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Nature Medicine

Fulvio D'Angelo, Michele Ceccarelli, Tala, Luciano Garofano, Jing Zhang, Véronique Frattini, Francesca P Caruso, Genevieve Lewis, Kristin D Alfaro, Luc Bauchet, Giulia Berzero, David Cachia, Mario Cangiano, Laurent Capelle, John de Groot, Francesco DiMeco, François Ducray, Walid Farah, Gaetano Finocchiaro, Stéphane Goutagny, Carlos Kamiya-Matsuoka, Cinzia Lavarino, Hugues Loiseau, Véronique Lorgis, Carlo E Marras, Ian McCutcheon, Do-Hyun Nam, Susanna Ronchi, Veronica Saletti, Romuald Seizeur, John Slopis, Mariona Suñol, Fanny Vandenbos, Pascale Varlet, Dominique Vidaud, Colin Watts, Viviane Tabar, David E Reuss, Seung-Ki Kim, David Meyronet, Karima Mokhtari, Hector Salvador, Krishna P Bhat, Marica Eoli, Marc Sanson, Anna Lasorella, Antonio Iavarone
Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma)...
December 10, 2018: Nature Medicine
Vivek Swarup, Flora I Hinz, Jessica E Rexach, Ken-Ichi Noguchi, Hiroyoshi Toyoshiba, Akira Oda, Keisuke Hirai, Arjun Sarkar, Nicholas T Seyfried, Chialin Cheng, Stephen J Haggarty, Murray Grossman, Vivianna M Van Deerlin, John Q Trojanowski, James J Lah, Allan I Levey, Shinichi Kondou, Daniel H Geschwind
Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks...
December 3, 2018: Nature Medicine
Lucas D Trucco, Piyushkumar A Mundra, Kate Hogan, Pablo Garcia-Martinez, Amaya Viros, Amit K Mandal, Nicolas Macagno, Caroline Gaudy-Marqueste, Donald Allan, Franziska Baenke, Martin Cook, Clare McManus, Berta Sanchez-Laorden, Nathalie Dhomen, Richard Marais
The melanoma genome is dominated by ultraviolet radiation (UVR)-induced mutations. Their relevance in disease progression is unknown. Here we classify melanomas by mutation signatures and identify ten recurrently mutated UVR signature genes that predict patient survival. We validate these findings in primary human melanomas; in mice we show that this signature is imprinted by short-wavelength UVR and that four exposures to UVR are sufficient to accelerate melanomagenesis.
December 3, 2018: Nature Medicine
Jiahao Chen, Yun-Ruei Kao, Daqian Sun, Tihomira I Todorova, David Reynolds, Swathi-Rao Narayanagari, Cristina Montagna, Britta Will, Amit Verma, And Ulrich Steidl
Myelodysplastic syndromes (MDS) frequently progress to acute myeloid leukemia (AML); however, the cells leading to malignant transformation have not been directly elucidated. As progression of MDS to AML in humans provides a biological system to determine the cellular origins and mechanisms of neoplastic transformation, we studied highly fractionated stem cell populations in longitudinal samples of patients with MDS who progressed to AML. Targeted deep sequencing combined with single-cell sequencing of sorted cell populations revealed that stem cells at the MDS stage, including immunophenotypically and functionally defined pre-MDS stem cells (pre-MDS-SC), had a significantly higher subclonal complexity compared to blast cells and contained a large number of aging-related variants...
December 3, 2018: Nature Medicine
Teri A Manolio
No abstract text is available yet for this article.
December 3, 2018: Nature Medicine
Vancheswaran Gopalakrishnan, Robert R Jenq
No abstract text is available yet for this article.
December 3, 2018: Nature Medicine
Rik Ossenkoppele, Oskar Hansson
No abstract text is available yet for this article.
December 3, 2018: Nature Medicine
Matteo Menotti, Chiara Ambrogio, Taek-Chin Cheong, Chiara Pighi, Ines Mota, Seth H Cassel, Mara Compagno, Qi Wang, Riccardo Dall'Olio, Valerio G Minero, Teresa Poggio, Geeta Geeta Sharma, Enrico Patrucco, Cristina Mastini, Ramesh Choudhari, Achille Pich, Alberto Zamo, Roberto Piva, Silvia Giliani, Luca Mologni, Clayton K Collings, Cigall Kadoch, Carlo Gambacorti-Passerini, Luigi D Notarangelo, Ines M Anton, Claudia Voena, Roberto Chiarle
In T lymphocytes, the Wiskott-Aldrich Syndrome protein (WASP) and WASP-interacting-protein (WIP) regulate T cell antigen receptor (TCR) signaling, but their role in lymphoma is largely unknown. Here we show that the expression of WASP and WIP is frequently low or absent in anaplastic large cell lymphoma (ALCL) compared to other T cell lymphomas. In anaplastic lymphoma kinase-positive (ALK+) ALCL, WASP and WIP expression is regulated by ALK oncogenic activity via its downstream mediators STAT3 and C/EBP-β. ALK+ lymphomas were accelerated in WASP- and WIP-deficient mice...
December 3, 2018: Nature Medicine
Wouter Scheper, Sander Kelderman, Lorenzo F Fanchi, Carsten Linnemann, Gavin Bendle, Marije A J de Rooij, Christian Hirt, Riccardo Mezzadra, Maarten Slagter, Krijn Dijkstra, Roelof J C Kluin, Petur Snaebjornsson, Katy Milne, Brad H Nelson, Henry Zijlmans, Gemma Kenter, Emile E Voest, John B A G Haanen, Ton N Schumacher
Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites1 . However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8+ T cells in ovarian and colorectal cancer-two tumor types for which T cell infiltrates form a positive prognostic marker2,3 ...
December 3, 2018: Nature Medicine
Yinghong Wang, Diana H Wiesnoski, Beth A Helmink, Vancheswaran Gopalakrishnan, Kati Choi, Hebert L DuPont, Zhi-Dong Jiang, Hamzah Abu-Sbeih, Christopher A Sanchez, Chia-Chi Chang, Edwin R Parra, Alejandro Francisco-Cruz, Gottumukkala S Raju, John R Stroehlein, Matthew T Campbell, Jianjun Gao, Sumit K Subudhi, Dipen M Maru, Jorge M Blando, Alexander J Lazar, James P Allison, Padmanee Sharma, Michael T Tetzlaff, Jennifer A Wargo, Robert R Jenq
In the version of this article originally published, an author was missing from the author list. Alexander J. Lazar should have been included between Jorge M. Blando and James P. Allison. The author has been added to the list, and the author contributions section has been updated to include Alexander J. Lazar's contribution to the study. The error has been corrected in the print, PDF and HTML versions of the manuscript.
November 27, 2018: Nature Medicine
Khyati N Shah, Roma Bhatt, Julia Rotow, Julia Rohrberg, Victor Olivas, Victoria E Wang, Golzar Hemmati, Maria M Martins, Ashley Maynard, Jonathan Kuhn, Jacqueline Galeas, Hayley J Donnella, Swati Kaushik, Angel Ku, Sophie Dumont, Gregor Krings, Henry J Haringsma, Liliane Robillard, Andrew D Simmons, Thomas C Harding, Frank McCormick, Andrei Goga, Collin M Blakely, Trever G Bivona, Sourav Bandyopadhyay
Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity...
November 26, 2018: Nature Medicine
Frederike Bensch, Elly L van der Veen, Marjolijn N Lub-de Hooge, Annelies Jorritsma-Smit, Ronald Boellaard, Iris C Kok, Sjoukje F Oosting, Carolina P Schröder, T Jeroen N Hiltermann, Anthonie J van der Wekken, Harry J M Groen, Thomas C Kwee, Sjoerd G Elias, Jourik A Gietema, Sandra Sanabria Bohorquez, Alex de Crespigny, Simon-Peter Williams, Christoph Mancao, Adrienne H Brouwers, Bernard M Fine, Elisabeth G E de Vries
Programmed cell death protein-1/ligand-1 (PD-1/PD-L1) blockade is effective in a subset of patients with several tumor types, but predicting patient benefit using approved diagnostics is inexact, as some patients with PD-L1-negative tumors also show clinical benefit1,2 . Moreover, all biopsy-based tests are subject to the errors and limitations of invasive tissue collection3-11 . Preclinical studies of positron-emission tomography (PET) imaging with antibodies to PD-L1 suggested that this imaging method might be an approach to selecting patients12,13 ...
November 26, 2018: Nature Medicine
Simone Caielli, Diogo Troggian Veiga, Preetha Balasubramanian, Shruti Athale, Bojana Domic, Elise Murat, Romain Banchereau, Zhaohui Xu, Manjari Chandra, Cheng-Han Chung, Lynnette Walters, Jeanine Baisch, Tracey Wright, Marilynn Punaro, Lorien Nassi, Katie Stewart, Julie Fuller, Duygu Ucar, Hideki Ueno, Joseph Zhou, Jacques Banchereau, Virginia Pascual
Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE)1 . Follicular helper T cells (TFH cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers2 . Here, we describe a CXCR5- CXCR3+ programmed death 1 (PD1)hi CD4+ helper T cell population distinct from TFH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis...
November 26, 2018: Nature Medicine
Mirja Rotinen, Sungyong You, Julie Yang, Simon G Coetzee, Mariana Reis-Sobreiro, Wen-Chin Huang, Fangjin Huang, Xinlei Pan, Alberto Yáñez, Dennis J Hazelett, Chia-Yi Chu, Kenneth Steadman, Colm M Morrissey, Peter S Nelson, Eva Corey, Leland W K Chung, Stephen J Freedland, Dolores Di Vizio, Isla P Garraway, Ramachandran Murali, Beatrice S Knudsen, Michael R Freeman
Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease...
November 26, 2018: Nature Medicine
Rishu Agarwal, Yih-Chih Chan, Constantine S Tam, Tane Hunter, Dane Vassiliadis, Charis E Teh, Rachel Thijssen, Paul Yeh, Stephen Q Wong, Sarah Ftouni, Enid Y N Lam, Mary Ann Anderson, Christiane Pott, Omer Gilan, Charles C Bell, Kathy Knezevic, Piers Blombery, Kathleen Rayeroux, Adrian Zordan, Jason Li, David C S Huang, Meaghan Wall, John F Seymour, Daniel H D Gray, Andrew W Roberts, Mark A Dawson, Sarah-Jane Dawson
Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI-SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease...
November 19, 2018: Nature Medicine
Marjorie Z Imperial, Payam Nahid, Patrick P J Phillips, Geraint R Davies, Katherine Fielding, Debra Hanna, David Hermann, Robert S Wallis, John L Johnson, Christian Lienhardt, Rada M Savic
The version of this article originally published was not open access. This article should have been open access. The error has been fixed, and the article is now open access.
November 14, 2018: Nature Medicine
Ana Mendanha Falcão, David van Bruggen, Sueli Marques, Mandy Meijer, Sarah Jäkel, Eneritz Agirre, Samudyata, Elisa M Floriddia, Darya P Vanichkina, Charles Ffrench-Constant, Anna Williams, André Ortlieb Guerreiro-Cacais, Gonçalo Castelo-Branco
Multiple sclerosis (MS) is characterized by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs). We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells. Surprisingly, EAE-specific OL lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context...
November 12, 2018: Nature Medicine
Yinghong Wang, Diana H Wiesnoski, Beth A Helmink, Vancheswaran Gopalakrishnan, Kati Choi, Hebert L DuPont, Zhi-Dong Jiang, Hamzah Abu-Sbeih, Christopher A Sanchez, Chia-Chi Chang, Edwin R Parra, Alejandro Francisco-Cruz, Gottumukkala S Raju, John R Stroehlein, Matthew T Campbell, Jianjun Gao, Sumit K Subudhi, Dipen M Maru, Jorge M Blando, Alexander J Lazar, James P Allison, Padmanee Sharma, Michael T Tetzlaff, Jennifer A Wargo, Robert R Jenq
We report the first case series of immune checkpoint inhibitors (ICI)-associated colitis successfully treated with fecal microbiota transplantation, with reconstitution of the gut microbiome and a relative increase in the proportion of regulatory T-cells within the colonic mucosa. These preliminary data provide evidence that modulation of the gut microbiome may abrogate ICI-associated colitis.
November 12, 2018: Nature Medicine
Ziming Wang, Ethan G Aguilar, Jesus I Luna, Cordelia Dunai, Lam T Khuat, Catherine T Le, Annie Mirsoian, Christine M Minnar, Kevin M Stoffel, Ian R Sturgill, Steven K Grossenbacher, Sita S Withers, Robert B Rebhun, Dennis J Hartigan-O'Connor, Gema Méndez-Lagares, Alice F Tarantal, R Rivkah Isseroff, Thomas S Griffith, Kurt A Schalper, Alexander Merleev, Asim Saha, Emanual Maverakis, Karen Kelly, Raid Aljumaily, Sami Ibrahimi, Sarbajit Mukherjee, Michael Machiorlatti, Sara K Vesely, Dan L Longo, Bruce R Blazar, Robert J Canter, William J Murphy, Arta M Monjazeb
The recent successes of immunotherapy have shifted the paradigm in cancer treatment, but because only a percentage of patients are responsive to immunotherapy, it is imperative to identify factors impacting outcome. Obesity is reaching pandemic proportions and is a major risk factor for certain malignancies, but the impact of obesity on immune responses, in general and in cancer immunotherapy, is poorly understood. Here, we demonstrate, across multiple species and tumor models, that obesity results in increased immune aging, tumor progression and PD-1-mediated T cell dysfunction which is driven, at least in part, by leptin...
November 12, 2018: Nature Medicine
Daniel A Pollyea, Brett M Stevens, Courtney L Jones, Amanda Winters, Shanshan Pei, Mohammad Minhajuddin, Angelo D'Alessandro, Rachel Culp-Hill, Kent A Riemondy, Austin E Gillen, Jay R Hesselberth, Diana Abbott, Derek Schatz, Jonathan A Gutman, Enkhtsetseg Purev, Clayton Smith, Craig T Jordan
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Leukemia stem cells (LSCs) drive the initiation and perpetuation of AML, are quantifiably associated with worse clinical outcomes, and often persist after conventional chemotherapy resulting in relapse1-5 . In this report, we show that treatment of older patients with AML with the B cell lymphoma 2 (BCL-2) inhibitor venetoclax in combination with azacitidine results in deep and durable remissions and is superior to conventional treatments...
November 12, 2018: Nature Medicine
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