Ten Commandments for a Good Scientist
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Pancreatic Fibroblast Heterogeneity: from Development to Cancer
cells Review Pancreatic Fibroblast Heterogeneity: From Development to Cancer 1, 2, 2,3 Paloma E. Garcia y, Michael K. Scales y, Benjamin L. Allen and Marina Pasca di Magliano 2,3,4,* 1 Program in Molecular and Cellular Pathology, University of Michigan Medical School, University of Michigan, Ann Arbor, MI 48105, USA; [email protected] 2 Department of Cell and Developmental Biology, University of Michigan Medical School, University of Michigan, Ann Arbor, MI 48109, USA; [email protected] (M.K.S.); [email protected] (B.L.A.) 3 Rogel Cancer Center, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA 4 Department of Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA * Correspondence: [email protected]; Tel.: +1-734-276-7104 Authors contributed equally to this work. y Received: 22 October 2020; Accepted: 10 November 2020; Published: 12 November 2020 Abstract: Pancreatic ductal adenocarcinoma (PDA) is characterized by an extensive fibroinflammatory microenvironment that accumulates from the onset of disease progression. Cancer-associated fibroblasts (CAFs) are a prominent cellular component of the stroma, but their role during carcinogenesis remains controversial, with both tumor-supporting and tumor-restraining functions reported in different studies. One explanation for these contradictory findings is the heterogeneous nature of the fibroblast populations, and the different roles each subset might play in carcinogenesis. Here, we review the current literature on the origin and function of pancreatic fibroblasts, from the developing organ to the healthy adult pancreas, and throughout the initiation and progression of PDA. We also discuss clinical approaches to targeting fibroblasts in PDA. Keywords: fibroblasts; pancreas; cancer-associated fibroblasts; pancreas development; pancreatic cancer; tumor microenvironment; hedgehog; transforming growth factor Beta 1. -
Identification of GA-Binding Protein Transcription Factor Alpha Subunit
International Journal of Molecular Sciences Article Identification of GA-Binding Protein Transcription Factor Alpha Subunit (GABPA) as a Novel Bookmarking Factor Shunya Goto 1, Masashi Takahashi 1, Narumi Yasutsune 1, Sumiki Inayama 1, Dai Kato 2, Masashi Fukuoka 3, Shu-ichiro Kashiwaba 1 and Yasufumi Murakami 1,2,* 1 Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo 125-8585, Japan; [email protected] (S.G.); [email protected] (M.T.); [email protected] (N.Y.); [email protected] (S.I.); [email protected] (S.K.) 2 Order-MadeMedical Research Inc., 208Todai-Kashiwa VP, 5-4-19 Kashiwanoha, Kashiwa-shi, Chiba-ken 277-0882, Japan; [email protected] 3 Department of Molecular Pharmacology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-3-5876-1717 (ext. 1919); Fax: +81-3-5876-1470 Received: 7 February 2019; Accepted: 27 February 2019; Published: 4 March 2019 Abstract: Mitotic bookmarking constitutes a mechanism for transmitting transcriptional patterns through cell division. Bookmarking factors, comprising a subset of transcription factors (TFs), and multiple histone modifications retained in mitotic chromatin facilitate reactivation of transcription in the early G1 phase. However, the specific TFs that act as bookmarking factors remain largely unknown. Previously, we identified the “early G1 genes” and screened TFs that were predicted to bind to the upstream region of these genes, then identified GA-binding protein transcription factor alpha subunit (GABPA) and Sp1 transcription factor (SP1) as candidate bookmarking factors. -
Activated Peripheral-Blood-Derived Mononuclear Cells
Transcription factor expression in lipopolysaccharide- activated peripheral-blood-derived mononuclear cells Jared C. Roach*†, Kelly D. Smith*‡, Katie L. Strobe*, Stephanie M. Nissen*, Christian D. Haudenschild§, Daixing Zhou§, Thomas J. Vasicek¶, G. A. Heldʈ, Gustavo A. Stolovitzkyʈ, Leroy E. Hood*†, and Alan Aderem* *Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103; ‡Department of Pathology, University of Washington, Seattle, WA 98195; §Illumina, 25861 Industrial Boulevard, Hayward, CA 94545; ¶Medtronic, 710 Medtronic Parkway, Minneapolis, MN 55432; and ʈIBM Computational Biology Center, P.O. Box 218, Yorktown Heights, NY 10598 Contributed by Leroy E. Hood, August 21, 2007 (sent for review January 7, 2007) Transcription factors play a key role in integrating and modulating system. In this model system, we activated peripheral-blood-derived biological information. In this study, we comprehensively measured mononuclear cells, which can be loosely termed ‘‘macrophages,’’ the changing abundances of mRNAs over a time course of activation with lipopolysaccharide (LPS). We focused on the precise mea- of human peripheral-blood-derived mononuclear cells (‘‘macro- surement of mRNA concentrations. There is currently no high- phages’’) with lipopolysaccharide. Global and dynamic analysis of throughput technology that can precisely and sensitively measure all transcription factors in response to a physiological stimulus has yet to mRNAs in a system, although such technologies are likely to be be achieved in a human system, and our efforts significantly available in the near future. To demonstrate the potential utility of advanced this goal. We used multiple global high-throughput tech- such technologies, and to motivate their development and encour- nologies for measuring mRNA levels, including massively parallel age their use, we produced data from a combination of two distinct signature sequencing and GeneChip microarrays. -
Independence of Hif1a and Androgen Signaling Pathways in Prostate Cancer
bioRxiv preprint doi: https://doi.org/10.1101/848424; this version posted November 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Independence of HIF1a and androgen signaling pathways in prostate cancer Maxine GB Tran1, 2*, Becky AS Bibby3†*, Lingjian Yang3, Franklin Lo1, Anne Warren1, Deepa Shukla1, Michelle Osborne1, James Hadfield1, Thomas Carroll1, Rory Stark1, Helen Scott1, Antonio Ramos-Montoya1, Charlie Massie1, Patrick Maxwell1, Catharine ML West3, 4, Ian G. Mills5,6** and David E. Neal1** 1Uro-oncology Research Group, Cancer Research UK Cambridge Institute, Cambridge, CB02 0RE, United Kingdom 2UCL division of Surgery and Interventional Science, Royal Free Hospital, Pond Street, London NW3 2QG 3Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital NHS Trust, Manchester, M20 4BX, United Kingdom 4Manchester Biomedical Research Centre, University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom. 5Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, BT9 7AE, United Kingdom 6Nuffield Department of Surgical Sciences, University of Oxford, OX3 9DU, UK *These authors contributed equally to this work **These authors contributed equally to this work †Corresponding author email: Becky Bibby, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital NHS Trust, Manchester, M20 4BX, United Kingdom, [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/848424; this version posted November 26, 2019. -
Prospective Isolation of NKX2-1–Expressing Human Lung Progenitors Derived from Pluripotent Stem Cells
The Journal of Clinical Investigation RESEARCH ARTICLE Prospective isolation of NKX2-1–expressing human lung progenitors derived from pluripotent stem cells Finn Hawkins,1,2 Philipp Kramer,3 Anjali Jacob,1,2 Ian Driver,4 Dylan C. Thomas,1 Katherine B. McCauley,1,2 Nicholas Skvir,1 Ana M. Crane,3 Anita A. Kurmann,1,5 Anthony N. Hollenberg,5 Sinead Nguyen,1 Brandon G. Wong,6 Ahmad S. Khalil,6,7 Sarah X.L. Huang,3,8 Susan Guttentag,9 Jason R. Rock,4 John M. Shannon,10 Brian R. Davis,3 and Darrell N. Kotton1,2 2 1Center for Regenerative Medicine, and The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. 3Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA. 4Department of Anatomy, UCSF, San Francisco, California, USA. 5Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. 6Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, Massachusetts, USA. 7Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA. 8Columbia Center for Translational Immunology & Columbia Center for Human Development, Columbia University Medical Center, New York, New York, USA. 9Department of Pediatrics, Monroe Carell Jr. Children’s Hospital, Vanderbilt University, Nashville, Tennessee, USA. 10Division of Pulmonary Biology, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA. It has been postulated that during human fetal development, all cells of the lung epithelium derive from embryonic, endodermal, NK2 homeobox 1–expressing (NKX2-1+) precursor cells. -
Intratumoral Estrogen Disposition in Breast Cancer
Published OnlineFirst March 9, 2010; DOI: 10.1158/1078-0432.CCR-09-2481 Published Online First on March 9, 2010 as 10.1158/1078-0432.CCR-09-2481 Clinical Human Cancer Biology Cancer Research Intratumoral Estrogen Disposition in Breast Cancer Ben P. Haynes1, Anne Hege Straume3,4, Jürgen Geisler6, Roger A'Hern7, Hildegunn Helle5, Ian E. Smith2, Per E. Lønning3,5, and Mitch Dowsett1 Abstract Purpose: The concentration of estradiol (E2) in breast tumors is significantly higher than that in plas- ma, particularly in postmenopausal women. The contribution of local E2 synthesis versus uptake of E2 from the circulation is controversial. Our aim was to identify possible determinants of intratumoral E2 levels in breast cancer patients. Experimental Design: The expression of genes involved in estrogen synthesis, metabolism, and sig- naling was measured in 34 matched samples of breast tumor and normal breast tissue, and their corre- lation with estrogen concentrations assessed. Results: ESR1 (9.1-fold; P < 0.001) and HSD17B7 (3.5-fold; P < 0.001) were upregulated in ER+ tumors compared with normal tissues, whereas STS (0.34-fold; P < 0.001) and HSD17B5 (0.23-fold; P < 0.001) were downregulated. Intratumoral E2 levels showed a strong positive correlation with ESR1 expression in all patients (Spearman r = 0.55, P < 0.001) and among the subgroups of postmenopausal (r = 0.76, P < 0.001; n = 23) and postmenopausal ER+ patients (r = 0.59, P = 0.013; n = 17). HSD17B7 expression showed a significant positive correlation (r =0.59,P < 0.001) whereas HSD17B2 (r = −0.46, P = 0.0057) and HSD17B12 (r = −0.45, P = 0.0076) showed significant negative correlations with intratumoral E2 in all patients. -
Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug
cancers Article Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug Response Genes in Pediatric Acute Myeloid Leukemia David G.J. Cucchi 1 , Costa Bachas 1 , Marry M. van den Heuvel-Eibrink 2,3, Susan T.C.J.M. Arentsen-Peters 3, Zinia J. Kwidama 1, Gerrit J. Schuurhuis 1, Yehuda G. Assaraf 4, Valérie de Haas 3 , Gertjan J.L. Kaspers 3,5 and Jacqueline Cloos 1,* 1 Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; [email protected] (D.G.J.C.); [email protected] (C.B.); [email protected] (Z.J.K.); [email protected] (G.J.S.) 2 Department of Pediatric Oncology/Hematology, Erasmus MC–Sophia Children’s Hospital, 3015 CN Rotterdam, The Netherlands; [email protected] 3 Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; [email protected] (S.T.C.J.M.A.-P.); [email protected] (V.d.H.); [email protected] (G.J.L.K.) 4 The Fred Wyszkowski Cancer Research, Laboratory, Department of Biology, Technion-Israel Institute of Technology, 3200003 Haifa, Israel; [email protected] 5 Emma’s Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, 1081 HV Amsterdam, The Netherlands * Correspondence: [email protected] Received: 21 April 2020; Accepted: 12 May 2020; Published: 15 May 2020 Abstract: Novel treatment strategies are of paramount importance to improve clinical outcomes in pediatric AML. Since chemotherapy is likely to remain the cornerstone of curative treatment of AML, insights in the molecular mechanisms that determine its cytotoxic effects could aid further treatment optimization. -
ERG Dependence Distinguishes Developmental Control of Hematopoietic Stem Cell Maintenance from Hematopoietic Specification
Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification Samir Taoudi,1,2,6 Thomas Bee,3 Adrienne Hilton,1 Kathy Knezevic,3 Julie Scott,4 Tracy A. Willson,1,2 Caitlin Collin,1 Tim Thomas,1,2 Anne K. Voss,1,2 Benjamin T. Kile,1,2 Warren S. Alexander,2,5 John E. Pimanda,3 and Douglas J. Hilton1,2 1Molecular Medicine Division, The Walter and Eliza Institute of Medical Research, Melbourne, Parkville, Victoria 3052, Australia; 2Department of Medical Biology, The University of Melbourne, Melbourne, Parkville, Victoria 3010, Australia; 3Lowy Cancer Research Centre, The Prince of Wales Clinical School, University of New South Wales, Sydney 2052, Australia; 4Microinjection Services, The Walter and Eliza Institute of Medical Research, Melbourne, Parkville, Victoria 3052, Australia; 5Cancer and Haematology Division, The Walter and Eliza Institute of Medical Research, Melbourne, Parkville, Victoria 3052, Australia Although many genes are known to be critical for early hematopoiesis in the embryo, it remains unclear whether distinct regulatory pathways exist to control hematopoietic specification versus hematopoietic stem cell (HSC) emergence and function. Due to their interaction with key regulators of hematopoietic commitment, particular interest has focused on the role of the ETS family of transcription factors; of these, ERG is predicted to play an important role in the initiation of hematopoiesis, yet we do not know if or when ERG is required. Using in vitro and in vivo models of hematopoiesis and HSC development, we provide strong evidence that ERG is at the center of a distinct regulatory program that is not required for hematopoietic specification or differentiation but is critical for HSC maintenance during embryonic development. -
Ubiquitin-Mediated Control of ETS Transcription Factors: Roles in Cancer and Development
International Journal of Molecular Sciences Review Ubiquitin-Mediated Control of ETS Transcription Factors: Roles in Cancer and Development Charles Ducker * and Peter E. Shaw * Queen’s Medical Centre, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK * Correspondence: [email protected] (C.D.); [email protected] (P.E.S.) Abstract: Genome expansion, whole genome and gene duplication events during metazoan evolution produced an extensive family of ETS genes whose members express transcription factors with a conserved winged helix-turn-helix DNA-binding domain. Unravelling their biological roles has proved challenging with functional redundancy manifest in overlapping expression patterns, a common consensus DNA-binding motif and responsiveness to mitogen-activated protein kinase signalling. Key determinants of the cellular repertoire of ETS proteins are their stability and turnover, controlled largely by the actions of selective E3 ubiquitin ligases and deubiquitinases. Here we discuss the known relationships between ETS proteins and enzymes that determine their ubiquitin status, their integration with other developmental signal transduction pathways and how suppression of ETS protein ubiquitination contributes to the malignant cell phenotype in multiple cancers. Keywords: E3 ligase complex; deubiquitinase; gene fusions; mitogens; phosphorylation; DNA damage 1. Introduction Citation: Ducker, C.; Shaw, P.E. Cell growth, proliferation and differentiation are complex, concerted processes that Ubiquitin-Mediated Control of ETS Transcription Factors: Roles in Cancer rely on careful regulation of gene expression. Control over gene expression is maintained and Development. Int. J. Mol. Sci. through signalling pathways that respond to external cellular stimuli, such as growth 2021, 22, 5119. https://doi.org/ factors, cytokines and chemokines, that invoke expression profiles commensurate with 10.3390/ijms22105119 diverse cellular outcomes. -
To Study Mutant P53 Gain of Function, Various Tumor-Derived P53 Mutants
Differential effects of mutant TAp63γ on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By Shama K Khokhar M.Sc., Bilaspur University, 2004 B.Sc., Bhopal University, 2002 2007 1 COPYRIGHT SHAMA K KHOKHAR 2007 2 WRIGHT STATE UNIVERSITY SCHOOL OF GRADUATE STUDIES Date of Defense: 12-03-07 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY SHAMA KHAN KHOKHAR ENTITLED Differential effects of mutant TAp63γ on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science Madhavi P. Kadakia, Ph.D. Thesis Director Daniel Organisciak , Ph.D. Department Chair Committee on Final Examination Madhavi P. Kadakia, Ph.D. Steven J. Berberich, Ph.D. Michael Leffak, Ph.D. Joseph F. Thomas, Jr., Ph.D. Dean, School of Graduate Studies 3 Abstract Khokhar, Shama K. M.S., Department of Biochemistry and Molecular Biology, Wright State University, 2007 Differential effect of TAp63γ mutants on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression. p63, a member of the p53 gene family, known to play a role in development, has more recently also been implicated in cancer progression. Mice lacking p63 exhibit severe developmental defects such as limb truncations, abnormal skin, and absence of hair follicles, teeth, and mammary glands. Germline missense mutations of p63 have been shown to be responsible for several human developmental syndromes including SHFM, EEC and ADULT syndromes and are associated with anomalies in the development of organs of epithelial origin. -
HSD17B10 Gene Hydroxysteroid 17-Beta Dehydrogenase 10
HSD17B10 gene hydroxysteroid 17-beta dehydrogenase 10 Normal Function The HSD17B10 gene provides instructions for making a protein called HSD10. This protein is located within mitochondria, the energy-producing centers inside cells, where it has several different functions. The HSD10 protein is important for the production (synthesis) of proteins in mitochondria. (While most protein synthesis occurs in the fluid surrounding the nucleus, called the cytoplasm, a few proteins are synthesized in the mitochondria.) During protein synthesis, whether in the cytoplasm or in mitochondria, molecules called transfer RNAs (tRNAs) help assemble protein building blocks (amino acids) into the chains that form proteins. The HSD10 protein is involved in making functional mitochondrial tRNA. It forms a complex with an enzyme called TRMT10C to modify tRNAs so that they are more stable and can function properly. In addition, the complex interacts with another enzyme called PRORP to perform an enzymatic function called mitochondrial RNase P ( mtRNase P) that cuts precursor RNA molecules, which is an essential step to generating tRNA molecules. Normal mitochondrial protein production, which requires tRNAs, is essential for the formation of the protein complexes that convert the energy from food into a form cells can use. The HSD10 protein also plays an important role in processing several substances in the body. It helps break down the amino acid isoleucine. Specifically, it is responsible for the fifth step in this process, in which 2-methyl-3-hydroxybutyryl-CoA is converted into 2- methylacetoacetyl-CoA. Through a similar mechanism, the HSD10 protein also processes a group of fats called branched-chain fatty acids. -
GABPA Is a Master Regulator of Luminal Identity and Restrains Aggressive Diseases in Bladder Cancer
Cell Death & Differentiation (2020) 27:1862–1877 https://doi.org/10.1038/s41418-019-0466-7 ARTICLE GABPA is a master regulator of luminal identity and restrains aggressive diseases in bladder cancer 1,2,3 3,4 5 2,5 5 3 5 5 Yanxia Guo ● Xiaotian Yuan ● Kailin Li ● Mingkai Dai ● Lu Zhang ● Yujiao Wu ● Chao Sun ● Yuan Chen ● 5 6 3 1,2 1,2 3,7 Guanghui Cheng ● Cheng Liu ● Klas Strååt ● Feng Kong ● Shengtian Zhao ● Magnus Bjorkhölm ● Dawei Xu 3,7 Received: 3 June 2019 / Revised: 20 November 2019 / Accepted: 21 November 2019 / Published online: 4 December 2019 © The Author(s) 2019. This article is published with open access Abstract TERT promoter mutations occur in the majority of glioblastoma, bladder cancer (BC), and other malignancies while the ETS family transcription factors GABPA and its partner GABPB1 activate the mutant TERT promoter and telomerase in these tumors. GABPA depletion or the disruption of the GABPA/GABPB1 complex by knocking down GABPB1 was shown to inhibit telomerase, thereby eliminating the tumorigenic potential of glioblastoma cells. GABPA/B1 is thus suggested as a cancer therapeutic target. However, it is unclear about its role in BC. Here we unexpectedly observed that GABPA ablation 1234567890();,: 1234567890();,: inhibited TERT expression, but robustly increased proliferation, stem, and invasive phenotypes and cisplatin resistance in BC cells, while its overexpression exhibited opposite effects, and inhibited in vivo metastasizing in a xenograft transplant model. Mechanistically, GABPA directly activates the transcription of FoxA1 and GATA3, key transcription factors driving luminal differentiation of urothelial cells. Consistently, TCGA/GEO dataset analyses show that GABPA expression is correlated positively with luminal while negatively with basal signatures.