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https://www.readbyqxmd.com/read/27880934/tumors-with-unmethylated-mlh1-and-the-cpg-island-methylator-phenotype-are-associated-with-a-poor-prognosis-in-stage-ii-colorectal-cancer-patients
#1
Tao Fu, Yanliang Liu, Kai Li, Weiwei Wan, Emmanouil P Pappou, Christine A Iacobuzio-Donahue, Zachary Kerner, Stephen B Baylin, Christopher L Wolfgang, Nita Ahuja
We previously developed a novel tumor subtype classification model for duodenal adenocarcinomas based on a combination of the CpG island methylator phenotype (CIMP) and MLH1 methylation status. Here, we tested the prognostic value of this model in stage II colorectal cancer (CRC) patients. Tumors were assigned to CIMP+/MLH1-unmethylated (MLH1-U), CIMP+/MLH1-methylated (MLH1-M), CIMP-/MLH1-U, or CIMP-/MLH1-M groups. Age, tumor location, lymphovascular invasion, and mucin production differed among the four patient subgroups, and CIMP+/MLH1-U tumors were more likely to have lymphovascular invasion and mucin production...
November 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27729459/early-detection-of-lung-cancer-using-dna-promoter-hypermethylation-in-plasma-and-sputum
#2
Alicia Hulbert, Ignacio Jusue Torres, Alejandro Stark, Chen Chen, Kristen Rodgers, Beverly Lee, Candace Griffin, Andrew Yang, Peng Huang, John Wrangle, Steven A Belinsky, Tza-Huei Wang, Stephen C Yang, Stephen B Baylin, Malcolm V Brock, James G Herman
PURPOSE: CT screening can reduce death from lung cancer. We sought to improve the diagnostic accuracy of lung cancer screening using ultrasensitive methods and a lung cancer specific gene panel to detect DNA methylation in sputum and Plasma. EXPERIMENTAL DESIGN: This is a case-control study of subjects with suspicious nodules on CT imaging. Plasma and sputum were obtained pre-operatively. Cases (n=150) had pathological confirmation of node negative (stage I and IIA) non-small cell lung cancer...
October 11, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27728808/enhancing-the-cytotoxic-effects-of-parp-inhibitors-with-dna-demethylating-agents-a-potential-therapy-for-cancer
#3
Nidal E Muvarak, Khadiza Chowdhury, Limin Xia, Carine Robert, Eun Yong Choi, Yi Cai, Marina Bellani, Ying Zou, Zeba N Singh, Vu H Duong, Tyler Rutherford, Pratik Nagaria, Søren M Bentzen, Michael M Seidman, Maria R Baer, Rena G Lapidus, Stephen B Baylin, Feyruz V Rassool
Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites...
October 10, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27660325/tankyrase-inhibition-promotes-a-stable-human-na%C3%A3-ve-pluripotent-state-with-improved-functionality
#4
Ludovic Zimmerlin, Tea Soon Park, Jeffrey S Huo, Karan Verma, Sarshan R Pather, C Conover Talbot, Jasmin Agarwal, Diana Steppan, Yang W Zhang, Michael Considine, Hong Guo, Xiufeng Zhong, Christian Gutierrez, Leslie Cope, M Valeria Canto-Soler, Alan D Friedman, Stephen B Baylin, Elias T Zambidis
The derivation and maintenance of human pluripotent stem cells (hPSCs) in stable naïve pluripotent states has a wide impact in human developmental biology. However, hPSCs are unstable in classical naïve mouse embryonic stem cell (ESC) WNT and MEK/ERK signal inhibition (2i) culture. We show that a broad repertoire of conventional hESC and transgene-independent human induced pluripotent stem cell (hiPSC) lines could be reverted to stable human preimplantation inner cell mass (ICM)-like naïve states with only WNT, MEK/ERK, and tankyrase inhibition (LIF-3i)...
December 1, 2016: Development
https://www.readbyqxmd.com/read/27643594/methylation-of-mgmt-is-associated-with-poor-prognosis-in-patients-with-stage-iii-duodenal-adenocarcinoma
#5
Tao Fu, Anup Sharmab, Fei Xie, Yanliang Liu, Kai Li, Weiwei Wan, Stephen B Baylin, Christopher L Wolfgang, Nita Ahuja
BACKGROUND: O6-methylguanine-DNA methyltransferase (MGMT) methylation status has not been extensively investigated in duodenal adenocarcinoma (DA). The aim of this study was to evaluate the MGMT methylation status and examine its possible prognostic value in patients with stage III DA. METHODS: Demographics, tumor characteristics and survival were available for 64 patients with stage III DA. MGMT methylation was detected by using MethyLight. A Cox proportional hazard model was built to predict survival, adjusted for clinicopathological characteristics and tumor molecular features, including the CpG island methylator phenotype (CIMP), microsatellite instability (MSI), and KRAS mutations...
2016: PloS One
https://www.readbyqxmd.com/read/27634286/genome-wide-positioning-of-bivalent-mononucleosomes
#6
Subhojit Sen, Kirsten F Block, Alice Pasini, Stephen B Baylin, Hariharan Easwaran
BACKGROUND: Bivalent chromatin refers to overlapping regions containing activating histone H3 Lys4 trimethylation (H3K4me3) and inactivating H3K27me3 marks. Existence of such bivalent marks on the same nucleosome has only recently been suggested. Previous genome-wide efforts to characterize bivalent chromatin have focused primarily on individual marks to define overlapping zones of bivalency rather than mapping positions of truly bivalent mononucleosomes. RESULTS: Here, we developed an efficacious sequential ChIP technique for examining global positioning of individual bivalent nucleosomes...
September 15, 2016: BMC Medical Genomics
https://www.readbyqxmd.com/read/27629931/targeting-the-cancer-epigenome-for-therapy
#7
Peter A Jones, Jean-Pierre J Issa, Stephen Baylin
Next-generation sequencing has revealed that more than 50% of human cancers harbour mutations in enzymes that are involved in chromatin organization. Tumour cells not only are activated by genetic and epigenetic alterations, but also routinely use epigenetic processes to ensure their escape from chemotherapy and host immune surveillance. Hence, a growing emphasis of recent drug discovery efforts has been on targeting the epigenome, including DNA methylation and histone modifications, with several new drugs being tested and some already approved by the US Food and Drug Administration (FDA)...
September 15, 2016: Nature Reviews. Genetics
https://www.readbyqxmd.com/read/27573823/vitamin-c-increases-viral-mimicry-induced-by-5-aza-2-deoxycytidine
#8
Minmin Liu, Hitoshi Ohtani, Wanding Zhou, Andreas Due Ørskov, Jessica Charlet, Yang W Zhang, Hui Shen, Stephen B Baylin, Gangning Liang, Kirsten Grønbæk, Peter A Jones
Vitamin C deficiency is found in patients with cancer and might complicate various therapy paradigms. Here we show how this deficiency may influence the use of DNA methyltransferase inhibitors (DNMTis) for treatment of hematological neoplasias. In vitro, when vitamin C is added at physiological levels to low doses of the DNMTi 5-aza-2'-deoxycytidine (5-aza-CdR), there is a synergistic inhibition of cancer-cell proliferation and increased apoptosis. These effects are associated with enhanced immune signals including increased expression of bidirectionally transcribed endogenous retrovirus (ERV) transcripts, increased cytosolic dsRNA, and activation of an IFN-inducing cellular response...
September 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27467919/unraveling-the-molecular-pathways-of-dna-methylation-inhibitors-human-endogenous-retroviruses-induce-the-innate-immune-response-in-tumors
#9
Reiner Strick, Pamela L Strissel, Stephen B Baylin, Katherine B Chiappinelli
Loss of DNA methylation can activate endogenous retroviral expression and dsRNA in cancer cells. This leads to induction of toll-like receptor signaling stimulating an antiviral interferon response. Recent findings provide a therapeutic rationale for combining DNA methylation inhibitors with blockage of immune checkpoint proteins to fight cancer.
May 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27197249/jacob-monod-the-lac-operon-and-the-pajama-experiment-gene-expression-circuitry-changing-the-face-of-cancer-research
#10
Stephen B Baylin
No abstract text is available yet for this article.
April 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27194046/epigenetic-determinants-of-cancer
#11
REVIEW
Stephen B Baylin, Peter A Jones
SUMMARYEpigenetic changes are present in all human cancers and are now known to cooperate with genetic alterations to drive the cancer phenotype. These changes involve DNA methylation, histone modifiers and readers, chromatin remodelers, microRNAs, and other components of chromatin. Cancer genetics and epigenetics are inextricably linked in generating the malignant phenotype; epigenetic changes can cause mutations in genes, and, conversely, mutations are frequently observed in genes that modify the epigenome...
2016: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/27064190/inhibiting-dna-methylation-causes-an-interferon-response-in-cancer-via-dsrna-including-endogenous-retroviruses
#12
Katherine B Chiappinelli, Pamela L Strissel, Alexis Desrichard, Huili Li, Christine Henke, Benjamin Akman, Alexander Hein, Neal S Rote, Leslie M Cope, Alexandra Snyder, Vladimir Makarov, Sadna Budhu, Dennis J Slamon, Jedd D Wolchok, Drew M Pardoll, Matthias W Beckmann, Cynthia A Zahnow, Taha Merghoub, Timothy A Chan, Stephen B Baylin, Reiner Strick
No abstract text is available yet for this article.
February 25, 2016: Cell
https://www.readbyqxmd.com/read/26988985/combining-epigenetic-and-immunotherapy-to-combat-cancer
#13
REVIEW
Katherine B Chiappinelli, Cynthia A Zahnow, Nita Ahuja, Stephen B Baylin
The most exciting recent advance for achieving durable management of advanced human cancers is immunotherapy, especially the concept of immune checkpoint blockade. However, with the exception of melanoma, most patients do not respond to immunotherapy alone. A growing body of work has shown that epigenetic drugs, specifically DNA methyltransferase inhibitors, can upregulate immune signaling in epithelial cancer cells through demethylation of endogenous retroviruses and cancer testis antigens. These demethylating agents may induce T-cell attraction and enhance immune checkpoint inhibitor efficacy in mouse models...
April 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/26894863/a-new-immunohistochemistry-prognostic-score-ips-for-recurrence-and-survival-in-resected-pancreatic-neuroendocrine-tumors-pannet
#14
Antonio Viúdez, Filipe L F Carvalho, Zahra Maleki, Marianna Zahurak, Daniel Laheru, Alejandro Stark, Nilofer Z Azad, Christopher L Wolfgang, Stephen Baylin, James G Herman, Ana De Jesus-Acosta
Pancreatic neuroendocrine tumor (PanNET) is a neoplastic entity in which few prognostic factors are well-known. Here, we aimed to evaluate the prognostic significance of N-myc downstream-regulated gen-1 (NDRG-1), O6-methylguanine DNA methyltransferase (MGMT) and Pleckstrin homology-like domain family A member 3 (PHLDA-3) by immunohistochemistry (IHC) and methylation analysis in 92 patients with resected PanNET and follow-up longer than 24 months. In multivariate analyses, ki-67 and our immunohistochemistry prognostic score (IPS-based on MGMT, NDRG-1 and PHLDA-3 IHC expression) were independent prognostic factors for disease-free-survival (DFS), while age and IPS were independent prognostic factors for overall survival (OS)...
May 3, 2016: Oncotarget
https://www.readbyqxmd.com/read/26768237/epigenetic-therapeutics-a-new-weapon-in-the-war-against-cancer
#15
REVIEW
Nita Ahuja, Anup R Sharma, Stephen B Baylin
The past 15 years have seen an explosion of discoveries related to the cellular regulation of phenotypes through epigenetic mechanisms. This regulation provides a software that packages DNA, without changing the primary base sequence, to establish heritable patterns of gene expression. In cancer, many aspects of the epigenome, controlled by DNA methylation, chromatin, and nucleosome positioning, are altered as one means by which tumor cells maintain abnormal states of self-renewal at the expense of normal maturation...
2016: Annual Review of Medicine
https://www.readbyqxmd.com/read/26719529/targeting-calcium-signaling-induces-epigenetic-reactivation-of-tumor-suppressor-genes-in-cancer
#16
Noël J-M Raynal, Justin T Lee, Youjun Wang, Annie Beaudry, Priyanka Madireddi, Judith Garriga, Gabriel G Malouf, Sarah Dumont, Elisha J Dettman, Vazganush Gharibyan, Saira Ahmed, Woonbok Chung, Wayne E Childers, Magid Abou-Gharbia, Ryan A Henry, Andrew J Andrews, Jaroslav Jelinek, Ying Cui, Stephen B Baylin, Donald L Gill, Jean-Pierre J Issa
Targeting epigenetic pathways is a promising approach for cancer therapy. Here, we report on the unexpected finding that targeting calcium signaling can reverse epigenetic silencing of tumor suppressor genes (TSG). In a screen for drugs that reactivate silenced gene expression in colon cancer cells, we found three classical epigenetic targeted drugs (DNA methylation and histone deacetylase inhibitors) and 11 other drugs that induced methylated and silenced CpG island promoters driving a reporter gene (GFP) as well as endogenous TSGs in multiple cancer cell lines...
March 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/26536169/comprehensive-molecular-characterization-of-papillary-renal-cell-carcinoma
#17
W Marston Linehan, Paul T Spellman, Christopher J Ricketts, Chad J Creighton, Suzanne S Fei, Caleb Davis, David A Wheeler, Bradley A Murray, Laura Schmidt, Cathy D Vocke, Myron Peto, Abu Amar M Al Mamun, Eve Shinbrot, Anurag Sethi, Samira Brooks, W Kimryn Rathmell, Angela N Brooks, Katherine A Hoadley, A Gordon Robertson, Denise Brooks, Reanne Bowlby, Sara Sadeghi, Hui Shen, Daniel J Weisenberger, Moiz Bootwalla, Stephen B Baylin, Peter W Laird, Andrew D Cherniack, Gordon Saksena, Scott Haake, Jun Li, Han Liang, Yiling Lu, Gordon B Mills, Rehan Akbani, Mark D M Leiserson, Benjamin J Raphael, Pavana Anur, Donald Bottaro, Laurence Albiges, Nandita Barnabas, Toni K Choueiri, Bogdan Czerniak, Andrew K Godwin, A Ari Hakimi, Thai H Ho, James Hsieh, Michael Ittmann, William Y Kim, Bhavani Krishnan, Maria J Merino, Kenna R Mills Shaw, Victor E Reuter, Ed Reznik, Carl S Shelley, Brian Shuch, Sabina Signoretti, Ramaprasad Srinivasan, Pheroze Tamboli, George Thomas, Satish Tickoo, Kenneth Burnett, Daniel Crain, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph D Paulauskis, Robert J Penny, Candace Shelton, W Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Melissa T Avedon, Jay Bowen, Julie M Gastier-Foster, Mark Gerken, Kristen M Leraas, Tara M Lichtenberg, Nilsa C Ramirez, Tracie Santos, Lisa Wise, Erik Zmuda, John A Demchok, Ina Felau, Carolyn M Hutter, Margi Sheth, Heidi J Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C Zenklusen, Jiashan Zhang, Brenda Ayala, Julien Baboud, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Adrian Ally, Miruna Balasundaram, Saianand Balu, Rameen Beroukhim, Tom Bodenheimer, Christian Buhay, Yaron S N Butterfield, Rebecca Carlsen, Scott L Carter, Hsu Chao, Eric Chuah, Amanda Clarke, Kyle R Covington, Mahmoud Dahdouli, Ninad Dewal, Noreen Dhalla, Harsha V Doddapaneni, Jennifer A Drummond, Stacey B Gabriel, Richard A Gibbs, Ranabir Guin, Walker Hale, Alicia Hawes, D Neil Hayes, Robert A Holt, Alan P Hoyle, Stuart R Jefferys, Steven J M Jones, Corbin D Jones, Divya Kalra, Christie Kovar, Lora Lewis, Jie Li, Yussanne Ma, Marco A Marra, Michael Mayo, Shaowu Meng, Matthew Meyerson, Piotr A Mieczkowski, Richard A Moore, Donna Morton, Lisle E Mose, Andrew J Mungall, Donna Muzny, Joel S Parker, Charles M Perou, Jeffrey Roach, Jacqueline E Schein, Steven E Schumacher, Yan Shi, Janae V Simons, Payal Sipahimalani, Tara Skelly, Matthew G Soloway, Carrie Sougnez, Angela Tam, Donghui Tan, Nina Thiessen, Umadevi Veluvolu, Min Wang, Matthew D Wilkerson, Tina Wong, Junyuan Wu, Liu Xi, Jane Zhou, Jason Bedford, Fengju Chen, Yao Fu, Mark Gerstein, David Haussler, Katayoon Kasaian, Phillip Lai, Shiyun Ling, Amie Radenbaugh, David Van Den Berg, John N Weinstein, Jingchun Zhu, Monique Albert, Iakovina Alexopoulou, Jeremiah J Andersen, J Todd Auman, John Bartlett, Sheldon Bastacky, Julie Bergsten, Michael L Blute, Lori Boice, Roni J Bollag, Jeff Boyd, Erik Castle, Ying-Bei Chen, John C Cheville, Erin Curley, Benjamin Davies, April DeVolk, Rajiv Dhir, Laura Dike, John Eckman, Jay Engel, Jodi Harr, Ronald Hrebinko, Mei Huang, Lori Huelsenbeck-Dill, Mary Iacocca, Bruce Jacobs, Michael Lobis, Jodi K Maranchie, Scott McMeekin, Jerome Myers, Joel Nelson, Jeremy Parfitt, Anil Parwani, Nicholas Petrelli, Brenda Rabeno, Somak Roy, Andrew L Salner, Joel Slaton, Melissa Stanton, R Houston Thompson, Leigh Thorne, Kelinda Tucker, Paul M Weinberger, Cynthia Winemiller, Leigh Anne Zach, Rosemary Zuna
BACKGROUND: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist. METHODS: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis...
January 14, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/26418030/interview-with-stephen-b-baylin
#18
Stephen B Baylin
Stephen B Baylin is a codirector of the Cancer Biology Program at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the Virginia and DK Ludwig Professor of Oncology and Medicine. Baylin attended Duke University, where he earned his medical degree and completed his internship and first year residency in internal medicine. He then worked for 2 years at the National Heart and Lung Institute of the NIH. In 1971, he joined the departments of oncology and medicine at Johns Hopkins University School of Medicine...
2015: Epigenomics
https://www.readbyqxmd.com/read/26317466/inhibiting-dna-methylation-causes-an-interferon-response-in-cancer-via-dsrna-including-endogenous-retroviruses
#19
Katherine B Chiappinelli, Pamela L Strissel, Alexis Desrichard, Huili Li, Christine Henke, Benjamin Akman, Alexander Hein, Neal S Rote, Leslie M Cope, Alexandra Snyder, Vladimir Makarov, Sadna Budhu, Sadna Buhu, Dennis J Slamon, Jedd D Wolchok, Drew M Pardoll, Matthias W Beckmann, Cynthia A Zahnow, Taha Merghoub, Taha Mergoub, Timothy A Chan, Stephen B Baylin, Reiner Strick
We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a type I interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response 2-fold and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response...
August 27, 2015: Cell
https://www.readbyqxmd.com/read/26186941/mismatch-repair-proteins-recruit-dna-methyltransferase-1-to-sites-of-oxidative-dna-damage
#20
Ning Ding, Emily M Bonham, Brooke E Hannon, Thomas R Amick, Stephen B Baylin, Heather M O'Hagan
At sites of chronic inflammation, epithelial cells are exposed to high levels of reactive oxygen species and undergo cancer-associated DNA methylation changes, suggesting that inflammation may initiate epigenetic alterations. Previously, we demonstrated that oxidative damage causes epigenetic silencing proteins to become part of a large complex that is localized to GC-rich regions of the genome, including promoter CpG islands that are epigenetically silenced in cancer. However, whether these proteins were recruited directly to damaged DNA or during the DNA repair process was unknown...
June 2016: Journal of Molecular Cell Biology
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