen to fuse. Other (fused) units physically attached to the surface of co-cultured Sarcina lutea cells. Regenerating units contained electron-dense formations (bacterial chromosomes? fusogenic phage?) (Sinkovics J Die Grundlagen der Virusforschung Ungarischen Akademie der Wissenschaften, 1956; Acta Microbiol Hung 1957;4:59–75; Nature 1958;181:566–567; Acta Microbiol Immunol Hung 2001;48:115–127; Studia Physiologica Scientia Budapest 2001;9:1–151; Hungarian (Magyar) Epidemiology 2008;5/3–4:237–255; Idem 2009;6:60; Sinkovics JG & Horvath JC Viruses ancient biomolecules. Cancer Research at the Millenium. The University of Texas M.D. Anderson Cancer Center, Houston, TX, 2000; pp 122–123). Cited in I.C. Gunsalus & R.Y. Stanier: The Bacteria, Academic Press N.Y., 1960; vol I: 345–6; A.J. Salle: Fundamental Principles of Bacteriology, 5th ed., McGraw Hill, N.Y. 1961; p 77. Author presented the cell wall-free plasma as a representative of primordial life forms (Sinkovics J: Pre-cellular forms of life in microbiology (in Hungarian). Biológiai Közlemények (Biological Publications) 1954;2:69–81. Gratitude to Elek Farkas† for allowing the conduct of these experimentations in 1954–5 at his Department of Virology in the State Institute of Public Health, (OKI) Budapest.

Figure 15. Individual Cells of Acholeplasma laidlawii Gamaleya PG8 strain release exosomes (Chernov VM Chernova OA et al, Kazan Institute Biochemistry Appendix 2 Explanations to the Figures*) 613

Biophysics, Russian Academy of Sciences, Kazan, Russian Federation. The Scientific World J 2012; article ID 315474). The 400–600 nm diameter Acholeplasma cells (like other prokaryota) release extracellular vesicles of bilayered membranes in sizes of 70–200 nm diameter enriched in virulence proteins (Chernov VM et al The Scientific World J 2011;11:1120–1130; J Proteomics 3014;110:117– 128). Acholeplasma cells carry a single circular chromosome of 1497 kb, 1.5 Mb; its rRNA operons and flanking tRNAs are depicted. A map of its genetic elements is constructed. Glycolysis from D-glucose is its ATP generating pathway (Kube M et al J Microbiol Biotechnol 2014;24:19–36). In addition to its lytic phages, the group 1 acholeplasmavirus is non-cytocidal, non-lytic; the cells remain chronically infected and undergo fusion (Brunner H et al Zbl Bakteriologie A 1980;248:120–128; Liss A & Ritter BE J Gen Microbiol 1885;131:1713–1718).

History of pleuropneumonia Mollicutes and L-forms of bacteria. Sabin AB. The ﬁltrable microörganisms of the pleuropneumonia group. Bacteriol Rev 1941;5:1– 67. Sinkovics J. A new chapter in bacteriology: Pleuropneumonia-like growth. Orvosi Hetilap 1955;96:1401–1408 (illustrated). Sinkovics JG. Die Grundlagen der Virusforchung. Ungarischen Akademie der Wissenschaften, Budapest, 1956.

Figure 16. Acholeplasma laidlawii Кyльтypa клeтoк микoплaзмы. Ponomareva Anastasiya A. Kazan Scientiﬁc Centre Russian Academy of Sciences, Kazan, Russia. The cell membrane of the mycoplasma Acholeplasma laidlawii is cholesterol-free; its genome consists of 1,469,992 base pairs containing 34 tRNA genes and 1,469,992 ORFs; it carries two mRNA operons. Source: gratitude to Anastasiya Ponomareva A.

Figure 17. Nonlytic MVL-3 Viral (Phage) Particles form a chain of single particles aligned alongside the inner aspect of the cell membrane of an Acholeplasma laidlawii cell (Gourlay RN Wyld SG Bland PA. J Gen Virol 1979;42:315–322). Such cells fuse (Haberer K, Maniloff J, Gerling D. J Virol 1980;36:264–270; Brunner H, Schaar H, Krauss H. Zbl Bakteriologie Hygiene I Abt Orig, Gustav Fischer Verlag, Berlin, Jena, Stuttgart, Germany; New York USA.1980;248:120–128).

Demonstration by electron microscopy of intracellular virus in Acholeplasma laidlawii infected with either MV-L3 or a similar but serologically distinct virus (BN1 virus).

Figure 18. Illustration 1: Thin section of two Acholeplasma laidlawii cells attached to each other by one non-lytic MVL3 phage particle before fusion. Fused cells appeared as giant cells. Mature MVL3 particles formed single (or double) lines just beneath the cell membranes, with the viral tails pointed toward the inner cell aspect of the membrane (Haberer K Maniloff J Gerling D J Virol 1980;36:264–270). From the Department of Microbiology, University Rochester Medical Center, Rochester, NY. Publisher: Journal of Virology. 614 Appendix 2 Explanations to the Figures*)

Illustration 2/3: The JA1 Acholeplasma strain harbors a nonlytic phage that fused the cells into large conglomerates. The conglomerates were 20-fold larger than the individual cells. Fusion of mycoplasma cells, not endomitoses, formed the large conglomerates. Longitudinal formations of fused cells extrude long ﬁlamentous structures, assume “tumor-like growth” patterns, and retain the enveloped virus particles (Brunner H, Schaar H, Krauss H. Zentralblatt für Bakteriologie Hygiene 1980;248:120–128). Shown here with gratitude to Professor H Brunner.

Further morphological studies on highly polymorph Acholeplasma cells: Polak-Vogelzang AA, Samson RA, De Leeuw GT Canad J Microbiol 1979;25:1373–1380.

Figure 19. T2 bacteriophages attach to the surface of a bacterial cell before pen- etration of the cytoplasm; the infected cell will be lysed. Phage http://en.wikipedia. org/wiki/File:Phage.jpg by Dr Graham Beards http://en.wikipedia.org/wiki/User: Graham_Beards is licensed under CC BY-SA 3.0 http://creativecommons.org/ licenses/by-sa/3.0/.

Bacteriophages of archaea and prokaryota transferred horizontally host cell genes; established temperate non-lytic relationships with some of their hosts; and laid down the basic biochemistry of virus-host relationship (Félix D’Herelle: “Le Bacteriophage”, Monographs Pasteur Institut, Masson, Paris 1921; Hugó von Preisz: “Die Bakteriophagie” Fischer, Germany, 1925. Luria SE & Delbrück M Genetics 1943;28:491–511; Lwoff A, by Morange M J Biosci 2005;30:591–594).

Figure 20. CRISPR (clustered regularly interspaced short palindromic repeats). The First Antiviral (Antiphage) Defense of Bacteria CRISPR [2342]. Schematic rep- resentation of the crRNA maturation/processing and Cas9-crRNA-tracrRNA complex assembly pathways (see text). (A). The wild-type CRISPR locus is transcribed as a long pre-crRNA molecule. Cas9 promotes pre-crRNA: tracrRNA duplex formation. The tracrRNA /pre-crRNA duplex regions are recognized and cleaved by the host RNase III to generate effector complexes that undergo further trimming at the 5' end by unknown nuclease(s) to produce mature Cas9-crRNA-tracrRNA complexes. (B) Short pre-crRNA transcripts produce functional effector complexes in the absence of RNase III (Karvelis T et al RNA Biol 2013;10:841-851).

Figure 21. Prokaryotes (and archaea) evolved upon a network of laterally transferred genes (Kunin V & C.A, Ouzounis Genome Research 2003;13:1589–1594). In the spheroplast community of the ﬁrst unicellular microorganisms, the genomes were wide open to gene losses and gains. Discarded or lost genes were replaced by sought after, readily accepted and put-into-service newly acquired genes. Apparently, at that stage, the gene product proteins caused no major immunological conﬂicts. Genes that existed within the clade were transferred by routes of conjugation (J. Lederberg). Bacteriophages and viruses were the vectors of large transferred genes. Viral cell surface receptors might have posed a restriction, but once in Appendix 2 Explanations to the Figures*) 615 the cytoplasm, the new genes readily entered the chromosomes (since nuclei and nuclear membranes did not as yet exist). Cell-fusogenic viruses must have mightily contributed to genomic transfers (Sinkovics JG. Acta Microbiol Immunol Hung 2001;48:115–121). In case of endosymbiosis in unicellular eukaryotes, the symbionts (mitochondria; plastids) exchanged their genes with those of the host cell nuclei, usually from the symbiont to the host. In many unicellular eukaryotes, there is a genetic micro-, and a somatic macronucleus (MIC/MAC) . The micronuclei carry numerous retrotransposons; these are meticulously excised and expunged when, after cell divisions or conjugations, the genomic micronucleus forms the genome of the somatic macronucleus. This is the line above which the widely spread promiscuity of horizontal gene transfers were curtailed, but never eliminated (Sinkovics JG Int J Oncol 2009;35:441–465; Adv Exp Med Biol 2011;714:5–89). Network of Horizontally Transferred Genes in Prokaryota and Archaea. With kind permission ©Barth F. Smeths PhD All rights reserved 2015.

Figure 22. Phylogenetic and symbiogenetic tree of living organisms. Recommended for reading: Koonin EV. Carl Woese’s vision of cellular evolution and the domains of life. RNA Biology 2014;11:197–204. Kutschera U. From the scala naturae to the symbiogenetic and dynamic tree of life. Biol Direct 2011;6:33. doi:10.1186/1745- 6150-6-33. Phylogenetic and Symbiogenetic Tree of Living Organisms. Konstantin Mereschkowsky’s Symbiogenesis by Cell Fusions in 1910 http://commons. wikimedia.org/wiki/File:Tree_of_Living_Organisms_2.png by Maulucioni http:// es.wikipedia.org/wiki/Usuario:Maulucioni and Doridi licensed under CC BY-SA 3.0.

Figure 23. Mitochondria, © AbD Serotec. All rights reserved. The mitochondrial inner and outer membranes undergo permeability transition. In this reaction, ANT (adenine nucleoside translocator) of the inner membranes activates voltage-dependent anion channels in the outer membrane. Water-soluble cytosolic substances enter the mitochondrial matrix. The membranes rupture with the release of cytochrome C and Bax (Bcl-2-associated X protein). Bax blocks Bcl-XL (B-cell lymphoma-leukemia gene-2, extra-large). CARD (caspase recruitment domain) in Apaf (apoptotic protease-activating factor) in the apoptosome releases and cleaves the procaspases. Caspase cascade is initiated with intranuclear fragmentation of the DNA. The mitochondrial internal apoptosis differs from the FasL→FasR-initiated (apoptosis stimulating fragment) cell surface-localized external apoptosis. The bio-philosophical connotations of the apoptotic phenomena (“cell suicide”) are widely disputed. In ontogenesis (in the cocoons of insects; in precursor organs of the mammalian kidney, etc.) tissue anlagen are readily dissolved by apoptosis, to be replaced by the permanently functional organ. In malignantly transformed cells, the RNA/DNA complex forcefully inhibits the apoptotic processes. Bcl-2 gene anti-sense inhibitors, microRNA Bcl-2 mRNA inhibitors, or BCL-2 enzyme-protein small molecular inhibitors occasionally overcome the blockade and force the initiation of cancer cell apoptosis. Anti-cancer cell lymphocyte-mediated immune reactions naturally (or by genetic engineering of the lymphocytes’ TCR) aiming at apoptosis induction in the cancer cell, referred to in the late 1960s early 1970s as 616 Appendix 2 Explanations to the Figures*)

“nuclear clumping” (photographed and discussed in J.G. Sinkovics: “Cytolytic Immune Lymphocytes…” Schenk Buchverlag, Passau/Budapest, 2008).

Figure 24. Chloroplast Stroma. The thylakoid lumen. Phospholipid thylakoid membranes. Of 335 thylakoid proteins, 89 are operational in the lumen. Antenna proteins (photosystems I/II chlorophylls, carotenoids, phycobiliproteins) harvest light. From the chloroplasts, chlorophyll genes were transferred into the cell nucleus. Light-induced water oxidation (splitting) by photosystem II is generating oxygen, protons and electrons in the oxygen evolving complex; protons pumped across the thylakoid membrane from stroma to lumen; electron transport in the cytochrome b67 complex; plastoquinone reduced by ferredoxin; reduced plastoquinol oxidized by cytochrome b67 protein; ATP synthase activated by the proton gradient generates ATP. Proton concentration gradient across thylakoid membrane is 10,000-fold up, as compared to a 10-fold gradient across mitochondrial inner membrane.

Figure 25. Ribosomes. Did precellular sites of protein synthesis exist? Ribozymes and RNA-binding proteins appear to have been in existence and in action. Indeed, a globe-wide network of a Ribonucleoprotein World was fully operational. Ribozyme- and microRNA-packed exosomes released from extant cells (prokaryota; uni- and multicellular eukaryota) represent a form of retrograde evolution to the precellular ribosome level? (Sinkovics JG European J Microbiol Immunol 2015;5:25–43). Viroids are relics of that world. Fusing viroids might have formed the ﬁrst precellular large viruses. Did DNA join in, or appeared ﬁrst only in the protocells? What primordial enzymes carried out the deoxyribosylation of the RNA molecule, or could the DNA molecule be synthesized from nucleotides same as the RNA had come to its existence eons earlier? Matthaei and Nirenberg utilized E. coli ribosomes working extracellularly for the discovery of the gene code (Proc Natl Acad Sci USA 1961;47:1580–1586; 1961;47:1588–1602). The RNA-binding proteins (domains, RBD) appear to have existed in the precellular world, predating LUCA, the last universal common ancestor. The RNA methylases of the Rossmann-fold class are assumed to be of pre-LUCA origin. Figure 1 of the cited article shows the RNA-binding THUMP domain (thiouridine synthase, methylase, pseudouridine synthase) being present in LUCA, as it was transferred from there into each one of the three derivative kingdoms. These base N-methylases share the [N/D]PP[Y/F] motif (asparagine/aspartic acid; proline, proline; tyrosine/phenylalanine) at the end of their strand 4 (Anantharaman V, Koonin EV, Aravind L. Nucleic Acids Res 2002;30:1427–1467). For ribosome evolution, see Appendix 1. mRA interactions http://commons.wikimedia.org/wiki/File:mRNA- interaction.png by Sverdrup licensed under CC BY-SA 3.0.

Figure 26. The Argonautes represent highly conserved primordial gene silencing systems. The argonaute (AGO) proteins mediate gene silencing by RNA interference (iRNA) in the RNA-induced silencing complex (RISC). Of four human argonautes (hAGO), only hAGO2 slices naturally RNA, but both hAGO1 and hAGO4 could be transformed into RNA-slicers. The slicer enzyme is guided to its mRNA target by a Appendix 2 Explanations to the Figures*) 617 small interfering siRNA. When inactive, the guide strand rests in the Mid-domain (middle) by its 5' end and in the PAZ domain (PIWI/Argonaute/Zwille, ZLL) by its 3' end. The active guide strand is phosphorylated at its 5' end. The PIWI domain (wimpy testicle, drosophila) is an RNAse. The triad DDH (aspartate- aspartate-histidine) signiﬁes catalysis. The catalytic tetrad is DEDH (aspartic acid, glutamic acid, histidine). In the hAgo1-let-7 complex, nucleotides 21 and 22 of miR let-7 are bound to the PAZ domain. hAgo2 forms complexes with the N domain (duplex unwinding in RISC assembly) and with miR-20a; and the N domain (the “duplex wedge”)makes contact with let-7 (letter; lethal). The N domain of hAgo2 activates slicing in hAgo3. The PIWI domain is subject to mutation L674F (leucine, phenylalanine) in hAGO1. The double mutation F676L and Q677P (glutamine, leucine) disabled (no slicing) hAGO2 (Faehnie CR et al Cell Rep 2013;3:1901–1909. W.M. Keck Structural Biology Laboratory; Greg Hannon’s Laboratory; Howard Hughes Medical Institute Cold Spring Harbor Laboratory; Leemor Joshua-Tor Laboratory). RNAse endonucleases, the intranuclear Drosha class II (invertebrate Pasha), and the cytoplasmic Dicer class III process (shorten pri-miRs into 60–70 hairpin sequences) and load (processed sequences) into RISC (Laboratory RNA Biology Max Planck Institute Biochemistry, Am Klopferspitz 18, Martinsried 82152 Germany). The ancestors of the green alga, Chlamydomonas reinhardtii, already possessed and forwarded the zwille (zll) genes into plants (Arabidopsis thaliana) to encode AGO proteins (ZLL) that maintain shoot meristem stem cells for new organ (leaves, branches, angiogenesis, ﬂowers) formation in plant embryos. Zll-mutant plants overexpress the erecta receptor (ER) kinase, and its ligands, regulators of vascular cell organization and replication (Czyzewicz N et al J Exp Bot 2013;64:5281–5296; Tucker et al BMC Genomics 2013;14:809; Uchida N & Tasaka M J Exp Bot 2013;64:5335–5343). Downstream of ER, a MAPK cascade drives proliferation of some selected cell clones. The activated ER sequence expresses a multiplicity of introns. The Wuschel homeobox ligands promote vascular cell proliferation (Etchells JP et al Development 2013;140:2224– 2234; Karve R et al RNA 2011;17:1907–1921; Meng X et al Plant Cell 2012;24:4948–4960). The AGO proteins engage in small smRNA silencing. Should Ago proteins silence a gene(s) encoding cell proliferation inhibitory factors, they may indirectly promote cell proliferations; should the proliferating cells carry a gain-of-function mutation, those cells may end up as a malignantly transformed stem cell clone. Illustration: Faehnle CR, Elkayam E, Haase AD, Hannon GJ, Joshua-Tor L. The Making of a Slicer: Activation of Human Argonaute-1. Cell Reports 2013;3 (6):1901–1909. doi:10.1016/j.celrep.2013.05.033. RISC RNA-induced silencing complex [2343].

Figure 27. MicroRNAs. The intranuclear Drosha releases pri-miRNA →pre-miRNA to the cytoplasm. The cytoplasmic RNAse Dicer generates the duplex dsRNAs (miRNA/miRNA). The corresponding strand within RISC (RNA-induced silencing complex) aligns to the untranslated region (UTR) of the targeted mRNA and cleaves it. miRNAs may act as oncogenes, or as tumor suppressor genes. Federica Calore & Muller Fabbri (Department Molecular Virology, Immunology, Medical Genetics. Ohio State University Columbus, OH 43210). 618 Appendix 2 Explanations to the Figures*)

MicroRNAs and Cancer. Atlas of Genetics and Cytogenetics in Oncology Haematology 2011 pp 1–27. The microRNAs Drosha & Dicer miRNA http:// commons.wiikimedia.org/wiki/File:miRNA.svg by Kelvinsong licensed under CC BY 3.0.

Figure 28. Pseudouridylation [2344] H/ACA-box signature hairpin adenine cytosine adenine. Functional in archaea. Appear in ﬁrst stem loop in Ciona intestinalis. Described in Giardia and Trichomonas. Human box H/ACA analyzed (Chen XS Penny D Collins LJ BMC Genomics 2011;12:550. Kiss AM Jády B Bertrand E Kiss T Mol Cell Biol 2004;21:5797–5807).

Figure 29. Kaposi Sarcoma. The most prominent herpesviral particles in KS cells are those of the KSHV/HHV-8 agents (illustrated in: Sinkovics JG “Cytolytic Immune Lymphocytes…” Schenk Buchverlag Passau/Budapest 2008) (147). The chaperon heat shock proteins mightily contributed to the survival of primordial archaeons, prokaryotes and unicellular eukaryotes in the overheated environment of the ancient Earth. Cellular and virally encoded oncoproteins continue to enlist a special form of HSP for their own protection: the enriched-in-tumor-cells etHsp90 (Moulick K et al Nat Chem Biol 2011;7:818–826). These transformed cells suc- cessfully practice anti-apoptotic defense and encode proto-oncogenic pathways (NFκB; PI3K/Akt; Bcl-2). Antagonized are FLIP, FLICE-inhibitory proteins, FADD-like IL-1β converting enzyme; Fas-associated death domain; Fas, fragment apoptosis signaling. Tumor cells induced and/or promoted by gammaherpesviruses Epstein-Bar virus (HHV4) and/or Kaposi sarcoma-associated herpesvirus (HHV8) encode oncoproteins that engage etHsp90 for their own protection. In primary effusion lymphoma (PEL), KSHV/HHV-8 with or without EBV, with or without HIV-1, is the leading pathogen (Matolcsy A Nádor RG Cesarman E Knowles DM Am J Pathol 1998;153:1609–1614). In PEL cell lines and in human PEL cells grown in mice, investigational small molecular inhibitor PU-H71 destabilized the oncoprotein protective effect of etHsp90 on KSHV/HHV8-induced oncoproteins. The BCL2 oncoprotein antagonist obatoclax (patented GX15-070) synergized in PEL cell-killing through autophagy and apoptosis with the patented PU-H71 etHsp90 antagonist (Najar U et al Blood 2013;122:2837–2847; Ojala PM Blood 2013;122:2767–2768). Herpesvirally infected cells often induce the release of latent retroviruses. This is very evident in KSHV/HHV8-infected KS cells of endothelial cell origin, even in the classical Mediterranean KS cell lines. The released retrovirus particles are not those of HIV-1, or related viruses, neither morphologically, nor immunohistochemically. In immunohistochemistry, the KS-related retroviral structural proteins were not identical with those of the human T cell lymphotrophic retrovirus (HTLV-1), but were related to those retroviral particles that occasionally appeared in Reed-Sternberg cells of Hodgkin’s disease (F Györkey† unpublished). In indirect immunoﬂuorescence assays, patients with KS yielding these cell lines appeared to have circulating antibodies reacting with budding retroviral envelope antigens (Sinkovics JG. Cytolytic Immune Lymphocytes… Schenk Buchverlag, Passau/Budapest, 2008; Sinkovics JG & Horvath JC in “Kaposi sarcoma a breeding Appendix 2 Explanations to the Figures*) 619 ground of herpesviruses” Int J Oncol 1999;14:615–646, Errata: Int J Oncol 2005;27:5–47) (Figure 30).

Figure 30. Endogenous Retrovirus Activated in KS. Herpesvirally infected cells often induce the release of latent (endogenous) retroviruses (reviewed in Sinkovics JG Acta Microbiol Immunol Hung 2010;57:253–347). This is very evident in KSHV/HHV-8-infected KS cells of endothelial origin. The released retrovirus particles are not those of HIV-1, or related viruses, neither morphologically, nor immunohistochemically. In immunohistochemistry, the KS-related retroviral structural proteins were not identical with those of the human T cell lymphotrophic retrovirus (HTLV-1). Immunohistochemical relationship with retroviral particles budding from Reed-Sternberg cells of Hodgkin’s disease was found (unpublished, F Györkey †). In indirect immunoﬂuorescence assays, patients with KS yielding these cell lines circulated antibodies reacting with budding retroviral envelope antigens (Sinkovics JG “Cytolytic Immune Lymphocytes…” Schenk Buchverlag, Passau/Budapest 2008; Sinkovics JG & Horvath JC Kaposi sarcoma… herpesviruses. Int J Oncol 199;14:615–646; Errata: Int J Oncol 2005;27:5–47) (Figure 29). Illustration. A male patient of the Veterans’ Administration Hospital, Houston, TX, originally diagnosed with classical Mediterranean KS, that later turned out to be AIDS-associated, yielded cells of sarcomatoid morphology in primary tissue culture. The cells concealed herpesvirus-like particles, but yielded budding retroviral particles. The retroviral particles were neither those of HIV-1 nor HTLV-1. The patient circulated immunoglobulins reacting in indirect immunoﬂuorescence assays with the envelopes of the budding retroviral particles. First published in Sinkovics JG et al Orvosi Hetilap 2006;147:617–621; re-published as Fig 4.18a, b in Sinkovics JG: “Cytolytic Immune Lymphocytes…” Schenk Buchverlag, Passau/Budapest, 2008 (147).

Figure 31. Entamoeba histolytica [2345] trophozoite by confocal microscopy. Endoplasmic reticulum stained green (Parasitology Research Springer Link). Genome clues (Matt Berriman, Wellcome Trust Sanger Institute). Complete genome sequencing for E. histolytica is available. The intracellular parasite Entamoeba invadens operates extrachromosomal ribosomal RNA genes. Adaptations to different hosts (E. invadens to reptiles) results in non-circular transcripts of ncRNAs deriving from the rDNA locus (Northern hybridization). In contrast, human-adapted intracellular E. histolytica works with circular transcripts (Ojha S et al Mol Biochem Parasitol 2013;pii:S0166-6851(13)00150-3). The large number of protein phosphatases propagating intracellular signals makes up to 3.1% of the proteome of E. histolytica (Anwar T & Gourinath S PLoS One 2013;8(11):e78714). E. histolytica evolutionarily conserves polyadenylation sequences in its mRNAs 3'- UTRs. Some of its mRNAs are subjected to decay by iRNAs (López-Camatrillo C et al Wiley Interdiscip Rev RNA 2013 Nov 8). Under oxygen-restricted conditions, the aerobic ATP-generating mitochondria of E. histolytica undergo transformations into mitochondrion-related organelles (mitosomes, hydrogenosomes) (Makiuchi T 620 Appendix 2 Explanations to the Figures*)

& Nozaki T Biochimie 2014;10:3–17). The amoeboid locomotion is comparable to that of tissue-invading cancer cells (see text).

Figure 32. Tetrahymena Molecular Biology I. Twi12 association with tRNA fragments. (A) The schematics show the strategy of ZZTwi12 transgene knock-in and endogenous TWI12 locus knockout; the latter is evidenced with Southern blot data using Nhel-digested genomic DNA at right. The position of the Southern blot probe is indicated in the TWI12 locus schematic with a thin gray line. (B) RNAs copuriﬁed with Twi12 in vegetative growth (veg) or after 12 h of starvation (st12) were stained directly with SYBR Gold in comparison with size-selected total RNA from the same cultures. (C) The composition of sRNA library sequencing reads is depicted for reads with either a perfect match to the genome or a single internal mismatch as indicated. (D) Read numbers for tRNA fragments copuriﬁed with Twi12 were plotted relative to tRNA gene copy number as an approximation of full-length tRNA abundance. The labels of some data points at left were removed for clarity. mtGluTCC, SecTCA, ThrCGT, mtHisGTG. Pseud indicates combined reads from the 11 annotated tRNA pseudogenes, and mt indicates mitochondrial. This verbatim quotation from the article is very complex. The reader is advised to print out the entire text of the article (Couvillion MT, Sachidanandam R, Collins K. Department of Molecular and Cell Biology, University of California, Berkeley, CA. Genes Dev 2010;24:2742–2747) (125b).

Figure 33. Tetrahymena Molecular Biology II. Retention of the tRNA 3' fragment as the tightly bound strand. (A) Blot hybridization of Twi12-bound tRNAs was performed using probes complementary to the 5' or 3' end of several abundant tRNAs. Direct SYBR Gold staining of Twi12-bond sRNAs is shown at left for reference. (B) Arrowheads and lines indicate the potential processing positions and detected sRNAs, respectively, for two of the tRNAs from A. The 3' CCA nucleotide of a mature tRNA are not illustrated. (C) Twi12-associated sRNAs were directly stained after RNP isolation using two different gentle, nondenaturing buffer conditions. (D) Twi12-associated sRNAs were 5' end-labeled after isolation using stringent puriﬁcation conditions, with or without prior cross-linking; different concentrations of urea were used for washes prior to RNA extraction. (E-G) Twi12-cross-linked sRNAs washed with 2 M urea were used for blot hybridization to detect speciﬁc tRNA fragmentation (Shown in E) and for library construction. The length distribution of sequencing reads (F) is shown for 3' fragments that match the genome perfectly or have untemplated 3' C, CC, or CCA, with the combined nucleotide frequency at each position (G) revealing a 5' sequence signature. This verbatim quotation from the article is very complex. The reader is advised to print out the entire text of the article (Couvillion MT, Sachidanandam R, Collins K Department of Molecular and Cell Biology, University of California, Berkeley, CA. Genes Dev 2010;24:2742–2747) (125b).

Figure 34. The Synovial Sarcoma fusion oncoprotein was recognized as New York NY-ESO cancer testis class (CTA) antigen (Ayyoub M et al Cancer Immun 2004 Appendix 2 Explanations to the Figures*) 621

4:7). The fusion oncogene t(X;18)(p11.2;q11.2) was originally described in A.A. Sandberg’s laboratory in the 1980s. The cadherin-binding protein, β-catenin (β-C) connects the cytoplasmic tail of E-cadherin to the actin cytoskeleton. When β- catenin translocates into the nucleus, the sarcoma cell assumes spindle cell morphology. With β-C remaining in the cell membrane and cytoplasm, the sarcoma cell exhibits the epithelioid phenotype. The SSX1→Snail zink finger fusion protein is a strong antagonist of the repressor of the E-cadherin promoter. The SSX2→Slug fusion protein is a weak antagonist of the repressor of the E-cadherin promoter. When the repressor of the E-cadherin promoter prevails (suppressing E-cadherin), synovial sarcoma cells assume the monophasic spindle cell state (reviewed in Sinkovics JG Expert Rev Anticancer Ther 2007;7:31–56). Cadherin genes and proteins (lefftyrin, coherin, hedgeling) appeared first in the last common ancestor of choanoflagellates and metazoans, and in the single celled choanoflagellates (C. owczarzaki; Salpingoeca rosetta), before the divergence of the metazoan lineage. The sponge, Oscarella carmela possesses cytoplasmic β-catenin-binding cadherins with cytoplasmic tail (Nichols SA et al Proc Natl Acad Sci USA 2012;109:13046–13051). The basic evolution of cadherins predated that of the metazoans. The pre-metazoan pre-choanoflagellates’ cadherins can not be recognized beyond the first bilaterians. The cadherins in the cytoplasmic bridges of S. rosetta are different from the metazoan cadherins. Tyrosine kinases appeared first in C. owczarzaki as ligands in search of receptors; their receptors appeared later in single cells of multicellular metazoans (Suga H et al Sci Signal 2012;5(222)ra36). Illustration : Nichols SA Department of Biological Sciences, University of Denver, Denver, CO 80208; Roberts BW Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720. Within the Wnt pathway (Figure 7), the position of Dishevelled (Dsh) at the animal pole of the female pronucleus in the unfertilized egg of the sea anemone (Nematostella vectensis) is opposed to the vegetal pole, where Dsh is degraded. The position of Dsh determines the site of gastrulation, while β-catenin stabilizes the endoderm (Lee PN et al Dev Biol 2007;310:169–86). The ancient physiologically installed β-catenin becomes a DNA-binding proto-oncogene activator protein in the vertebrate mammalian hosts within the Wnt oncogenic pathway [2346].

Figure 35. Medical History. In the late 1960s, a middle aged male patient MDAH#73587 yielded established cell lines from his large locally invasive but not known to be metastatic chondrosarcoma of his right hip. His blood contained circulating small compact T lineage lymphocytes (later immune T cells), which promptly surrounded his tumor cells and lysed them in vitro. A healthy control individual (this author, JGS) yielded small compact circulating lymphocytes (later: immune T cells), which practiced emperipolesis over the patient’s allogeneic chondrosarcoma cells, but refrained from attacking them. Instead, the healthy control released large granular lymphocytes (later: natural killer NK cells), which firmly attached to the allogeneic chondrosarcoma cells and eventually lysed them (Sinkovics JG Pathol Oncol Res 2004;10:174–187). NCI project site visitors considered that the healthy donor rejected a latent incipient chondrosarcoma (without 622 Appendix 2 Explanations to the Figures*) knowing it). The healthy male donor (JGS) then documented that his blood contained large granular lymphocytes, which attached to and lysed female breast cancer and ovarian carcinoma cells (Sinkovics JG, Reeves WJ, Cabiness JR. J Natl Cancer Inst 1972:48:1145–1149; Proc 63rd Ann Meet Am Assoc Cancer Res 1972; #57). Then the NCI project site visitors declared that the chamber-slide assay in use produced “in vitro artifacts”, since no specific immune reactions should occur without preimmunization and that such reactions were not observed in the Hellströms’ laboratory. However, that laboratory used a colony inhibitory assay for gross inspection, and without the actual visualization of individual attacker lymphocytes. In contrast, the chamber-slide assay in the author’s Lab visualized and clearly individually distinguished the attacker lymphocytes (in Appendix 1). Illustration: Figures 1–2. The chondrosarcoma cell line, advanced passages, in the late 1960s. Figures 3–4. The patient’s small compact T lymphocytes collected and purified from peripheral blood killed in vitro autologous chondrosarcoma cells in 24–48 h. Figures 5 and 6. Healthy donor’s (JGS) small compact lymphocytes practice emperipolesis, but refrain from attacking allogeneic chondrosarcoma cells. Large granular lymphoid cells (arrows) firmly attach to, and eventually lyse, allogeneic chondrosarcoma cells. These pictures are among the first photographs taken in the Sinkovics Lab of “large granular lymphocytes” attacking allogeneic human tumor cells without any pre-immunization (J.G. Sinkovics et al in: “Leukemia-Lymphoma” M.D. Anderson Hospital 14th Clinical Symposium in 1969. Year Book Medical Publishers, Chicago, 1970; Cancer 1971;27:782–793; The 7th San Francisco Cancer Symposium, Front Radiat Ther Oncol 1972;7:141– 154). Further medical historical event: upon first sight of the large granular lymphoid cells (later: NK cells), chief pathologist James Butler suggested that they looked “monocyte-like” (even though the large granular cells failed to phagocytose bacteria) (Figure 27 citation) (278).

Illustration: Reproduction of microphotographs from the early 1970s from J.G. Sinkovics In: “Cytolytic Immune Lymphocytes” Schenk Buchverlag, Passau/Budapest 2008, page 120. 10.10. (147) Patient’s autologous lymphocytes attack chondrosarcoma cells and induce “nuclear clumping” (later: apoptosis). Several attacker lymphocytes lose their morphological integrity. 10.11. Autologous small compact lymphocytes (later: immune T cells) kill by cytoplasmic lysis squamous carcinoma cells of the nasopharynx. 10.12. Two autologous immune T cells kill by total disintegration a melanoma cell. 10.13 and 10.14. Immune T cells of patients with rhabdomyosarcoma attack and lyse allogeneic rhabdomyosarcoma cells. Using immune T cells (and not NK cells) in an allogeneic encounter indicates tumor-speciﬁc immune reaction to a shared tumor antigen in rhabdomyosarcomas.

Figure 36. Medical History concerning NK cells. Small compact lymphocytes (recognized later as immune T cells) of the patient with chondrosarcoma surrounded and killed the autologous tumor cells (in color). Of the control lymphocytes deriving from this author (black and white), the small compact lymphocytes refrained from attack, instead large granular lymphocytes (later recognized as Appendix 2 Explanations to the Figures*) 623 natural killer NK cells) attached to the tumor cells to eventually lyse them (see previous Figure 35). Reviewed with dates of the photographs cited (Sinkovics JG Pathology Oncology Research 2004;10:174–187). The tumor antigens, that autologous immune T cells or autologous and allogeneic NK cells were attacking, were not identiﬁed (presumed were ampliﬁed fetal antigens; mutated oncoproteins; NY-ESO antigens; HiWi antigens).

Illustrations: 1, Large granular lymphocytes (NK cells) and small compact lymphocytes (immune T cells) of a patient (LN, MDAH#90641) with metastatic liposarcoma in remission after receiving chemoimmunotherapy including viral oncolysate (VO) added, attack in vitro a sarcoma cell deriving from the allogeneic sarcoma cell line #3743 from which the VO was prepared (Presented at the 22nd Annual Clinical Conference at M.D. Anderson Hospital in 1978; cited in ref 147). In Illustration 2, a graph prepared by H David Kay and Harikishan Thota in 1971 in the Sinkovics Lab clearly shows that the healthy author’s (JGS) large granular lymphocytes killed allogeneic tumor cells in vitro: an immune reaction without pre-immunisation (30c). Reprinted in the “Atlas. Effectors of Anti-Tumor Immunity” by M Kiselevsky. Springer Verlag, 2008.

Figure 37. The Hydra. The entire genome of the hydra (H. magnipapillata; H. vulgaris) has been sequenced. These diploblasts lack mesoderm, but the genes ancestral to the generation of mesoderm (snail, twist and their high mobility group protein forkhead, FoxA), are present. Other genes “in the waiting” are those of the photoreceptors, may be ancestral to the eye-encoding pax6/Pax6 cluster to come. Homologs of the vertebrate stem cells (Klf4, Oct4, Sox2, Nanog) are not detectable, but cells interstitially located in the parenchyma are multipotent stem cells. The cnidaria hydra possess and express the LIM protein complex (LIM homeobox Table XVI). LIM and ROCK (Rho-associated coiled coil kinase) proteins drive the amoeboid locomotion in human cancer (breast and prostate) cells. Of the six LIM homeobox clusters, the Hydra utilizes four (Srivastava M et al BMC Biol 2010 18;8:4). The hox/Hox gene/protein clusters of bilaterians to follow later are predated by a very active Wnt signaling pathway (both Disheveled and β-catenin). The Wnt system encodes the regeneration of mutilated body parts, both in Hydra, Hydractinia and Nematostella vectensis. The bone morphogenetic pathway (BMP2/4 and TGFβ/Dpp transforming growth factor decapentaplegic, drosophila) and its antagonists chordin and gremlin, are operational in the Hydra/Hydractinia, even though morphological symmetry in these hosts is not yet present. This system will encode the Spemann-Mangold organizer in the newt (vide infra). Plasmid DNA injections created transgenic Hydra and Hydractinia species (Trevino M et al Dev Dyn 2011;240:2673–2679; Technau U & Steele RE Development 2011;138:1447–1466). In the evolution of its genome, the hydra experienced invasions of transposable elements, lateral gene transfers (some large bacterial genes inserted) and the retention of stem cells for its physiological ontogenesis, may be for its reversal from mature to immature cells, and for the rapid regeneration of lost body parts (like its head) (Chapman et al Nature 2010;464:592–596.) 624 Appendix 2 Explanations to the Figures*)

Figure 38. The Spemann-Mangold Organizer [2347]. Cells of the gray crescent in the gastrulating amphibian (frog; newt) embryo form the notochord. Cells of the gray crescent of the newt blastula transplanted ventrally into another newt blasto- coel induced the development of another notochord located ventrally. It was not the transplanted gray crescent cells that grew into the second notochord; the transplanted gray crescent cells induced the recipient host’s ectodermal cells to develop into notochords. Otherwise host bone morphogenetic proteins (BMP) would have converted the ectodermal cells into skin cells (epidermis). The transplanted gray crescent cells produced the host BMP antagonist proteins chordin and noggin, that prevented the trans-speciation of ectoderm into epidermis; thus, in absence of BMP, the ectoderm continued its predetermined physiological course to form notochords and central nervous systems. Other factors interacting, especially in the drosophila (insects, crustaceans, arachnids, annelid worms), are ADMP (anti-dorsaling morphogenetic protein), ACVR2A (activin A receptor type 2A), protein Nodal, and its antagonists, proteins Cerberus and Lefty. Another Nodal and Wnt antagonist is DKK-1 (dickkopf); SOG (short gastrulation) interacts with SMAD (signaling mothers against decapentaplegic, dpp, TGFβ). In the drosophila, the dorsally acting dpp (TGFβ) is blocked by the ventrally acting SOG. Insects develop ventral nerve cords (Inui M et al Proc Natl Acad Sci USA 2012;109:15354-15359; Spemann H & Mangold H (neé H. Pröscholdt: Transplantation Versuche… Über Induktion von Embryonalanlagen durch Implantation…Universität Freiburg-Breisgau). Induction of embryonic primordia by implantation of organizers from a species, 1923-4. Reprinted Int J Dev Biol 2001;45:13–38)

Figure 39. Caenorhabditis. A nematode living in the soil and feeding on bacteria with a difficult name to apply: caenos for recent, rhabdos for a wand (slender stick). Hermaphrodite females (XX) in vast majority of the population consist of 959 individually recognized cells; extremely rare males (X0) operate 1031 cells. The first totipotent cells of the embryo hatching from the eggs are asymmetrically dividing stem cells. In ontogenesis, some cells are eliminated by apoptosis. The 100-million base pairs C. elegans genome is condensed into six chromosomes; mitochondrial genomes further contribute. Individual genes frequently function arranged in operons. Distressed (starving) larvae enter the dauer stage: resist stress without ageing. Orthologs of the anaplastic lymphoma kinase (alk/ALK) proto-oncogene and TGFβ (DAF7) signaling establish the state of dauer in the larva. The scd gene (suppressor of constitutive dauer) fails to oppose. Further pathways activated in the dauer state are the IGF, TGFβ, SMAD, and v-Ski (Sloan-Kettering avian sarcoma retroviral isolates). Is the state of dauer in a larva analogous to a human pediatric tumor? Some mRNAs are destroyed by RNA interference (iRNA). There is H3K4 methylation and H4 acetylation. The miRNA let-7 (lethal, letter 7) induces cell differentiation and in vertebrate mammalian hosts is a suppressor of ras/Ras oncogenes/oncoproteins (deletion of let-7 may be lethal). In the healthy caenorhabditis, let-7 and argonaute (argonaute-like gene and protein, alg/ALG) synergize in the elimination of potentially harmful mRNAs. Let-7 is essential for the differentiation of the uterus and vulva. Let-7 deficient nematodes Appendix 2 Explanations to the Figures*) 625 experience the replication of undifferentiated vulvar cells and the rupture of the hypercellular organ (a lethal outcome). Are these “ulcers that do not heal” cancers? Insulin-like growth factor-(IGF-) blocked individuals extend their life-span three-fold. Wild Caenorhabditis strains are infected with positive-sense RNA nodaviruses (Le Blanc, Orsay, Santeuil strains). A state of viral carriership is established (Franz CJ et al J Virol 2012;86:11940. González-Aguilera C et al Brief Funct Genomics 2013 Dec 10. Hunter SE et al PLoS 2013;9(3):e1003353. Reiner DJ et al Curr Biol 2008;18:1101–1109. Gal, TZ; Glazer, I; Koltai, H (2004). “An LEA (protein late embryogenesis abundant) group 3 family member is involved in survival of C. elegans during exposure to stress”. FEBS Letters 2004;577: 21–26. doi:10.1016/j.febslet.2004.09.049. PMID 15527756. http://en. wikipedia.org/wiki/File:Caenorhabditis_elegans_hermaphrodite_adult-en.svg by KDS444 licensed under CC BY-SA 3.0.

Figure 40. SOX2 Gene amplification and protein overexpression foretell more favorable clinical course of squamous cell lung cancer. Strong nuclear immunohistochemistry in squamous lung carcinoma cells in a sample (a). Lung squamous carcinoma cells with amplified and non-amplified Sox2 (b). No SOX2 amplification in tumor cells (c). Normal bronchial epithelial cells show limited confined SOX2 expression (d) (Wilbertz T et al, Mod Pathol 2011;24:944–953).

Figure 41. The Human Stem Cell Transcription factor SOX2 protein is encoded from chromosome 3q26.3-q27. The intranuclear SOX2 protein binds a receptive high mobility group (HMG) protein DNA domain (Tables XI/I and XI/II). Co-expressed with embryonic stem cell factors NANOG and Oct3/4, the SOX2 protein reprograms terminally differentiated cells into pluripotent cells. Certain human parenchymal cells expressing high levels of ampliﬁed SOX2 protein assume constitutive and incessant mitotic activity and grow into tumors with propensity to be invasive and metastatic. Sinonasal undifferentiated and inverted papillomatous carcinomas were driven by highly ampliﬁed SOX2 oncoprotein. The relapse rates of these tumors were increased. The early expression of SOX2 protein indicates inductive rather than promotional role for SOX2. SOX2-positive tumors developed more lymph node metastases than SOX2-negative tumors (Schröck A et al, PLoS One 2013;8(3):e59)

Figure 42. Notch [2350]. Gene mastermind is a notch signal effector in the drosophila. The human homolog of the drosophila notch gene is TAN-1 (T cell leukemia translocation-associated Notch homologue). The translocation is at t(7;9) (q34;q34.3). The locus 9q34.3 is homologous with the drosophila notch gene. The constitutively activated gene encodes the overproduction of gamma-secretase. The extracellular domain of TAN-1 is EGF-like; the intracellular domain is ankyrin-rich and as such is inhibitory to DNA-binding of the p50 subunit of NFκB. Exceptional IkB protein Bcl-3 acts like TAN-1. TAN-1 and Bcl-3 reverse transcriptional inhibition imposed on them by high levels of p50 dimers. In this case, TAN-1 promotes NFкB-dependent gene expression resulting in T cell activation; so does a truncated 626 Appendix 2 Explanations to the Figures*)

TAN-1 protein (Aster J et al Cold Spring Harb Symp Quant Biol 1994;59:125–136. Ellisen LW et al Cell 1991;66:649–661. Guan E et al J Exp Med 1996;183:2025– 2032. Pear WS & Aster JC Curr Opin Hematol 2004;11:426–433). Porphyromonas gingivalis induces proliferation of vascular smooth muscle cells by activating TGFβ and Notch signaling (Zhang B et al BMC Genomics 2013;14:770). See Notch activation in pediatric brain tumors (ependymoma) in the text.

Figure 43. An Annelid. The ancestral bilaterian protostome marine annelids are represented by Platynereis dumerilii. The triploblastic polychaete, P. dumerilii displays a far advanced neuropeptid network. Its Wnt and FGF ligand-to-receptor systems are highly active in its embryo. Its germ cells provide the progeny; the stem cell compartments lay down the organs consisting of somatic cells. No uncontrolled constitutively replicating stem cell clones (tantamount to tumors) have so far been reported (Conzelmann M et al BMC Genomics 2013;14(1):906; Denes AS et al Cell 2007:129:277–288). The achaete scute neurogenic genome (see Nematostella; Amphioxus) in its vertical evolutionary ascent uses P. dumerilii as one of its sta- tions (Simionato E et al BMC Evol Biol 2006;8:170). Illustration: Unpublished illustration of Dr Nicole Rebscher, University of Marburg, Germany; shown with gratitude.

Figure 44. Viral Oncolysates (VO) with, or without chemotherapy, were effective cancer vaccines before the era of molecular virology. H Koprowski and J Lindenmann independently prepared viral lysates of cultured tumor cells and used the cell-free lysates for immunization of tumor-bearing mice. Viral oncolysates contained the live oncolytic virus and a mixture of unidentified tumor antigens. Some of the antigens were recombined proteins of the viral and cell membrane envelopes/capsids. As such, these antigens were immunogenic in the hosts that would not have responded to their own self cell surface antigens. Tumor-bearing mice, rendered tumor-free upon immunization with viral oncolysates, specifically rejected challenge with large doses of live cells of the same tumor (oncolytic virus-free inocula) that they were bearing, but rejected upon pre-immunization with their viral lysates (Koprowski H et al Texas Rep Biol Med 1957;15:11–128; Lindenmann J & Klein PA. “Immunological Aspects of Viral Oncolysis”. Springer Verlag, Berlin-Heidelberg-New York, 1967). WA Cassel (Emory University, Atlanta, GA), and JG Sinkovics (University of Texas MD Anderson Hospital, Houston TX) prepared viral oncolysates in the 1970s for clinical use in patients with metastatic melanoma (Cassel WA, VO in itself without chemotherapy), and metastatic melanoma and sarcoma (Sinkovics JG, in combination of VO with chemotherapy). In not prospectively randomized patient populations, both investigators reported partial remissions with prolongation of life. Cassel and Murray DR excelled in being able to record durable complete remissions. JG Sinkovics and Plager C were first to report synergism of VO and chemotherapy, manifesting in prolongation of remission duration and life over chemotherapy alone (vide infra). These investigators concluded that viral oncolysates first performed viral oncolysis, and then tumor cells undergoing lysis induced anti-tumor immunity. Sinkovics, Appendix 2 Explanations to the Figures*) 627

Cabiness J, Kay HD, Thota H, and clinical associates reported antibody and lymphocyte-mediated immune reactions quantitatively increasing in responding (and in non-responding) patients (Cassel WA et al In: “Viral Therapy of Human Cancers” edited/authored by JG Sinkovics & JC Horvath, Marcel Dekker, New York, 2005; Pp 677–689; Sinkovics JG “Cytolytic Immune Lymphocytes…” Schenk Buchverlag, Passau/Budapest, 2008; Sinkovics J G & Horvath JC Arch Immunol Ther Experiment, Wroclaw, Poland; Birkhäuser Verlag, Basel 2008;56S:1–59). Citations from other investigators using viral oncolysates for human cancer therapy (P Hersey; MK Wallack; V Schirrmacher) are provided (in “Viral Therapy of Human Cancers”, vide supra). Illustration: Tumor cells are shown undergoing viral lysis by PR8 influenza A virus, or NDV, before removal of all cellular debris. The final cell-free products were reached by carrying out a rigid triple-controlled protocol, providing a cell debris-free supernatant. Dieter Gröschel ascertained bacteriological sterility (including mycoplasma) and freedom from endotoxins (by limulus assay) of the final preparations. Not UV-irradiated pre- parates were used for human inoculations. However, even UV-irradiated VO preparations contained residual live oncolytic viruses (Horvath JC, Horak A, Sinkovics JG. Proc Am Assoc Cancer Res 86th Ann Meet Toronto Canada 1995;36:493#2619). Autologous viral oncolysates were preferred over allogeneic preparations. Non-prospectively randomized patients in need of treatment were accepted and were tested clinically and by laboratory technology for response (or failure thereof) (Sinkovics JG & Horvath JC Int J Oncol 2006;29:765-777).

Figure 45. Coelomocytes [2351]. Innate immune coelomocytes of sea urchin Strongylocentrotus purpuratus. The polygonal P cells possess Sp-185-333-positive perinuclear vesicles. The small S phagocytic cells are Sp-185-333 positive. The discoid D phagocytic cells are Sp-185-333 negative (Brockton V et al George Washington University, Washington DC Cell Sci 2008;121:339–348). Progenitors of the variable leucine-rich repeats receptors (LRR/VLR) of the lamprey are present in the sea urchin genome in addition to 222 Toll-like receptors (TLR). The Toll-interleukin 1 receptor (TIR) and the MYd88 (myelogeous) domains are functional. IL-1 and IL-17 and their receptors are present. The recombination activator genes and proteins rag/RAG1/2 and the Immunoglobulin variable domain V genes are present for an unidentified (not adaptive immunity) function. The Transib family transposons’ DNA inserts encoded first the V(D)J/RAG1-2/RSS complex (variable/diversity/joining; recombination activating genes; recombination signal sequences). In the genomes of the sea urchin, amphioxus, hydra and starlet sea anemone (Nematostella) elements of the system occur singly and unlinked to one another. The entire system worked in unison first in the sharks (chondrichtyes) (Kapitonov V & Jurka J PLoS Biol 2005;3(6):e181; Fugmann S et al Proc Natl Acad Sci USA 2006;103:3728–3733; Rast JP et al Science 2006;314:952–956). The herbicide glyphosate induces DNA-damage in sea urchin embryos, however no excessive abnormal cell proliferations resulted (Bellé R et al J Soc Biol 2007;201:317–327). The sea urchin telomerases, contrary to the rules that invariant identity of crucial catalytic enzymes maintains cell survival lengths, are highly 628 Appendix 2 Explanations to the Figures*) hypervariable (Wells TG etal Mol Biol Cell 2009;20:464–480). Yet the life span of individual sea urchins extends 100 years.

Figure 46. The urochordate Botryllus (B. schlosseri) lives in colonies, in which individual members of the colony share a tunic and a circulatory system within it. In the haemolymph, one of the circulating cells expresses recognition toward self versus non-self. A colony approaching to fuse with a sedentary colony, may be recognized as non-self. The intruder cells will be killed by a process of dissolution. The process of rejection leaves behind scars in each colonies. The cells responsible to kill the allo-incompatible colony are the ancestors of the vertebrate mammalian natural killer (NK) cells (Khalturin K et al Proc Natl Acad Sci USA 2003;100:622–627). Poster presentation at M.D. Anderson Hospital’s Symposium “Cancer Immunity: Challenges for the Next Decade” by Sinkovics JG, Horvath JC, Kay HD on “From the origin of NK cells in the Botryllus to their interaction with syncytiotrophoblasts in the placenta” Abstracts 2003; #1–33:117. The fusion-histocompatibility gene locus consists of two cFuHC genes, one secreted, one membrane-bound (both referred to as fosmid). A third related gene encodes the Botryllus histocompatibility factor (BHF), representing the faculty of the general tunicate allorecognition. Colonies able to fuse must carry histocompatible BHFs. Cells of blood vessels express BHF the most. The reaction of fusion versus rejection is determined by BHF in an as yet unknown mechanism. In the fused chimeric colonies, the stem cells of each colony strive to take over by eliminating the other colonies stem cells. Reconciliation in a mixed genotype is possible (Voskoboynik A et al Science 2013;341:384–387). Observe tunicate genes organized into operons and transcribed in single mRNAs in contrast to amphioxus and vertebrates operating operon-free genomes (Holland LZ J Exp Zool B Mol Dev Evol 2014. doi:10.1002/jez.b.22569). Addition in Appendix 1.

Figure 47. Of the AID/APOBEC enzymes [2352], the activation-induced cytidine deaminase (AID) converts cytosine to uracil. This enzyme is active in somatic hypermutation and class-switch recombination in adaptive immunity (see text). The eight human APOBECs (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) primarily restrict retrotransposons and retroviral genomic expressions. Human HIV-1 and papillomaviral genomes induce APOBEC overexpression (without or with mutagenesis induction). APOBECs specifically target as their exclusive substrate ssDNA, inducing in them cytosine to guanine (C→G) and cytosine to thymine (C→T) substitutions. The C→G and C→T substitutions are recognized as APOBEC signature mutations. Clustered mutations are termed kataegis, Greek for escalating thunderstorms (originally written in Russian Cyrillic letters). APOBEC signature mutations in exomes are common in adenocarcinomas (non-existent in acute myeloid leukemias). The figure shows APOBEC-signature mutations in four breast cancer subtypes (luminal A, luminal B, basal-like, and HER2-enriched). The HER2 protein was considered to be amplified, not mutated; however, it contains high copy number variations due to frequent APOBEC signature mutations. APOBEC cytidine deaminases are a significant source of mutagenesis in the genomes of human cancers, to the extent that they may act as human Appendix 2 Explanations to the Figures*) 629 cancer-driver mutations (Roberts SA et al Nat Gen 2013 Sept 45(9):970-976; Sinkovics JG Acta Microbiol Immunol Hung 2010;57:253–347). Author’s comment. The archaic APOBECs induce point mutations “in the waiting” to blindly prepare single cells for survival in any future environmental changes? The AID/APOBEC enzymes are installed to provide antiviral immunity to the cell, but by mis-mutating ssDNAs bring about an eventually fatal outcome to the host by the overreproduction of immortalized cells? Or, is the initiation of immortalized cells an inherent faculty of the RNA/DNA complex carried out in this case by the AID/APOBEC protein?

Figure 48. Reed-Sternberg (RS) Cells of Hodgkin’s lymphoma (HL) are originally mononucleated, but eventually become bi- and multinucleated giant cells. Sinkovics and Shullengerger CC observed these cells in primary bone marrow or lymph node cultures at standstill for several weeks: no RS cells in mitosis could be seen and photographed. Sinkovics repeatedly proposed in lectures (Honolulu, Hawaii; Padua, Italy; M.D. Anderson Hospital, Houston, TX; ASCO, Los Angeles, CA) that RS cells were the products of cell fusions mediated by EBV and an endogenous retrovirus, and thus they were “natural hybridomas” (Sinkovics JG et al Blood 1964;24:389–401; Lancet 1970; 1 (7638):139–140; 1975;2(7933):506–7; Crit Rev Immunol 1991;11:33–63; Leukemia 1992; 6S3:495–535). The cell fusion theory of RS cells was cited by P. Mauch & J. O. Armitage in Holland & Frei “Cancer Medicine” 5th ed. B.C. Decker Inc. Hamilton London 2000 p 2014. However, the German literature forcefully opposed cell fusion in RS cells: “Cell fusion is not involved in the generation of … Reed-Sternberg cell line” (Re D et al Am J Hematol 2001;67:6–9). “Evidence that Reed-Sternberg cells do not represent cell fusions” (Küppers R et al Blood 2001;97:818–821). Endomitosis without cell divisions was suggested for the generation of giant multinucleated RS cells. Michels and Sinkovics independently argued that the cell fusion theory had experimental support (Michels KB Eur J Cancer Prev 1995;4:379–388; Sinkovics JG Acta Microbiol Immunol Hung 2005;52:1–40). Long term time-lapse microscopy recently revealed that fusion and re-fusion of the HL mononuclear cells are the main route of RS cell formation. Mononuclear RS cells separated by division re-unite by fusions (Rengstl B et al Proc Natl Acad Sci USA 2013; 110:20729–20734; Commun Integr Biol 2014;7:e38602). However, the viruses (EBV; endogenous retrovirus) suspected to induce these cell fusions (Sinkovics JG Crit Rev Immunol 1991;11:33–63) received no attention at all. The RS cell-rich syncytial variant HL cells were repeatedly described (Lee SG et al Int J Hematol 2015;101:107–108), but without adequate virological studies performed. The RS cells possess a malignantly transformed genome and the V(D)J immunoglobulin pathway (however defective, due to loss of normal B cell characteristics) of the original B cells. The expression of B cell receptor in RS cells is lost due to loss-of-function mutations in its promoter. These are the SPI/POU protein mutations (serine protease inhibitor SPI proto-oncogene; Pit-1, pituitary-speciﬁc; Oct-1 octamer-binding; Unc-86 uncoordinated protein, caenorhabditis) (Vockerodt M et al Chin J Cancer 2014;33:591–597). The classical hybridoma cells possess the 630 Appendix 2 Explanations to the Figures*) transformed genome of a malignantly transformed cell and the V(D)J hypersomatic mutation of a normal immunoglobulin-producer B cell. The RS cell possesses both criteria: a transformed genome and the basic B cell V(D)J pathway; thus, it qualiﬁes to the pathognomonic position of a natural hybridoma. It frequently openly expresses EBV, and silently an endogenous retrovirus. Its endogenous retroviral expression is suppressed by acetylation of its inserted proviral genome, which can be activated by deacetylation to express the endogenous retrovirus (Kewitz S & Staege MS Front Oncol 2013;3:179).

Illustration: Thirty years old male patient (MR) at St. Joseph’s Hospital Tampa FL in mid-1990s with Reed-Sternberg cells of lymphocyte-rich mixed cellularity Hodgkin’s disease in lymph nodes and in the bone marrow. His RS cells expressed EBV antigens (no speciﬁcs available). History revealed clinically diagnosed infectious mononucleosis in young age with full recovery. Patient achieved uneventful complete remission on ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy. Later, upon a fall at his home resulting in multiple leg fractures and moving about on crutches, he was found in relapse with bone marrow aspirate positive for many mononuclear and multinuclear RS cells. His circulating T cell population presumably contained EBV-reactive CD4/8+ memory cells. He was started on M.D. Anderson Hospital’s low dose paclitaxel chemotherapy (Younes A et al Ann Oncol 2001;12:923–927). He was infused with autologous CD4/8+ T cells (5x108 cells/mL x8). Bone marrow aspirates showed apoptotic RS cells and mononuclear RS cells dissolving upon contact with immune T cells (shown). Patient sustained good granulocyte count in afebrile state. He was considered to be in second complete remission. Later in 2001 he was admitted in the night through the Emergency Room to the Intensive Care Unit in Gram-negative septic and hemorrhagic shock; was attended immediately and in full. Expired a few hours later. No necropsy was performed (Sinkovics JG & Horvath JC Internat J Oncol 2001;19:473–488; Erratum 2005;27:5–47).

Illustration: Elongated double-nucleated large RS cell surrounded by small, compact lymphocytes (immune T cells); one lymphocyte overlying lower end of the RS cell (Sinkovics JG et al Br J Med 1970;1:172–173). Copyright Printer William Lewis Ltd, Cardiff, Great Britain). This is an example of emperipolesis; no cytoplasmic lysis or nuclear clumping (apoptosis) in the RS cell is evident. RS cells acquire resistance to immune T cells. Mononuclear RS cells are lysed by autologous cytotoxic lymphocytes; multinucleated RS cells are resistant to, or are protected by Treg cells against, cytotoxic lymphocytes (shown) (Sinkovics JG et al Brit Med J Jan 17 1970;1:172–173; Int J Oncol 2012;40:305–349). RS cells harbor herpesviral (EBV) and endogenous retroviral particles (Sinkovics JG & Györkey F J Med 1973;4:283–317; Sinkovics JG & Horvath JC Int J Oncol 1999;14:615–646. Erratum idem 2005;27:5–47; Sinkovics JG “Cytolytic Immune Lymphocytes…” Schenk Buchverlag, Passau/Budapest, 2008). RS cells offer a wide array of antigenic targets for monoclonal antibodies, NK- and immune T cells. NK cells attack RS cells in the antibody-directed cell-mediated cytotoxicity reaction with the help of Appendix 2 Explanations to the Figures*) 631 lymphokines IL-2/IL-12 (Jahn T et al PLoS One 2012;7(9):e4448). The anti-CD30 moab conjugated to auristatin E was generated for therapy (Stein H, Diehl V Hematol Oncol Clin North Am 2014;28(1);1–11. doi:10.1016/j.hoc.2013.10.007).

Figure 49. G4 quadruplex DNA. The DNA-protein complex 6-base pair repeat telomeres are synthesized by the telomerase reverse transcriptase (TERT). Re-capped chromosomal ends are protected from end-to-end fusions. The ciliate, Stylonychia lemnae renews its telomeres of 36 nucleotides in its dividing macronucleus. The G-rich 3’-overhang is formed by the last 16 nucleotides. The overhang adopts a subtelomeric guanine-quadruplex DNA structure. The G-rich quadruplex DNA structures are both parallel- and antiparallel-stranded. Two overhangs mediate end-to-end association in four-stranded conformations. The formations are stabilized by hydrogen-bonded guanine quartets. Specific single-chain fragments (scFv) recognize the parallel G-quadruplexes in millions of minichromosomes in the macronuclei. The telomeres receive their caps in the replication bands of the quadruplexes in the macronucleus at each cell division. Telomere capping is accomplished by t-loops, TEBP (telomere-binding protein), and by the G-quadruplex; TEBP and G-4 are interacting (Schaffitzel C et al Proc Natl Acad Sci USA 2001;98:8572–8577). Illustration: G-quadruplex DNA in the macronuclear telomeres of Stylonychia lemnae. Christiane Schaffitzel et al, Proc Natl Acad Sci USA. 2001 July 17;98(15):8572–8577.

Figure 50. PTEN. The tumor suppressor gene and gene product protein PTEN (phosphatase tensin homolog deleted on chromosome ten, human 10q23.3) (Table VIII), is the natural inhibitor of oncogenes PI3K/Akt (phosphatidyl inositol kinase 3; protein kinase 3; phosphatidylinositol 3 phosphate; Jacob Fürth’sAK mouse strain thymic lymphoma retroviral oncogene; phosphoinosite-dependent kinase). The PTEN protein inactivates PIP3 by dephosphorylation; PDK1 (phosphoinositol-dependent kinase) is not recruited to the plasma membrane to activate Akt by phosphorylation. Sarah M. Planchon et al, The nuclear affairs of PTEN. J Cell Sci 2008 121:249–253. doi:10.1242/jcs.022459

Highly malignant adenocarcinoma cells (prostate cancer; triple-negative breast cancer; colorectal cancer) with deleted PTEN (Carver BS et al Nat Genet 2009;41:619–624; Karseladze AI et al Arkh Pathol (Russian) 2010;72:20–23; Kato S et al Int J Cancer 2007;121:1771–1778; Perrone et al Ann Oncol 2009;20:84–90; Reid AH et al Mod Pathol 2012; 25:902–910; Sircar K et al J Pathol 2009;218:505–513; Yoshimoto M et al Genes Chromosomes Cancer 2012;51:149–160). MicroRNA-122 is a promoter of the PI3K/Akt oncogenic pathway (Lian JH et al Asian Pac J Cancer Prevent 2013;14:5017– 5021). The mRNA of the tumor suppressor gene GAS1 (growth arrest speciﬁc) is targeted for destruction by overexpressed miR-34a. The GAS1-blockade results in the overproduction of PI3K/Akt/Bad (Bcl-2 antagonist of cell death) with cancers (papillary carcinoma of thyroid) developing (Ma Y et al Biochem Biophys Res Commun 2013;441:958–963). The activated (phosphorylated) Akt oncoprotein targets intranuclear DNA oncogenes (mammalian target of rapamycin mTOR; mitogen-activated 632 Appendix 2 Explanations to the Figures*) protein kinase MAPK; vascularendothelial growthfactor VEGF) (Shafee N et alCancer Lett 2009;282:109–115; Teng HF et al Mol Cell Endocrinol 2014;383:147–158). PI3K/Akt inhibitors in clinical trials are bortezomib, resveratrol, and small molecular inhibitors of oncogenes/oncoproteins (Ge J et al Biomed Environ Sci 2013;26:902–911; Lin L Int J Oncol 2014;44:557–561; Polivka J & Janku F Pharmacol Ther 2013; pii:50163–7258(13)992404; Qazi AK et al Anticancer Agents Mol Chem 2013;13:1552–1564).PI3K/AKT/mTORpatentedsmallmolecularinhibitors(LY2949; GDC-0980; NVR-BEZ-235 etc) are awaiting their clinical trials.

Figure 51. Ancient Chinese Yin (black) Yang (white). Forces (energies) in the Universe act and counteract, expand and contract, change hot to cold, light to dark and back in continuous movement. Immune T cells and regulatory T cells balance each other (Bluestone JA: The yin and yang of interleukin-2-mediated immunotherapy. N Engl J Med 2011;365:2129–2131).

Figure 52. Placental syncytins. Endogenous retroviral syncytin genes format the two-layered multinucleated murine placental syncytiotrophoblasts at the feto-maternal interface. Two distinct retroviral genes were retroinscribed into the ancestral rodent genome. These proviral genes are expressed in unison, but work independently in the fetus to format the fetal organ placenta. The mouse, rabbit and human syncytin genes are related. Anne Dupressoir A et al, Proc Natl Acad Sci USA 2011;108:E1164–1173 PNAS. doi:10.1073/pnas.1112304108

Figure 53. The Team of Ferenc Györkey†, Joseph (József) Sinkovics and Jeno (Jenő) Szakacs has engaged for several decades in the search of retroviral particles in human tissue specimens submitted to their laboratories. Illustration 1. Györkey and Sinkovics discovered endoplasmic tubuloreticular structures in lymphocytes and parenchymal cells of patients with systemic lupus erythematosus and pre-AIDS era classical Mediterranean Kaposi’s sarcoma cells (shown) (Gyorkey F & Sinkovics JG Lancet 1971;1(7690):131–132; Gyorkey F et al Am J Med 1972;53:148–158; Lancet 1982;2(8305):984–5). Cited in ref 147, ﬁg 4.1: in kidney glomerular cell of patient with SLE. Mistakenly, they regarded the tubuloreticular structures to be incomplete retroviral particles developing in the endoplasmic reticulum. In association with these structures, budding retroviral particles were also observed. Dorothea Zucker-Franklin has also seen an association between the tubuloreticular structures and the retroviral particles in lupus and in KS cells (Zucker-Franklin D N Engl J Med 1983;300;837– 838). However, the tubuloreticular structures proved to be nucleic acid-free; they were formed in the presence of excessive type I IFN production. Once the tubuloreticular structures proved to be not of retroviral origin, literature citations ceased for both the tubuloreticular structures and the co-existing, genuine retroviral particles (shown in SLE cells). A seemingly valid co-existence of the tubuloreticular structures and budding retroviral particles in human sarcoma cells remains present (shown). Illustrations 2/3/4: endogenous retroviral particles budding from kidney glomerular cells of patients with SLE. Cited in ref 147 page 48 Fig 4.3/4/5. Illustrations 5/6: human soft tissue sarcoma cells with budding retroviral particles. Cited in ref 147 Appendix 2 Explanations to the Figures*) 633 pages 251, 252, Fig 1212 and Fig 1213. The co-existence of HHV8/KSHV with endogenous retroviral particles in KS cells has been repeatedly documented (Sinkovics J G et al Orvosi Hetilap (Hungary) 2006;147:617–621; Sinkovics JG “Cytolytic Immune Lymphocytes…” Schenk Buchverlag Passau/Budapest) (Figures 29 and 30). Clariﬁcation: Szepesházi K Lapis K et al Orvosi Hetilap Budapest 1977;118:315–318.

Figure 54. The Naegleria. The life cycle of N. fowleri consists of three stages: flagellate (converting a trophozoite), amoeba, and cyst. Moving on highly mobile by lobodium pseudopodia, the amoeboid trophozoites infect the meninges. Mitochondria secure the aerobic metabolism of the trophozoites. The most versatile genome of the N. gruberi is able to re-format its entire microtubular cytoskeleton when it transforms from an amoeba into a flagellate. To form the flagella, it syn- chronizes some 82 genes. Not the flagellar, but its centriole gene cluster consists of 55 genes. Some of its centriol genes are conserved up to the human genome. Its centrosome-localized conserved centriole component contains genes orthologous with some of those expressed in HeLa cells (Fritz-Laylin KL & Cande WZ J Cell Sci 2010;123:4024–4031) http://jcs.biologists.org/cgi/content/full/123/23/4024/DC1.

Figure 55. Two Different Tumors with Fusion Oncoproteins: African Burkitt’s Lymhoma (BL) with, and Congenital Mesoblastic Nephroma (Fibrosarcoma) (CMN/IFS) without, a Host Immune Response. Epstein-Barr virus attacks a host immunologically overburdened by plasmodia and assorted pathogens. The endem- ically spreading external viral pathogen EBV induces the malignant transformation in African teenagers. Chromosomal breaks form the c-myc/IgH fusion oncogene/oncoprotein by the translocation t(8:12)(q24;q32). In the attacked B lymphocytes, class switching and V(D)J somatic hypermutations are not accomplished. EBV EBNA1-6 and LMP1-2 immortalize the B lymphocytes in the viral latency III program. Additional oncogenes (NFκB; T cell leukemia 1 from chromosome 14q32.1) are recruited. Chemical inhibitor of c-Myc 10058-F inhibited the growth of BL cells. The “starry sky” (shown) histological pattern is that of macrophages phagocytosing antibody-coated lymphoma cells as reproduced as such in the mouse (Sinkovics JG et al J Inf Dis 1969;120:250–254). There are host immune reactions to BL cells. Combination chemotherapy induces remissions (with relapses). Natural measles virus infection may induce remission due to viral oncolysis. In non-endemic sporadic Western Hemisphere BL cells, the same translocation can occur without EBV. BL occurs in HIV-1 infected patients. Diffuse large B-cell lymphomas occur with or without EBV, but with t(8:12)(q24;q32. In this entity, c-Myc inhibits NFκB and IFN-response (Burmeister T et al Mol Oncol 2013;7:850– 858; Faumont N et al J Virol 2009;83:5014–5027; Kiss C et al Proc Natl Acad Sci USA 2003;100:4813–4818; J Virol Methods 2003;107:195–203). EBV is known to physiologically persist in memory B lymphocytes; the pathogenesis of BL involves the memory B lymphocytes. The EBV-encoded nuclear antigen (EBNA1) escapes recognition by immune T cells of the host. However, EBNA1 is associated with latent membrane protein antigens’ (LMP1/2) expression. BL cells constitutively express EBV oncoprotein LMP1 (Hochberg D et al Proc Natl Acad Sci USA 634 Appendix 2 Explanations to the Figures*)

2004;101:139–44). EBNA2 is responsible for the latent immortalization of EBV-infected BL cell by activating Notch signaling. The EBNA2 transcriptional transactivator TAT protein downregulates LMP1/2 production and induces cessation of BL cell proliferation (Farrell et al Proc Natl Acad Sci USA 2004;101:4625–30). In proliferating BL cells, the promoters of cell cycle suppressor genes p16INK4A and p14ARF are hypermethylated and thus inactivated (Nagy E et al Eur J Cancer 2003;39:2298–2300; Anticancer Res 2005;25:2153–2160). In contrast, the constitutively activated CDK4/6 is de-activated by its molecular inhibitor palbociclib.

The ETV6/NTRK3 fusion oncoprotein (ETS translocation variant of reticuloendotheliosis bird retrovirus E twenty-six; neurotrophin tyrosine receptor kinase) induces secretory basal cell breast cancers in premenarcheal teenager girls, or teenager boys (Yorozya K et al Jpn J Clin Oncol 2012;42:208–211; Szanto J et al Breast 2004;13:439–442). The congenital CMN/IFS kidney tumors express the ETV6/NTRK3 translocation-encoded t(12;15)(p13;q25) oncoprotein with or without trisomy of chromosome 11. Whether these two tumors are identical or different is still debated. The fusion of bands 12p13 of gene ETV6 and band 15p15 of gene NTRK3 is the hallmark of these tumors (they do not occur in adulthood ﬁbrosar- comas). The tumor’s energy is carbohydrate-intake dependent with insulin-like growth factor and insulin receptor substrate (IGF2; IRS1) overexpression (Adem C et al Mod Pathol 2001;14:1246–1251; Argani P et al Mod Pathol 2000;13;29–36; Gisselsson D et al Mod Pathol 2001;14:1246–1251; Morrison et al Oncogene 2002;21:5684–5695; Watanabe N et al Cancer Genet Cytogenet 2002;136:10–16). Transmission electron microscopy so far revealed no viral particles (PCR, Immunohistochemistry for viral-encoded proteins; Y. Chang’s technology for the ﬁrst isolation of KSHV and Merkel cell polyomavirus have not as yet been applied) (Knezevich SR et al Cancer Res 1998;58:5046–5048; Rubin BP et al Am J Pathol 1998;153:1451–1458; Ramachadran C et al Pediatr Dev Pathol 2001;4:402–411). The fetal innate and maternal passive immune faculties of the fetus and newborn apparently mount no immune reactions to these tumor cells: they appear to be accepted as self. Illustration: Sinkovics JG Pienta JR Trujillo J Ahearn MJ University of Texas MD Anderson Hospital, Houston, Texas. An immunological explanation for the starry sky histological pattern of a lymphoma. J Inf Dis 1969;120:250–254. Illustration: David Gisselsson, University Hospital, Lund, Sweden. FISH: G-banded chromosome 12 with ETV6 and KRAS2 probes.

Figure 56. The Life Cycle of Phytophthora infestans [2357]. P. infestans gains virulence and drug resistance by gene fusion. Fusion occurs between the disease resistant recombinase gene (DRR206) and β-glucoronidase (GUS). Cis-regulatory elements involved are the wound/pathogen inducible box genes (W/P box). Fusion with the Fusarium solani phaseolae DNAse gene (FsphDNase) provided resistance against Pseudomonas syringae (Choi JJ et al Phytopathology 2004;94:651–660). The class WRKY proteins, sometimes with GQK (trp, arg, lys, tyr; glyc, gln, lys), are segmentally duplicated DNA-binding transcription factors in plant cells (Arabidopsis thaliana; Solanum lycopersicum, the tomato; Petroselinum crispum, Appendix 2 Explanations to the Figures*) 635 the parsley; Vitis vinifera, the grape; Nicotiana benthamiana, the tobacco; Erysiphe necator, the mildew); appearing first in Chlamydomonas reinhardtii (but absent in animals). Occur in the amoeba: Dictyostelium discoideum. Act as first defensive signalers (Eulgem T et al EMBO J 1999;18:4689–4699; Guo C et al J Exp Bot 2014. doi:10.1093/jxb/eru007). WRKY proteins protect Phytophthora infestans against its pathogens. It is the mitogen-activated protein kinase (MAPK) pathway that activates WRKY proteins by phosphorylation (Ishihama N et al Plant Cell 2011;23:1153– 1170). The MAPK is a frequently used proto-oncogenic pathway in transformed eukaryotic cells. Large peripheral vesicle proteins transiently fused by dynamine interaction in some oomycetes in the Phytophthora genus. These proteins are secreted as an introductory act to host tissue invasion. Similarly, fibrosarcoma cells are known to practice cargo release (exocytosis) from superficial vesicles (Jaiswal Rivera Simon et al Cell 2009;137:1308–1319; Zhang W et al PeerJ 2013;1:e221).

Figure 57. Showing some of the first human NK cell pictures. Ewing sarcoma cells carry the EWS-FLI-1 translocation t(11;22)(q24;q12) at Friend leukemia insertion site (Fli), express cancer-testis antigens, and are attacked by host lymphocytes, both immune T cells and NK cells. The first human NK cells viewed in the late 1960s are shown; cited from Sinkovics JG et al Leukemia Lymphoma. Yearbook Medical Publisher Pp 53–92, 1970) (278). The first Ewing sarcoma cell line was established by author JGS and associates from 10 year old female patient (MDAH#79610) at the Section of Clinical Tumor Virology & Immunology of M.D. Anderson Hospital in 1970 (shown in its 50th in vitro passage). At that time it has just become known that patients’ small compact lymphocytes (later: immune T cells) reacted to autologous (and related allogeneic) tumors, and large granular lymphocytes (later: NK cells, red arrows) reacted to autologous and allogeneic tumors (shown in Figures 35 and 36) and that healthy tumor-free individuals also possessed these latter cells (Sinkovics JG Györkey F et al Methods Cancer Res Academic Press 1978;XIV:243–323; Sinkovics JG et al Leukemia-Lymphoma Year Book Medical Publishers 1970; 53–92; Management Bone & Soft Tissue Tumors. Year Book Medical Publishers 1977;361–410; Sinkovics JG, Plager C et al Canad J Surg 1977;20:542–546; Oncology 1980;37:114–119). Since then, the chemo-radiotherapy-resistant Ewing sarcomas have become targets of immunotherapy with anti-IGF-R or anti-CD99 monoclonal antibodies, and biological interventions (EWS-FLI gene silencing; αTNF/TRAIL induction; TGFβ induction with rapamycin and mTOR inhibition; PARP-cleavage by the pan-cycline kinase inhibitor flavopiridol). Autologous immune T cells and/or allogeneic NK cells attack Ewing sarcoma cells. Type I IFNs induce apoptosis of EWS cells through the activation of TNFα-inducing ligand (TRAIL). Expression of ligand NKG2D (stimulated by histone deacetylase inhibitors, or by lentiviral transduction) renders EWS cells susceptible to native or activated NK cell therapy. Chondromodulin-, or enhancer of zeste-stimulated HLA-A0201+ dendritic cells rendered allo-restricted HLA-A201− CD8+ T lymphocytes cytotoxic to EWS cells. Anchor-residue reinforced EWS-FLI-1 peptides induced T lymphocytes to attack EWS xenografts (Berhuis D et al Clin Sarcoma Res 2012;2(1):8; Cho D et al Clin 636 Appendix 2 Explanations to the Figures*)

Cancer Res 2010;16:3901–3909; Evans CH et al Clin Cancer Res 2012;18:5341– 5351; Kelleher FC & Thomas DM Clin Sarcoma Res 2012;2(1):6; Lehner M et al PLoS One 2012;7(2):e31210; Mahlendorf DE & Staege MS Cancer Biol Ther 2013;14:254–261; Thiel U et al Br J Cancer 2011;104:948–956). FLI = Friend leukemia insertion site. Illustrations: 1, 2. Sarcoma cell attacked by autologous small compact lymphocytes (later: immune T cells) and large granular lymphocytes (later: NK cells) shown in 1969 at M.D. Anderson Hospital Symposium “Leukemia-Lymphoma” (Sinkovics JG et al Year Book Medical Publishers, Chicago, 1970 Pp 53–92) (278). Picture of medical historic value showing for the ﬁrst time NK cells attacking a human cancer cell. 3. Ewing sarcoma cell line established from patient MDAH#79610) identiﬁed as that of a Ewing’s sarcoma cell with t(11;22) (24;q12) by pathologist Bruce McKay who prepared the transmission electron microscopic picture (Sinkovics JG, Plager C et al Immunotherapy of human sarcomas. In: “Management of Primary Bone & Soft Tissue Tumors”. Year Book Medical Publishers, Chicago, 1977 Pp 361–410.

Figure 58. BRAF mutations. The rat ﬁbrosarcoma retrovirus incorporated in its genome the host cell proto-oncogenes rafABC: c-raf → v-raf (Rapp UR et al Proc Natl Acad Sci USA 1983;80:4218–4222). The raf (rat ﬁbrosarcoma) proto- oncogenes are widely spread in vertebrate mammalian hosts. The Braf gene is subject to gain-of-function point mutations in its nucleotide BRAF V600E (valine; glutamic acid in exon 11, codon 600). The mutated genome is constitutively active in many different human tumors: melanoma (60%), hairy cell leukemia (100%), splenic B cell lymphoma, histiocytic sarcoma, platelet-derived growth factor receptor PDGFR-negative gastrointestinal stromal tumors, some (40%), papillary thyroid carcinoma, some colon carcinoma (10%). Constitutively activated MEK and ERK pathways (MAPK/ERK kinase; mitogen-activated protein kinases; extracellular signal-regulated kinase) result in non-stop cell divisions. This mutation does not trans-speciate the cell in which it is active (morphologically different tumor cells carry the same mutations and retain their native morphology). Melanoma and hairy cell leukemia showed clinical response to type I IFNα. All BRAF-mutated tumor cells respond with cessation of growth and apoptotic death to the small molecular inhibitor vemurafenib. Patients with melanoma treated with vemurafenib may develop squamous cell carcinoma of the skin. These tumors commonly remain localized and are curable with surgical excision. On rare occasion, these tumors display eruptive features and malignant behavior. It is not yet clear what genomic mutations induce these tumors (Mays R et al J Cutan Med Surg 2013;17:419–422 Illustrations: Human melanoma cells with melanosome. EBV particles released from hairy leukemia cells (Sinkovics JG et al Methods Cancer Res 1978;XIV:243–323; Lancet 1975;1:749– 750; Ann Int Med 1976;85:532–533; N Engl J Med 1976;295:1016).

Figure 59.FasL→ FasR-Induced Mitosis. Short term (several months) in vitro established human melanoma cells deriving from patients with metastatic disease expressed the Fas receptor (R, fragment apoptosis signaling). These melanoma cells were exposed to highly puriﬁed Fas ligand (FasL). Figures shown were prepared by Appendix 2 Explanations to the Figures*) 637

Joseph C. Horvath for publication (vide infra). Instead of apoptotic cell death, as expected, FasL induced mitoses of FasR+ melanoma cells. Melanoma cells are known to undergo chromosomal breaks involving chromosome 1, with the locus of granulocyte colony stimulating factor receptor at 1p32-34 (Tweardy DJ et al Blood 1991;79:1148–54), and that of chromosome 10, with the locus of FasR (receptor, CD95) at 10q23-26 (Lichter P et al Genomics 1992;14:179–180). In order to explain how FasL-to-FasR could induce a mitotic response, it was postulated that the broken chromosomes 1 and 10 fused and generated a new fusion product gene of FasR and GCSF-R as t(1;10)(p32;q23-26). The signal conduction pathway of the gene product protein placed the FasR on the cell surface. Upon capturing FasL by FasR at the cell surface, signaling traveled through the cytoplasm into the G-CSF-R fragment of the fusion protein, that induced mitosis within the nucleus (Sinkovics JG & Horvath JC Int J Oncol 2001;19:473–488; Horvath JC et al Proc 89th Ann Meet Am Assoc Cancer Res 1998;38:2371 #584; Sinkovics JG Acta Microbiol Immunol Hung 1997;44:295–307. Erratum. In the MS FasR was correctly spelled CD95). The generation of this pathway in vivo as proposed receives support from experiments in which effective signals depended on the cytoplasmic region of chimeric FasR and G-CSF-R receptors: FasR cytoplasmic region induced apoptosis and G-CSF-R cytoplasmic region induced mitosis of leukocytes carrying the arti- ficially prepared chimeric receptors (Takahashi T et al J Biol Chem 1996;271:17555–17560). Karyotyping of the melanoma cells expressing patho- logically formed chimeric receptors with FasR on the cell surface and G-CSF-R in the cytoplasm would provide the final proof. Human B cell lymphoblasts release exosomes constitutively that induce apoptotic death in CD4+ T lymphocytes (Klinker MW et al Front Immunol 2014.doi:10.3389/fimmu.2014.00144). Illustrations: Published figure showing soluble FasL stimulating mitoses of FasR+ melanoma cells and anti-FasL antibody abrogating the effect (Sinkovics JG & Horvath JC Internat J Oncology 2001;19:473–488. Errata: Typographic error in the cartoon. Idem 2005;27:33). FasL-to-FasR. Ralph Budd, Vermont Center for immunobiology and Infectious Diseases. University of Vermont. Abbreviations: FLICE: Fas-associated death domain-like IL-1β-converting enzyme (caspase 8). TRAF: tumor necrosis factor receptor TNFR-associated factor. GCSF-R human granulocyte colony stimulating factor receptor (M Kimmel & S Corey in Frontiers in Oncology, 2013. doi:10.3389/fonc.2013.00089)

Figure 60. HHV6.*) History.The replication of human herpesvirus 6 is within the host cell nucleus. Immature viral particles bud out of the nucleus and become tegumented in the cytoplasm. Tegumented virions are taken up by the Golgi apparatus to receive their glycoprotein envelope. The egress of mature virus particles is through the cell membrane. Infected children experience the skin rash of roseola (exanthema subitum) consequential of viremia, also involving the cerebrum and meninges. Thereafter the viral genome rests in infected cells (commonly in lymphocytes; some parenchymal cells) in a stage of life-long latency. In latency, the viral genome integrates itself into chromosomes and is passed to cellular progenies, germ cells included. Cells taken up HHV-6A genomes will not allow the integration 638 Appendix 2 Explanations to the Figures*) of HHV-6B genomes. During its integration via homologous recombination, the HHV-6 genome loses 79 of its nucleotides. The chromosomal subtelomeric region is the favored viral integration site. The viral gene U94 encodes protein RepH6; enzyme RepH6 functions as an endonuclease, helicase, or ATPase. HHV-6 RepH6 might have derived from an adenoassociated viral gene incorporated into an ancestral HHV-6 genome now recognized as HHV-6 gene U94. HHV-6-infected lymphocytes may form syncytia. The gene product protein of HHV-6 gene U24 share amino acid identity with the myelin basic protein. Immune T cells attacking HHV-6 may attack also cells expressing myelin basic protein and thus induce the clinical picture of multiple sclerosis. During HIV-1-induced AIDS, HHV-6 becomes reactivated and mature virions appear in the blood. The inherited familial HHV-6 syndrome is a serious ailment (Arbuckle JH et al Proc Natl Acad Sci USA 2020;107:5563–5568; Virology 2013;442:3–11). Peter Medveczky con- siders familial HHV-6 syndrome to be a clinical form of the chronic fatigue syndrome. Illustration: FISH documentation of subtelomeric HHV-6 genomic integrat. *) Isao Miyoshi’s group ﬁnds HHV6 in Burkitt’s lymphoma (Daibata M et al Br J Haematol 1998;102:1307–1313). Isao Miyoshi and this author served together in fellowship in 1959 at MD Anderson Hospital (cited in [147]).

Figure 61. H. H. Niller’s Presention at his inaugural honorary membership lecture at the 14th International Congress of the Hungarian Society of Microbiology in 2003 at Balatonfüred, Hungary. The topic was a particular genomic segment of the Epstein-Barr virus. This viral genomic segment located within the EBER1 promoter appeared to be co-linear with a part of a sequence in the human immunoglobulin locus V(D)J. The co-linear human genomic sequence is within the 5'-end of the human lambda light chain immunoglobulin locus. Niller proposed that these two genomic segments derive from a common ancestor and reached the human genome through herpesviral vectoring. The original acquisition of the sequence in question might have occurred horizontally at the era of the ﬁrst gnathostomata, from where the genomic segment was passed vertically up to Homo. Niller’s idea ﬁts into a scenario whereby protocells on one side of the ping-pong table evolved and acquired DNA replicons from viruses evolving on the opposite side of the ping-pong table. There, tRNAs evolved into transposable element, retroviruses and DNA viruses (without explaining how RNA has become DNA). In the possession of DNA replicons of viral derivation, the protocells separated their soma (cytoplasm) from their germ line (nucleus) (Niller HH et al Acta Microbiol Immunol Hung 2004;51:469–484). The long ago formed separation of the RNA and retroviral camp of virologists may argue with the DNA virus camp in proposing that retrotransposons provided the basic genomic elements to the gnathostomata sharks (Kapitonov W & Jurka J PLoS Biol 3(6):e181), and that herpesviral ancestors acquired their adaptive viral genomic elements more recently from hosts higher up on the evolutionary scale already being in the possession of these elements well established. The ancient herpesviral genomic segments inserted into the amphioxus genome (Savin KW et al Virol J 2010;7:308) may hold the trump card. Appendix 2 Explanations to the Figures*) 639

Figure 62. Class I Retrotransposons use RNA-mediated, Class II DNA transposons use DNA-mediated mechanisms for their transposition. Retrotransposons far out- number DNA transposons in the human genome. Non-LTR (long terminal repeats) short and long interspersed nuclear elements (SINE; LINE) are the most numerous transposons. The two ORFs of the 6 kbp LINEs encode an endonuclease and a reverse transcriptase. The endonuclease performs the nick on the ssDNA and the reverse transcriptase converts the RNA into DNA for insertion. The excised autonomous Class II DNA transposons encode the transposase that fits to their own inverted terminal repeats (ITR). The ITRs of a non-autonomous Class II DNA transposon depend on another transposon’s transposase for insertion (trans-supplementing the transposase protein). The first dormant transposase reconstructed from the fish genome is the “Sleeping Beauty” (Z. Ivics, Zs Izsvák, R.H. Plasterk et al Cell 1997;901:501–510; Nat Methods 2009;6:415–422). Reconstructed natural Class II DNA transposons from insects, fish and amphibians are the Sleeping Beauty, Frog Prince, Hsmart, Mariner, Minos, Tol2, piggyBack (from the insect cabbage looper Trichoplusia ni) and piggyBat (from the little brown bat Myotis lucifugus), and a synthesized mammalian Class I non-LTR-retrotransposon (ORFeus for mice). Disregarding for practical purposes, in the evolutionary drive that transposons exerted since the generation of life (Dupeyron M et al Mob DNA 2014;29:5:4; Feschotte C & Pritham EJ Annu Rev Genet 2007;41:331–368; Pace JK II & Feschotte C Genome Res 2007;17:422–432; Skipper KA et al J Biomed Sci 2013;20:92), they may serve as vehicles of inserted genes and thus for gene therapy. In contrast to virally-vectored gene therapy, the gene-carrier transposons induce no neutralizing antibodies or immune reactions in the treated hosts, and their cargo capacity extend to large transgenes (Hong IS et al PLoS One 2014;9(1):e86324; Swierczek M, Izsvák Z, Ivics Z Expert Opin Biol Ther 2012;12(2):139–153; Human Gene Ther 2011;22(9):1043–1051). They may contribute to gene recombinations and mutations (known in the Daphnia; in crustaceans) (Schaack S et al Genome Biol 2010;1104):R46). They may spread horizontally (extensively, known in the drosophila) (Bartolomé C et al Genome Biol 2009;20(2):R22; Dupeyron M et al MobDNA 2014;5(1):4; Schaack S et al Trends Ecol Evol 2010;25:537–546). Zoltán Ivics, Zsuzsanna Izsvák et al Max Delbrück Center for Molecular Medicine, Berlin, Germany. Nat Methods June 2009;6:415–422. SBTS3 http://commons.wikimediua. org/wiki/File:SBTS3.png by Perryhackett licensed under CC BY.

Figure 63. Neurospora crassa. Barbara McClintock identified first that the chromosomes in the fungal genome (Neurospora) were eukaryotic. E.T. Tatum and G.W. Beadle won the Nobel prize for showing in 1941 that the Neurospora haploid genome works by the “one gene one enzyme” basic rule. Neurospora cells harbor mitochondria. The mitochondrial genomic introns revealed the process of self-splicing, and that interfering RNA (iRNA) could eliminate mRNAs issued by DNA genes. Neurospora cells’ haploid genome contains approx 10,000 genes. Neurospora cells change their haploid genome to diploid at conjugation. The genome returns to haploid state by methylating, thus silencing, the cytosines in both copies of duplicated sequences. Neurospora cells operate PARP (poly(ADP-ribose) 640 Appendix 2 Explanations to the Figures*) polymerase) (Table II) orthologs of the mammalian cells’ PARPs for ss/dsDNA break repairs and polyADP-ribozylation (Kothe GO et al Fungal Genet Biol 2010;47:297–309). In hyperosmotic stress (or due to mutations), the evolutionarily highly conserved PP2A class of phosphatases interact with the MAPK pathway; PP2A dephosphorylates and thus inactivates MAPK. Loss-of-function mutated phosphatases fail to stop MAPK. Hyperactive MAPKs induce excessive hyphal growth. The unregulated cell proliferation does not respond to inhibitors (the tert-butylhydroperoxide, t-BuOOH (Sigma), becomes ineffective). Inactivation by dephosphorylation of gene cdc-14 (cell division cycle) leads to unopposed activity of cdk-1 (cycle dependent kinase) resulting in incessant mitoses. In these cells the microtubule-attaching mitosis inhibitor benomyl becomes ineffective (Bennett LD et al Eukaryot Cell 2013;12:59–69; Ghosh A et al G3: Genes Genomes Genetics 2014;4:349–365). The Neurospora cell photoreceptors VIVID and White Collar (WC) activate the cells’ circadian rhythm, which is regulated by the clock genes/proteins ATF/CREB (activating transcription factor; cyclicAMP-responsive element-binding protein; adenosine monophosphate). These genes/proteins syn- chronize Neurospora cell divisions (Hong CI et al Proc Natl Acad Sci USA 2014;11: 1397–1402; Lamb TM et al Fungal Genet Biol 2012;49:180–188). The Neurospora clock gene frq (frequency) is shared with other fungi (Magnaporthe, Podospora). The frq and catp (clock ATPase) genes regulate histones in the nucleosome. The ccg2 (clock-controlled gene) encodes the spore surface rodlets. The bd (band) and fluffy genes induce high GTP (guanine triphosphate) levels and conidia (asexual spores) formation; they are activated by ROS (reactive oxygen species) and by receptor WC. Comment. The two Neurospora bd genes are ancestral to eukaryotic proto-oncogenes ras (rat sarcoma). Mutated Neurospora hyphal cells grow like chemotherapy-resistant human cancer cells. The descendants of Neurospora clock gene mRNAs and clock proteins respond to circadian rhythm in human cancer cells (naevus; cutaneous and uveal melanoma) (Lengyel Z et al Tumour Biol 2013;34: 811–819; Gamaleia NF et al Exp Oncol 2006;28;54–60; Otálora BB et al J Pineal Res 2008;44:307–315; Riabykh TP et al Vest Ross Akad Med Nauk 200;8:30–33). In the mammalian genome, target sites for the CREB proteins are proto-oncogenes AKT, Fos and Jun (AK mouse retroviral thymic lymphoma oncogene; Finkel murine osterosarcoma retroviral oncogene; bird reticuloendothelial retroviral oncogene 17; seventeen in Japanese is jun). Comment. Vertebrate mammalian (human) cells in the process of their malignant transformation regress to the level of the cell survival pathways of ancient eukaryotes. Ancient cry (circadian rhythm) genes may be distant orthologs of vertebrate mammalian (human) genes. The human tumor pinealoma possibly shares circadian rhythm genomic features with the ancestral genes operating in Neurospora crassa (in Appendix 1).

Figure 64. The Guardian of the Genome. The p53p63 genes underwent over one billion years of evolution from the sea anemone to the human genome. The caenorhabditis’ hybrid gene p53p73 (C. elegans p53, CEP-1) duplicated to produce the vertebrates’ p53 gene (Belyi VA et al Cold Spring Harb Perspect Biol 2010;2: a001 198). The p53 gene is a target of DNA-binding proteins that regulate its Appendix 2 Explanations to the Figures*) 641 activation or suppression. Anti-apoptotic microRNA-125b (oncomir miR-125b) (Table XXIII) by suppressing tumor suppressors CDKN2A/ink4a/14ARF (cyclin-dependent kinase; alternative reading frame), upregulates murine double minute (MDM) and its homologs (Amir S et al PLoS One 2013;8:e61064). The human gene product protein p53 is encoded from 17p13.1 and is synthesized in the ribosome. The p53 protein either succumbs to ubiquitination by MDM (or is guided into mitochondria by the MDM antagonist small molecule nutlin) (Lee S-Y et al Int J Oncol 2013; 10:1027–1035). Within mitochondria the p53 protein activates the intrinsic mitochondrial apoptotic death of the cell (The p53 protein may enter the nucleus in order to activate its numerous target genes (Vogelstein B et al Nature 2000;408:307–310), among them PUMA (p53-upregulated mediator of apoptosis), and pro-apoptotic BAX (Bcl2-associated X protein). The NADH-quinone oxidoreductase translocates protons through membranes. It started its activity in prokaryotes and continued it in the mitochondria of eukaryota. In dysfunctional mitochondria, p53 activity is reversibly (by chloramphenicol) suppressed; apoptosis induction is stalled; and cells are protected against gamma-irradiation- (γIR-) induced death. Cancer cells gain survival advantage (Compton S et al J Biol Chem 2011;286:20297–20312). The ancient NDUFA gene encodes the MWFE protein (abbreviations explained in text) (Au HC et al Proc Natl Acad Sci USA 1999;96: 4354–4359) . Constitutively overproduced (due to such NDUFA promoters, resulting in MWFE mRNA overexpression), or mutated MWFE accelerate cell growth (Yadava N et al J Biol Chem 2002;277:21221–21230). Illustration: p53 protein reacts with its target DNA. Cho et al Science 1994;265:346. Springer ML et al Genes Dev 1992;6:346–355.

Figure 65. Aberrant Mitoses lead to Aneuploidy. The consequences may be apoptotic cell death, autophagy, or malignant transformation. Illustration: Kops GJPL, Weaver BAA, Cleveland DW. Nature Reviews Cancer 2005;5:773–786.

Figure 66. Pettenkoferien. Hugo von Preisz, professor & chairman of the Institute of Bacteriology at the Péter Pázmány University in Budapest, Hungary devoted two decades for the study to the phenomenon of “Pettenkoferien”, that was ﬁrst observed by Ph. Kuhn and K. Sternberg. He then published a lavishly illustrated monumental article on his studies in 1937 in the Zentralblatt für Bakteriologie (Erste Abteilung / Originale Juli 12 1937; Band 139, Heft 5/6 Seiten 225–268 mit XIII Tafeln; Verlag von Gustav Fischer in Jena). What he believed he was observing was not a symbiotic relationship between bacteria and a protozoal parasite, the imaginary Pettenkoferia. It was the response of the bacterial genome to an attack by low dose LiCl put in the media. The living matter responded with the creation of an inexhaustible variety of morpho-biochemical life forms from “punktförmige Körperchen mit Wachstum”, “größere Keimlinge”, and the most spectacular “Riesenformen”. For this author, what Professor Preisz viewed with astonishment was the ancient scenario of primordial spheroplasts surviving “at the edge” in the hostile environment of the ancient Earth, as replayed in his culture vessels (Table XIV). 642 Appendix 2 Explanations to the Figures*)

Figure 67. Vascular Mimicry. Tumor cells recruit host vascular endothelial cells in the form of primitive blood vessels by secreting the VEGFs to be captured by VEGF-Rs on the neighboring endothelial cells. Tumor-friendly M2 Mϕs may be producing the VEGFs. The bone marrow upon receiving appropriate signals from tumor cells releases immature vascular endothelial cells, which travel to the tumor bed and line up into vascular channels. Certain tumor cells are able to genetically transspeciate themselves into vascular endothelial-like cells, which form primitive channels, that can circulate blood into the tumor bed. Gene activations and silencing include EphA2 receptors, cadherin VE, focal adhesion kinase (FAK), extracellular regulated kinase ERK1/2, and PI3K (Döme et al Am J Pathol 2007;170:1–15; Hess AR et al Dev Dyn 2007;236:3283–3296; Sharma N et al Prostate 2002;50:189–201). Uveal melanoma cells in the process of transformation into vasculogenic morphology, expressed the stem cell marker CD271 (NGFR, p45NTR nerve growth factor neurotrophin receptor) (Valyi-Nagy K et al Mol Vis 2012;18:588–592). In the placenta of the fetus, syncytiotrophoblasts are known to transspeciate themselves into artery-like blood vessels. In choriocarcinoma, an abundance of endotheial cell-like syncytiotrophoblasts provide the tumor’s major blood supply (Shih I-M Mod Pathol 2011;24:646–652). Illustration: Uveal melanoma cells in culture display vasculogenic mimicry pattern and express CD271 (shown in Fig 2 of the cited article) (Valyi-Nagy K et al Mol Vis 2012;18:588–592)

Figure 68. Autophagy. Under lymphocyte attack, human sarcoma cells extensively vacuolized their cytoplasm, but remained metabolically alive. These unusual cells were viewed and photographed in the late 1960s. Then the phenomenon of autophagy was not recognized as such. Some sort of tumor cell dormancy was considered (Sinkovics JG J Med edited by Julian Ambrus Sr 1970;1:15–25; 313– 326; reproduced in Sinkovics JG “Cytolytic Immune Lymphocytes…” Schenk Buchverlag, Passau/Budapest, 2008) (147).

Figure 69. Neuroblastoma (NB). Undifferentiated high grade tumor cells (showing ganglioneuromatous features; or rosette-formation elsewhere) are shown. The tumor cells express chromogranin, synaptophysin, vimentin, neurofilament and neuron-specific enolase. In the genome there is N-myc amplification; deletion of subtelomeric region at 1p36.33; low expression of maturation factor TrkA (tropomyosin receptor kinase). In sporadic (not the familial) NB tumors the NBPF gene (neuroblastoma breakpoint-family member) undergoes copy number variations in 1q21.1 deletion, or in 1q21.1 duplication. The entire NBPF gene underwent duplication during primate evolution. A human endogenous retroviral LTR has been inserted in one of the introns of the NBPF3 gene. On occasion, gene NBPF1 fuses with gene ACCN: t(1;17)(p36.2;q11.2) (ACCN = ASIC, acid sensing proton-gated ion channel) (Diskin SJ et al Nature 2009;459:987–991; Vandepoele K et al Mol Biol Evol 2005;22:2265–2274; PLoS One 3(5):e2207; Virology 2007;362:1–5). The LMO1 gene is duplicated. The homeobox LMO proteins (LIM Only) (Table XVI) are evolutionarily conserved (schistosoma; caenorhabditis; drosophila). LMO2 is a human leukemia oncogene/oncoprotein (El Appendix 2 Explanations to the Figures*) 643

Omari K Blood 2001;117:2145–2154; Matthews JM et al Nat Rev Cancer 2013;13: 111–122; Smith S et al PLoS One 9(1):e85883). The amoeba and the amoeboid cancer cells use LIM domain proteins for their locomotion (Guetta D et al PLoS One 2010;5(12):e15249). Additional information in the Appendix 1.

Figure 70. Pediatric Rhabdomyosarcoma of the orbit in the 1960s at M.D. Anderson Hospital’s Sarcoma Service (Author’s material). Treated with surgery (enucleation; orbital exenteration), radiotherapy and chemotherapy (actinomycin D, cyclophosphamide, vincristine); later, doxorubicin (Adriamycin), ifosfamide (Ifex), with prolongation of life with without cure. One eye lost, life saved in the 2010s. Intergroup Rhabdomyosarcoma Study Group / Children’s Oncology Group report: sarcoma-free survival 92% at median 7 years; survival 82% at 5 years after relapse from remission(s) (Ranet B Pediatric Blood Cancer 2013;60:371–376). For relapses intensive chemoradiotherapy is recommended still with “curative intent”. Late general health adverse side effects of chemoradiotherapy are signiﬁcant (Hudson MM et al JAMA 2013;309:2371–81; Hofman MC et al J Clin Oncol 2013;31:2799–2805; St. Jude’s Pediatric Oncology Hospital annual reports). Possible targeted epigenetic therapy emerges. The BMP2 (bone morphogenetic protein) promoter is silenced, especially in a-rhabdomyosarcoma. Demethylation by 5-Aza-2'-deoxycytidine (Decitabine) released BMP production with reduced viability of rhabdomyosarcoma cells resulting (Wolf S et al Int J Oncol 2014 Feb 27. doi:10.3892/ijo.2014/2312). Osteo-, rhabdomyo-, and Ewing-sarcoma cells treated with 5-Aza-2'dc overexpressed their MHC and NY-ESO-1 antigens (MAGE-A1/3) and become susceptible to the hosts’ cytotoxic immune T lymphocytes (Krishnadas DK et al Tumour Biol 2014;35:5753–5762). Sirtuin (silent information regulators) histone deacetylases and ADP-ribosyl transferases prolong cellular life and are highly upregulated in synovial and rhabdomyosarcoma cells (and in several other malignantly transformed, such as leukemia and glioblastoma, cells). Tenovin-6- and anti-Sirt siRNA-treated sarcoma cells ceased proliferating due to increased levels of cell cycle inhibitors, inhibited autophagic ﬂux, and restored p53-mediated apoptosis, but did not interact with the fusion oncoprotein FOXO/PAX (Ma L et al Cell Death Dis 2014;5(10):e1483). For cytotoxicity of NK and immune T lymphocytes to autologous sarcoma cells discovered in the late 1960s, see Sinkovics JG “Cytolytic Immune Lymphocytes…” 2008 Schenk Buchverlag, Passau/Budapest. Illustration: Sinkovics JG, Pp 417–488 in Monograph on Recent Trends in Cancer Chemotherapy. JR Chowdhury S Mitra. Chittaranjan National Cancer Research Centre, Calcutta, India. Terese Winslow. All rights reserved.

Figure 71. The Cancer Stem Cell is a mutated normal progenitor cell, or stem cell. The mutation constitutively turns on the stem cell genes (FAK, Nanog, c-Myc, Oct, Sox, Kﬂ, etc) (Table IX). The mutated stem cell will not differentiate. It may stop its asymmetric divisions (a self renewed stem cell, and a differentiating somatic daughter cell), and instead produces two undifferentiated stem cells. It has reactivated the genetically encoded ancient “cell survival pathways”, which have been encoded by proto-oncogenes. The process is dominated by the constitutive 644 Appendix 2 Explanations to the Figures*) expression of faculties for resistance to apoptosis, and to chemical and radiation exposure. The transforming cell assumes the locomotion of an amoeba by remodeling its cytoskeleton in the process of epithelial-to-mesenchymal transition. It hides its MHC-expressed antigens like a parasitic unicellular pathogen (Entamoeba, Giardia; Trichomonas; Naegleria; Plasmodia; Theileria; Trypanosoma; Neurospora; Phytophthora). It demands blood supply like a syncytiotrophoblast by inducing host ﬁbroblasts and macrophages for its exocrine supply; or trans-speciates itself in imitating vascular endothelial cells in lining up into a primitive tubular structure with red blood cells inside (vasculogenic mimicry). Mutated cancer stem cells were generated in therapeutically γ-irradiated human breast cancer tissue. No indication for abandoning cancer radiotherapy (Pajonk F Dept Radiology Oncology David Geffen School of Medicine University of California Los Angeles CA). Terese Winslow. All rights reserved.

Figure 72. A Murine Hybridoma. In the 1960s at the Section of Clinical Tumor Virology & Immunology of The University of Texas M.D. Anderson Hospital, the leukemogenic retrovirus-producer murine lymphoma cell line #620 was maintained by cell passages in vivo and in tissue cultures in vitro. In the mid-1960s in the in vitro cultures large round lymphoid cells appeared spontaneously and grew in suspension cultures (cell line #818). The large round cells were tetra-, or polyploid. In mice these cells grew in large haemorrhagic ascitic and invasive lymphomas. It was determined that these large round cells were the fusion products of the diploid #620 cells and normal plasma cells, which secreted immunoglobulins specific to the retroviral particles budding from the surface of #620 cells. In the fusion product #818 cell, its immune plasma cell component secreted the immunoglobulins, which neutralized the retrovirus released from the #620 cells (Sinkovics JG et al In: Leukemia-Lymphoma. YearBook Medical Publisher 1970; pp 53–92; J Inf Dis 1969;119:19–38; Lancet 1970;1:139–140; Cancer Res 1981;41:1246–1247; Rev Inf Dis 1983;5:9–34; Bull Mol Med 2005;26:61–80; Acta Microbiol Immunol Hung 2005;52:1–40). The virus-neutralizing antibodies were precipitated by Roman Pienta, who also confirmed the validity of the virus neutralization experiments (M.D. Anderson Hospital Research Report, vide infra). Eiichi Shirato found these antibodies weakly effective in inhibiting the growth of #620 cells (Shirato E et al Oncology 1972;26:80–86). The tetra- or polyploid #818 cells formed a permanent suspension culture cell line in vitro, which was maintained in the Author’s Lab and also by M.D. Anderson’s chief pathologist Jose Trujillo (Cancer Res 1970;30:540–545). Macrophages attacked and lysed the antibody-coated tetra- or polyploid #818 cells, thus portraying the “starry sky” phenomenon (Butler J et al Am J Pathol 1967;51:629–637; Sinkovics JG et al J Inf Dis 1969;120:250–254). The actual fusion of #620 diploid lymphoma cells with antibody-secreting immune plasma cells could be reproduced in the peritoneal cavity of mice inoculated sep- arately but simultaneously with #620 lymphoma cells and immune plasma cells (see Illustration). This was independently confirmed by H. David Kay (Research Report of M.D. Anderson Hospital 1970; pp 331–336; 1972; pp 473–476; 1974 pp 447– 455). Milton Wainwright (University Sheffield, Sheffield, UK) after interviewing H. Appendix 2 Explanations to the Figures*) 645

D. Kay, Jose Trujillo and this author (JGS), studying laboratory note books, and contemporary laboratory photographs, declared that the first natural hybridoma and the hybridoma principle (continuous antibody secretion by immune plasma cells fused with lymphoma cells) was discovered by J.G. Sinkovics and first presented in lectures in 1969 (Wainright M Perspect Biol Med 1992;35:372–379). Similar credit Sinkovics received from plenary session speaker M. D. Scharff at the 18th Annual Conference of the Infectious Diseases Society of America in 1980 in New Orleans (Yelton DE & Scharff MD Annu Rev Biochem 1981;50:657–680), and through the invitation of Jerome Vaeth for a comprehensive presentation on natural hybridomas at the 24th San Francisco Cancer Symposium (Sinkovics JG Front Rad Ther Oncol “The earliest concept of the hybridoma principle…” 1990;24:18–31.*) *) The editors of the Cancer Research accepted documentation of the discovery and existence of a murine natural hybridoma in 1960–70s (Sinkovics JG Cancer Research 1981;41:1296–1. The Iuliu Haţieganu University of Cluj Napoca (Kolozsvár) Romania gave Sinkovics the “Out-Nobel Award, 2005” for the discovery of the first “natural hybridoma” in the mid-1960s (Bull Mol Med 2005;26:61–80). In ten years of its availability in culture, neither Sinkovics nor Trujillo have ever received a request for the #620/#818 cell lines for independent studies, and the work with these cell lines was not cited in the literature.

Figure 73. Combined Chemoimmunotherapy. The first report on this initially discouraged modality of treatment for metastatic sarcomas was generated at the Department of Medicine, The University of Texas M.D. Anderson Hospital, as first reported by Sinkovics JG, Plager C, Romero J, in Neoplasm Immunity: Solid Tumor Therapy. A University of Chicago Symposium, February 24/25 1977. Crispen RG editor. Franklin Institute Press, Philadelphia Pp 211–219, 1977 (Library of Congress Catalog Card Number 77-777-79. International Standard Book Number 0-89168-000-4). This article is cited in Sinkovics JG & Horvath JC Internat J Oncol 2006;29:765–777. Patients (odd numbers reporting for treatment) in the third group receiving cyclophosphamide/doxorubicin-based chemotherapy, BCG and viral oncolysate (VO) immunotherapy were directly compared with patients in the second group (even numbers reporting for treatment) receiving identical chemotherapy with BCG (without VO). Patients in the first group received standard cyclophosphamide/doxorubicin-based chemotherapy only (no VO; no BCG) at the same Institution preceding and during the administration of the chemoimmunotherapy protocol to the alternatingly registered patients of the second and third groups (cohorts). Patients in the first group could be considered to be contemporaneous historical controls of the second and third groups of patients. This clinical trial was supported by private donations raised by the Head of the Department of Medicine, Clifton Dexter Howe, who supervised/supported this clinical trial. C D Howe originally intended the publication of this clinical trial in the N Engl J Med with his co-authorship. The first author (JGS) was discouraged: for a clinical trial not supported and funded by the NCI, he expected adverse criticism and humiliating rejection. A preliminary presentation in the volume of a distinguished Chicago conference was a guarantee for a publication. That 646 Appendix 2 Explanations to the Figures*) publication could have served as a platform for a NCI-approved second randomized clinical trial. C D Howe agreed; he did not oppose the presentation of the material at the Chicago symposium, reserved his co-authorship and offered his support in a NCI-approved future randomized clinical trial, but declined his co-authorship for the current publication as a book chapter. The patients enlisted in this clinical trial were co-attended by assistant internist-medical oncologist Nicholas Papadopoulos.

Figure 74. The Front Cover of the Volume containing the presentations given at the 14th Annual Clinical Conference on Cancer in 1969 at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Texas. The illustration was taken from the printed presentation entitled Relationship between Lymphoid Neoplasms and Immunologic Functions, by J.G. Sinkovics, E. Shirato, F. Gyorkey, J.R. Cabiness and C.D. Howe, Pp 53–92 (278). This article contains the ﬁrst view of a murine natural hybridoma and the ﬁrst photographs of human large granular lymphoid cells (later: NK cells) attacking human tumor cells. Published by Year Book Medical Publishers, Inc, Chicago, 1970 (Library of Congress Catalog Card Number 74–119578. International Standard Book Number 0-8151-0207-0). Cited in Sinkovics JG Bulletin Molecular Medicine 2005;26:61–80; Sinkovics JG Cytolytic Immune Lymphocytes.Schenk BuchVerlag, Passau/Budapest, 2008. View similar illustration of hybridoma formation on the cover of the volume “The 24th San Francisco Cancer Symposium” (cited in Figure 71). *) *) The Author’s two invited presentations at The San Francisco Cancer Symposia were 1, on cytotoxic large granular human lymphocytes; and 2, on natural hybridomas (Front Rad Therap Oncol 1972;7:141–154; 1990;24:18–31).

Figure 75. Of the Staff, Department of Medicine, The University of Texas M.D. Anderson Hospital and Tumor Institute, mid-1970s. From left to right, Sebron Culpepper Dale, associate internist, internal medicine, staff health care. Clifton Dexter Howe, board-certified internist, professor of medicine, medical oncologist, Head, Department of Medicine. Joseph Géza Sinkovics, professor of medicine; board-certified specialist in clinical pathology, laboratory medical virology, public health, internal medicine, infectious diseases, and medical oncology; medical oncologist, board eligible hematologist; Chief, Section (Laboratories) Clinical Tumor Virology & Immunology; Chief, Melanoma/Sarcoma Clinics and in-Patient Services. C. Charles Shullenberger, professor of medicine, Mayo Clinics-trained board-certified internist, hematologist; Chief, Section of Hematology (Laboratories; Clinics; in-Patient Services). References

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Note: Page numbers followed by f and t indicate ﬁgures and tables, respectively

A Activation-induced deaminases (AIDs), 309 Abalone herpesvirus (AbHV-1), 239, 586 Acute myeloid leukemia (AML), 134, 431 ABC ATPase SMC superfamily proteins, 248 Acute promyelocytic leukemia, 248–250 Acanthamoeba castellani, 392 Acyrthosiphon pisum, point mutations, 177 Achaete-scute, 383–386 Adaptive immunity, 105–109 complex (AS-C), 385 genomics of, insertions of evolution of, 507t ancient retrovirus and pre-EBV helix-loop-helix proteins, 553, 555 herpesvirus, cooperation of, homolog (ASH), 379 231–235 oncogenesis, 507–508t Epstein-Barr virus, 235–238, 236f Achole, 41–42 Harbingers, 242–245, 243f Acholeplasma, 40, 41–42 paleogenomics, 238–242 viruses, 42–44, 42f, 43f self-assembly, elements of, 111–120 Acholeplasma axanthum (A. axanthum), 41 unreliable enzymes of, 308–310 Acholeplasma granularum (A. granularum), 41 Adenomatous polyposis coli (APC), 79, 81 Acholeplasma laidlawii (A. laidlawii), 42 Adenovirus, 247 Entner-Doudoroff carbohydrate metabolism and YY proteins, 133–134 of, 41 Adipose tissue-derived stromal cells, 223 life cycle of, 40f A-DNA, 1, 2 transmission electron microscopy of, 40f Adoptive immune T lymphocyte, 447–451 viruses, 38, 42–44, 42f, 43f, 46, 47 Aeropyrum pernix, primordial fused genes, 157 Acholeplasma pyrophylus (A. pyrophylus), 38, Afrotheria, 138 41 Aggregatibacter actinomycetemcomitans (A. Acidithiobacillus thiooxidans, 5 actinomycetemcomitans), 308 Acquired immunodeﬁciency syndrome Agnatha (AIDS), 512t, 547 adaptive immune system without immune APOBEC-mediated protection, 209 globulins, 108–109, 108f HIV-induced, 208 microRNAs, 106–108 -related KS, 190 stepwise diversiﬁcation, 105–106, 106f, virus, 112 107f Activation-induced cytidine deaminase, 25–26, Agrobacterial oncogenesis, 522t 108–109, 108f Agrobacterium, T-DNA transfer and, 2 ancient genes of, 202–204 Agrobacterium tumefaciens, 500t -induced dsDNA breaks and translocations, Aiptasia pallida, 232 114–115, 116t, 117t AKNA factor, 355–356 lymphoma and, 112–114 Akt pathway, 68 non-Ig genes targeted by, 112–114 Aldehyde dehydrogenases (ALDH), 333, 334, as potential activator of oncogenes, 204 385

Allogeneic hematopoietic stem cell APOBEC (apolipoprotein B-editing enzyme transplantation, 448 catalytic), 10, 36, 25–26, 207–209, Alloherpesviridae, 239, 240 413, 474 All trans-retinoic acid (ATRA), and ancient genes of, 202–204 neuroblastoma, 360 APOBEC-1, 209 Alvinella pompejana, 392 as potential activator of oncogenes, 204 Amino acids (aa), 3, 41, 74 Apoptosis aromatic, 502t by DNA fragmentation, 233 coexistence before cells, 31–33 induced, 352, 369 hydrophobic, 168, 189, 502t Apoptosis-prone transformed cells, 350 xenopus type III IFN, 93 Apoptosis-stimulating proteins (ASPP), 342 Aminopterin-methotrexate (MTX), 452 and gestational choriocarcinoma, 402 Amoebae, 62–64 Apoptotic protease-activating factor (APAF), phagocytose bacteria, for nourishment, 63 322 tumor cells, transformation of Aquifex aeolicus (A. aeolicus), 5, 38, 57, 76 fusion, 483–485 primordial fused genes, 164 invasion, 483–485 Aquiﬁcales, 41 locomotion, 483–485 Arabidopsis thaliana, 496 phagocytosis, 483–485 G4 DNA motifs, 129 Amoeba histolytica (A. histolytica), 64f Arachnida, 320 Amoebozoan Dictyostelium, 8, 9 Archaea, 35–36, 76–89 Amphidinium carterae, 257–258 horizontal-transfer gene network, 47f AmphiGILT, 91t Archaeoglobus fulgidus, 57, 76, 505t Amphimedon queenslandica (A. Okazaki fragments, 381 queenslandica), 70t, 350, 380, 599 Archaeopteryx, 8 Amphioxus tsingtauense, 273 Archaeopteryx lithographica (A. Anaplastic lymphoma, 362–364 lithographica), 326 of mature T cells, 518t Argatroban, for neuroblastoma, 359 Anaplastic lymphoma kinase (Alk), 146, 431, Argonautes (AGO), 56–59, 57f, 65–75 432, 556 donors of, 76–89 Ancient Earth RNA-induced slicing complex (RISC), 57, biomolecules on, 32 57f primordial genes conserved as stem cell Armillaria bulbosa, 129 genes/proto-oncogenes, 31–34 Armillaria ostoyae, 129 Aneuploidy, 299–301, 300f, 436, 553 Artemia salina, 384 genetic instability and, 501t Arthrobacter luteus, 218, 470 AngHV1, 240 ASCL1, 385, 508t Angioneogenesis, 312t Ash genes, 16, 358, 507t, 561, 562, 581 Angiosarcomas, 189–190 Aspergillus nidulans, 263 Anguilla japonica, 241 Aspergillus niger, 260 Ansamycin/allylamino-17-demethoxy- Atavistic endotoxin, 492 geldanamycin (17-AAG), 506t Atavistic metamorphosis, 493 Anthozoa, 77 Ataxia telangiectasia mutated (ATM) proteins, Anti-apoptosis, 341–344 113 Antigen-presenting cells (APCs), 235 Ateles paniscus, 471 Anti-p53 MDM, 344–345 Ath5 gene, 81 Apaf-1 (apoptotic protease-activating factor-1), Atorvastatin, 441 368 ATP-binding cassette (ABC) proteins, 14, 22 Aphidicolin, 253 Aurora-kinase oncogenesis, 252, 299–300 Index 799

Autophagy, 351–353, 351f introns, 262 Aves, 8 Bombyx mori (B. mori), 321–322, 324 AVRblb2 protein, 163 achaete-scute, 383–384, 385 Axinib (Inlyta, Pfizer), 455 Bone morphogenetic protein (BMP), 172 Axitinib (Sutent; Inlyta, Pfizer), 455 Bortezomib, 453 Axl gene Bosutinib (Pfizer), 452 chromosomal localization of, 182 Botryllus, 106, 107f, 342 Gas6-driven, 184 Botryllus schlosseri (B. schlosseri), 106, 411 Axons, 20 BRAF oncoproteins, 173, 174f, 556 Brain-derived neurotrophic factor (BDNF), 294 B Branchiostoma, 112 Babesia, 512t Branchiostoma belcheri (B. belcheri), 212t, primordial fused genes, 165 273 Bacillaceae, 40 Branchiostoma floridae (B. floridae), 7, 77, Bacillus, 113, 132 177, 212t, 238, 273, 288, 314, 384 Bacillus anthracis (B. anthracis), introns, 260 Branchiostoma mediterranean (B. Bacillus subtilis (B. subtilis), 248 mediterranean), 212t introns, 260 Branchiostoma tsingtauense (B. tsingtauense), Bacteriophages, 45f 212t, 273 Bacteroides, enterotoxigenic, 11 Brassicaceae, 387 Bacteroides fragilis, 120 BRCA1, 196 -induced colonic adenocarcinomas, 311 BRCA2, 172, 196 primordial fused genes, 157 Breast carcinoma (BC), 428t Balanced chromosomal rearrangement, 10–11 Breast tumor-initiating cells (BTIC), 80 Bax (Bcl-2-associated X protein), 146 Bromodomain (BRD) genes, 170–171 B-cell lymphocytes, 204 Brugia malayi, 213t receptors, 21 Bruton tyrosine kinase (BTK), 21, 22, 452–453 B-cell lymphoblastic leukemia, 448 BTG3 gene, 294–295 B-cell lymphomas, 509t, 518t Burkitt's lymphoma (BL), 113, 152, 160, 237, biotherapy for, 520–521t 309, 430, 459 diffuse large (DLBCL), 310 bcl-2 and, 358, 420 BCG (Bacille Calmette-Guerin), 527, 528, 532, c-myc in, 115, 202, 588 537 EBV in, 132, 224 Bcl-2, 10, 26, 94, 250, 278, 279, 310, 337, 398, translocation, 159 420 and Burkitt's lymphoma, 358 C and follicular lymphoma, 358 Cadherins/catenins, 503–504t and neuroblastomas, 359 E-cadherin, 191, 337, 339, 340 and rhabdomyosarcoma, 368–370 N-cadherin, 337 Bcl-6, 203, 275, 310, 418 Caenorhabditis Bdelloidea, 124 activated oncogenes in, 82f B-DNA, 2 aging, health care of, 86–87 Beauveria bassiana, 306 hypoglycemic, 144–145 Benzimidazole, 17 Caenorhabditis elegans (C. elegans), 81–82, β-catenin, 79–81, 191–192 85–86 destroyer complex, 81 anti–apoptosis, 341, 344 HMG proteins, 213–214t Lag-1 in, 87 in ontogenesis, 11, 12 Caldiarchaeum, 292 Bet proteins, 204–205 Cancer cell cytoplasm, 334–356 Bevacizumab anti-neoangiogenesis therapy, AKNA, 355–356 335–336, 358, 395 anti-apoptosis, 341–344 Biomolecules, on ancient Earth, 32 anti-p53 MDM, 344–345 bmi-1 gene, 222 apoptosis-prone transformed cells, 350 Bodo saltans, 301 autophagy, 351–353, 351f 800 Index

Cancer cell cytoplasm (cont.) Chimeric antigen receptor (CAR), 318 epithelial-to-mesenchymal transition, Chlamydia psittaci-induced periorbital 336–341 lymphomas, 311 navitoclax, 350–351 Chlamydomonas oncogenic fusion oncoproteins, cellular MCD4 gene, ancestry, 437 viability and, 353–355 primordial fused genes, 158 oyster leukemia, 349–350 Chlamydomonas moewusii (C. moewusii), 268 vasculogenic mimicry, 334–336, 336f Chlamydomonas reinhardtii (C. reinhardtii), Cancer cell nucleus, 333–334 59, 76, 498 Cancer stem cells, 192t. See also Stem cells asymmetrical cell divisions, 329 ontogenesis, reversal of, 414t introns, 293 Candida, 7 morphological metamorphoses, 319 Candida albicans, 258, 260, 408, 505t primordial fused genes, 164, 213t Capsaspora owczarzaki, 497 zeste of, 485–486 Carbohydrate metabolism, 41, 124 Chlorocebus aethiops, 204 in archaic cell communities, 152–156 Chloroplasts, 51–54, 54f Warburg-type, 151–152 Choanoflagellates, 7, 77, 127–128, 392–395 Carcinoma cells, introns in, 280–283 Choanozoa, 77 Cavimorpha, 138 Chondrichtyes, 250 CCAAT enhancer-binding protein-ß (C-EBP), Choriocarcinoma, gestational, 401–404 60 Choriomeningitis virus (CMV) infections, 417 CEACAM (carcinoembryonic antigen-related Chromalveolate, 76 cell adhesion molecule), 280–281 Chronic lymphocytic leukemia (CLL), 22 Cell cannibalism, 395, 554 Chronic myelogenous leukemia (CML) Cell death. See Apoptosis imatinib mesylate for, 115 Cell rescue, 425–427 Philadelphia chromosome in, 165–166 Cell survival pathways, 74, 425, 494, Ciona, 79, 112, 244 502–504t, 553 Ciona intestinalis (C. intestinalis), 89, 499 ancient, 7, 16, 21–23, 25 adaptive immunity, 241 PI3K, 15, 125 and Ewing sarcoma, 174 primordial, 56 introns, 274 of unicellular life forms, 201–202 response to sugar intake, 143 Cellular like forms Circular RNA (circRNA), 2, 523t embedded doctrines of, 410–411 Circulating tumor cells, release of, 434–435 retro(lenti)- and herpesviruses, criminal Cisplatin, for hepatoblastoma, 401 collusion of, 411–413 13-Cis-retinoic acid (CRA), and retrospective glance of, 407–410 neuroblastoma, 360 Cellular RNA/DNA, 181–183 Cleft lip and palate (CL/P), faults in complex Cercopithecus aethiops, 204 pathways, 514–515t Cerebral cortex, human, 19–21 Clostridium innocuum (C. innocuum), 41 Chagraff rule, 3 Clostridium ramosum (C. ramosum), 41 CHARGE syndrome, 244 Clustered regularly interspersed short Chemobrain syndrome, 528 palindromic repeat (CRISPR), 64, Chemokines, 36, 509t 308, 408 Chemotherapy, 527–530 -associated complex for antiviral defense combination, 531 (CASCADE), 45, 55 Chemotons, 31, 32 -associated genes (CAS), 45, 46f, 55 Childhood first antiviral defense, 55–56 anaplastic lymphoma, 362–364 pathway, 36 lymphomas/leukemias, 518–519t primordial faculties, preservation of, 56 neuroblastomas, 358–362 Clytia hemisphaerica, 394 rhabdomyosarcoma, 364–368, 365f c-MET (hepatocyte growth factor receptor), 13 Index 801 c-myc, 10, 17, 26, 60, 250, 310, 358, 398, 496 Decitabine, for rhabdomyosarcoma, 372 Cnidaria, 77, 78f Deinococcus radiodurans (D. radiodurans), Coelacanth, 8 17, 121, 248, 426 Coelenterata, 77 primordial fused genes, 157 Coelomocytes, 106f radiation-resistant, 6 Coiled coil, nucleotide-binding, leucine rich Deleted in liver cancer-1 (DLC-1), 459. repeat (CC-NB-LRR) proteins, 163 See also GTPase-activating protein Colon cancer, staging in, 11, 12 Delta-like ligand 1 (DLL1), and gestational Colony stimulating factor-1 receptor (CSF1R), choriocarcinoma, 402 155 Dendritic cells (DCs), 235 Computer biologists, 414–416 intron changes in, 286–287 Conatumumab, for rhabdomyosarcoma, 369 plasmacytoid, 97 Conditionally replicating adenoviruses sarcoma, 71t, 419 (CRAd), 101–102 vaccines, 443 Confuciusornis sanctus, 321 DENN proteins, 407 Consummate bioengineer, 26–28 2-Deoxy-D-glucose (2DG), 155 Copidosoma floridanum, 323 -induced aRMS cell death, 376 CpG islands, 309 Desmoplastic small round cell tumor Crenarchaea, 38 (DSRCT), 431 fuselloviruses, 44–45, 46 Dick-1, 79 Crenarchaeota, 251 Dickkopf (DKK) genes, 78, 79, 385–386 CRISP3 gene, 171 Dictyostelium, 253 Cryptococcus neoformans Amoebozoan Dictyostelium, 8, 9f introns, 268 metamorphosis bordering trans-speciation primordial fused genes, 158 in, 7 Cryptosporidia, 126t Dictyostelium discoideum (D. discoideum), 62, primordial fused genes, 165 392, 408, 496 CtBorDx (cyclophosphamide, bortezomib, carbohydrate metabolism, 152 dexamethasone), 452 introns, 261, 268, 292 Cyanidoschyzon, primordial fused genes, 158 oncogenic fusion oncoproteins, 353 Cyanophycea, 77 primordial fused genes, 160 Cybertoxicity, 73f Diplonema papillatum, primordial fused genes, Cyclic AMP-responsive element-binding 164 protein and modulator (CREM), DJ-1 protein, 211, 213–214 172–173 DJ-1/ThiJ/Pfpl protein superfamily, 217t Cyclophosphamide (Cytoxan), 451 DNA for metastatic neuroblastoma, 373 A-DNA, 1, 2 Cyclostomata (lamprey), 105, 178 B-DNA, 2 CyHV3, 240 break repair, inhibiting, 196t, 198 Cysteine-rich protein (CRP) LIM kinase, 367t cellular, 181–183 Cytokine-induced killer (CIK) cells, 370 dsDNA, 114–115, 116t, 117t, 195, 196t Cytokines, 97–98 mitochondrial, 516–517t oncogenes, release of, 434–435 D propellers, 122–125 Dabrafenib (Tafinlar, GlaxoSmithKline), 455 replication, 256 daf (decay accelerating factor) gene, 87 retrotransposon-derived, 26 Danio rerio , 91t, 314, 382. See also Zebrafish sliding clamp, 251–256 Daphnia pulex, 265, 266, 288 translesional synthesis, 194, 195 Dasatinib (Sprycel, BristolMyersSquibb), 452, X ray diffraction of, 1, 2 489 Z-DNA, 1 interaction with immune lymphocytes, 490t DNA methyltransferases (DNMT), 415 DCAF12 gene, 272 (cytosine-5-) methyltransferase 1 (DNMT- DCAMKL (Double-Cortin and Calmodulin 1), 140 Kinase-like), 89–90 Double agent enzymes, 194–195 802 Index

Doublecortin (DCX), 90 Enzalutamide (Xtandi, Astellas), 455 Down syndrome, HMG proteins and, 215t Ephidius ervi, 324 Doxorubicin Ephydatia fluviatilis, 392 for hepatoblastoma, 401 Epidermal growth factor receptors (EGF-R), for metastatic neuroblastoma, 373 13, 430 drh (Dicer-related helicase) genes, 86 Epigenomics Drosophila, 76–89, 112 elementary, 291–297 hypoglycemic, 144–145 germ line, sanctity of, 294–297 JAK mutation in, 95–96 restless, 291–294 longevity assurance gene, 87–88, 88f Epithelial-to-mesenchymal transition, 13, triangle between YP, Piwi and Hh, 67 336–341, 398, 434 zeste of, 485 EPIYA (glutamic acid-proline-isoleucine- Drosophila melanogaster, 322 tyronine-alanine) motif, 157 achaete-scute, 383 Eps15 (EGFR epidermal growth factor receptor anti-apoptosis, 341 pathway substrate), 148 Drosophilalet-7, 83 Epstein-Barr virus (EBV) dsDNA adaptive immune system, 309 breaks and translocations, AID-induced, human, 60, 62, 80t 114–115, 116t, 117t retroviruses, 224–225 repair, 195, 196t transposable and signal sequences, Dunaliella, 253 235–238, 236f and YY proteins, 131–133 E ERK/MAPK, 144 EBNALP, 225 Erlotinib (Tarceva, Genentech), 454 E-cadherin, 191, 337, 339, 340 Erythropoietins (EPO), 312, 430, 508t Ecklonia cava, Ki-67 and, 382 miR-17-92, 221 Ecteinascidia turbinata, 72t receptor, 430 Ecteinascidins (Trabectedin, Yondelis), 72t, in JAK2 activation, 270 454 Escherichia coli (E. coli), 248, 499 Edwardsiella, 233 bacteriophage-infected cosmid library, 182 EFCAB6 gene, 210, 211 extracellular ribosomes, 3 EHBP-1 (Eps homology domain binding G4 DNA motifs, 129 protein), 148 primordial fused genes, 157 Ehrlichia, carbohydrate metabolism, 153 ribosomal RNA synthesis in, 304 Endogenous oncogenesis, 420–422 spheroplasts of, 38 Endogenous retroviruses, 150f ETS (erythroblast transformation-specific; E- interaction twenty-six) domain protein, 172 in mTOR pathway, 149–151 Eubacteria, 35 with Rab proteins, 149–151 Eukaryotes, 35–36, 38–49 Kaposi sarcoma, 61f balancing acts, 122–130, 123f, 126–127t, as oncogene activators, 468–474 128f reactivation, 434–435 Crenarchaea, division, 38 RNA/DNA complex, 387–390 horizontal-transfer gene network, 47f Endosomal sorting complex required for primordial fused genes, 157–160, 161f transport of endocytic cargo recreation of, 45–49 (ESCRT), 147 response to sugar intake, 143–144 Endotoxin septic shock, 492 spheroplasts, 38 Entamoeba histolytica (E. histolytica), 74, 124, tree of living organisms, 48f 392 unicellular, primordial resistance of, 121 carbohydrate metabolism, 153 Euryarchaeota, 251 introns, 260 Everolimus (Afinitor, Novartis), 455 primordial fused genes, 164 Ewing's sarcoma, 71t Index 803

ATF/CREB oncogenes in, 174 Gastrointestinal stromal tumors (GIST), 68 -ATF1, 172–173 Geﬁtinib (Iressa, Astra Zeneca), 454 oncogenes, 169–170, 170f Gene fusions, 23–24 Excavata, 76 Genitourinary (GU) tract Exogenous oncogenesis, 420–422 infections in, 421 retroviral genes in, 476–477 F viral-induced carcinoma, 420 FARP1 gene, 270 Genomic chaos. See Aneuploidy Fas-associated death domain (FADD), 368 Genomic imprinting Fasciola gigantica, 211 living fossils, 137–138 FasL-induced mitosis, 174–175, 176f retroviral inheritance, 216–217 Felis cattus endogenous retrovirus (FcEV), 469 Gestational choriocarcinoma, 401–404 Ferroplasma acidarmanus, 17, 121 Giardia, 58–59 FGF-R1/TACC proteins, 283 introns, 258 Fibroblast growth factors (FGF), 430 PI3K pathway in, 7 5-Fluorouracil (5-FU), 452 Giardia intestinalis, 76, 124 for hepatoblastoma, 401 Giardia lamblia (G. lamblia), 258, 260 fmr (fragile mental retardation) gene, 167 Glossina, 262 Foamy spumaviruses, 207 Glucose dehydrogenase (GDH). See H6PD Focal adhesion kinase (FAK), 427 Glucose-6-phosphate dehydrogenase (G6PD), FOLFIRI regimen, 13, 14 158 FOLFOX regimen, 13 Glyceraldehyde-3-phosphate dehydrogenase Follicular lymphoma, 358 (GAPDH), 155 bcl-2 and, 358 Glycogen synthase kinase-3 (GSK3), 78–80, FOXO (forkhead box transcription factor), 144, 80t 145 Glycolysis, 23, 369 Free living or parasitic unicellular eukaryotes, inhibitor 2-DG, 376 312t. See also Unicellular parasites mitochondrial, 430 Friend, Charlotte, 221–222 Warburg’s aerobic not-mitochondrial, Fusarium graminearum, introns and, 263 15–16 Fusarium oxysporum, Mauriceville plasmid Warburg-type, 154, 282, 369, 473 and, 386 Glycosyl-phosphatidylinositol (GPI) molecule, Fuselloviridae, 388 87 Fuselloviruses, of Crenarchaea, 44–45, 46 Gnathostomata, 111–120 AID-induced dsDNA breaks and G translocations, 114–115, 116t, 117t Gain-of-function mutations, 23–24, 25 enzyme AID targets non-Ig genes, 112–114 of β-catenin, 191 immunological lymphomagenesis, 118–120 of BTK gene, 71t Reed-Sternberg cells engagement in genomic mutations, 27 ménage à quatre, 115–118, 119f point mutation, 11, 15, 26, 28, 190, 398 Gonium multicoccum, 268 c-kit proto-oncogene, 431 Granular lymphoid cells, 73f proto-oncogene, 210 Granule lattice (GRL) proteins, 262 the Rac1 gene, 485 Granulocyte colony stimulating factor receptor rafB (BRAF) proto-oncogene, 173 (G-CSF-R), 175 of Smo, 277 GTPase-activating protein, 484–485 thrombopoietin receptor (TPO-R) gene, 96 GTPases Galleria mellonella, 323 -activating protein (GAP), 146, 148, 484 Gamma interferon-inducible lysosomal thiol Rab family, 147–149 (GILT) reductase, 91–92, 91t Gammaretrovirus, 208 H Ganglion mother cells (GMC), 87 H6PD, 158–159 Gas6 protein, 184–186 Haloarcula marismortui, 179 804 Index

Halobacteriales (Haloarchaea), 251 Tat, 80t Halobacterium salinarum, carbohydrate viral infectivity factor (Vif), 208 metabolism, 152 and YY proteins, 131–133 Haloferax volcanii (H. volcanii), 217t HIWI (human PIWI), 24, 57, 59, 66, 68 carbohydrate metabolism, 152, 153 antigens, 68–69, 73–74 first TSP protein, 486t Hodgkin lymphoma, 26 Hippopotamus amphibius (H. amphibius), 241 Homo sapiens, 413, 474 Haploid germ cells, 6 CBF–1 in, 87 HARB1 protein, 244 Horologists, 417–419 Harbingers, 242–245, 243f Host cell factor-1 (HCF-1), 86 Hayflick rule, 15, 493 Host cell genomic mRNAs, 59–62 Heat shock proteins (HSP) Hostenia miamia, 314 hyperthermic therapy, 506t Host immune reactions, tumor growth primordial, 505–506t enhanced, 312t as protector of oncogenes, 505–506t Howe, Clifton Dexter, 534–541 Hedgehog pathway, 67 farewell, 547–548 in ontogenesis, 11, 12 memory of, 548–551, 550f HeLa cells, 26, 479, 302 Human cerebral cortex, 19–21 Helicobacter, 120 Human endogenous retroviruses (HERV) Helicobacter pylori, 120 RNA, 217–218 -induced gastric MALT lymphomas, 311 Human face, retroviral inheritance of, 207–224 introns, 260 insertional mutagenesis, 209–216, primordial fused genes, 157 212–213t, 214–216t Hepatoblastoma, 401 new services rendered by inserted genes, HER2/neu oncoproteins, 447 216–219 Herpes simplex virus (HSV), 230 Retroviruses R Us, 207–209 Herpesvirus ateles, 471 retroviruses spread in laboratory, 223 Herpesvirus saimiri (H. saimiri), 209, 412, 471 viruses collaboration, 219–221 Herpesviruses wnt proto-oncogenes, cooperation of, 221 EBV, 224–225 HurIFNα therapy, 190 genomic intrusions of, 224–231 Hybridoma formation, 473f HHV8-related, 208 Hydractinia, 77 KSHV, 225–227 Hydractinia echinata, 16 and retro(lenti)-viruses, criminal collusion Hydractinia symbiolongicarpus, 232–233 of, 411–413 Hydra magnipapillata (H. magnipapillata), tankyrase interaction, 230–231 350, 390, 466, 496 HERV-WE1 gene, 219, 220 Hydra vulgaris (H. vulgaris), 380 Hh shared sarcoma genomics, 277–280 achaete-scute, 384 HHV-6, 236 Hylobates agilis, 207 telomere attraction, 227–230, 229f Hyper-CVAD regimen, 453 HHV8 Hypercycling peptides, autocatalytic latency-associated nuclear antigen of, 224 chiroselective reactions of, 33 -related herpesviruses, 208 Hyperglycemic Drosophila, 144–145 High mobility group (HMG) proteins, Hypoglycemic Caenorhabditis, 144-145 210–211, 356, 485, 502t Hypoxanthine phosphoribosyltransferase human cancer growth induced and/or (HPRT), 468 promoted by, 214–216f of unicellular eukaryotic ancestors, I 212–213t Ibrutinib, 22 Histone deacetylase inhibitors (HDACI), for for chronic lymphocytic leukemia, 22 neuroblastoma, 359 for mantle cell lymphoma, 22 HIV-1, 131–133. See also Acquired Idelalisib, 452 immunodeficiency syndrome IKBKE (inhibitor kappa light chain enhancer B (AIDS) cells), 416–417 Index 805

Imatinib mesylate (Gleevec, Novartis), 452 in carcinoma cells, 280–283 for chronic myelogenous leukemia, 115 changes in dendritic cells and immune Imiquimod, for neuroblastoma, 373 lymphocytes, 286–287 Immune lymphocytes, intron changes in, fate of, 269–273 286–287 Hh shared sarcoma genomics, 277–280 Immune T cells, recognition of, 533 of LECA, 258, 259t, 264, 265, 269, 275, Immunity-related GTPase (IRG) protein, 92 289 Immunoglobulin gene (IgH), 10 in leukemogenesis, fate of, 269–271 Immunological lymphomagenesis, 118–120 loss of, 94, 263 Immunological surveillance, 10 natural products, impact of, 283–284 Immunotherapy, for melanoma, 456t of oncogenomics, hidden, 275–277 IMP-1 protein, 313 in ontogenesis, 284–286 Inflammatory carcinogenesis, 26, 310–311, -poor genomes, 257–263 427 resting gene transforms into oncogenesis, Insertional mutagenesis, 209–216, 212–213t, impact of, 267–269 214–216t -rich genomes, 257–263 Insulin-like growth factor (IGF), 430 undisciplined, 257–290 -binding protein 2 (IGFBP), 204 Ipilimumab, 23 IGF-1, 86 Irs-1, 60 1-R, 13 Isochrysis, 253 IGF-2, 137–138, 140 in placental syncytiotrophoblasts, 140 J in poecilia fishes, 141 Jaagsiekte retrovirus (JSRV), 471 receptors and ligands, long trajectory of, JAK mutation 143–156 in Drosophila, 95–96 Insulin receptor substrate-1 (IRS-1), 147 /FERM mutations, 270 Interferons (IFN), 91–98, 509t human, 96 -deficient tumor cells, oncolytic viruses in, JAK/STAT signaling, 97 98–99 activated by IFN-alpha, 91–92, 530–531 IFNβ, 98 IFN-γ, 91–98 type I IFN, 94–95 type I target genes, 96 IFNαβ, 92-94 JNK protein, 79 JAK/STAT activated by, 94–95 Interleukins (IL), 509t K IL-1, 96, 97 Kaposi sarcoma, 190 converting enzyme (ICE), 322 endogenous retroviruses, 61f IL-1β, 172, 227, 278, 432, 468 herpesviruses (KSHV), 60, 60f, 62, 80t, IL-2, 210, 227, 316, 317, 509t 209, 220, 225–227 IL-3, 227 Keratinocyte growth factor (KGF), 430 IL-4, 97, 509t Ki-67, 24, 382–383 IL-6, 96, 97, 98, 172, 190, 226, 227, 468, Kinetoplastids, 7 509t Klebsiella pneumoniae (K. pneumoniae), 260 IL-8, 112, 468 Koacervats, 32 IL-10, 97, 240, 316 Krebsbacillus, 491 IL-12, 98, 316 Kupffer cells, 13, 311 IL-13, 97 IL-15, 445, 509t L IL-17, 112 Laboratory technology IL-27, 98 cellular RNA/DNA, 181–183 Intron(s) nomenclature clarification, 183–187 amphioxus species, 273–275 Lactococcus lactis (L. lactis), 288, 289 ancestors of, 263–267 Laminas, and neuroblastoma, 361 biology, latest on, 287–290 Lapatinib (Tykerb, GlaxoSmithKline), 454 806 Index

Last Eukaryotic Common Ancestor (LECA), Lithospermum erythrorhizon, 352 463, 496, 553 Living fossils, 137–141 introns of, 258, 259t, 264, 265, 269, 275, genomic imprinting, 137–138 289 meiotic errors, 140 morphological metamorphoses, 319 placental syncytiotrophoblasts, 138–140, Late membrane protein (LMP) mRNAs, 60, 62 139f Latency-associated nuclear antigen (LANA), poecilia ﬁshes, 140–141 224, 292 viviparity, 137–138 Laurasiatheria, 138 Lmbr1, 273, 274 Lausannevirus, 247 Long terminal repeats (LTRs), 14, 37 LecRK–I, 163 Loss-of-function mutations, 15, 140, 429, 600, Legionella drancourtii, 63 629 Legionella pneumophila, morphological of ELG in budding yeast, 500t metamorphoses, 319 in Hirschsprung’s disease, 190 Leishmania, and carbohydrate metabolism, 153 integrated HHV-6 genome (CIHHV), 229 Leishmania amazonensis, strand-switch of mitochondrial gene, 52, 54 regions (SSRs) of, 355 point mutation, 72t, 174, 364 Leishmania braziliensis, 75 key genes for, 514t Leishmania donovani (L. donovani), 128 of prmt-1 gene, 328 interaction with PCNA, 252 PTEN gene, 125, 339 Leishmania major (L. major), 76 of Rab and/or DENN proteins, 485 interaction with PCNA, 252 of Sox2, 83 Lenalidomide, 452, 453 tumor suppressor genes, 25, 222, 354, 442 Leucine rich repeats (LRR), 105, 308 Apc, 363 Leukemia gld, 145 acute myeloid, 431 tudor gene, 171 chronic lymphocytic, 22 Lovastatin, 441 mixed lineage, 167 Ludus vitalis (alloy of philosophy), 3 myelogenous, 518–519t Lycopersicon esculentum (L. esculentum), 177 chronic, 115, 165–166 Lycopersicon pimpinellifolium (L. pennellii), oyster, 349–350 177 precursor B cell acute lymphoblastic, 518t Lymphocytes, HiWi antigens and, 68–69, retroviral mouse, 518t 73–74 Leukemic retroviruses, 208 Lymphocytic choriomeningitis virus (LCMV), Leukemogenesis, 215t 390 introns in, fate of, 269–271 Lymphoma Lexatumumab, for rhabdomyosarcoma, 369 activation-induced cytidine deaminase and, Lieberkühn crypts, 22 112–114 stem cells in, 11, 14 anaplastic, 362–364, 518t Ligands-to-growth factor receptors, 508t B cell, 518t, 520–521t Limulus polyphemus, 321 Burkitt's, 358 Lin, 82–85 Hodgkin, 26 lin-4, 82 lymphoplasmacytic plasmablastic, 518t lin-7, 82-83, 85 MALT, 357 lin-28, 83, 85 mantle cell, 22 Lipoprotein receptor-related protein (LRP), 78, Lymphomagenesis, 113, 250 81 immunological, 118–120 Listeria vaccine, 374t Lymphoplasmacytic plasmablastic lymphoma, Lithium chloride (LiCl), 80t, 305t 518t Index 807

Lymphosarcoma, 70–71t immune T cells and NK cells, recognition Lynch syndrome, 7, 26, 467, 554 of, 533 private donors support to immunotherapy, M 533–534 MAFs (musculoaponeurotic ﬁbrosarcoma) MDM, 11, 134, 427 proto-oncogenes, 155 anti-p53, 344–345 Magnaporthe grisea, 263 and sarcoma, 71–72t MAGUK (membrane-associated guanylate MDM2 protein, and rhabdomyosarcoma, 365 kinase) protein, 394 MDR1 protein, 313 Malacoherpesviridae, 239, 240, 241, 249 Mechlorethamine (Mustargen), 451 Malignantly transformed cells, 14t, 15, 17–18, Megavirus chilensis, 63 214t, 313t MER signaling/pathway, 185–186 ancestral arginine methyltransferases, 329 Mesenchymal stem cells (MSC), 380 and ancient unicellular eukaryotic cells, 56, Mesotoga prima (M. prima), 388 125, 521 Metalloproteinases (MMPs), 148 aneuploidy, 436 Metazoan HMG proteins, 212–213t cell survival pathways, 23, 343 Micromonas pusilla (M. pusilla), 265 centrosome ampliﬁcation, 495 Microphthalmia-associated transcription factor genetic instability, 466 (MITF), 338 genomic introns, 296 MicroRNAs (mRNAs), 2, 6, 34, 36, 56–64 human survivin gene, 368 activation-induced cytidine deaminase, IGF-to-R pathway expropriation, 151 114-115 mitotic errors, 301 agnathan, 106–108 RNA-derived mutators, 468 amoebae, 62–64 system expropriation, 507–510t Argonautes, 56–59, 57f tenascins (TNs), 397t Dicer, 57, 58f, 59, 74 trans-speciation, 336, 336f donors of, 76–89 Malignant peripheral nerve sheath tumor Drosha, 57, 58f, 59 (MPNST), 13, 37 host cell genomic, 59–62 MALT lymphoma, 311, 357 interfering/inhibitory, 457–459 Manduca sexta, 324 late membrane protein, 60, 62 Mannose 6-phosphate/IGF2 receptor (M6P/ Nanog, 83, 84, 402 IGF2R), 137–138 p53-induced miR-145, 59–60 Mantle cell lymphoma (MCL), 22 viral genomic, 59–62 Marine annelid, stem cells replication in, 93f YY proteins, regulation of, 134–135 Marseillevirus, 247 Mimivirus, 247 MART (melanoma antigen recognized T cells) Mitochondria, 48f, 51–54 proteins, 387 in oncogenesis, 516–517t Mast cells, 13 Mitochondrial DNA (mtDNA), 383, 516–517t Matrix metalloproteinases (MMP), 282, 336 Mitochondrial RNA editing factor 1 (MEF1), Mauriceville 319 plasmid, 4, 386–387 Mitogen inducible genes (Mig), 335 retroplasmid (mRP), 259t, 464 Mitosis, FasL-induced, 174–175, 176f MD Anderson Hospital Comprehensive Cancer Mitotic errors. See Aneuploidy Center (MDACCC), history of, Mitotic exit network (MEN), 148 527–551 Mixed lineage leukemia (MLL), 167 basic science research, 541–547, 542f Mollicutes, origin of, 40–41 BCG, 527–530 Moloney, John, 222–223 cancer biotherapy, natural IFN-alpha for, Moloney leukemogenic retrovirus, 395 530–531 Moloney mouse leukemia-sarcoma retroviral cancer chemotherapy, 527–530 (MMLV) provirus, 222 combination chemotherapy, 531 Monoclonal antibodies, 449–451 Howe, Clifton Dexter, 534–541, 547–548 Monoclonal immunotoxins, 449–451 808 Index

Monocyte-macrophage colony-stimulating achaete-scute, 384 factor receptor-1 (CSF-R1), adaptive immunity, 241–242 487–489t HMG protein, 212t Monosiga, 11, 79 Neoneurogenesis, 312t Monosiga brevicollis, 127, 128, 393–394, 396, Nerve growth factors (NGF), 430 465 Neurabin-II, 90 primordial fused genes, 164 Neuroblastomas, 507t Monosiga ovata (M. ovata), 128, 191, 392, biology of, 358f 394, 511t of childhood, 358–362 hoglet gene of, 201 Neuroﬁbromatosis gene (nf1), 13, 146 Moraxella bovis, 182 Neurons, 20 Multifactorial resistance phenotypes, 452 Neurospora crassa, 168 Multiple sclerosis associated retrovirus hyphal hyperproliferations in, 255f (MSRV), 220 introns, 263 Mutator pheno-genotypes, 500–501t Mauriceville plasmid, 386–387 Mutator phenotype, 26 Neurotrophic tyrosine receptor kinase (NTRK), Mya arenaria, 349 145 Mycoplasma fermentans (M. fermentans), 44 NFκB, 509t Mycoplasma penetrans (M. penetrans), 44 /STAT pathway, 23 Mycoplasmataceae, 41 Nhej1, 273, 274 Mycoplasmatales, 40 Nicotinamide adenine dinucleotide phosphate Myeloblastosis (MYB) protein, 245 (NADPH), 158 Myelogenous leukemia, 518–519t Niller, H.-H., 235–238 Mytilus trossulus (M. trossulus), 345, 349 herpesviral genomes, 236f Myxoid/Round Cell Liposarcoma (MyLSrc), Nilotinib (Tasigna, Novartis), 452 72t Nitrosopumilus maritimus, 46 genomics of, 117t N-myc downstream-regulated gene 1 (NDRG- 1), 172, 416 N nok/NOK gene, 178 Naegleria, 24, 496 Nomenclature clariﬁcation, 183–187 carbohydrate metabolism, 153 Non-coding RNA (ncRNA), 2, 4, 34, 522–523t trans-speciating transformations of, 154f -derived cDNA libraries generated, 522t Naegleria fowleri, and carbohydrate Notch, 90 metabolism, 153–154 Nuclear factor of activated T cells (NFATC), Naegleria gruberi (N. gruberi), and 204 carbohydrate metabolism, 154 Nucleoporin, 17 NAIF1 protein, 244 Nucleotides. See also Oligonucleotides Nanog mRNA, 83, 84, 402 coexistence before cells, 31–33 Naphthoquinones, 155 extra, 124 National Cancer Institute (NCI), 531–532 Nutlin, 72t Natrialba magadii, 389 Nyctotherus, 122 Natural killer (NK) cells, 13, 18, 97, 100 NY-ESO antigens, 444 in antibody-dependent cell-mediated and sarcoma, 70t cytotoxic reactions, 59 recognition of, 533 O therapy, 447–351 Oblimersen (Genasense), 453 Natural products, impact on introns, 283–284 Oct4, 60, 83–85 Navitoclax, 350–351 Oikopleura dioica, and introns, 263 N-cadherin, 337 Okazaki fragments, 380-382, 398 NDUFA1 gene, 270 Oligonucleotides, 411, 415, 457, 458t Nematode viruses, 85–86 Oncogene-derived protein kinases, targeted Nematostella, 11, 79, 554 small molecular inhibitors of, Nematostella vectensis (N. vectensis), 77, 189, 451–457 191, 314, 380 Oncogenesis, 25, 492, 555, 556 Index 809

achaete-scute, 507–508t Paramecium chlorella, 248 agrobacterial, 522t Paramecium tetraurelia (P. tetraurelia), 58, 77 Aurora-kinase, 252 introns, 257 endogenous, 420-422 primordial fused genes, 165 exogenous, 420–422 Pasteurellaceae, 308 gene transforms into, resting, 267–269 Pax6, 81 heat shock proteins, 505–506t Pazopanib (Votrient, GlaxoSmithKline), 454 mitochondria in, 516–517t Pediatric lymphomas/leukemias, 518–519t ncRNAs in, 522–523t Pediatric myelodysplasia, 518–519t PCNA in, 502t Pediatric rhabdomyosarcoma, 364–368, 365f Polo-kinase, 252 PEG10, 138 Oncogenic fusion oncoproteins, cellular Pembrolizumab, 23 viability and, 353–355 Penicillium funiculosum, 183 Oncogenome, 24–26 Pentose phosphate pathway (PPP), 155 primordial, 427–437 Peponocephala electra, 241 strategy of, 425–438 Perkinsus marinus, 467 Oncolytic viral therapy, 444–447 Peroxisome proliferator-activated receptors OncomiRs, 4589–459t (PPAR), 53t, 86 Oncoproteins, release of, 434–435 Pettenkoferia, 302–304, 303f Ontogenesis, introns in, 284–286 Pﬁesteria piscicida (P. piscicida), 253 Opisthokonta, 76, 77, 497 Phallusia nigra, 394 Organelles, 51–55 Phascolarctos cinereus, 471 chloroplasts, 51–54, 54f Phosphoinositide-dependent kinase-1 (PDK1), mitochondria, 51–54 144 ribosome, 55, 55f 6-Phosphogluconolactonase (6PGL), 159 Ornithorhynchus anatinus, 137 Physarium polycephalum, 496 Ostreococcus lucimarinus, 257 Physeter macrocephalus, 241 Ovarian carcinoma, physiological growth Phytophthora, 17 factors for, 316–318 primordial fused genes, 160, 162–164, 162f Oxytricha, 7, 481 virulence factors and transposable elements Oxytricha fallax (O. fallax), 122 of, 511–512t Oxytricha nova, 212t Phytophthora brassicae, primordial fused Oxytricha trifallax (O. trifallax), 17, 122, 466 genes, 163 Oyster herpes viruses (OsHV-1), 239 Phytophthora infestans (P. infestans), 387, 499 Oyster leukemia, 349–350 primordial fused genes, 160, 163, 164 Phytophthora sojae, primordial fused genes, P 160, 162 p38 mitogen-activated protein kinase (MAPK), Phytoplasmas, sequence-variable mosaics, 41 97–98 PI3K, 15 p53, 11, 13, 68, 134, 279, 341, 343–344 cell survival pathway, 125 co-evolution of, 71–72t in Giardia, 7, 125 -induced miR-145, 59–60 /Akt, 508t pro-apoptotic, 271f germline mutation of, 126–127t, 128f Paleogenomics, 238–242 PiggyBacs, 7 Panobinostat, 455 Pithecanthropine hominids, 27 Pan troglodytes, 207 Pituitary tumor-transforming gene-1 (PTTG), Papillomavirus, 400 337 E6 oncoprotein, 248 PIWI RNA, 24, 57, 59, 65–75, 390–392 and YY proteins, 133 donors of, 76–89 Papovaviruses, 247 Placenta, as pseudomalignant organ, 18, 19 Parabodo caudatus, primordial fused genes, Placental syncytiotrophoblasts, 138–140, 139f 164 Plasmacytoid dendritic cells (pDC), 97 Parachlamydia acantamoebae, 63 Plasmodia, 17, 496 Paramecium bursaria chlorella, 63 carbohydrate metabolism, 153 810 Index

primordial fused genes, 165 Primordial spheroplasts, 35–36 Plasmodium falciparum (P. falciparum), 76, Progeria, 192–193 465 Prokaryotes, 35, 76–89 interaction with PCNA, 251 cell wall-free, 39f Okazaki fragments, 380–381 horizontal-transfer gene network, 47f primordial fused genes, 158, 159, 162 tree of living organisms, 48f Plasmodium vivax, 260 Proliferating cell nuclear antigen (PCNA), Platelet-derived growth factors (PDGF), 430 194–195, 502t Platynereis dumerilii, 92 as ancient DNA-proliferator, 251–256 achaete-scute, 384 Okazaki fragments, 380–382 Poecilia ﬁshes, 140–141 in oncogenesis, 502t Polo-kinase oncogenesis, 252 Promyelocytic leukemia (PML) protein, Polyadenosine diphosphate ribose polymerase 248–249 (PARP), 53t, 197, 255–256, 371 Prostate carcinoma (PC), 428–429t Polynem (Pln), 16 Protein arginine methyltransferases (PAMT), Polyomaviruses, 420–421 497. See also Protein R-CH3 Polypeptides, 3 methyltransferases (PRMTs) Pomalidomide, 452 Protein R-CH3 methyltransferases (PRMTs), Ponatinib (Iclusig, ARIAD), 452 328–329, 368, 383, 502–503t Pongo pygmaeus, 207 Proteins repressive complex (PRC), 371 Porifera, 77 Protocells, 32 Porphyromonas gingivalis, 308 Proto-oncogenes Poxviruses, 35, 36 ancestors of, 379–380 PRC17 protein (polycomb group repressive classical, 511t complex), 148–149 generation of, 145–147 PRDM genes, 203–204 primordial genes conserved as, 31–34 Precursor B cell acute lymphoblastic leukemia, resident, as recipients, 209–216, 212–213t, 518t 214–216t Pre-immunization, immune reaction without, Protospacer adjacent motifs (PAMs), 308 410 prp8 gene, 263 Primitive neuroectodermal tumors (PNETs), Pseudogenes, 205–206 385 Pseudomonas, 499 Primordial fused genes, 157–179 introns, 260 conserved as stem cell genes/proto- Pseudomonas aeruginosa, 505t oncogenes, 31–34 Pseudomonas caudatum (P. caudatum), 505t exchange of, 164–165 Pseudorca crassidens, 241 extant unicellular eukaryotes, 157–160, Pseudouridylation, 58f 161f Pseudovasculogenesis, 433 FasL-induced mitosis, 174–175, 176f Pseudovirions, 464 gene ampliﬁcations and duplications, 175, PSMB (proteasome subunit β-type) proteins, 177 91t in old men, 171–172 PTEN, 13, 15, 125–126, 126–127t, 145, 197, oncogenes/oncoproteins fusion, guidelines 282–283, 339, 415 for, 165–167 intranuclear sumoylated, 127t Phytophthora, 160, 162–164, 162f PI3K/AKT, germline mutation of, point mutations, 175, 177 126–127t, 128f promiscuity in, 167–171, 170f Pyrobaculum aerophilum (P. aerophilum), treacherous tumor, 172–174, 174f 498–499 tyrosine kinase nok/NOK, 178 Pyrococcus, 56 Primordial oncogenome, 427–437 Pyrococcus furiosus, 76 Index 811

carbohydrate metabolism, 152 RNA Pyruvate dehydrogenase phosphatase (PDP), cellular, 181–183 145 circular, 2, 523t competing endogenous, 206 Q -dependent RNA polymerases (RdRp), 62 Quantitative PCR, 220 -derived mutators, 466–468 real-time, 298 HIWI, 24, 57, 59, 65–75 reverse transcription, 222 -induced slicing complex (RISC), 57, 57f, Quantitative trait loci, 500t 59 interference (RNAi), 56, 57, 59 R mRNAs. (See MicroRNAs (mRNAs)) Rab family GTPases, 147–149 non-coding, 2, 4, 34, 522–523t Rab proteins, endogenous retrovirus genes PIWI, 24, 57, 59, 65–75, 390–392 interaction with, 149–151 polymerases (RNAP), 41 Rad51, 197–198 post-transcriptional modification, 74–75 rag genes, 111–113, 218, 234, 244 scan, 65 RanGTPases (Ras-related nuclear protein), 407 shRNAs(. See Small hepatin RNAs ras genes, 304–308 (shRNAs)) phylogenetic analysis of, 306–307 siRNA (. See Small interfering RNA Ras-Raf-MEK-ERK pathway, 145 (siRNA)) RBP-J (recombination signal binding protein RNA/DNA complex, 2, 4, 7, 121–130 for immunoglobulin kappa J region), adaptive immune system, unreliable 225, 285 enzymes of, 308–310 R-CHOP chemotherapy regimen, for mantle endogenous retroviruses, 387–390 cell lymphoma, 223 enseal into and fly out of cocoon, 321–324 Receptor activator of NFκB/receptor ligand gills transform to lungs, 320–321 (RANKL), 113–114 inflammatory carcinogenesis, 310–311 Reed-Sternberg cells, 554 Ki-67, 382–383 engagement in ménage à quatre, 115–118 malignant transformation of cells, 299–318 extracting guarded secrets from, 474–476 malignant tumors, 399–400 origin of, 119f Martian, 28 Regorafenib (Stivarga, Bayer), 455 Mauriceville plasmid, 386–387 Regulatory T (Treg) cells, 13 morphological metamorphoses, 318–320 RET/PTC, 190–191 mtDNA, 383 Retinoblastoma, 400t Okazaki fragments, 380–382 Retinoic acid-induced heparin-binding protein oncogenic, 13, 16 (RIHBT), 431 Pettenkoferia, 302–304, 303f Retro(lenti) -and herpesviruses, criminal phenomenal physiological tasks, 318–330 collusion of, 411–413 PIWI RNA, 24, 57, 59, 65–75, 390–392 Retroviral mouse leukemias, 518t primordial, 25, 28, 33–34, 379–405, 494 Rev1 polymerase, 194–195 shark bites, 324–325 Rhizome, 463 stem cells, asymmetric mitoses of, 327–329 Rhizopus, 158 taxa, phylogenic shifting of, 325–327 Ribonucleoproteins (RNP), 31, 33 therapeutic interventions, impact of, Ribosome, 55, 55f 395–399 Rituximab, 452, 454 transforming, 23 RIZ genes, 204 unicellular life forms, 311, 313–316 812 Index

RNF113B gene, 271 Sequence-variable mosaics (SVM), 41 Rnf32, 273, 274 SETMAR protein, 244 rNMPs, 252–253 Severe combined immunodeﬁciency (SCID), ROCK/pMLC2 pathway, 416 210 Romidepsin, and synovial sarcoma, 372 Shank protein, 498 RUNX (runt–related transcription factor), 155, SHOX (stature homeobox-containing) gene, 364 294 Signaling lymphocyte-activation molecule- S associated protein (SLAM; SAP), 97 Saccharomyces, 7, 122, 299 Signal recognition particle (SRP), 304–305 Saccharomyces cerevisiae (S. cerevisiae), 76, Signal transducers and activators of 414, 496 transcription (STAT), 23, 68, Fip1 of, 166 412–413 HMG protein, 212t cell survival pathway, 393 interaction with PCNA, 251 pathway, 95, 96, 97 introns, 258, 262, 266, 269, 289 PI3K phosphorylation, 125 Pak enzymes, 393 protein (STAT92E), 93 Saccharomyces paradoxus (S. paradoxus), 262 Signal transduction ATPases (STAND), 248 Saccharomyces pombe, 328 Simian sarcoma virus (SSV), 471 Saimiri sciureus, 412, 471 Simkania negevensis, 343 Sal ﬂies, 477–479 Simvastatin, 441 Salinomycin, 13 SIN1 protein, 94 Salpingoeca rosetta (S. rosetta), 497 SIR (silent information regulator), 86 Sarcina lutea, 38, 304 SIRs/sirtuins, 89 Sarcoma, 68–69 rhabdomyosarcoma, 365f dendritic cell, 71t SIVcpz, 207 Ewing's, 71t. See also Ewing’s sarcoma Sleeping beauty transposon system, 243f genomics, 116t SLX4 DNA repair protein, 53t Hh shared, 277–280 Small hepatin RNAs (shRNAs), 5–6 immunobiology, 70–73t Small interfering RNA (siRNA), 2, 57, 62 immunotherapy, 70–73t metazoan gametogenesis, regulation of, 83 Kaposi (. See Kaposi sarcoma) nanoparticle encapsulated, 89–90 lymphosarcoma, 70–71t Smo, 275 rhabdomyosarcoma, 364–368, 365f SNARE proteins (soluble NSF attachment synovial, 69f, 116t, 338 protein receptor, N-ethylmaleimide- Staphyloccous aureus (S. aureus), 260 sensitive factor), 148 Scan RNAs (scnRNA), 65 Solanum melongena, 387 Schistosoma, 7 Solanum stoloniferum (S. stoloniferum), 163 Schistosoma haematobium (S. haematobium), Somatic cells, 6, 10, 11, 13–16 465 Somatic hypermutation (SHM), 202, 309 Schistosoma japonicum (S. japonicum), 465 Sorafenib, 432 Schistosoma mansoni (S. mansoni), 465 Sox Schizosaccharomyces pombe, 496 oncoprotein, 84f Argonaute gene in, 465 Sox2, 4, 33, 60, 81, 83–84, 416, 553 Pak enzymes, 393 Y chromosome-embedded (SRY), 5 primordial fused genes, 164 Spheroplasts Schmidtea mediterranea, 391 malleable, 38 Schwann cells, malignant sarcoma of, 37 primordial, 35–36 SDHD (succinate dehydrogenase subunit D) Spi-1 protein, 221 genes, 138 Spindle-shaped viruses (SSV), 44 Seed and soil hypothesis, 185 Staphylococcus, 499 Index 813

Stem cells, 6–18 TDRD1 protein, 171, 172 ancient, 77–79, 78f Telomerase reverse transcriptase transcripts asymmetric mitoses of, 327–329 (TERT), 261, 388 cancer, 192t Telomeres DNA/RNA complex, 8–9 G4 quadruplex in, 122 in Lieberkühn crypts, 11, 14 HHV-6 attraction, 227–230, 229f Streblomastix strix (S. strix), 263 length, of Trypanosoma, 128–129 Streptococcus pyogens (S. pyogens), 260 Temsirolimus (Torisel, Wyeth), 455 Streptomyces anulatus, 130 Tenascins (TNs), 395, 397t Streptomyces hygroscopicus, 471 Teneurins (TNe), 396, 397t Streptomyces parvulus, 95 Tetrahymena, 7, 65–67 Stromal cell-derived factor (SDF), 13 molecular biology, 65f, 66f Strongylocentrotus, 244 Tetrahymena histone methyltransferase Strongylocentrotus purpuratus (S. purpuratus), (TXR1), 495 77, 105 Tetrahymena pyriformis, response to sugar adaptive immunity, 242 intake, 143 HMG protein, 212t Tetrahymena thermophila (T. thermophila), 74, introns, 288 76, 77, 464, 517 Stylonychia lemnae, 122 HMG protein, 212t Suberites domuncula (Demospongiae), 7, 21 introns, 261 Suberoylanilide hydroxamic acid (SAHA), for primordial fused genes, 158, 165 neuroblastoma, 359 Tetraspanins, 486–487t SuFu protein, 275, 276 Thalassiosira, 158 Sulfolobales, 38 Thalassiosira pseudonana, 263 Sulfolobus acidocaldarius, 5, 17, 38, 47, 121 Theileria, 17, 24, 312t, 496 Sulfolobus solfataricus, 17 carbohydrate metabolism, 153 carbohydrate metabolism, 153 primordial fused genes, 165 CASCADE, 45 Theileria annulate (T. annulate) mRNA, 57 carbohydrate metabolism, 154 Sunitinib, 432, 455 morphological metamorphoses, 319 Survivin gene, 79, 90, 94, 166, 254 Theileria parva (T. parva) arsenic trioxide (A2O3, ATO) and, 249 carbohydrate metabolism, 154 DJ-1 co-expression, 211 morphological metamorphoses, 319 downregulation in, 345 Therapeutic cancer vaccines, 442–444, 443t during ontogenesis, 368 Thermococcales, 38 Synapses, 20 Thermococcus kodakarensis, 505t Syncytins, 139f, 219, 469 Thermococcus prieurii, 389 Syncytiotrophoblasts, 18 Thermoﬁlum pendens, 164 placental, 138–140, 139f Thermoplasmales, 38 Synovial sarcoma (SS), 116t, 338 Thermoproteales, 38 fusion oncoprotein, 69f Thermotogales, 38, 41 Syntaxin, 148 Thermus aquaticus, 17, 121 Synthetic lethality, 195–198, 196t, 441 Thermus thermophilus, 57 Syntrophus aciditrophicus, 121 Thrombopoietin receptor gene (TPO-R), 96 SYPCP synaptonemal complex protein, 53t TIE1/2 proteins, 190 T lymphocytes, 13 T adoptive immune, 447 Takifugu rubripes, 235, 314 CD4+, 131, 297, 444 Tankyrase, 230–231 CD8+, 98, 297, 448 Taxa, phylogenic shifting of, 325–327 TH-17, 96 T-cell acute lymphoblastic leukemia-associated Thermotogales maritime (T. maritima), 38, 41 antigen (TALLA), 431 TMPRSS2/ERG protein, 171, 172 TCF/LEF proteins, 79 TNF-related apoptosis-inducing ligand T-DNA, horizontal transfer of, 2 (TRAIL), 368 814 Index

Toll/IL-1 receptor (TIR), 92 interaction with PCNA, 251–252 Toll-like receptors (TLRs), 59 introns, 262 TOR (target of rapamycin), 144 primordial fused genes, 164 Totiviridae, 59 Trypanosoma cruzi (T. cruzi), 7, 75, 76, 128 Toxoplasma, 165 HMG protein, 212t Toxoplasma gondii, 75 interaction with PCNA, 252 interaction with PCNA, 251 oncogenic fusion oncoproteins, 354 primordial fused genes, 158 primordial fused genes, 164 Trametinib (Mekinist, GlaxoSmithKline), 455 Trypanosoma gambiense (T. gambiense), 75, Transformed cells, 10, 11, 15–18, 22, 23, 129 26–27, 28 Trypanosoma montezumae, asymmetrical cell Transforming growth factor-α (TGFα), 509t divisions, 328 Transforming growth factor-αβ (TGFαβ), 402, Tumor cell endosomes, release of, 434–435 508–509t Tumor cell-killer lymphoid cells, 99–100 Transforming growth factor-β (TGFβ), 96 Tumor growth, epigenome/epigenetic control crossveinless-2 (C-2) protein, 380 of, 459–461 Drosophila decapentaplegic orthologs, Tumor immunology, epigenetics of, 368–378, 508t, 582 374–375t inhibin, 508t Tumor-nest vascularization, 433–434 PDP and, 145 Tumor suppressor genes, 10, 11, 13, 16 protection against metastases, 421 Tyrosine kinase proteins, invasion of, 189–191 in sarcoma genomics, 116t in TTRP formation, 411 U Translesional DNA synthesis (TLS), 194, 195 Unicellular ciliate protozoon, 568 Transposon kinetoplastids, 7, 330 -activated oncogenes, 512–513t Unicellular eukaryotes, 7, 13, 56, 266 mutagenesis, 512t evolution, 395–396 sleeping beauty transposon system, 243f lithium chloride (LiCl), 305t Trans-speciated defensive cells, 419–420 activated cell pathways, and cancer, Trastuzumab (Herceptin, Genentech), 454 312–313t TRF (telomere restriction fragment; telomeric Unicellular life sustenance, error or inherent repeat-binding factor), 198 attributes for, 201–206 Trichoderma harzanium, and Mauriceville activation-induced cytidine deaminase, plasmid, 386 202–204 Trichomonas, 7, 58–59, 306, 499 ancient cell survival pathways, 201–202 Trichomonas vaginalis (T. vaginalis), 124, APOBEC, 202–204 245, 306 Bet proteins, 204–205 carbohydrate metabolism, 152 pseudogenes, 205–206 introns, 258, 260, 266 Unicellular parasites, 165, 407 TvMULE1, 465 parasitic microorganisms, 24 Trichoplusia ni (cabbage looper moth), 481, cancer cell viewed as, 483 512t, 568 ancient CSF-R1 becomes an Trichostatin, for neuroblastoma, 359 oncoprotein, 487–489t Triose-phosphate isomerase (TPI), 155 DENN protein, 485 tRNA, 34 GTPase-activating protein, 484–485 Trypanosoma, 7, 17, 426 transmembrane proteins (TSP), carbohydrate metabolism, 153 486–487t telomere length, 128–129 zeste of Chlamydomonas reinhardtii, Trypanosoma brucei (T. brucei), 7, 14–15, 485–486 74–75, 129, 387 zeste of Drosophila, 485 asymmetrical cell divisions, 328 Unicellular pathogenic eukaryotes, 126t HMG protein, 212t Ustilago, 158 Index 815

V Xenotropic murine leukemia virus-related Van Gogh (VANG) protein, 87 retrovirus (XMRV), 208–209, 223 Variable lymphocyte receptors (VLRs), 105, Xiphosura, 321 308 Vascular endothelial cells, 13 Y Vasculogenic mimicry (VM), 334–336, 336f, Yarrowia lipolytica, 269, 408 433–434 YB proteins (Y box-binding protein), 67 VCBP genes, 238–239 Yersinia, 499 Vemurafenib (Zelboraf, Plexxicon, Roche), Yixianornis grabaui, 321 455 Young hosts, cancers in, 357–358 Very large GTPase-inducible (VLIG) proteins, Yuyuanozoon magnificissimi, 275 92 YY proteins, G4 quadruplex promoters of, Vesicle-associated membrane protein (VAMP), 131–135, 132f 148 adenovirus, 133–134 -like regimen, 534 EBV, 131–133 Vespertiliones, 8 genome counters, guardian of, 134 Vetulicolians, 275 HIV-1, 131–133 Vetulicola cuneata (V. cuneata), 275 papillomavirus, 133 v-eyk protein, 186 regulated by microRNAs, 134–135 Vibrio cholerae introns, 260 Z primordial fused genes, 157 Z-DNA, 1 Vincristine, for hepatoblastoma, 401 ZEBRA, ankyrin protein, 237 Viral chromatin-interacting proteins, 247–248 ZRE DNA-binding site, 238 Viral genomic mRNAs, 59–62 Zebrafish Viral oncolysates, 100–103, 101f anti-p53 MDM, 354 Virology fish-specific genome duplications, 314 advanced, 37 IFNs, 93 basic, 36 Ki-67 antigen, 382 Viruses collaboration, 219–221 NEMO in, 411 Volvox, 329–330 PSMB proteins, 91t Volvox carteri, 498 retinoblastoma tumor suppressor genes (Rb), 400t W VLR-like genes, 108 Warburg’s aerobic not-mitochondrial Zhongjianornis yangi, 321 glycolysis, 15–16 Zink finger gene family, 203 Warburg-type glycolysis, 154, 282, 369, 473 Zink finger lymphocyte differentiation factor, Werner syndrome, 192–193 111 Wnt signaling/pathway, 80–81, 80t, 191–192 Zink finger proteins, 287, 438 cooperation in retroviral inheritance, 221 Krüppel-like, 281, 437 HMG proteins, 213–214t LZT protein transporter, 339 in ontogenesis, 11, 12 myc-associated (MAZ) transcription factor, unicellular life forms, 201–202 280 Wuchereria bancrofti, 213t of pannier gene, 385 RNF113B, 269 X Sal, 477 Xanthomonas oryzae, 419 SCAN, 389 Xath5, 81 ZEB1/2 (E-box-binding), 313 Xenarthra, 138 ZFP509, 400t Xenopus laevis (X. laevis), 92 ZNF198, 277 Ziv-aflibercept (Zaltrap, Sanofi), 455