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Nature Medicine

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https://www.readbyqxmd.com/read/28805822/intrinsic-bet-inhibitor-resistance-in-spop-mutated-prostate-cancer-is-mediated-by-bet-protein-stabilization-and-akt-mtorc1-activation
#1
Pingzhao Zhang, Dejie Wang, Yu Zhao, Shancheng Ren, Kun Gao, Zhenqing Ye, Shangqian Wang, Chun-Wu Pan, Yasheng Zhu, Yuqian Yan, Yinhui Yang, Di Wu, Yundong He, Jun Zhang, Daru Lu, Xiuping Liu, Long Yu, Shimin Zhao, Yao Li, Dong Lin, Yuzhuo Wang, Liguo Wang, Yu Chen, Yinghao Sun, Chenji Wang, Haojie Huang
Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising anticancer therapies. The gene encoding the E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) is the most frequently mutated in primary prostate cancer. Here we demonstrate that wild-type SPOP binds to and induces ubiquitination and proteasomal degradation of BET proteins (BRD2, BRD3 and BRD4) by recognizing a degron motif common among them. In contrast, prostate cancer-associated SPOP mutants show impaired binding to BET proteins, resulting in decreased proteasomal degradation and accumulation of these proteins in prostate cancer cell lines and patient specimens and causing resistance to BET inhibitors...
August 14, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28805821/opposing-effects-of-cancer-type-specific-spop-mutants-on-bet-protein-degradation-and-sensitivity-to-bet-inhibitors
#2
Hana Janouskova, Geniver El Tekle, Elisa Bellini, Namrata D Udeshi, Anna Rinaldi, Anna Ulbricht, Tiziano Bernasocchi, Gianluca Civenni, Marco Losa, Tanya Svinkina, Craig M Bielski, Gregory V Kryukov, Luciano Cascione, Sara Napoli, Radoslav I Enchev, David G Mutch, Michael E Carney, Andrew Berchuck, Boris J N Winterhoff, Russell R Broaddus, Peter Schraml, Holger Moch, Francesco Bertoni, Carlo V Catapano, Matthias Peter, Steven A Carr, Levi A Garraway, Peter J Wild, Jean-Philippe P Theurillat
It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants...
August 14, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28805820/prostate-cancer-associated-spop-mutations-confer-resistance-to-bet-inhibitors-through-stabilization-of-brd4
#3
Xiangpeng Dai, Wenjian Gan, Xiaoning Li, Shangqian Wang, Wei Zhang, Ling Huang, Shengwu Liu, Qing Zhong, Jianping Guo, Jinfang Zhang, Ting Chen, Kouhei Shimizu, Francisco Beca, Mirjam Blattner, Divya Vasudevan, Dennis L Buckley, Jun Qi, Lorenz Buser, Pengda Liu, Hiroyuki Inuzuka, Andrew H Beck, Liewei Wang, Peter J Wild, Levi A Garraway, Mark A Rubin, Christopher E Barbieri, Kwok-Kin Wong, Senthil K Muthuswamy, Jiaoti Huang, Yu Chen, James E Bradner, Wenyi Wei
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer...
August 14, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28759053/the-eukaryotic-gut-virome-in-hematopoietic-stem-cell-transplantation-new-clues-in-enteric-graft-versus-host-disease
#4
Jérôme Legoff, Matthieu Resche-Rigon, Jerome Bouquet, Marie Robin, Samia N Naccache, Séverine Mercier-Delarue, Scot Federman, Erik Samayoa, Clotilde Rousseau, Prescillia Piron, Nathalie Kapel, François Simon, Gérard Socié, Charles Y Chiu
Much attention has been focused on the role of the bacterial microbiome in human health, but the virome is understudied. Although previously investigated in individuals with inflammatory bowel diseases or solid-organ transplants, virome dynamics in allogeneic hematopoietic stem cell transplantation (HSCT) and enteric graft-versus-host disease (GVHD) remain unexplored. Here we characterize the longitudinal gut virome in 44 recipients of HSCT using metagenomics. A viral 'bloom' was identified, and significant increases were demonstrated in the overall proportion of vertebrate viral sequences following transplantation (P = 0...
July 31, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28759051/implications-of-human-genetic-variation-in-crispr-based-therapeutic-genome-editing
#5
David A Scott, Feng Zhang
CRISPR-Cas genome-editing methods hold immense potential as therapeutic tools to fix disease-causing mutations at the level of DNA. In contrast to typical drug development strategies aimed at targets that are highly conserved among individual patients, treatment at the genomic level must contend with substantial inter-individual natural genetic variation. Here we analyze the recently released ExAC and 1000 Genomes data sets to determine how human genetic variation impacts target choice for Cas endonucleases in the context of therapeutic genome editing...
July 31, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28759052/d-mannose-induces-regulatory-t-cells-and-suppresses-immunopathology
#6
Dunfang Zhang, Cheryl Chia, Xue Jiao, Wenwen Jin, Shimpei Kasagi, Ruiqing Wu, Joanne E Konkel, Hiroko Nakatsukasa, Peter Zanvit, Nathan Goldberg, Qianming Chen, Lingyun Sun, Zi-Jiang Chen, WanJun Chen
D-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of D-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of D-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3(+) regulatory T cells (Treg cells) in mice...
July 24, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28777794/the-missing-pieces-lack-of-zika-data-from-africa-complicates-search-for-answers
#7
Nicole Wetsman
No abstract text is available yet for this article.
August 4, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28777793/resolving-a-chronic-inflammation-mystery
#8
Ben Roediger, Wolfgang Weninger
No abstract text is available yet for this article.
August 4, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28777792/lessons-from-reservoirs
#9
EDITORIAL
(no author information available yet)
No abstract text is available yet for this article.
August 4, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28777791/antimalarial-drug-resistance-linking-plasmodium-falciparum-parasite-biology-to-the-clinic
#10
REVIEW
Benjamin Blasco, Didier Leroy, David A Fidock
The global adoption of artemisinin-based combination therapies (ACTs) in the early 2000s heralded a new era in effectively treating drug-resistant Plasmodium falciparum malaria. However, several Southeast Asian countries have now reported the emergence of parasites that have decreased susceptibility to artemisinin (ART) derivatives and ACT partner drugs, resulting in increasing rates of treatment failures. Here we review recent advances in understanding how antimalarials act and how resistance develops, and discuss new strategies for effectively combatting resistance, optimizing treatment and advancing the global campaign to eliminate malaria...
August 4, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28777790/a-three-drug-combination-to-treat-braf-mutant-cancers
#11
Ari J Firestone, Jeff Settleman
No abstract text is available yet for this article.
August 4, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28777789/corrigendum-is-autoimmunity-the-achilles-heel-of-cancer-immunotherapy
#12
Carl H June, Jeremy T Warshauer, Jeffrey A Bluestone
No abstract text is available yet for this article.
August 4, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28777788/calculated-risk-a-new-single-nucleotide-polymorphism-linked-to-severe-influenza-disease
#13
Amie J Eisfeld, Yoshihiro Kawaoka
No abstract text is available yet for this article.
August 4, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28777787/corrigendum-analysis-of-self-antigen-specificity-of-islet-infiltrating-t-cells-from-human-donors-with-type-1-diabetes
#14
Jenny Aurielle B Babon, Megan E DeNicola, David M Blodgett, Inne Crèvecoeur, Thomas S Buttrick, René Maehr, Rita Bottino, Ali Naji, John Kaddis, Wassim Elyaman, Eddie A James, Rachana Haliyur, Marcela Brissova, Lut Overbergh, Chantal Mathieu, Thomas Delong, Kathryn Haskins, Alberto Pugliese, Martha Campbell-Thompson, Clayton Mathews, Mark A Atkinson, Alvin C Powers, David M Harlan, Sally C Kent
No abstract text is available yet for this article.
August 4, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28777786/breaking-through-how-researchers-are-gaining-entry-into-barricaded-bacteria
#15
Shraddha Chakradhar
No abstract text is available yet for this article.
August 4, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28777785/erratum-mutational-landscape-of-metastatic-cancer-revealed-from-prospective-clinical-sequencing-of-10-000-patients
#16
Ahmet Zehir, Ryma Benayed, Ronak H Shah, Aijazuddin Syed, Sumit Middha, Hyunjae R Kim, Preethi Srinivasan, Jianjiong Gao, Debyani Chakravarty, Sean M Devlin, Matthew D Hellmann, David A Barron, Alison M Schram, Meera Hameed, Snjezana Dogan, Dara S Ross, Jaclyn F Hechtman, Deborah F DeLair, JinJuan Yao, Diana L Mandelker, Donavan T Cheng, Raghu Chandramohan, Abhinita S Mohanty, Ryan N Ptashkin, Gowtham Jayakumaran, Meera Prasad, Mustafa H Syed, Anoop Balakrishnan Rema, Zhen Y Liu, Khedoudja Nafa, Laetitia Borsu, Justyna Sadowska, Jacklyn Casanova, Ruben Bacares, Iwona J Kiecka, Anna Razumova, Julie B Son, Lisa Stewart, Tessara Baldi, Kerry A Mullaney, Hikmat Al-Ahmadie, Efsevia Vakiani, Adam A Abeshouse, Alexander V Penson, Philip Jonsson, Niedzica Camacho, Matthew T Chang, Helen H Won, Benjamin E Gross, Ritika Kundra, Zachary J Heins, Hsiao-Wei Chen, Sarah Phillips, Hongxin Zhang, Jiaojiao Wang, Angelica Ochoa, Jonathan Wills, Michael Eubank, Stacy B Thomas, Stuart M Gardos, Dalicia N Reales, Jesse Galle, Robert Durany, Roy Cambria, Wassim Abida, Andrea Cercek, Darren R Feldman, Mrinal M Gounder, A Ari Hakimi, James J Harding, Gopa Iyer, Yelena Y Janjigian, Emmet J Jordan, Ciara M Kelly, Maeve A Lowery, Luc G T Morris, Antonio M Omuro, Nitya Raj, Pedram Razavi, Alexander N Shoushtari, Neerav Shukla, Tara E Soumerai, Anna M Varghese, Rona Yaeger, Jonathan Coleman, Bernard Bochner, Gregory J Riely, Leonard B Saltz, Howard I Scher, Paul J Sabbatini, Mark E Robson, David S Klimstra, Barry S Taylor, Jose Baselga, Nikolaus Schultz, David M Hyman, Maria E Arcila, David B Solit, Marc Ladanyi, Michael F Berger
No abstract text is available yet for this article.
August 4, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28777784/the-epigenome-editors-how-tools-such-as-crispr-offer-new-details-about-epigenetics
#17
Cassandra Willyard
No abstract text is available yet for this article.
August 4, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28714991/resolution-of-inflammation-by-interleukin-9-producing-type-2-innate-lymphoid-cells
#18
Simon Rauber, Markus Luber, Stefanie Weber, Lisa Maul, Alina Soare, Thomas Wohlfahrt, Neng-Yu Lin, Katharina Dietel, Aline Bozec, Martin Herrmann, Mark H Kaplan, Benno Weigmann, Mario M Zaiss, Ursula Fearon, Douglas J Veale, Juan D Cañete, Oliver Distler, Felice Rivellese, Costantino Pitzalis, Markus F Neurath, Andrew N J McKenzie, Stefan Wirtz, Georg Schett, Jörg H W Distler, Andreas Ramming
Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as the mediators of a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired ILC2 proliferation and activation of regulatory T (Treg) cells, and resulted in chronic arthritis with excessive cartilage destruction and bone loss...
August 2017: Nature Medicine
https://www.readbyqxmd.com/read/28714990/an-approach-to-suppress-the-evolution-of-resistance-in-braf-v600e-mutant-cancer
#19
Yaohua Xue, Luciano Martelotto, Timour Baslan, Alberto Vides, Martha Solomon, Trang Thi Mai, Neelam Chaudhary, Greg J Riely, Bob T Li, Kerry Scott, Fabiola Cechhi, Ulrika Stierner, Kalyani Chadalavada, Elisa de Stanchina, Sarit Schwartz, Todd Hembrough, Gouri Nanjangud, Michael F Berger, Jonas Nilsson, Scott W Lowe, Jorge S Reis-Filho, Neal Rosen, Piro Lito
The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAF(amp)) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment...
August 2017: Nature Medicine
https://www.readbyqxmd.com/read/28714989/correction-of-a-splicing-defect-in-a-mouse-model-of-congenital-muscular-dystrophy-type-1a-using-a-homology-directed-repair-independent-mechanism
#20
Dwi U Kemaladewi, Eleonora Maino, Elzbieta Hyatt, Huayun Hou, Maylynn Ding, Kara M Place, Xinyi Zhu, Prabhpreet Bassi, Zahra Baghestani, Amit G Deshwar, Daniele Merico, Hui Y Xiong, Brendan J Frey, Michael D Wilson, Evgueni A Ivakine, Ronald D Cohn
Splice-site defects account for about 10% of pathogenic mutations that cause Mendelian diseases. Prevalence is higher in neuromuscular disorders (NMDs), owing to the unusually large size and multi-exonic nature of genes encoding muscle structural proteins. Therapeutic genome editing to correct disease-causing splice-site mutations has been accomplished only through the homology-directed repair pathway, which is extremely inefficient in postmitotic tissues such as skeletal muscle. Here we describe a strategy using nonhomologous end-joining (NHEJ) to correct a pathogenic splice-site mutation...
August 2017: Nature Medicine
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