Integrative Computational Approach Identifies Drug Targets in CD4+ T
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Bevacizumab Plus Fotemustine As First-Line Treatment in Metastatic Melanoma Patients: Clinical Activity and Modulation of Angiogenesis and Lymphangiogenesis Factors
Published OnlineFirst October 28, 2010; DOI: 10.1158/1078-0432.CCR-10-2363 Clinical Cancer Cancer Therapy: Clinical Research Bevacizumab plus Fotemustine as First-line Treatment in Metastatic Melanoma Patients: Clinical Activity and Modulation of Angiogenesis and Lymphangiogenesis Factors Michele Del Vecchio1, Roberta Mortarini2, Stefania Canova1, Lorenza Di Guardo1, Nicola Pimpinelli3, Mario R. Sertoli4, Davide Bedognetti4, Paola Queirolo5, Paola Morosini6, Tania Perrone7, Emilio Bajetta1, and Andrea Anichini2 Abstract Purpose: To assess the clinical and biological activity of the association of bevacizumab and fotemustine as first-line treatment in advanced melanoma patients. Experimental Design: Previously untreated, metastatic melanoma patients (n ¼ 20) received bevaci- zumab (at 15 mg/kg every 3 weeks) and fotemustine (100 mg/m2 by intravenous administration on days 1, 8, and 15, repeated after 4 weeks) in a multicenter, single-arm, open-label, phase II study. Primary endpoint was the best overall response rate; other endpoints were toxicity, time to progression (TTP), and overall survival (OS). Serum cytokines, angiogenesis, and lymphangiogenesis factors were monitored by multiplex arrays and by in vitro angiogenesis assays. Effects of fotemustine on melanoma cells, in vitro, on vascular endothelial growth factor (VEGF)-C release and apoptosis were assessed by ELISA and flow cytometry, respectively. Results: One complete response, 2 partial responses (PR), and 10 patients with stable disease were observed. TTP and OS were 8.3 and 20.5 months, respectively. Fourteen patients experienced adverse events of toxicity grade 3–4. Serum VEGF-A levels in evaluated patients (n ¼ 15) and overall serum proangiogenic activity were significantly inhibited. A significant reduction in VEGF-C levels was found in several post-versus pretherapy serum samples. -
A Disease Spectrum for ITPA Variation: Advances in Biochemical and Clinical Research Nicholas E
Burgis Journal of Biomedical Science (2016) 23:73 DOI 10.1186/s12929-016-0291-y REVIEW Open Access A disease spectrum for ITPA variation: advances in biochemical and clinical research Nicholas E. Burgis Abstract Human ITPase (encoded by the ITPA gene) is a protective enzyme which acts to exclude noncanonical (deoxy) nucleoside triphosphates ((d)NTPs) such as (deoxy)inosine 5′-triphosphate ((d)ITP), from (d)NTP pools. Until the last few years, the importance of ITPase in human health and disease has been enigmatic. In 2009, an article was published demonstrating that ITPase deficiency in mice is lethal. All homozygous null offspring died before weaning as a result of cardiomyopathy due to a defect in the maintenance of quality ATP pools. More recently, a whole exome sequencing project revealed that very rare, severe human ITPA mutation results in early infantile encephalopathy and death. It has been estimated that nearly one third of the human population has an ITPA status which is associated with decreased ITPase activity. ITPA status has been linked to altered outcomes for patients undergoing thiopurine or ribavirin therapy. Thiopurine therapy can be toxic for patients with ITPA polymorphism, however, ITPA polymorphism is associated with improved outcomes for patients undergoing ribavirin treatment. ITPA polymorphism has also been linked to early-onset tuberculosis susceptibility. These data suggest a spectrum of ITPA-related disease exists in human populations. Potentially, ITPA status may affect a large number of patient outcomes, suggesting that modulation of ITPase activity is an important emerging avenue for reducing the number of negative outcomes for ITPA-related disease. -
Analysis of Gene Expression Data for Gene Ontology
ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION A Thesis Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Master of Science Robert Daniel Macholan May 2011 ANALYSIS OF GENE EXPRESSION DATA FOR GENE ONTOLOGY BASED PROTEIN FUNCTION PREDICTION Robert Daniel Macholan Thesis Approved: Accepted: _______________________________ _______________________________ Advisor Department Chair Dr. Zhong-Hui Duan Dr. Chien-Chung Chan _______________________________ _______________________________ Committee Member Dean of the College Dr. Chien-Chung Chan Dr. Chand K. Midha _______________________________ _______________________________ Committee Member Dean of the Graduate School Dr. Yingcai Xiao Dr. George R. Newkome _______________________________ Date ii ABSTRACT A tremendous increase in genomic data has encouraged biologists to turn to bioinformatics in order to assist in its interpretation and processing. One of the present challenges that need to be overcome in order to understand this data more completely is the development of a reliable method to accurately predict the function of a protein from its genomic information. This study focuses on developing an effective algorithm for protein function prediction. The algorithm is based on proteins that have similar expression patterns. The similarity of the expression data is determined using a novel measure, the slope matrix. The slope matrix introduces a normalized method for the comparison of expression levels throughout a proteome. The algorithm is tested using real microarray gene expression data. Their functions are characterized using gene ontology annotations. The results of the case study indicate the protein function prediction algorithm developed is comparable to the prediction algorithms that are based on the annotations of homologous proteins. -
(12) Patent Application Publication (10) Pub. No.: US 2004/0224012 A1 Suvanprakorn Et Al
US 2004O224012A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0224012 A1 Suvanprakorn et al. (43) Pub. Date: Nov. 11, 2004 (54) TOPICAL APPLICATION AND METHODS Related U.S. Application Data FOR ADMINISTRATION OF ACTIVE AGENTS USING LIPOSOME MACRO-BEADS (63) Continuation-in-part of application No. 10/264,205, filed on Oct. 3, 2002. (76) Inventors: Pichit Suvanprakorn, Bangkok (TH); (60) Provisional application No. 60/327,643, filed on Oct. Tanusin Ploysangam, Bangkok (TH); 5, 2001. Lerson Tanasugarn, Bangkok (TH); Suwalee Chandrkrachang, Bangkok Publication Classification (TH); Nardo Zaias, Miami Beach, FL (US) (51) Int. CI.7. A61K 9/127; A61K 9/14 (52) U.S. Cl. ............................................ 424/450; 424/489 Correspondence Address: (57) ABSTRACT Eric G. Masamori 6520 Ridgewood Drive A topical application and methods for administration of Castro Valley, CA 94.552 (US) active agents encapsulated within non-permeable macro beads to enable a wider range of delivery vehicles, to provide longer product shelf-life, to allow multiple active (21) Appl. No.: 10/864,149 agents within the composition, to allow the controlled use of the active agents, to provide protected and designable release features and to provide visual inspection for damage (22) Filed: Jun. 9, 2004 and inconsistency. US 2004/0224012 A1 Nov. 11, 2004 TOPCAL APPLICATION AND METHODS FOR 0006 Various limitations on the shelf-life and use of ADMINISTRATION OF ACTIVE AGENTS USING liposome compounds exist due to the relatively fragile LPOSOME MACRO-BEADS nature of liposomes. Major problems encountered during liposome drug Storage in vesicular Suspension are the chemi CROSS REFERENCE TO OTHER cal alterations of the lipoSome compounds, Such as phos APPLICATIONS pholipids, cholesterols, ceramides, leading to potentially toxic degradation of the products, leakage of the drug from 0001) This application claims the benefit of U.S. -
The Role of Polyamine Uptake Transporters on Growth and Development of Arabidopsis Thaliana
THE ROLE OF POLYAMINE UPTAKE TRANSPORTERS ON GROWTH AND DEVELOPMENT OF ARABIDOPSIS THALIANA Jigarkumar Patel A Dissertation Submitted to the Graduate College of Bowling Green State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY May 2015 Committee: Paul Morris, Advisor Wendy D Manning Graduate Faculty Representative Vipaporn Phuntumart Scott Rogers Ray Larsen © 2015 Jigarkumar Patel All Rights Reserved iii ABSTRACT Paul Morris, Advisor Transgenic manipulation of polyamine levels has provided compelling evidence that polyamines enable plants to respond to environmental cues by activation of stress and developmental pathways. Here we show that the chloroplasts of A. thaliana and soybeans contain both an arginine decarboxylase, and an arginase/agmatinase. These two enzymes combine to synthesize putrescine from arginine. Since the sequences of plant arginases show conservation of key residues and the predicted 3D structures of plant agmatinases overlap the crystal structure of the enzyme from Deinococcus radiodurans, we suggest that these enzymes can synthesize putrescine, whenever they have access to the substrate agmatine. Finally, we show that synthesis of putrescine by ornithine decarboxylase takes place in the ER. Thus A. thaliana has two, and soybeans have three separate pathways for the synthesis of putrescine. This study also describes key changes in plant phenotypes in response to altered transport of polyamines. iv Dedicated to my father, Jayantilal Haribhai Patel v ACKNOWLEDGMENTS I would like to thank my advisor, Dr. Paul F. Morris, for helping me learn and grow during my Ph.D. Dr. Morris has an open door policy, and he was always available to answer my questions and provide helpful suggestions. -
Electronic Supplementary Material (ESI) for Molecular Biosystems
Electronic Supplementary Material (ESI) for Molecular BioSystems. This journal is © The Royal Society of Chemistry 2015 Table S5 Mass data of proteins identified with label free shotgun proteomics a #Alt. Proteins; b Scores; c #Peptides; d SC [%]; e RMS90 [ppm]; f Rank; g Median(Controls:GLP1); h #(Controls:GLP1); i CV [%](Controls:GLP1); l Median(Controls:Palmitate); m #(Controls:Palmitate) ; n CV [%](Controls:Palmitate); o Median(Controls:GLP1 + Palmitate); p #(Controls:GLP1 + Palmitate); q CV [%](Controls:GLP1 + Palmitate) MW OK Accession Protein pI a b c d e f g h i l m n o p q [kDa] 78 kDa glucose-regulated protein OS=Rattus 1672.6 true GRP78_RAT 72.3 4.9 1 22 39 1.48 1 1.16 6 20.53 1.18 9 9.56 1.24 10 13.52 norvegicus GN=Hspa5 PE=1 SV=1 (M:1672.6) Endoplasmin OS=Rattus norvegicus 1253.0 true ENPL_RAT 92.7 4.6 1 23 29 3.34 2 0.85 8 33.34 1.19 6 39.58 1.18 10 28.11 GN=Hsp90b1 PE=1 SV=2 (M:1253.0) Stress-70 protein, mitochondrial OS=Rattus 1138.8 true GRP75_RAT 73.8 5.9 1 17 28.7 1.18 3 1.21 5 7.62 0.78 1 1.1 8 8.04 norvegicus GN=Hspa9 PE=1 SV=3 (M:1138.8) Protein disulfide-isomerase A3 OS=Rattus 1035.4 true PDIA3_RAT 56.6 5.8 1 16 35.2 2.84 4 0.94 3 17.22 1.15 4 26.62 1.25 4 7.86 norvegicus GN=Pdia3 PE=1 SV=2 (M:1035.4) Aconitate hydratase, mitochondrial 983.8 true ACON_RAT OS=Rattus norvegicus GN=Aco2 PE=1 85.4 8.7 1 19 31.4 2.72 5 0.89 2 23.6 1.21 2 9.25 0.89 3 32.87 (M:983.8) SV=2 60 kDa heat shock protein, mitochondrial 906.9 true CH60_RAT OS=Rattus norvegicus GN=Hspd1 PE=1 60.9 5.8 1 13 32.5 3.26 6 1.05 5 13.15 1.01 2 32.54 1.01 -
Expressed Sequence Tag Analysis of the Response of Apple
Physiologia Plantarum 133: 298–317. 2008 Copyright ª Physiologia Plantarum 2008, ISSN 0031-9317 Expressed sequence tag analysis of the response of apple (Malus x domestica ‘Royal Gala’) to low temperature and water deficit Michael Wisniewskia,*, Carole Bassetta,*, John Norellia, Dumitru Macarisina, Timothy Artlipa, Ksenija Gasicb and Schuyler Korbanb aUnited States Department of Agriculture – Agricultural Research Service (USDA-ARS), Appalachian Fruit Research Station, 2217 Wiltshire Road, Kearneysville, WV 25430, USA bDepartment of Natural Resources and Environmental Sciences, University of Illinois, 310 ERML, 1201 W. Gregory Drive, Urbana, IL 61801, USA Correspondence Leaf, bark, xylem and root tissues were used to make nine cDNA libraries from *Corresponding author, non-stressed (control) ‘Royal Gala’ apple trees, and from ‘Royal Gala’ trees e-mail: [email protected]; exposed to either low temperature (5°C for 24 h) or water deficit (45% of [email protected] saturated pot mass for 2 weeks). Over 22 600 clones from the nine libraries # Received 26 September 2007; revised 3 were subjected to 5 single-pass sequencing, clustered and annotated using January 2008 BLASTX. The number of clusters in the libraries ranged from 170 to 1430. Regarding annotation of the sequences, BLASTX analysis indicated that within doi: 10.1111/j.1399-3054.2008.01063.x the libraries 65–72% of the clones had a high similarity to known function genes, 6–15% had no functional assignment and 15–26% were completely novel. The expressed sequence tags were combined into three classes (control, low-temperature and water deficit) and the annotated genes in each class were placed into 1 of 10 different functional categories. -
HMG-Coa Reductase (HMGCR)
HMG-CoA Reductase (HMGCR) HMG-CoA Reductase (HMGCR) is the rate-limiting enzyme for cholesterol synthesis in the conversion of HMG-CoA to mevalonate. HMGCR is found in eukaryotes and prokaryotes. The phylogenetic analysis has revealed two classes of HMG-CoA reductase, the Class I enzymes of eukaryotes and some archaea and the Class II enzymes of eubacteria and certain other archaea. Both in eukaryotes and in archaebacteria the enzyme HMGCR is known to catalyze an early reaction unique to isoprenoid biosynthesis. In humans, the HMG-CoA reductase reaction is rate-limiting for the biosynthesis of cholesterol and therefore constitutes a prime target of drugs that reduce serum cholesterol levels. www.MedChemExpress.com 1 HMG-CoA Reductase (HMGCR) Inhibitors (3R,5R)-Rosuvastatin (3R,5S)-Fluvastatin Cat. No.: HY-17504C ((3R,5S)-XU 62-320 free acid) Cat. No.: HY-14664B (3R,5R)-Rosuvastatin is the (3R,5R)-enantiomer of (3R,5S)-Fluvastatin is the Rosuvastatin. Rosuvastatin is a competitive 3R,5S-isomer Fluvastatin. Fluvastatin (XU HMG-CoA reductase inhibitor with an IC50 of 11 62-320 free acid) is a first fully synthetic, nM. Rosuvastatin potently blocks human competitive HMG-CoA reductase inhibitor with ether-a-go-go related gene (hERG) current with an an IC50 of 8 nM. IC50 of 195 nM. Purity: >98% Purity: >98% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 1 mg, 5 mg (3S,5R)-Fluvastatin D6 sodium (3S,5R)-Fluvastatin sodium ((3S,5R)-XU 62-320 D6) Cat. No.: HY-14664CS ((3S,5R)-XU 62-320) Cat. -
RT² Profiler PCR Array (Rotor-Gene® Format) Human Amino Acid Metabolism I
RT² Profiler PCR Array (Rotor-Gene® Format) Human Amino Acid Metabolism I Cat. no. 330231 PAHS-129ZR For pathway expression analysis Format For use with the following real-time cyclers RT² Profiler PCR Array, Rotor-Gene Q, other Rotor-Gene cyclers Format R Description The Human Amino Acid Metabolism I RT² Profiler PCR Array profiles the expression of 84 key genes important in biosynthesis and degradation of functional amino acids. Of the 20 amino acids required for protein synthesis, six of them (arginine, cysteine, glutamine, leucine, proline, and tryptophan), collectively known as the functional amino acids, regulate key metabolic pathways involved in cellular growth, and development, as well as other important biological processes such as immunity and reproduction. For example, leucine activates mTOR signaling and increases protein synthesis, leading to lymphocyte proliferation. Therefore, a lack of leucine can compromise immune function. Metabolic pathways interrelated with the biosynthesis and degradation of these amino acids include vitamin and cofactor biosynthesis (such as SAM or S-Adenosyl Methionine) as well as neurotransmitter metabolism (such as glutamate). This array includes genes for mammalian functional amino acid metabolism as well as genes involved in methionine metabolism, important also for nutrient sensing and sulfur metabolism. Using realtime PCR, you can easily and reliably analyze the expression of a focused panel of genes involved in functional amino acid metabolism with this array. For further details, consult the RT² Profiler PCR Array Handbook. Shipping and storage RT² Profiler PCR Arrays in the Rotor-Gene format are shipped at ambient temperature, on dry ice, or blue ice packs depending on destination and accompanying products. -
Loss of Fam60a, a Sin3a Subunit, Results in Embryonic Lethality and Is Associated with Aberrant Methylation at a Subset of Gene
RESEARCH ARTICLE Loss of Fam60a, a Sin3a subunit, results in embryonic lethality and is associated with aberrant methylation at a subset of gene promoters Ryo Nabeshima1,2, Osamu Nishimura3,4, Takako Maeda1, Natsumi Shimizu2, Takahiro Ide2, Kenta Yashiro1†, Yasuo Sakai1, Chikara Meno1, Mitsutaka Kadota3,4, Hidetaka Shiratori1†, Shigehiro Kuraku3,4*, Hiroshi Hamada1,2* 1Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan; 2Laboratory for Organismal Patterning, RIKEN Center for Developmental Biology, Kobe, Japan; 3Phyloinformatics Unit, RIKEN Center for Life Science Technologies, Kobe, Japan; 4Laboratory for Phyloinformatics, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan Abstract We have examined the role of Fam60a, a gene highly expressed in embryonic stem cells, in mouse development. Fam60a interacts with components of the Sin3a-Hdac transcriptional corepressor complex, and most Fam60a–/– embryos manifest hypoplasia of visceral organs and die in utero. Fam60a is recruited to the promoter regions of a subset of genes, with the expression of these genes being either up- or down-regulated in Fam60a–/– embryos. The DNA methylation level of the Fam60a target gene Adhfe1 is maintained at embryonic day (E) 7.5 but markedly reduced at –/– *For correspondence: E9.5 in Fam60a embryos, suggesting that DNA demethylation is enhanced in the mutant. [email protected] (SK); Examination of genome-wide DNA methylation identified several differentially methylated regions, [email protected] (HH) which were preferentially hypomethylated, in Fam60a–/– embryos. Our data suggest that Fam60a is †These authors contributed required for proper embryogenesis, at least in part as a result of its regulation of DNA methylation equally to this work at specific gene promoters. -
Mergeomics: Multidimensional Data Integration to Identify Pathogenic Perturbations to Biological Systems
Shu et al. BMC Genomics (2016) 17:874 DOI 10.1186/s12864-016-3198-9 METHODOLOGY ARTICLE Open Access Mergeomics: multidimensional data integration to identify pathogenic perturbations to biological systems Le Shu1, Yuqi Zhao1, Zeyneb Kurt1, Sean Geoffrey Byars2,3, Taru Tukiainen4, Johannes Kettunen4, Luz D. Orozco5, Matteo Pellegrini5, Aldons J. Lusis6, Samuli Ripatti4, Bin Zhang7, Michael Inouye2,3,8, Ville-Petteri Mäkinen1,9,10,11* and Xia Yang1,12* Abstract Background: Complex diseases are characterized by multiple subtle perturbations to biological processes. New omics platforms can detect these perturbations, but translating the diverse molecular and statistical information into testable mechanistic hypotheses is challenging. Therefore, we set out to create a public tool that integrates these data across multiple datasets, platforms, study designs and species in order to detect the most promising targets for further mechanistic studies. Results: We developed Mergeomics, a computational pipeline consisting of independent modules that 1) leverage multi-omics association data to identify biological processes that are perturbed in disease, and 2) overlay the disease- associated processes onto molecular interaction networks to pinpoint hubs as potential key regulators. Unlike existing tools that are mostly dedicated to specific data type or settings, the Mergeomics pipeline accepts and integrates datasets across platforms, data types and species. We optimized and evaluated the performance of Mergeomics using simulation and multiple independent datasets, and benchmarked the results against alternative methods. We also demonstrate the versatility of Mergeomics in two case studies that include genome-wide, epigenome-wide and transcriptome-wide datasets from human and mouse studies of total cholesterol and fasting glucose. -
Inosine in Biology and Disease
G C A T T A C G G C A T genes Review Inosine in Biology and Disease Sundaramoorthy Srinivasan 1, Adrian Gabriel Torres 1 and Lluís Ribas de Pouplana 1,2,* 1 Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, 08028 Barcelona, Catalonia, Spain; [email protected] (S.S.); [email protected] (A.G.T.) 2 Catalan Institution for Research and Advanced Studies, 08010 Barcelona, Catalonia, Spain * Correspondence: [email protected]; Tel.: +34-934034868; Fax: +34-934034870 Abstract: The nucleoside inosine plays an important role in purine biosynthesis, gene translation, and modulation of the fate of RNAs. The editing of adenosine to inosine is a widespread post- transcriptional modification in transfer RNAs (tRNAs) and messenger RNAs (mRNAs). At the wobble position of tRNA anticodons, inosine profoundly modifies codon recognition, while in mRNA, inosines can modify the sequence of the translated polypeptide or modulate the stability, localization, and splicing of transcripts. Inosine is also found in non-coding and exogenous RNAs, where it plays key structural and functional roles. In addition, molecular inosine is an important secondary metabolite in purine metabolism that also acts as a molecular messenger in cell signaling pathways. Here, we review the functional roles of inosine in biology and their connections to human health. Keywords: inosine; deamination; adenosine deaminase acting on RNAs; RNA modification; translation Citation: Srinivasan, S.; Torres, A.G.; Ribas de Pouplana, L. Inosine in 1. Introduction Biology and Disease. Genes 2021, 12, 600. https://doi.org/10.3390/ Inosine was one of the first nucleobase modifications discovered in nucleic acids, genes12040600 having been identified in 1965 as a component of the first sequenced transfer RNA (tRNA), tRNAAla [1].