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Nature Medicine

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https://www.readbyqxmd.com/read/29035371/lncrna-mir100hg-derived-mir-100-and-mir-125b-mediate-cetuximab-resistance-via-wnt-%C3%AE-catenin-signaling
#1
Yuanyuan Lu, Xiaodi Zhao, Qi Liu, Cunxi Li, Ramona Graves-Deal, Zheng Cao, Bhuminder Singh, Jeffrey L Franklin, Jing Wang, Huaying Hu, Tianying Wei, Mingli Yang, Timothy J Yeatman, Ethan Lee, Kenyi Saito-Diaz, Scott Hinger, James G Patton, Christine H Chung, Stephan Emmrich, Jan-Henning Klusmann, Daiming Fan, Robert J Coffey
De novo and acquired resistance, which are largely attributed to genetic alterations, are barriers to effective anti-epidermal-growth-factor-receptor (EGFR) therapy. To generate cetuximab-resistant cells, we exposed cetuximab-sensitive colorectal cancer cells to cetuximab in three-dimensional culture. Using whole-exome sequencing and transcriptional profiling, we found that the long non-coding RNA MIR100HG and two embedded microRNAs, miR-100 and miR-125b, were overexpressed in the absence of known genetic events linked to cetuximab resistance...
October 16, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29035370/natural-killer-cells-migrate-into-and-control-simian-immunodeficiency-virus-replication-in-lymph-node-follicles-in-african-green-monkeys
#2
Nicolas Huot, Beatrice Jacquelin, Thalia Garcia-Tellez, Philippe Rascle, Mickaël J Ploquin, Yoann Madec, R Keith Reeves, Nathalie Derreudre-Bosquet, Michaela Müller-Trutwin
Natural killer (NK) cells play an essential role in antiviral immunity, but knowledge of their function in secondary lymphoid organs is incomplete. Lymph node follicles constitute a major viral reservoir during infections with HIV-1 and simian immunodeficiency virus of macaques (SIVmac). In contrast, during nonpathogenic infection with SIV from African green monkeys (SIVagm), follicles remain generally virus free. We show that NK cells in secondary lymphoid organs from chronically SIVagm-infected African green monkeys (AGMs) were frequently CXCR5(+) and entered and persisted in lymph node follicles throughout the follow-up (240 d post-infection)...
October 16, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29035369/epigenetic-suppression-of-hippocampal-calbindin-d28k-by-%C3%AE-fosb-drives-seizure-related-cognitive-deficits
#3
Jason C You, Kavitha Muralidharan, Jin W Park, Iraklis Petrof, Mark S Pyfer, Brian F Corbett, John J LaFrancois, Yi Zheng, Xiaohong Zhang, Carrie A Mohila, Daniel Yoshor, Robert A Rissman, Eric J Nestler, Helen E Scharfman, Jeannie Chin
The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer's disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood...
October 16, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29035368/activation-of-intestinal-hypoxia-inducible-factor-2%C3%AE-during-obesity-contributes-to-hepatic-steatosis
#4
Cen Xie, Tomoki Yagai, Yuhong Luo, Xianyi Liang, Tao Chen, Qiong Wang, Dongxue Sun, Jie Zhao, Sadeesh K Ramakrishnan, Lulu Sun, Chunmei Jiang, Xiang Xue, Yuan Tian, Kristopher W Krausz, Andrew D Patterson, Yatrik M Shah, Yue Wu, Changtao Jiang, Frank J Gonzalez
Nonalcoholic fatty liver disease is becoming the most common chronic liver disease in Western countries, and limited therapeutic options are available. Here we uncovered a role for intestinal hypoxia-inducible factor (HIF) in hepatic steatosis. Human-intestine biopsies from individuals with or without obesity revealed that intestinal HIF-2α signaling was positively correlated with body-mass index and hepatic toxicity. The causality of this correlation was verified in mice with an intestine-specific disruption of Hif2a, in which high-fat-diet-induced hepatic steatosis and obesity were substantially lower as compared to control mice...
October 9, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29035367/targeting-glioma-stem-cells-through-combined-bmi1-and-ezh2-inhibition
#5
Xun Jin, Leo J Y Kim, Qiulian Wu, Lisa C Wallace, Briana C Prager, Tanwarat Sanvoranart, Ryan C Gimple, Xiuxing Wang, Stephen C Mack, Tyler E Miller, Ping Huang, Claudia L Valentim, Qi-Gang Zhou, Jill S Barnholtz-Sloan, Shideng Bao, Andrew E Sloan, Jeremy N Rich
Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A...
October 9, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29035366/cytoplasmic-p53-couples-oncogene-driven-glucose-metabolism-to-apoptosis-and-is-a-therapeutic-target-in-glioblastoma
#6
Wilson X Mai, Laura Gosa, Veerle W Daniels, Lisa Ta, Jonathan E Tsang, Brian Higgins, W Blake Gilmore, Nicholas A Bayley, Mitra Dehghan Harati, Jason T Lee, William H Yong, Harley I Kornblum, Steven J Bensinger, Paul S Mischel, P Nagesh Rao, Peter M Clark, Timothy F Cloughesy, Anthony Letai, David A Nathanson
Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models...
October 9, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29035365/omega-3-fatty-acid-epoxides-are-autocrine-mediators-that-control-the-magnitude-of-ige-mediated-mast-cell-activation
#7
Yuta Shimanaka, Nozomu Kono, Yoshitaka Taketomi, Makoto Arita, Yoshimichi Okayama, Yuki Tanaka, Yasumasa Nishito, Tatsuki Mochizuki, Hiroyuki Kusuhara, Alexander Adibekian, Benjamin F Cravatt, Makoto Murakami, Hiroyuki Arai
Critical to the function of mast cells in immune responses including allergy is their production of lipid mediators, among which only omega-6 (ω-6) arachidonate-derived eicosanoids have been well characterized. Here, by employing comprehensive lipidomics, we identify omega-3 (ω-3) fatty acid epoxides as new mast cell-derived lipid mediators and show that they are produced by PAF-AH2, an oxidized-phospholipid-selective phospholipase A2. Genetic or pharmacological deletion of PAF-AH2 reduced the steady-state production of ω-3 epoxides, leading to attenuated mast cell activation and anaphylaxis following FcɛRI cross-linking...
October 9, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29035364/sympathetic-neuron-associated-macrophages-contribute-to-obesity-by-importing-and-metabolizing-norepinephrine
#8
Roksana M Pirzgalska, Elsa Seixas, Jason S Seidman, Verena M Link, Noelia Martínez Sánchez, Inês Mahú, Raquel Mendes, Vitka Gres, Nadiya Kubasova, Imogen Morris, Bernardo A Arús, Chelsea M Larabee, Miguel Vasques, Francisco Tortosa, Ana L Sousa, Sathyavathy Anandan, Erin Tranfield, Maureen K Hahn, Matteo Iannacone, Nathanael J Spann, Christopher K Glass, Ana I Domingos
The cellular mechanism(s) linking macrophages to norepinephrine (NE)-mediated regulation of thermogenesis have been a topic of debate. Here we identify sympathetic neuron-associated macrophages (SAMs) as a population of cells that mediate clearance of NE via expression of solute carrier family 6 member 2 (SLC6A2), an NE transporter, and monoamine oxidase A (MAOA), a degradation enzyme. Optogenetic activation of the sympathetic nervous system (SNS) upregulates NE uptake by SAMs and shifts the SAM profile to a more proinflammatory state...
October 9, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28985206/clonal-evolution-in-leukemia
#9
REVIEW
Adolfo A Ferrando, Carlos López-Otín
Human leukemias are liquid malignancies characterized by diffuse infiltration of the bone marrow by transformed hematopoietic progenitors. The accessibility of tumor cells obtained from peripheral blood or through bone marrow aspirates, together with recent advances in cancer genomics and single-cell molecular analysis, have facilitated the study of clonal populations and their genetic and epigenetic evolution over time with unprecedented detail. The results of these analyses challenge the classic view of leukemia as a clonal homogeneous diffuse tumor and introduce a more complex and dynamic scenario...
October 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28967921/defining-total-body-aids-virus-burden-with-implications-for-curative-strategies
#10
Jacob D Estes, Cissy Kityo, Francis Ssali, Louise Swainson, Krystelle Nganou Makamdop, Gregory Q Del Prete, Steven G Deeks, Paul A Luciw, Jeffrey G Chipman, Gregory J Beilman, Torfi Hoskuldsson, Alexander Khoruts, Jodi Anderson, Claire Deleage, Jacob Jasurda, Thomas E Schmidt, Michael Hafertepe, Samuel P Callisto, Hope Pearson, Thomas Reimann, Jared Schuster, Jordan Schoephoerster, Peter Southern, Katherine Perkey, Liang Shang, Stephen W Wietgrefe, Courtney V Fletcher, Jeffrey D Lifson, Daniel C Douek, Joseph M McCune, Ashley T Haase, Timothy W Schacker
In the quest for a functional cure or the eradication of HIV infection, it is necessary to know the sizes of the reservoirs from which infection rebounds after treatment interruption. Thus, we quantified SIV and HIV tissue burdens in tissues of infected nonhuman primates and lymphoid tissue (LT) biopsies from infected humans. Before antiretroviral therapy (ART), LTs contained >98% of the SIV RNA(+) and DNA(+) cells. With ART, the numbers of virus (v) RNA+ cells substantially decreased but remained detectable, and their persistence was associated with relatively lower drug concentrations in LT than in peripheral blood...
October 2, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28967920/keap1-loss-promotes-kras-driven-lung-cancer-and-results-in-dependence-on-glutaminolysis
#11
Rodrigo Romero, Volkan I Sayin, Shawn M Davidson, Matthew R Bauer, Simranjit X Singh, Sarah E LeBoeuf, Triantafyllia R Karakousi, Donald C Ellis, Arjun Bhutkar, Francisco J Sánchez-Rivera, Lakshmipriya Subbaraj, Britney Martinez, Roderick T Bronson, Justin R Prigge, Edward E Schmidt, Craig J Thomas, Chandra Goparaju, Angela Davies, Igor Dolgalev, Adriana Heguy, Viola Allaj, John T Poirier, Andre L Moreira, Charles M Rudin, Harvey I Pass, Matthew G Vander Heiden, Tyler Jacks, Thales Papagiannakopoulos
Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein. One approach to addressing this challenge is to define mutations that frequently co-occur with those in KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function mutations in the KEAP1 gene encoding Kelch-like ECH-associated protein 1 (refs. 2, 3, 4), a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response...
October 2, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28967919/chromosome-1q21-3-amplification-is-a-trackable-biomarker-and-actionable-target-for-breast-cancer-recurrence
#12
Jian Yuan Goh, Min Feng, Wenyu Wang, Gokce Oguz, Siti Maryam J M Yatim, Puay Leng Lee, Yi Bao, Tse Hui Lim, Panpan Wang, Wai Leong Tam, Annette R Kodahl, Maria B Lyng, Suman Sarma, Selena Y Lin, Alexander Lezhava, Yoon Sim Yap, Alvin S T Lim, Dave S B Hoon, Henrik J Ditzel, Soo Chin Lee, Ern Yu Tan, Qiang Yu
Tumor recurrence remains the main reason for breast cancer-associated mortality, and there are unmet clinical demands for the discovery of new biomarkers and development of treatment solutions to benefit patients with breast cancer at high risk of recurrence. Here we report the identification of chromosomal copy-number amplification at 1q21.3 that is enriched in subpopulations of breast cancer cells bearing characteristics of tumor-initiating cells (TICs) and that strongly associates with breast cancer recurrence...
September 25, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28920958/the-n-6-methyladenosine-m-6-a-forming-enzyme-mettl3-controls-myeloid-differentiation-of-normal-hematopoietic-and-leukemia-cells
#13
Ly P Vu, Brian F Pickering, Yuanming Cheng, Sara Zaccara, Diu Nguyen, Gerard Minuesa, Timothy Chou, Arthur Chow, Yogesh Saletore, Matthew MacKay, Jessica Schulman, Christopher Famulare, Minal Patel, Virginia M Klimek, Francine E Garrett-Bakelman, Ari Melnick, Martin Carroll, Christopher E Mason, Samie R Jaffrey, Michael G Kharas
N(6)-methyladenosine (m(6)A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m(6)A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m(6)A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth...
September 18, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28985215/angst-about-exclusivity-the-potential-cost-of-incentivizing-makers-of-generic-drugs
#14
Shraddha Chakradhar, Roxanne Khamsi
No abstract text is available yet for this article.
October 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28985214/cancer-stem-cells-revisited
#15
REVIEW
Eduard Batlle, Hans Clevers
The cancer stem cell (CSC) concept was proposed four decades ago, and states that tumor growth, analogous to the renewal of healthy tissues, is fueled by small numbers of dedicated stem cells. It has gradually become clear that many tumors harbor CSCs in dedicated niches, and yet their identification and eradication has not been as obvious as was initially hoped. Recently developed lineage-tracing and cell-ablation strategies have provided insights into CSC plasticity, quiescence, renewal, and therapeutic response...
October 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28985213/corrigendum-classification-and-characterization-of-microsatellite-instability-across-18-cancer-types
#16
Ronald J Hause, Colin C Pritchard, Jay Shendure, Stephen J Salipante
This corrects the article DOI: 10.1038/nm.4191.
October 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28985212/gdf15-and-energy-balance-homing-in-on-a-mechanism
#17
Irene Cimino, Anthony P Coll, Giles S H Yeo
No abstract text is available yet for this article.
October 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28985211/rationalizing-combination-therapies
#18
EDITORIAL
(no author information available yet)
No abstract text is available yet for this article.
October 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28985210/engineering-mecp2-to-spy-on-its-targets
#19
Patricia M Horvath, Lisa M Monteggia
No abstract text is available yet for this article.
October 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28985209/erratum-elimination-of-large-tumors-in-mice-by-mrna-encoded-bispecific-antibodies
#20
Christiane R Stadler, Hayat Bähr-Mahmud, Leyla Celik, Bernhard Hebich, Alexandra S Roth, René P Roth, Katalin Karikó, Özlem Türeci, Ugur Sahin
This corrects the article DOI: 10.1038/nm.4356.
October 6, 2017: Nature Medicine
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