Metformin action through the microbiome and bile acids Nat. Med. (IF 32.621) Pub Date : 2018-12-06 Grace L. Guo, Wen Xie
Metformin action through the microbiome and bile acidsMetformin action through the microbiome and bile acids, Published online: 06 December 2018; doi:10.1038/s41591-018-0273-6Metformin functions through a gut microbiome–bile acid–farnesoid X receptor axis to lower glucose in type 2 diabetes, revealing a new therapeutic target in this disease.
Treatments that made headlines in 2018 Nat. Med. (IF 32.621) Pub Date : 2018-12-06 Shraddha Chakradhar
Treatments that made headlines in 2018Treatments that made headlines in 2018, Published online: 06 December 2018; doi:10.1038/s41591-018-0292-3In 2018, drugs for rare conditions such as beta-thalassemia and forms of amyloidosis made it onto the approval mainstage in addition to drugs for more common diseases such as cancer. The gene-editing technology CRISPR slowly made strides into the therapeutic realm, while drugs for Alzheimer’s disease continued to falter, leaving a wide gap that is still in need of filling.
Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma Nat. Med. (IF 32.621) Pub Date : 2018-12-06 Guy Ledergor, Assaf Weiner, Mor Zada, Shuang-Yin Wang, Yael C. Cohen, Moshe E. Gatt, Nimrod Snir, Hila Magen, Maya Koren-Michowitz, Katrin Herzog-Tzarfati, Hadas Keren-Shaul, Chamutal Bornstein, Ron Rotkopf, Ido Yofe, Eyal David, Venkata Yellapantula, Sigalit Kay, Moshe Salai, Dina Ben Yehuda, Arnon Nagler, Lev Shvidel, Avi Orr-Urtreger, Keren Bahar Halpern, Shalev Itzkovitz, Ola Landgren, Jesus San-Miguel, Bruno Paiva, Jonathan J. Keats, Elli Papaemmanuil, Irit Avivi, Gabriel I. Barbash, Amos Tanay, Ido Amit
Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients.
Understanding genetic disease with electronic records Nat. Med. (IF 32.621) Pub Date : 2018-12-06 Hannah Stower
Understanding genetic disease with electronic recordsUnderstanding genetic disease with electronic records, Published online: 06 December 2018; doi:10.1038/s41591-018-0283-4Understanding genetic disease with electronic records
Diversifying clinical trials Nat. Med. (IF 32.621) Pub Date : 2018-12-06
Scientific common sense and social justice dictate that the safety and efficacy of new therapies must be tested in the patient populations in need of treatment. Yet a recent study found that African Americans have been dramatically underrepresented in US clinical trials for cancer drugs. Efforts to increase the participation of minorities in clinical trials must become a priority for all drug developers.
Most precise ‘surgery’ of cell carried out on neurons Nat. Med. (IF 32.621) Pub Date : 2018-12-04 Shraddha Chakradhar
Most precise ‘surgery’ of cell carried out on neurons Most precise ‘surgery’ of cell carried out on neurons, Published online: 04 December 2018; doi:10.1038/d41591-018-00002-5 New tweezer technology plucks out single organelles and could help in study of Parkinson’s
Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers Nat. Med. (IF 32.621) Pub Date : 2018-12-03 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. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8+ T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.
UK Biobank debuts as a powerful resource for genomic research Nat. Med. (IF 32.621) Pub Date : 2018-12-03 Teri A. Manolio
UK Biobank debuts as a powerful resource for genomic researchUK Biobank debuts as a powerful resource for genomic research, Published online: 03 December 2018; doi:10.1038/s41591-018-0276-3Analysis of the UK Biobank genetic and phenotypic data demonstrate the power of including a large population and detailed phenotyping in a prospective study to identify genetic and lifestyle factors related to health and disease.
Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia Nat. Med. (IF 32.621) Pub Date : 2018-12-03 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, Raffaele Ferrari, Jonathan D. Rohrer, Adaikalavan Ramasamy, John Hardy, Dena G. Hernandez, Michael A. Nalls, Andrew B. Singleton, John B. J. Kwok, Carol Dobson-Stone, William S. Brooks, Peter R. Schofield, Glenda M. Halliday, John R. Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Eric Haan, Isabel Hernández, Agustín Ruiz, Mercè Boada, Barbara Borroni, Alessandro Padovani, Nigel J. Cairns, Carlos Cruchaga, Giuliano Binetti, Roberta Ghidoni, Luisa Benussi, Gianluigi Forloni, Diego Albani, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimón, Alberto Lleó, Rafael Blesa, Maria Landqvist Waldö, Karin Nilsson, Christer Nilsson, Ian R. A. Mackenzie, Ging-Yuek R. Hsiung, David M. A. Mann, Jordan Grafman, Christopher M. Morris, Johannes Attems, Timothy D. Griff..
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. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.
Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level Nat. Med. (IF 32.621) Pub Date : 2018-12-03 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. Single-cell targeted resequencing of highly fractionated stem cells revealed a pattern of nonlinear, parallel clonal evolution, with distinct subclones within pre-MDS-SC and MDS-SC contributing to generation of MDS blasts or progression to AML, respectively. Furthermore, phenotypically aberrant stem cell clones expanded during transformation and stem cell subclones that were not detectable in MDS blasts became dominant upon AML progression. These results reveal a crucial role of diverse stem cell compartments during MDS progression to AML and have implications for current bulk cell–focused precision oncology approaches, both in MDS and possibly other cancers that evolve from premalignant conditions, that may miss pre-existing rare aberrant stem cells that drive disease progression and leukemic transformation.
Wiskott–Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma Nat. Med. (IF 32.621) Pub Date : 2018-12-03 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. In the absence of WASP, active GTP-bound CDC42 was increased and the genetic deletion of one CDC42 allele was sufficient to impair lymphoma growth. WASP-deficient lymphoma showed increased mitogen-activated protein kinase (MAPK) pathway activation that could be exploited as a therapeutic vulnerability. Our findings demonstrate that WASP and WIP are tumor suppressors in T cell lymphoma and suggest that MAP-kinase kinase (MEK) inhibitors combined with ALK inhibitors could achieve a more potent therapeutic effect in ALK+ ALCL.
Genetic characterization of amyloid-β and tau network spread Nat. Med. (IF 32.621) Pub Date : 2018-12-03 Rik Ossenkoppele, Oskar Hansson
Genetic characterization of amyloid-β and tau network spread Genetic characterization of amyloid-β and tau network spread , Published online: 03 December 2018; doi:10.1038/s41591-018-0277-2Protein-specific and shared genetic pathways influence the spread of amyloid-β and tau pathology. Hence, distinct gene expression profiles may induce regional vulnerability of the human cortex to the specific proteinopathies of Alzheimer’s disease.
Ultraviolet radiation–induced DNA damage is prognostic for outcome in melanoma Nat. Med. (IF 32.621) Pub Date : 2018-12-03 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.
Implicating or exonerating the gut microbiome in blood-borne infection Nat. Med. (IF 32.621) Pub Date : 2018-12-03 Vancheswaran Gopalakrishnan, Robert R. Jenq
Implicating or exonerating the gut microbiome in blood-borne infectionImplicating or exonerating the gut microbiome in blood-borne infection, Published online: 03 December 2018; doi:10.1038/s41591-018-0270-9StrainSifter is a tool that is able to identify the relatedness of a blood-borne infection to the gut microbiome using single-nucleotide variant data.
Author Correction: Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis Nat. Med. (IF 32.621) Pub Date : 2018-11-27 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
Author Correction: Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis Author Correction: Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis, Published online: 27 November 2018; doi:10.1038/s41591-018-0305-2 Author Correction: Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis
A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate Nat. Med. (IF 32.621) Pub Date : 2018-11-26 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)hiCD4+ helper T cell population distinct from TFH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis. These cells produce interleukin-10 (IL-10) and accumulate mitochondrial reactive oxygen species as the result of reverse electron transport fueled by succinate. Furthermore, they provide B cell help, independently of IL-21, through IL-10 and succinate. Similar cells are generated in vitro upon priming naive CD4+ T cells with plasmacytoid dendritic cells activated with oxidized mitochondrial DNA, a distinct class of interferogenic toll-like receptor 9 ligand3. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.
Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer Nat. Med. (IF 32.621) Pub Date : 2018-11-26 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. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance.
89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer Nat. Med. (IF 32.621) Pub Date : 2018-11-26 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 collection3,4,5,6,7,8,9,10,11. 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. Such a technique, however, requires substantial clinical development and validation. Here we present the initial results from a first-in-human study to assess the feasibility of imaging with zirconium-89-labeled atezolizumab (anti-PD-L1), including biodistribution, and secondly test its potential to predict response to PD-L1 blockade (ClinicalTrials.gov identifiers NCT02453984 and NCT02478099). We imaged 22 patients across three tumor types before the start of atezolizumab therapy. The PET signal, a function of tracer exposure and target expression, was high in lymphoid tissues and at sites of inflammation. In tumors, uptake was generally high but heterogeneous, varying within and among lesions, patients, and tumor types. Intriguingly, clinical responses in our patients were better correlated with pretreatment PET signal than with immunohistochemistry- or RNA-sequencing-based predictive biomarkers, encouraging further development of molecular PET imaging for assessment of PD-L1 status and clinical response prediction.
ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis Nat. Med. (IF 32.621) Pub Date : 2018-11-26 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. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.
Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma Nat. Med. (IF 32.621) Pub Date : 2018-11-19 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. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI–SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.
Publisher Correction: A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis Nat. Med. (IF 32.621) Pub Date : 2018-11-14 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
Publisher Correction: A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis Publisher Correction: A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis, Published online: 14 November 2018; doi:10.1038/s41591-018-0294-1 Publisher Correction: A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis
Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis Nat. Med. (IF 32.621) Pub Date : 2018-11-12 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, 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.
Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia Nat. Med. (IF 32.621) Pub Date : 2018-11-12 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 relapse1,2,3,4,5. 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. We hypothesized that these promising clinical results were due to targeting LSCs. Analysis of LSCs from patients undergoing treatment with venetoclax + azacitidine showed disruption of the tricarboxylic acid (TCA) cycle manifested by decreased α-ketoglutarate and increased succinate levels, suggesting inhibition of electron transport chain complex II. In vitro modeling confirmed inhibition of complex II via reduced glutathionylation of succinate dehydrogenase. These metabolic perturbations suppress oxidative phosphorylation (OXPHOS), which efficiently and selectively targets LSCs. Our findings show for the first time that a therapeutic intervention can eradicate LSCs in patients with AML by disrupting the metabolic machinery driving energy metabolism, resulting in promising clinical activity in a patient population with historically poor outcomes.
Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade Nat. Med. (IF 32.621) Pub Date : 2018-11-12 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. However, obesity is also associated with increased efficacy of PD-1/PD-L1 blockade in both tumor-bearing mice and clinical cancer patients. These findings advance our understanding of obesity-induced immune dysfunction and its consequences in cancer and highlight obesity as a biomarker for some cancer immunotherapies. These data indicate a paradoxical impact of obesity on cancer. There is heightened immune dysfunction and tumor progression but also greater anti-tumor efficacy and survival after checkpoint blockade which directly targets some of the pathways activated in obesity.
Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis Nat. Med. (IF 32.621) Pub Date : 2018-11-12 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. Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells. Finally, we demonstrate that OPCs can phagocytose and that MHC-II-expressing OPCs can activate memory and effector CD4-positive T cells. Our results suggest that OLs and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS.
A stratified approach to tuberculosis treatment Nat. Med. (IF 32.621) Pub Date : 2018-11-06 Gavin J. Churchyard
A stratified approach to tuberculosis treatmentA stratified approach to tuberculosis treatment, Published online: 06 November 2018; doi:10.1038/s41591-018-0244-yStratifying tuberculosis (TB) disease into minimal, moderate or severe disease may allow treatment duration to be tailored to disease severity. Minimal poor adherence is associated with poor treatment outcomes.
Rules of engagement in the gut microbiome Nat. Med. (IF 32.621) Pub Date : 2018-11-06 Elze Rackaityte, Susan V. Lynch
Rules of engagement in the gut microbiomeRules of engagement in the gut microbiome, Published online: 06 November 2018; doi:10.1038/s41591-018-0242-0In humans, niche-specific gastrointestinal microbiomes influence the colonization success of probiotic microbes. Microbiome reconstitution following antimicrobial perturbation is most successful using preperturbation autofecal microbial transplant.
Analyzing the drug overdose epidemic in the United States Nat. Med. (IF 32.621) Pub Date : 2018-11-06 Kate Gao
Analyzing the drug overdose epidemic in the United StatesAnalyzing the drug overdose epidemic in the United States, Published online: 06 November 2018; doi:10.1038/s41591-018-0261-xAnalyzing the drug overdose epidemic in the United States
Is earlier better for melanoma checkpoint blockade? Nat. Med. (IF 32.621) Pub Date : 2018-11-06 Caroline Robert
A neoadjuvant approach relying on the administration of combined anti-CTLA-4–anti-PD-1 treatment before lymph node surgery is evaluated in two phase 1 trials. Encouraging clinical, pathological and immunological responses to neoadjuvant therapy were observed, suggesting that this concept warrants further exploration; however, any future approach must address the unacceptably high toxicity of the regimens evaluated in these trials.
Confronting conflict of interest Nat. Med. (IF 32.621) Pub Date : 2018-11-06
Confronting conflict of interestConfronting conflict of interest, Published online: 06 November 2018; doi:10.1038/s41591-018-0256-7Recent news stories about conflict of interest in biomedical research have shaken up public and private institutions alike, but their focus was on clinical research. Amidst the renewed focus on conflicts of interest in clinical work, let’s not disregard the fact that financial conflicts also pose a concern to basic and preclinical research.
Individualized sepsis treatment using reinforcement learning Nat. Med. (IF 32.621) Pub Date : 2018-11-05 Suchi Saria
Individualized sepsis treatment using reinforcement learning Individualized sepsis treatment using reinforcement learning, Published online: 05 November 2018; doi:10.1038/s41591-018-0253-x Reinforcement learning is applied to two large databases of electronic health records for patients admitted to an intensive care unit to identify individualized treatment strategies for correcting hypotension in sepsis.
Radiotherapy induces responses of lung cancer to CTLA-4 blockade Nat. Med. (IF 32.621) Pub Date : 2018-11-05 Silvia C. Formenti, Nils-Petter Rudqvist, Encouse Golden, Benjamin Cooper, Erik Wennerberg, Claire Lhuillier, Claire Vanpouille-Box, Kent Friedman, Lucas Ferrari de Andrade, Kai W. Wucherpfennig, Adriana Heguy, Naoko Imai, Sacha Gnjatic, Ryan O. Emerson, Xi Kathy Zhou, Tuo Zhang, Abraham Chachoua, Sandra Demaria
Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma1,2,3, but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor4,5,6. The latter is essential for achieving abscopal responses in murine cancers6. The mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA-4 blockade remain unclear. Here we report that radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy7,8. Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-β after radiation and early dynamic changes of blood T cell clones were the strongest response predictors, confirming preclinical mechanistic data. Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation-induced exposure of immunogenic mutations to the immune system.
Longitudinal personal DNA methylome dynamics in a human with a chronic condition Nat. Med. (IF 32.621) Pub Date : 2018-11-05 Rui Chen, Lin Xia, Kailing Tu, Meixue Duan, Kimberly Kukurba, Jennifer Li-Pook-Than, Dan Xie, Michael Snyder
Epigenomics regulates gene expression and is as important as genomics in precision personal health, as it is heavily influenced by environment and lifestyle. We profiled whole-genome DNA methylation and the corresponding transcriptome of peripheral blood mononuclear cells collected from a human volunteer over a period of 36 months, generating 28 methylome and 57 transcriptome datasets. We found that DNA methylomic changes are associated with infrequent glucose level alteration, whereas the transcriptome underwent dynamic changes during events such as viral infections. Most DNA meta-methylome changes occurred 80–90 days before clinically detectable glucose elevation. Analysis of the deep personal methylome dataset revealed an unprecedented number of allelic differentially methylated regions that remain stable longitudinally and are preferentially associated with allele-specific gene regulation. Our results revealed that changes in different types of ‘omics’ data associate with different physiological aspects of this individual: DNA methylation with chronic conditions and transcriptome with acute events.
Expanded skin virome in DOCK8-deficient patients Nat. Med. (IF 32.621) Pub Date : 2018-11-05 Osnat Tirosh, Sean Conlan, Clay Deming, Shih-Queen Lee-Lin, Xin Huang, Beatrice B. Barnabas, Gerard G. Bouffard, Shelise Y. Brooks, Holly Marfani, Lyudmila Dekhtyar, Xiaobin Guan, Joel Han, Shi-ling Ho, Richelle Legaspi, Quino L. Maduro, Catherine A. Masiello, Jennifer C. McDowell, Casandra Montemayor, James C. Mullikin, Morgan Park, Nancy L. Riebow, Karen Schandler, Chanthra Scharer, Brian Schmidt, Christina Sison, Sirintorn Stantripop, James W. Thomas, Pamela J. Thomas, Meghana Vemulapalli, Alice C. Young, Helen C. Su, Alexandra F. Freeman, Julia A. Segre, Heidi H. Kong
Human microbiome studies have revealed the intricate interplay of host immunity and bacterial communities to achieve homeostatic balance. Healthy skin microbial communities are dominated by bacteria with low viral representation1,2,3, mainly bacteriophage. Specific eukaryotic viruses have been implicated in both common and rare skin diseases, but cataloging skin viral communities has been limited. Alterations in host immunity provide an opportunity to expand our understanding of microbial–host interactions. Primary immunodeficient patients manifest with various viral, bacterial, fungal, and parasitic infections, including skin infections4. Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare primary human immunodeficiency characterized by recurrent cutaneous and systemic infections, as well as atopy and cancer susceptibility5. DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes, regulates actin cytoskeleton, which is critical for migration through collagen-dense tissues such as skin6. Analyzing deep metagenomic sequencing data from DOCK8-deficient skin samples demonstrated a notable increase in eukaryotic viral representation and diversity compared with healthy volunteers. De novo assembly approaches identified hundreds of novel human papillomavirus genomes, illuminating microbial dark matter. Expansion of the skin virome in DOCK8-deficient patients underscores the importance of immune surveillance in controlling eukaryotic viral colonization and infection.
Cancer cells exploit an orphan RNA to drive metastatic progression Nat. Med. (IF 32.621) Pub Date : 2018-11-05 Lisa Fish, Steven Zhang, Johnny X. Yu, Bruce Culbertson, Alicia Y. Zhou, Andrei Goga, Hani Goodarzi
Here we performed a systematic search to identify breast-cancer-specific small noncoding RNAs, which we have collectively termed orphan noncoding RNAs (oncRNAs). We subsequently discovered that one of these oncRNAs, which originates from the 3′ end of TERC, acts as a regulator of gene expression and is a robust promoter of breast cancer metastasis. This oncRNA, which we have named T3p, exerts its prometastatic effects by acting as an inhibitor of RISC complex activity and increasing the expression of the prometastatic genes NUPR1 and PANX2. Furthermore, we have shown that oncRNAs are present in cancer-cell-derived extracellular vesicles, raising the possibility that these circulating oncRNAs may also have a role in non–cell autonomous disease pathogenesis. Additionally, these circulating oncRNAs present a novel avenue for cancer fingerprinting using liquid biopsies.
A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis Nat. Med. (IF 32.621) Pub Date : 2018-11-05 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
Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to <2+, HIV seropositivity and adherence of ≤90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations >6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the ‘one-size-fits-all’ treatment currently used worldwide.
Gut microbiota and intestinal FXR mediate the clinical benefits of metformin Nat. Med. (IF 32.621) Pub Date : 2018-11-05 Lulu Sun, Cen Xie, Guang Wang, Yue Wu, Qing Wu, Xuemei Wang, Jia Liu, Yangyang Deng, Jialin Xia, Bo Chen, Songyang Zhang, Chuyu Yun, Guan Lian, Xiujuan Zhang, Heng Zhang, William H. Bisson, Jingmin Shi, Xiaoxia Gao, Pupu Ge, Cuihua Liu, Kristopher W. Krausz, Robert G. Nichols, Jingwei Cai, Bipin Rimal, Andrew D. Patterson, Xian Wang, Frank J. Gonzalez, Changtao Jiang
The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis–GUDCA–intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia.
Neurogenetic contributions to amyloid beta and tau spreading in the human cortex Nat. Med. (IF 32.621) Pub Date : 2018-10-29 Jorge Sepulcre, Michel J. Grothe, Federico d’Oleire Uquillas, Laura Ortiz-Terán, Ibai Diez, Hyun-Sik Yang, Heidi I. L. Jacobs, Bernard J. Hanseeuw, Quanzheng Li, Georges El-Fakhri, Reisa A. Sperling, Keith A. Johnson
Tau and amyloid beta (Aβ) proteins accumulate along neuronal circuits in Alzheimer’s disease. Unraveling the genetic background for the regional vulnerability of these proteinopathies can help in understanding the mechanisms of pathology progression. To that end, we developed a novel graph theory approach and used it to investigate the intersection of longitudinal Aβ and tau positron emission tomography imaging of healthy adult individuals and the genetic transcriptome of the Allen Human Brain Atlas. We identified distinctive pathways for tau and Aβ accumulation, of which the tau pathways correlated with cognitive levels. We found that tau propagation and Aβ propagation patterns were associated with a common genetic profile related to lipid metabolism, in which APOE played a central role, whereas the tau-specific genetic profile was classified as ‘axon related’ and the Aβ profile as ‘dendrite related’. This study reveals distinct genetic profiles that may confer vulnerability to tau and Aβ in vivo propagation in the human brain.
Infant diet and maternal gestational weight gain predict early metabolic maturation of gut microbiomes Nat. Med. (IF 32.621) Pub Date : 2018-10-29 Aimee M. Baumann-Dudenhoeffer, Alaric W. D’Souza, Phillip I. Tarr, Barbara B. Warner, Gautam Dantas
Commensal gut bacterial communities (microbiomes) are predicted to influence human health and disease1,2. Neonatal gut microbiomes are colonized with maternal and environmental flora and mature toward a stable composition over 2–3 years3,4. To study pre- and postnatal determinants of infant microbiome development, we analyzed 402 fecal metagenomes from 60 infants aged 0–8 months, using longitudinal generalized linear mixed models (GLMMs). Distinct microbiome signatures correlated with breastfeeding, formula ingredients, and maternal gestational weight gain (GWG). Amino acid synthesis pathway accretion in breastfed microbiomes complemented normative breastmilk composition. Prebiotic oligosaccharides, designed to promote breastfed-like microflora5, predicted functional pathways distinct from breastfed infant microbiomes. Soy formula in six infants was positively associated with Lachnospiraceae and pathways suggesting a short-chain fatty acid (SCFA)-rich environment, including glycerol to 1-butanol fermentation, which is potentially dysbiotic. GWG correlated with altered carbohydrate degradation and enriched vitamin synthesis pathways. Maternal and postnatal antibiotics predicted microbiome alterations, while delivery route had no persistent effects. Domestic water source correlates suggest water may be an underappreciated determinant of microbiome acquisition. Clinically important microbial pathways with statistically significant dietary correlates included dysbiotic markers6,7, core enterotype features8, and synthesis pathways for enteroprotective9 and immunomodulatory10,11 metabolites, epigenetic mediators1, and developmentally critical vitamins12, warranting further investigation.
High prevalence of Streptococcus pyogenes Cas9-reactive T cells within the adult human population Nat. Med. (IF 32.621) Pub Date : 2018-10-29 Dimitrios L. Wagner, Leila Amini, Desiree J. Wendering, Lisa-Marie Burkhardt, Levent Akyüz, Petra Reinke, Hans-Dieter Volk, Michael Schmueck-Henneresse
The discovery of the highly efficient site-specific nuclease system CRISPR–Cas9 from Streptococcus pyogenes has galvanized the field of gene therapy1,2. The immunogenicity of Cas9 nuclease has been demonstrated in mice3,4. Preexisting immunity against therapeutic gene vectors or their cargo can decrease the efficacy of a potentially curative treatment and may pose significant safety issues3,4,5,6. S. pyogenes is a common cause for infectious diseases in humans, but it remains unclear whether it induces a T cell memory against the Cas9 nuclease7,8. Here, we show the presence of a preexisting ubiquitous effector T cell response directed toward the most widely used Cas9 homolog from S. pyogenes (SpCas9) within healthy humans. We characterize SpCas9-reactive T cells within the CD4/CD8 compartments for multi-effector potency, cytotoxicity, and lineage determination. In-depth analysis of SpCas9-reactive T cells reveals a high frequency of SpCas9-reactive regulatory T cells that can mitigate SpCas9-reactive effector T cell proliferation and function in vitro. Our results shed light on T cell–mediated immunity toward CRISPR-associated nucleases and offer a possible solution to overcome the problem of preexisting immunity.
Translational control of tumor immune escape via the eIF4F–STAT1–PD-L1 axis in melanoma Nat. Med. (IF 32.621) Pub Date : 2018-10-29 Michaël Cerezo, Ramdane Guemiri, Sabine Druillennec, Isabelle Girault, Hélène Malka-Mahieu, Shensi Shen, Delphine Allard, Sylvain Martineau, Caroline Welsch, Sandrine Agoussi, Charlène Estrada, Julien Adam, Cristina Libenciuc, Emilie Routier, Séverine Roy, Laurent Désaubry, Alexander M. Eggermont, Nahum Sonenberg, Jean Yves Scoazec, Alain Eychène, Stéphan Vagner, Caroline Robert
Preventing the immune escape of tumor cells by blocking inhibitory checkpoints, such as the interaction between programmed death ligand-1 (PD-L1) and programmed death-1 (PD-1) receptor, is a powerful anticancer approach. However, many patients do not respond to checkpoint blockade. Tumor PD-L1 expression is a potential efficacy biomarker, but the complex mechanisms underlying its regulation are not completely understood. Here, we show that the eukaryotic translation initiation complex, eIF4F, which binds the 5′ cap of mRNAs, regulates the surface expression of interferon-γ-induced PD-L1 on cancer cells by regulating translation of the mRNA encoding the signal transducer and activator of transcription 1 (STAT1) transcription factor. eIF4F complex formation correlates with response to immunotherapy in human melanoma. Pharmacological inhibition of eIF4A, the RNA helicase component of eIF4F, elicits powerful antitumor immune-mediated effects via PD-L1 downregulation. Thus, eIF4A inhibitors, in development as anticancer drugs, may also act as cancer immunotherapies.
Linking brain tumors and epileptic seizures Nat. Med. (IF 32.621) Pub Date : 2018-10-29 Jean M. Mulcahy Levy, Martin McMahon
Linking brain tumors and epileptic seizures Linking brain tumors and epileptic seizures, Published online: 29 October 2018; doi:10.1038/s41591-018-0249-6 Mutationally activated BRAF-V600E influences the behavior of different types of cells in the brain and leads to promotion of seizures as well as brain tumors, indicating how both can be pharmacologically targeted in the clinic.
Author Correction: Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma Nat. Med. (IF 32.621) Pub Date : 2018-10-25 Rodabe N. Amaria, Sangeetha M. Reddy, Hussein A. Tawbi, Michael A. Davies, Merrick I. Ross, Isabella C. Glitza, Janice N. Cormier, Carol Lewis, Wen-Jen Hwu, Ehab Hanna, Adi Diab, Michael K. Wong, Richard Royal, Neil Gross, Randal Weber, Stephen Y. Lai, Richard Ehlers, Jorge Blando, Denái R. Milton, Scott Woodman, Robin Kageyama, Daniel K. Wells, Patrick Hwu, Sapna P. Patel, Anthony Lucci, Amy Hessel, Jeffrey E. Lee, Jeffrey Gershenwald, Lauren Simpson, Elizabeth M. Burton, Liberty Posada, Lauren Haydu, Linghua Wang, Shaojun Zhang, Alexander J. Lazar, Courtney W. Hudgens, Vancheswaran Gopalakrishnan, Alexandre Reuben, Miles C. Andrews, Christine N. Spencer, Victor Prieto, Padmanee Sharma, James Allison, Michael T. Tetzlaff, Jennifer A. Wargo
Author Correction: Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma Author Correction: Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma, Published online: 25 October 2018; doi:10.1038/s41591-018-0251-z Author Correction: Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma
Publisher Correction: Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma Nat. Med. (IF 32.621) Pub Date : 2018-10-25 Rodabe N. Amaria, Sangeetha M. Reddy, Hussein A. Tawbi, Michael A. Davies, Merrick I. Ross, Isabella C. Glitza, Janice N. Cormier, Carol Lewis, Wen-Jen Hwu, Ehab Hanna, Adi Diab, Michael K. Wong, Richard Royal, Neil Gross, Randal Weber, Stephen Y. Lai, Richard Ehlers, Jorge Blando, Denái R. Milton, Scott Woodman, Robin Kageyama, Daniel K. Wells, Patrick Hwu, Sapna P. Patel, Anthony Lucci, Amy Hessel, Jeffrey E. Lee, Jeffrey Gershenwald, Lauren Simpson, Elizabeth M. Burton, Liberty Posada, Lauren Haydu, Linghua Wang, Shaojun Zhang, Alexander J. Lazar, Courtney W. Hudgens, Vancheswaran Gopalakrishnan, Alexandre Reuben, Miles C. Andrews, Christine N. Spencer, Victor Prieto, Padmanee Sharma, James Allison, Michael T. Tetzlaff, Jennifer A. Wargo
Publisher Correction: Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma Publisher Correction: Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma, Published online: 25 October 2018; doi:10.1038/s41591-018-0252-y Publisher Correction: Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma
Publisher Correction: Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia Nat. Med. (IF 32.621) Pub Date : 2018-10-23 Megan L. Gill, Peter J. Grahn, Jonathan S. Calvert, Margaux B. Linde, Igor A. Lavrov, Jeffrey A. Strommen, Lisa A. Beck, Dimitry G. Sayenko, Meegan G. Van Straaten, Dina I. Drubach, Daniel D. Veith, Andrew R. Thoreson, Cesar Lopez, Yury P. Gerasimenko, V. Reggie Edgerton, Kendall H. Lee, Kristin D. Zhao
Publisher Correction: Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia Publisher Correction: Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia, Published online: 23 October 2018; doi:10.1038/s41591-018-0248-7 Publisher Correction: Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia
The Artificial Intelligence Clinician learns optimal treatment strategies for sepsis in intensive care Nat. Med. (IF 32.621) Pub Date : 2018-10-22 Matthieu Komorowski, Leo A. Celi, Omar Badawi, Anthony C. Gordon, A. Aldo Faisal
Sepsis is the third leading cause of death worldwide and the main cause of mortality in hospitals1,2,3, but the best treatment strategy remains uncertain. In particular, evidence suggests that current practices in the administration of intravenous fluids and vasopressors are suboptimal and likely induce harm in a proportion of patients1,4,5,6. To tackle this sequential decision-making problem, we developed a reinforcement learning agent, the Artificial Intelligence (AI) Clinician, which extracted implicit knowledge from an amount of patient data that exceeds by many-fold the life-time experience of human clinicians and learned optimal treatment by analyzing a myriad of (mostly suboptimal) treatment decisions. We demonstrate that the value of the AI Clinician’s selected treatment is on average reliably higher than human clinicians. In a large validation cohort independent of the training data, mortality was lowest in patients for whom clinicians’ actual doses matched the AI decisions. Our model provides individualized and clinically interpretable treatment decisions for sepsis that could improve patient outcomes.
A biobank of patient-derived pediatric brain tumor models Nat. Med. (IF 32.621) Pub Date : 2018-10-22 Sebastian Brabetz, Sarah E. S. Leary, Susanne N. Gröbner, Madison W. Nakamoto, Huriye Şeker-Cin, Emily J. Girard, Bonnie Cole, Andrew D. Strand, Karina L. Bloom, Volker Hovestadt, Norman L. Mack, Fiona Pakiam, Benjamin Schwalm, Andrey Korshunov, Gnana Prakash Balasubramanian, Paul A. Northcott, Kyle D. Pedro, Joyoti Dey, Stacey Hansen, Sally Ditzler, Peter Lichter, Lukas Chavez, David T. W. Jones, Jan Koster, Stefan M. Pfister, Marcel Kool, James M. Olson
Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children’s Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models and seven cell lines representing 14 molecular subgroups of pediatric brain tumors. Patient-derived orthotopic xenograft models were found to be representative of the human tumors they were derived from in terms of histology, immunohistochemistry, gene expression, DNA methylation, copy number, and mutational profiles. In vivo drug sensitivity of targeted therapeutics was associated with distinct molecular tumor subgroups and specific genetic alterations. These models and their molecular characterization provide an unprecedented resource for the cancer community to study key oncogenic drivers and to evaluate novel treatment strategies.
Antigen discovery and specification of immunodominance hierarchies for MHCII-restricted epitopes Nat. Med. (IF 32.621) Pub Date : 2018-10-22 Daniel B. Graham, Chengwei Luo, Daniel J. O’Connell, Ariel Lefkovith, Eric M. Brown, Moran Yassour, Mukund Varma, Jennifer G. Abelin, Kara L. Conway, Guadalupe J. Jasso, Caline G. Matar, Steven A. Carr, Ramnik J. Xavier
Identifying immunodominant T cell epitopes remains a significant challenge in the context of infectious disease, autoimmunity, and immuno-oncology. To address the challenge of antigen discovery, we developed a quantitative proteomic approach that enabled unbiased identification of major histocompatibility complex class II (MHCII)–associated peptide epitopes and biochemical features of antigenicity. On the basis of these data, we trained a deep neural network model for genome-scale predictions of immunodominant MHCII-restricted epitopes. We named this model bacteria originated T cell antigen (BOTA) predictor. In validation studies, BOTA accurately predicted novel CD4 T cell epitopes derived from the model pathogen Listeria monocytogenes and the commensal microorganism Muribaculum intestinale. To conclusively define immunodominant T cell epitopes predicted by BOTA, we developed a high-throughput approach to screen DNA-encoded peptide–MHCII libraries for functional recognition by T cell receptors identified from single-cell RNA sequencing. Collectively, these studies provide a framework for defining the immunodominance landscape across a broad range of immune pathologies.
Publisher Correction: Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma Nat. Med. (IF 32.621) Pub Date : 2018-10-17 Noam Auslander, Gao Zhang, Joo Sang Lee, Dennie T. Frederick, Benchun Miao, Tabea Moll, Tian Tian, Zhi Wei, Sanna Madan, Ryan J. Sullivan, Genevieve Boland, Keith Flaherty, Meenhard Herlyn, Eytan Ruppin
Publisher Correction: Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma Publisher Correction: Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma, Published online: 17 October 2018; doi:10.1038/s41591-018-0247-8 Publisher Correction: Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma
Precision identification of diverse bloodstream pathogens in the gut microbiome Nat. Med. (IF 32.621) Pub Date : 2018-10-15 Fiona B. Tamburini, Tessa M. Andermann, Ekaterina Tkachenko, Fiona Senchyna, Niaz Banaei, Ami S. Bhatt
A comprehensive evaluation of every patient with a bloodstream infection includes an attempt to identify the infectious source. Pathogens can originate from various places, such as the gut microbiota, skin and the external environment. Identifying the definitive origin of an infection would enable precise interventions focused on management of the source1,2. Unfortunately, hospital infection control practices are often informed by assumptions about the source of various specific pathogens; if these assumptions are incorrect, they lead to interventions that do not decrease pathogen exposure3. Here, we develop and apply a streamlined bioinformatic tool, named StrainSifter, to match bloodstream pathogens precisely to a candidate source. We then leverage this approach to interrogate the gut microbiota as a potential reservoir of bloodstream pathogens in a cohort of hematopoietic cell transplantation recipients. We find that patients with Escherichia coli and Klebsiella pneumoniae bloodstream infections have concomitant gut colonization with these organisms, suggesting that the gut may be a source of these infections. We also find cases where typically nonenteric pathogens, such as Pseudomonas aeruginosa and Staphylococcus epidermidis, are found in the gut microbiota, thereby challenging the existing informal dogma of these infections originating from environmental or skin sources. Thus, we present an approach to distinguish the source of various bloodstream infections, which may facilitate more accurate tracking and prevention of hospital-acquired infections.
Gene editing for Duchenne muscular dystrophy Nat. Med. (IF 32.621) Pub Date : 2018-10-08 Hannah Stower
Gene editing for Duchenne muscular dystrophy Gene editing for Duchenne muscular dystrophy, Published online: 08 October 2018; doi:10.1038/s41591-018-0225-1 Gene editing for Duchenne muscular dystrophy
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