Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4 Nat. Med. (IF 32.621) Pub Date : 2018-09-17 Francesca Zanconato, Giusy Battilana, Mattia Forcato, Letizia Filippi, Luca Azzolin, Andrea Manfrin, Erika Quaranta, Daniele Di Biagio, Gianluca Sigismondo, Vincenza Guzzardo, Pascale Lejeune, Bernard Haendler, Jeroen Krijgsveld, Matteo Fassan, Silvio Bicciato, Michelangelo Cordenonsi, Stefano Piccolo
Cancer cells rely on dysregulated gene expression. This establishes specific transcriptional addictions that may be therapeutically exploited. Yet, the mechanisms that are ultimately responsible for these addictions are poorly understood. Here, we investigated the transcriptional dependencies of transformed cells to the transcription factors YAP and TAZ. YAP/TAZ physically engage the general coactivator bromodomain-containing protein 4 (BRD4), dictating the genome-wide association of BRD4 to chromatin. YAP/TAZ flag a large set of enhancers with super-enhancer-like functional properties. YAP/TAZ-bound enhancers mediate the recruitment of BRD4 and RNA polymerase II at YAP/TAZ-regulated promoters, boosting the expression of a host of growth-regulating genes. Treatment with small-molecule inhibitors of BRD4 blunts YAP/TAZ pro-tumorigenic activity in several cell or tissue contexts, causes the regression of pre-established, YAP/TAZ-addicted neoplastic lesions and reverts drug resistance. This work sheds light on essential mediators, mechanisms and genome-wide regulatory elements that are responsible for transcriptional addiction in cancer and lays the groundwork for a rational use of BET inhibitors according to YAP/TAZ biology.
Classification and mutation prediction from non–small cell lung cancer histopathology images using deep learning Nat. Med. (IF 32.621) Pub Date : 2018-09-17 Nicolas Coudray, Paolo Santiago Ocampo, Theodore Sakellaropoulos, Navneet Narula, Matija Snuderl, David Fenyö, Andre L. Moreira, Narges Razavian, Aristotelis Tsirigos
Visual inspection of histopathology slides is one of the main methods used by pathologists to assess the stage, type and subtype of lung tumors. Adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are the most prevalent subtypes of lung cancer, and their distinction requires visual inspection by an experienced pathologist. In this study, we trained a deep convolutional neural network (inception v3) on whole-slide images obtained from The Cancer Genome Atlas to accurately and automatically classify them into LUAD, LUSC or normal lung tissue. The performance of our method is comparable to that of pathologists, with an average area under the curve (AUC) of 0.97. Our model was validated on independent datasets of frozen tissues, formalin-fixed paraffin-embedded tissues and biopsies. Furthermore, we trained the network to predict the ten most commonly mutated genes in LUAD. We found that six of them—STK11, EGFR, FAT1, SETBP1, KRAS and TP53—can be predicted from pathology images, with AUCs from 0.733 to 0.856 as measured on a held-out population. These findings suggest that deep-learning models can assist pathologists in the detection of cancer subtype or gene mutations. Our approach can be applied to any cancer type, and the code is available at https://github.com/ncoudray/DeepPATH.
BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors Nat. Med. (IF 32.621) Pub Date : 2018-09-17 Hyun Yong Koh, Se Hoon Kim, Jaeson Jang, Hyungguk Kim, Sungwook Han, Jae Seok Lim, Geurim Son, Junjeong Choi, Byung Ouk Park, Won Do Heo, Jinju Han, Hyunjoo Jenny Lee, Daeyoup Lee, Hoon-Chul Kang, Minho Shong, Se-Bum Paik, Dong Seok Kim, Jeong Ho Lee
Pediatric brain tumors are highly associated with epileptic seizures1. However, their epileptogenic mechanisms remain unclear. Here, we show that the oncogenic BRAF somatic mutation p.Val600Glu (V600E) in developing neurons underlies intrinsic epileptogenicity in ganglioglioma, one of the leading causes of intractable epilepsy2. To do so, we developed a mouse model harboring the BRAFV600E somatic mutation during early brain development to reflect the most frequent mutation, as well as the origin and timing thereof. Therein, the BRAFV600E mutation arising in progenitor cells during brain development led to the acquisition of intrinsic epileptogenic properties in neuronal lineage cells, whereas tumorigenic properties were attributed to high proliferation of glial lineage cells. RNA sequencing analysis of patient brain tissues with the mutation revealed that BRAFV600E-induced epileptogenesis is mediated by RE1-silencing transcription factor (REST), which is a regulator of ion channels and neurotransmitter receptors associated with epilepsy. Moreover, we found that seizures in mice were significantly alleviated by an FDA-approved BRAFV600E inhibitor, vemurafenib, as well as various genetic inhibitions of Rest. Accordingly, this study provides direct evidence of a BRAF somatic mutation contributing to the intrinsic epileptogenicity in pediatric brain tumors and suggests that BRAF and REST could be treatment targets for intractable epilepsy.
Right data for right patient—a precisionFDA NCI–CPTAC Multi-omics Mislabeling Challenge Nat. Med. (IF 32.621) Pub Date : 2018-09-07 Emily Boja, Živana Težak, Bing Zhang, Pei Wang, Elaine Johanson, Denise Hinton, Henry Rodriguez
Right data for right patient—a precisionFDA NCI–CPTAC Multi-omics Mislabeling ChallengeRight data for right patient—a precisionFDA NCI–CPTAC Multi-omics Mislabeling Challenge, Published online: 07 September 2018; doi:10.1038/s41591-018-0180-xTo address a critical roadblock that can occur in translational and clinical research, the National Cancer Institute and the Food and Drug Administration, in coordination with the DREAM Challenges, are launching the first computational challenge using multi-omics datasets to detect and correct specimen mislabeling.
An option for treatment of multidrug-resistant HIV Nat. Med. (IF 32.621) Pub Date : 2018-09-07 Hannah Stower
An option for treatment of multidrug-resistant HIVAn option for treatment of multidrug-resistant HIV, Published online: 07 September 2018; doi:10.1038/s41591-018-0191-7An option for treatment of multidrug-resistant HIV
Preconception cold–induced epigenetic inheritance Nat. Med. (IF 32.621) Pub Date : 2018-09-07 Michael K. Skinner
Preconception cold–induced epigenetic inheritancePreconception cold–induced epigenetic inheritance, Published online: 07 September 2018; doi:10.1038/s41591-018-0187-3Preconception cold–induced alterations of sperm DNA methylation result in offspring with altered brown adipose tissue and improved adaptation to overnutrition and hypothermia.
Restoring sight with native cell reprogramming Nat. Med. (IF 32.621) Pub Date : 2018-09-07 Hannah Stower
Restoring sight with native cell reprogrammingRestoring sight with native cell reprogramming, Published online: 07 September 2018; doi:10.1038/s41591-018-0192-6Restoring sight with native cell reprogramming
Clarifying access to data Nat. Med. (IF 32.621) Pub Date : 2018-09-07
Clarifying access to dataClarifying access to data, Published online: 07 September 2018; doi:10.1038/s41591-018-0188-2To facilitate access to and improve the discoverability of the data in our papers, Nature Medicine is making the data availability statement in our papers more prominent and its language more transparent.
Wound, heal thyself Nat. Med. (IF 32.621) Pub Date : 2018-09-07 Shruti Naik
Wound, heal thyselfWound, heal thyself, Published online: 07 September 2018; doi:10.1038/s41591-018-0179-3An in vivo cellular reprogramming strategy to generate epithelial cells from wound mesenchymal cells promotes healing and provides a new avenue for the treatment of nonhealing wounds.
Modulating NAD+ metabolism to prevent acute kidney injury Nat. Med. (IF 32.621) Pub Date : 2018-09-03 Heerajnarain Bulluck, Derek J. Hausenloy
Modulating NAD+ metabolism to prevent acute kidney injuryModulating NAD<sup>+</sup> metabolism to prevent acute kidney injury, Published online: 03 September 2018; doi:10.1038/s41591-018-0181-9Impaired de novo NAD+ biosynthesis predisposes to acute kidney injury, and augmenting NAD+ metabolism with oral nicotinamide supplementation may prevent acute kidney injury.
A role for chromatin regulatory dynamics in breast cancer evolution Nat. Med. (IF 32.621) Pub Date : 2018-09-03 Christopher Probert, Christina Curtis
A role for chromatin regulatory dynamics in breast cancer evolutionA role for chromatin regulatory dynamics in breast cancer evolution, Published online: 03 September 2018; doi:10.1038/s41591-018-0182-8Enhancer profiling of breast tumors reveals that chromatin regulatory elements contribute to the clonal fitness landscape, treatment resistance and phenotypic divergence.
New machine-learning technologies for computer-aided diagnosis Nat. Med. (IF 32.621) Pub Date : 2018-09-03 Charles J. Lynch, Conor Liston
New machine-learning technologies for computer-aided diagnosisNew machine-learning technologies for computer-aided diagnosis, Published online: 03 September 2018; doi:10.1038/s41591-018-0178-4Machine learning can be used for computer-aided diagnosis of acute neurological events and retinal disease and can be incorporated into conventional clinical workflows to improve health outcomes.
Route of immunization defines multiple mechanisms of vaccine-mediated protection against SIV Nat. Med. (IF 32.621) Pub Date : 2018-09-03 Margaret E. Ackerman, Jishnu Das, Srivamshi Pittala, Thomas Broge, Caitlyn Linde, Todd J. Suscovich, Eric P. Brown, Todd Bradley, Harini Natarajan, Shu Lin, Jessica K. Sassic, Sean O’Keefe, Nickita Mehta, Derrick Goodman, Magdalena Sips, Joshua A. Weiner, Georgia D. Tomaras, Barton F. Haynes, Douglas A. Lauffenburger, Chris Bailey-Kellogg, Mario Roederer, Galit Alter
Antibodies are the primary correlate of protection for most licensed vaccines; however, their mechanisms of protection may vary, ranging from physical blockade to clearance via the recruitment of innate immunity. Here, we uncover striking functional diversity in vaccine-induced antibodies that is driven by immunization site and is associated with reduced risk of SIV infection in nonhuman primates. While equivalent levels of protection were observed following intramuscular (IM) and aerosol (AE) immunization with an otherwise identical DNA prime–Ad5 boost regimen, reduced risk of infection was associated with IgG-driven antibody-dependent monocyte-mediated phagocytosis in the IM vaccinees, but with vaccine-elicited IgA-driven neutrophil-mediated phagocytosis in AE-immunized animals. Thus, although route-independent correlates indicate a critical role for phagocytic Fc-effector activity in protection from SIV, the site of immunization may drive this Fc activity via distinct innate effector cells and antibody isotypes. Moreover, the same correlates predicted protection from SHIV infection in a second nonhuman primate vaccine trial using a disparate IM canarypox prime–protein boost strategy, analogous to that used in the first moderately protective human HIV vaccine trial. These data identify orthogonal functional humoral mechanisms, initiated by distinct vaccination routes and immunization strategies, pointing to multiple, potentially complementary correlates of immunity that may support the rational design of a protective vaccine against HIV.
Regional variation limits applications of healthy gut microbiome reference ranges and disease models Nat. Med. (IF 32.621) Pub Date : 2018-08-27 Yan He, Wei Wu, Hui-Min Zheng, Pan Li, Daniel McDonald, Hua-Fang Sheng, Mu-Xuan Chen, Zi-Hui Chen, Gui-Yuan Ji, Zhong-Dai-Xi Zheng, Prabhakar Mujagond, Xiao-Jiao Chen, Zu-Hua Rong, Peng Chen, Li-Yi Lyu, Xian Wang, Chong-Bin Wu, Nan Yu, Yan-Jun Xu, Jia Yin, Jeroen Raes, Rob Knight, Wen-Jun Ma, Hong-Wei Zhou
Dysbiosis, departure of the gut microbiome from a healthy state, has been suggested to be a powerful biomarker of disease incidence and progression1,2,3. Diagnostic applications have been proposed for inflammatory bowel disease diagnosis and prognosis4, colorectal cancer prescreening5 and therapeutic choices in melanoma6. Noninvasive sampling could facilitate large-scale public health applications, including early diagnosis and risk assessment in metabolic7 and cardiovascular diseases8. To understand the generalizability of microbiota-based diagnostic models of metabolic disease, we characterized the gut microbiota of 7,009 individuals from 14 districts within 1 province in China. Among phenotypes, host location showed the strongest associations with microbiota variations. Microbiota-based metabolic disease models developed in one location failed when used elsewhere, suggesting that such models cannot be extrapolated. Interpolated models performed much better, especially in diseases with obvious microbiota-related characteristics. Interpolation efficiency decreased as geographic scale increased, indicating a need to build localized baseline and disease models to predict metabolic risks.
Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase Nat. Med. (IF 32.621) Pub Date : 2018-08-27 Roger W. Hunter, Curtis C. Hughey, Louise Lantier, Elias I. Sundelin, Mark Peggie, Elton Zeqiraj, Frank Sicheri, Niels Jessen, David H. Wasserman, Kei Sakamoto
Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5′-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P2), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet–fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects.
Depicting the composition of gut microbiota in a population with varied ethnic origins but shared geography Nat. Med. (IF 32.621) Pub Date : 2018-08-27 Mélanie Deschasaux, Kristien E. Bouter, Andrei Prodan, Evgeni Levin, Albert K. Groen, Hilde Herrema, Valentina Tremaroli, Guido J. Bakker, Ilias Attaye, Sara-Joan Pinto-Sietsma, Daniel H. van Raalte, Marieke B. Snijder, Mary Nicolaou, Ron Peters, Aeilko H. Zwinderman, Fredrik Bäckhed, Max Nieuwdorp
Trillions of microorganisms inhabit the human gut and are regarded as potential key factors for health1,2. Characteristics such as diet, lifestyle, or genetics can shape the composition of the gut microbiota2,3,4,5,6 and are usually shared by individuals from comparable ethnic origin. So far, most studies assessing how ethnicity relates to the intestinal microbiota compared small groups living at separate geographical locations7,8,9,10. Using fecal 16S ribosomal RNA gene sequencing in 2,084 participants of the Healthy Life in an Urban Setting (HELIUS) study11,12, we show that individuals living in the same city tend to share similar gut microbiota characteristics with others of their ethnic background. Ethnicity contributed to explain the interindividual dissimilarities in gut microbiota composition, with three main poles primarily characterized by operational taxonomic units (OTUs) classified as Prevotella (Moroccans, Turks, Ghanaians), Bacteroides (African Surinamese, South-Asian Surinamese), and Clostridiales (Dutch). The Dutch exhibited the greatest gut microbiota α-diversity and the South-Asian Surinamese the smallest, with corresponding enrichment or depletion in numerous OTUs. Ethnic differences in α-diversity and interindividual dissimilarities were independent of metabolic health and only partly explained by ethnic-related characteristics including sociodemographic, lifestyle, or diet factors. Hence, the ethnic origin of individuals may be an important factor to consider in microbiome research and its potential future applications in ethnic-diverse societies.
The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space Nat. Med. (IF 32.621) Pub Date : 2018-08-27 Johanna Klughammer, Barbara Kiesel, Thomas Roetzer, Nikolaus Fortelny, Amelie Nemc, Karl-Heinz Nenning, Julia Furtner, Nathan C. Sheffield, Paul Datlinger, Nadine Peter, Martha Nowosielski, Marco Augustin, Mario Mischkulnig, Thomas Ströbel, Donat Alpar, Bekir Ergüner, Martin Senekowitsch, Patrizia Moser, Christian F. Freyschlag, Johannes Kerschbaumer, Claudius Thomé, Astrid E. Grams, Günther Stockhammer, Melitta Kitzwoegerer, Stefan Oberndorfer, Franz Marhold, Serge Weis, Johannes Trenkler, Johanna Buchroithner, Josef Pichler, Johannes Haybaeck, Stefanie Krassnig, Kariem Mahdy Ali, Gord von Campe, Franz Payer, Camillo Sherif, Julius Preiser, Thomas Hauser, Peter A. Winkler, Waltraud Kleindienst, Franz Würtz, Tanisa Brandner-Kokalj, Martin Stultschnig, Stefan Schweiger, Karin Dieckmann, Matthias Preusser, Georg Langs, Bernhard Baumann, Engelbert Knosp, Georg Widhalm, Christine Marosi, Johannes A. Hainfellner, Adelheid Woehrer, Christoph Bock
Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practice.
When the golden years turn blue Nat. Med. (IF 32.621) Pub Date : 2018-08-23 Nicole Wetsman
When the golden years turn blueWhen the golden years turn blue, Published online: 23 August 2018; doi:10.1038/s41591-018-0174-8Evolving research sheds light on a possibly unique form of depression among the elderly.
Publisher Correction: Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis Nat. Med. (IF 32.621) Pub Date : 2018-08-22 Peter Savas, Balaji Virassamy, Chengzhong Ye, Agus Salim, Christopher P. Mintoff, Franco Caramia, Roberto Salgado, David J. Byrne, Zhi L. Teo, Sathana Dushyanthen, Ann Byrne, Lironne Wein, Stephen J. Luen, Catherine Poliness, Sophie S. Nightingale, Anita S. Skandarajah, David E. Gyorki, Chantel M. Thornton, Paul A. Beavis, Stephen B. Fox, Phillip K. Darcy, Terence P. Speed, Laura K. Mackay, Paul J. Neeson, Sherene Loi
Publisher Correction: Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosisPublisher Correction: Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis, Published online: 22 August 2018; doi:10.1038/s41591-018-0176-6Publisher Correction: Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis
De novo NAD+ biosynthetic impairment in acute kidney injury in humans Nat. Med. (IF 32.621) Pub Date : 2018-08-20 Ali Poyan Mehr, Mei T. Tran, Kenneth M. Ralto, David E. Leaf, Vaughan Washco, Joseph Messmer, Adam Lerner, Ajay Kher, Steven H. Kim, Charbel C. Khoury, Shoshana J. Herzig, Mary E. Trovato, Noemie Simon-Tillaux, Matthew R. Lynch, Ravi I. Thadhani, Clary B. Clish, Kamal R. Khabbaz, Eugene P. Rhee, Sushrut S. Waikar, Anders H. Berg, Samir M. Parikh
Nicotinamide adenine dinucleotide (NAD+) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD+ biosynthesis from tryptophan is evolutionarily conserved yet considered supplanted among higher species by biosynthesis from nicotinamide (NAM). Here we show that a bottleneck enzyme in de novo biosynthesis, quinolinate phosphoribosyltransferase (QPRT), defends renal NAD+ and mediates resistance to acute kidney injury (AKI). Following murine AKI, renal NAD+ fell, quinolinate rose, and QPRT declined. QPRT+/− mice exhibited higher quinolinate, lower NAD+, and higher AKI susceptibility. Metabolomics suggested an elevated urinary quinolinate/tryptophan ratio (uQ/T) as an indicator of reduced QPRT. Elevated uQ/T predicted AKI and other adverse outcomes in critically ill patients. A phase 1 placebo-controlled study of oral NAM demonstrated a dose-related increase in circulating NAD+ metabolites. NAM was well tolerated and was associated with less AKI. Therefore, impaired NAD+ biosynthesis may be a feature of high-risk hospitalizations for which NAD+ augmentation could be beneficial.
Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent Nat. Med. (IF 32.621) Pub Date : 2018-08-20 Koki Fujimori, Mitsuru Ishikawa, Asako Otomo, Naoki Atsuta, Ryoichi Nakamura, Tetsuya Akiyama, Shinji Hadano, Masashi Aoki, Hideyuki Saya, Gen Sobue, Hideyuki Okano
Amyotrophic lateral sclerosis (ALS) is a heterogeneous motor neuron disease for which no effective treatment is available, despite decades of research into SOD1-mutant familial ALS (FALS). The majority of ALS patients have no familial history, making the modeling of sporadic ALS (SALS) essential to the development of ALS therapeutics. However, as mutations underlying ALS pathogenesis have not yet been identified, it remains difficult to establish useful models of SALS. Using induced pluripotent stem cell (iPSC) technology to generate stem and differentiated cells retaining the patients’ full genetic information, we have established a large number of in vitro cellular models of SALS. These models showed phenotypic differences in their pattern of neuronal degeneration, types of abnormal protein aggregates, cell death mechanisms, and onset and progression of these phenotypes in vitro among cases. We therefore developed a system for case clustering capable of subdividing these heterogeneous SALS models by their in vitro characteristics. We further evaluated multiple-phenotype rescue of these subclassified SALS models using agents selected from non-SOD1 FALS models, and identified ropinirole as a potential therapeutic candidate. Integration of the datasets acquired in this study permitted the visualization of molecular pathologies shared across a wide range of SALS models.
Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response Nat. Med. (IF 32.621) Pub Date : 2018-08-20 Peng Jiang, Shengqing Gu, Deng Pan, Jingxin Fu, Avinash Sahu, Xihao Hu, Ziyi Li, Nicole Traugh, Xia Bu, Bo Li, Jun Liu, Gordon J. Freeman, Myles A. Brown, Kai W. Wucherpfennig, X. Shirley Liu
Cancer treatment by immune checkpoint blockade (ICB) can bring long-lasting clinical benefits, but only a fraction of patients respond to treatment. To predict ICB response, we developed TIDE, a computational method to model two primary mechanisms of tumor immune evasion: the induction of T cell dysfunction in tumors with high infiltration of cytotoxic T lymphocytes (CTL) and the prevention of T cell infiltration in tumors with low CTL level. We identified signatures of T cell dysfunction from large tumor cohorts by testing how the expression of each gene in tumors interacts with the CTL infiltration level to influence patient survival. We also modeled factors that exclude T cell infiltration into tumors using expression signatures from immunosuppressive cells. Using this framework and pre-treatment RNA-Seq or NanoString tumor expression profiles, TIDE predicted the outcome of melanoma patients treated with first-line anti-PD1 or anti-CTLA4 more accurately than other biomarkers such as PD-L1 level and mutation load. TIDE also revealed new candidate ICB resistance regulators, such as SERPINB9, demonstrating utility for immunotherapy research.
Genetically engineered human cortical spheroid models of tuberous sclerosis Nat. Med. (IF 32.621) Pub Date : 2018-08-20 John D. Blair, Dirk Hockemeyer, Helen S. Bateup
Tuberous sclerosis complex (TSC) is a multisystem developmental disorder caused by mutations in the TSC1 or TSC2 genes, whose protein products are negative regulators of mechanistic target of rapamycin complex 1 signaling. Hallmark pathologies of TSC are cortical tubers—regions of dysmorphic, disorganized neurons and glia in the cortex that are linked to epileptogenesis. To determine the developmental origin of tuber cells, we established human cellular models of TSC by CRISPR–Cas9-mediated gene editing of TSC1 or TSC2 in human pluripotent stem cells (hPSCs). Using heterozygous TSC2 hPSCs with a conditional mutation in the functional allele, we show that mosaic biallelic inactivation during neural progenitor expansion is necessary for the formation of dysplastic cells and increased glia production in three-dimensional cortical spheroids. Our findings provide support for the second-hit model of cortical tuber formation and suggest that variable developmental timing of somatic mutations could contribute to the heterogeneity in the neurological presentation of TSC.
Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma Nat. Med. (IF 32.621) Pub Date : 2018-08-20 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
Immune checkpoint blockade (ICB) therapy provides remarkable clinical gains and has been very successful in treatment of melanoma. However, only a subset of patients with advanced tumors currently benefit from ICB therapies, which at times incur considerable side effects and costs. Constructing predictors of patient response has remained a serious challenge because of the complexity of the immune response and the shortage of large cohorts of ICB-treated patients that include both ‘omics’ and response data. Here we build immuno-predictive score (IMPRES), a predictor of ICB response in melanoma which encompasses 15 pairwise transcriptomics relations between immune checkpoint genes. It is based on two key conjectures: (i) immune mechanisms underlying spontaneous regression in neuroblastoma can predict melanoma response to ICB, and (ii) key immune interactions can be captured via specific pairwise relations of the expression of immune checkpoint genes. IMPRES is validated on nine published datasets1,2,3,4,5,6 and on a newly generated dataset with 31 patients treated with anti-PD-1 and 10 with anti-CTLA-4, spanning 297 samples in total. It achieves an overall accuracy of AUC = 0.83, outperforming existing predictors and capturing almost all true responders while misclassifying less than half of the nonresponders. Future studies are warranted to determine the value of the approach presented here in other cancer types.
Publisher Correction: Inactivating hepatic follistatin alleviates hyperglycemia Nat. Med. (IF 32.621) Pub Date : 2018-08-15 Rongya Tao, Caixia Wang, Oliver Stöhr, Wei Qiu, Yue Hu, Ji Miao, X. Charlie Dong, Sining Leng, Margaret Stefater, Nicholas Stylopoulos, Lin Lin, Kyle D. Copps, Morris F. White
Publisher Correction: Inactivating hepatic follistatin alleviates hyperglycemia Publisher Correction: Inactivating hepatic follistatin alleviates hyperglycemia, Published online: 15 August 2018; doi:10.1038/s41591-018-0129-0 Publisher Correction: Inactivating hepatic follistatin alleviates hyperglycemia
Automated deep-neural-network surveillance of cranial images for acute neurologic events Nat. Med. (IF 32.621) Pub Date : 2018-08-13 Joseph J. Titano, Marcus Badgeley, Javin Schefflein, Margaret Pain, Andres Su, Michael Cai, Nathaniel Swinburne, John Zech, Jun Kim, Joshua Bederson, J. Mocco, Burton Drayer, Joseph Lehar, Samuel Cho, Anthony Costa, Eric K. Oermann
Rapid diagnosis and treatment of acute neurological illnesses such as stroke, hemorrhage, and hydrocephalus are critical to achieving positive outcomes and preserving neurologic function—‘time is brain’1,2,3,4,5. Although these disorders are often recognizable by their symptoms, the critical means of their diagnosis is rapid imaging6,7,8,9,10. Computer-aided surveillance of acute neurologic events in cranial imaging has the potential to triage radiology workflow, thus decreasing time to treatment and improving outcomes. Substantial clinical work has focused on computer-assisted diagnosis (CAD), whereas technical work in volumetric image analysis has focused primarily on segmentation. 3D convolutional neural networks (3D-CNNs) have primarily been used for supervised classification on 3D modeling and light detection and ranging (LiDAR) data11,12,13,14,15. Here, we demonstrate a 3D-CNN architecture that performs weakly supervised classification to screen head CT images for acute neurologic events. Features were automatically learned from a clinical radiology dataset comprising 37,236 head CTs and were annotated with a semisupervised natural-language processing (NLP) framework16. We demonstrate the effectiveness of our approach to triage radiology workflow and accelerate the time to diagnosis from minutes to seconds through a randomized, double-blinded, prospective trial in a simulated clinical environment.
Clinically applicable deep learning for diagnosis and referral in retinal disease Nat. Med. (IF 32.621) Pub Date : 2018-08-13 Jeffrey De Fauw, Joseph R. Ledsam, Bernardino Romera-Paredes, Stanislav Nikolov, Nenad Tomasev, Sam Blackwell, Harry Askham, Xavier Glorot, Brendan O’Donoghue, Daniel Visentin, George van den Driessche, Balaji Lakshminarayanan, Clemens Meyer, Faith Mackinder, Simon Bouton, Kareem Ayoub, Reena Chopra, Dominic King, Alan Karthikesalingam, Cían O. Hughes, Rosalind Raine, Julian Hughes, Dawn A. Sim, Catherine Egan, Adnan Tufail, Hugh Montgomery, Demis Hassabis, Geraint Rees, Trevor Back, Peng T. Khaw, Mustafa Suleyman, Julien Cornebise, Pearse A. Keane, Olaf Ronneberger
The volume and complexity of diagnostic imaging is increasing at a pace faster than the availability of human expertise to interpret it. Artificial intelligence has shown great promise in classifying two-dimensional photographs of some common diseases and typically relies on databases of millions of annotated images. Until now, the challenge of reaching the performance of expert clinicians in a real-world clinical pathway with three-dimensional diagnostic scans has remained unsolved. Here, we apply a novel deep learning architecture to a clinically heterogeneous set of three-dimensional optical coherence tomography scans from patients referred to a major eye hospital. We demonstrate performance in making a referral recommendation that reaches or exceeds that of experts on a range of sight-threatening retinal diseases after training on only 14,884 scans. Moreover, we demonstrate that the tissue segmentations produced by our architecture act as a device-independent representation; referral accuracy is maintained when using tissue segmentations from a different type of device. Our work removes previous barriers to wider clinical use without prohibitive training data requirements across multiple pathologies in a real-world setting.
Author Correction: Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer Nat. Med. (IF 32.621) Pub Date : 2018-08-13 Yonathan Lissanu Deribe, Yuting Sun, Christopher Terranova, Fatima Khan, Juan Martinez-Ledesma, Jason Gay, Guang Gao, Robert A. Mullinax, Tin Khor, Ningping Feng, Yu-Hsi Lin, Chia-Chin Wu, Claudia Reyes, Qian Peng, Frederick Robinson, Akira Inoue, Veena Kochat, Chang-Gong Liu, John M. Asara, Cesar Moran, Florian Muller, Jing Wang, Bingliang Fang, Vali Papadimitrakopoulou, Ignacio I. Wistuba, Kunal Rai, Joseph Marszalek, P. Andrew Futreal
Author Correction: Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancerAuthor Correction: Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer, Published online: 13 August 2018; doi:10.1038/s41591-018-0173-9Author Correction: Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer
Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors Nat. Med. (IF 32.621) Pub Date : 2018-08-13 Pakawat Chongsathidkiet, Christina Jackson, Shohei Koyama, Franziska Loebel, Xiuyu Cui, S. Harrison Farber, Karolina Woroniecka, Aladine A. Elsamadicy, Cosette A. Dechant, Hanna R. Kemeny, Luis Sanchez-Perez, Tooba A. Cheema, Nicholas C. Souders, James E. Herndon, Jean-Valery Coumans, Jeffrey I. Everitt, Brian V. Nahed, John H. Sampson, Michael D. Gunn, Robert L. Martuza, Glenn Dranoff, William T. Curry, Peter E. Fecci
T cell dysfunction contributes to tumor immune escape in patients with cancer and is particularly severe amidst glioblastoma (GBM). Among other defects, T cell lymphopenia is characteristic, yet often attributed to treatment. We reveal that even treatment-naïve subjects and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T cell–deficient lymphoid organs. Missing naïve T cells are instead found sequestered in large numbers in the bone marrow. This phenomenon characterizes not only GBM but a variety of other cancers, although only when tumors are introduced into the intracranial compartment. T cell sequestration is accompanied by tumor-imposed loss of S1P1 from the T cell surface and is reversible upon precluding S1P1 internalization. In murine models of GBM, hindering S1P1 internalization and reversing sequestration licenses T cell–activating therapies that were previously ineffective. Sequestration of T cells in bone marrow is therefore a tumor-adaptive mode of T cell dysfunction, whose reversal may constitute a promising immunotherapeutic adjunct.
Author Correction: Metformin reverses established lung fibrosis in a bleomycin model Nat. Med. (IF 32.621) Pub Date : 2018-08-13 Sunad Rangarajan, Nathaniel B. Bone, Anna A. Zmijewska, Shaoning Jiang, Dae Won Park, Karen Bernard, Morgan L. Locy, Saranya Ravi, Jessy Deshane, Roslyn B. Mannon, Edward Abraham, Victor Darley-Usmar, Victor J. Thannickal, Jaroslaw W. Zmijewski
Author Correction: Metformin reverses established lung fibrosis in a bleomycin modelAuthor Correction: Metformin reverses established lung fibrosis in a bleomycin model, Published online: 13 August 2018; doi:10.1038/s41591-018-0170-zAuthor Correction: Metformin reverses established lung fibrosis in a bleomycin model
Publisher Correction: Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing Nat. Med. (IF 32.621) Pub Date : 2018-08-09 Xinyi Guo, Yuanyuan Zhang, Liangtao Zheng, Chunhong Zheng, Jintao Song, Qiming Zhang, Boxi Kang, Zhouzerui Liu, Liang Jin, Rui Xing, Ranran Gao, Lei Zhang, Minghui Dong, Xueda Hu, Xianwen Ren, Dennis Kirchhoff, Helge Gottfried Roider, Tiansheng Yan, Zemin Zhang
Publisher Correction: Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing Publisher Correction: Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing, Published online: 09 August 2018; doi:10.1038/s41591-018-0167-7 Publisher Correction: Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing
Author Correction: Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition Nat. Med. (IF 32.621) Pub Date : 2018-08-09 Gabrielle S. Wong, Jin Zhou, Jie Bin Liu, Zhong Wu, Xinsen Xu, Tianxia Li, David Xu, Steven E. Schumacher, Jens Puschhof, James McFarland, Charles Zou, Austin Dulak, Les Henderson, Peng Xu, Emily O’Day, Rachel Rendak, Wei-li Liao, Fabiola Cecchi, Todd Hembrough, Sarit Schwartz, Christopher Szeto, Anil K. Rustgi, Kwok-Kin Wong, J. Alan Diehl, Karin Jensen, Francesco Graziano, Annamaria Ruzzo, Shaunt Fereshetian, Philipp Mertins, Steven A. Carr, Rameen Beroukhim, Kenichi Nakamura, Eiji Oki, Masayuki Watanabe, Hideo Baba, Yu Imamura, Daniel Catenacci, Adam J. Bass
Author Correction: Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition Author Correction: Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition, Published online: 09 August 2018; doi:10.1038/s41591-018-0168-6 Author Correction: Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition
Publisher Correction: Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing Nat. Med. (IF 32.621) Pub Date : 2018-08-09 Lesley Hoyles, José-Manuel Fernández-Real, Massimo Federici, Matteo Serino, James Abbott, Julie Charpentier, Christophe Heymes, Jèssica Latorre Luque, Elodie Anthony, Richard H. Barton, Julien Chilloux, Antonis Myridakis, Laura Martinez-Gili, José Maria Moreno-Navarrete, Fadila Benhamed, Vincent Azalbert, Vincent Blasco-Baque, Josep Puig, Gemma Xifra, Wifredo Ricart, Christopher Tomlinson, Mark Woodbridge, Marina Cardellini, Francesca Davato, Iris Cardolini, Ottavia Porzio, Paolo Gentileschi, Frédéric Lopez, Fabienne Foufelle, Sarah A. Butcher, Elaine Holmes, Jeremy K. Nicholson, Catherine Postic, Rémy Burcelin, Marc-Emmanuel Dumas
Publisher Correction: Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing Publisher Correction: Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing, Published online: 09 August 2018; doi:10.1038/s41591-018-0169-5 Publisher Correction: Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing
Author Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring Nat. Med. (IF 32.621) Pub Date : 2018-08-07 Wenfei Sun, Hua Dong, Anton S. Becker, Dianne H. Dapito, Salvatore Modica, Gerald Grandl, Lennart Opitz, Vissarion Efthymiou, Leon G. Straub, Gitalee Sarker, Miroslav Balaz, Lucia Balazova, Aliki Perdikari, Elke Kiehlmann, Sara Bacanovic, Caroline Zellweger, Daria Peleg-Raibstein, Pawel Pelczar, Wolf Reik, Irene A. Burger, Ferdinand von Meyenn, Christian Wolfrum
Author Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring Author Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring, Published online: 07 August 2018; doi:10.1038/s41591-018-0162-z Author Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring
Publisher Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring Nat. Med. (IF 32.621) Pub Date : 2018-08-07 Wenfei Sun, Hua Dong, Anton S. Becker, Dianne H. Dapito, Salvatore Modica, Gerald Grandl, Lennart Opitz, Vissarion Efthymiou, Leon G. Straub, Gitalee Sarker, Miroslav Balaz, Lucia Balazova, Aliki Perdikari, Elke Kiehlmann, Sara Bacanovic, Caroline Zellweger, Daria Peleg-Raibstein, Pawel Pelczar, Wolf Reik, Irene A. Burger, Ferdinand von Meyenn, Christian Wolfrum
Publisher Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring Publisher Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring, Published online: 07 August 2018; doi:10.1038/s41591-018-0163-y Publisher Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring
Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound Nat. Med. (IF 32.621) Pub Date : 2018-08-06 Afam A. Okoye, Scott G. Hansen, Mukta Vaidya, Yoshinori Fukazawa, Haesun Park, Derick M. Duell, Richard Lum, Colette M. Hughes, Abigail B. Ventura, Emily Ainslie, Julia C. Ford, David Morrow, Roxanne M. Gilbride, Alfred W. Legasse, Joseph Hesselgesser, Romas Geleziunas, Yuan Li, Kelli Oswald, Rebecca Shoemaker, Randy Fast, William J. Bosche, Bhavesh R. Borate, Paul T. Edlefsen, Michael K. Axthelm, Louis J. Picker, Jeffrey D. Lifson
Prophylactic vaccination of rhesus macaques with rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) elicits immune responses that stringently control highly pathogenic SIV infection, with subsequent apparent clearance of the infection, in ~50% of vaccinees. In contrast, here, we show that therapeutic RhCMV/SIV vaccination of rhesus macaques previously infected with SIV and given continuous combination antiretroviral therapy (cART) beginning 4–9 d post-SIV infection does not mediate measurable SIV reservoir clearance during over 600 d of follow-up on cART relative to RhCMV/control vaccination. However, none of the six animals started on cART on day four or five, across both RhCMV/SIV- and RhCMV/control-vaccinated groups, those rhesus macaques with SIV reservoirs most closely resembling those of prophylactically RhCMV/SIV-vaccinated and protected animals early in their course, showed post-cART viral rebound with up to nine months of follow-up. Moreover, at necropsy, these rhesus macaques showed little to no evidence of replication-competent SIV. These results suggest that the early SIV reservoir is limited in durability and that effective blockade of viral replication and spread in this critical time window by either pharmacologic or immunologic suppression may result in reduction, and potentially loss, of rebound-competent virus over a period of ~two years.
Learning from bacterial competition in the host to develop antimicrobials Nat. Med. (IF 32.621) Pub Date : 2018-08-06 Manuela Raffatellu
In recent years, the alarming increase of antibiotic resistance, compounded by the simultaneous decrease in development of new antibiotics, has created serious concerns for public health. Moreover, current antibiotics also target the beneficial commensal microbes (microbiota) that inhabit our body, sometimes with significant health consequences. The answer to the antibiotic crisis thus involves broad, creative efforts to develop new treatments for infectious agents. Here I discuss what can be learned from investigating microbial competition in vivo and how this knowledge can be utilized to devise new narrow-spectrum therapeutics that target bacterial pathogens while minimizing deleterious effects to the microbiota.
Cellular origin of human cardiac macrophage populations Nat. Med. (IF 32.621) Pub Date : 2018-08-06 Freya R. Svedberg, Martin Guilliams
Cellular origin of human cardiac macrophage populations Cellular origin of human cardiac macrophage populations, Published online: 06 August 2018; doi:10.1038/s41591-018-0143-2 The human heart contains two macrophage populations with distinct self-maintenance and inflammatory functions. A shift in the balance between these macrophage populations correlates with left-ventricle remodeling and systolic function in patients with heart failure.
Keep off-target effects in focus Nat. Med. (IF 32.621) Pub Date : 2018-08-06
Keep off-target effects in focus Keep off-target effects in focus, Published online: 06 August 2018; doi:10.1038/s41591-018-0150-3 Concerns about potential unintended DNA changes that might accidentally arise from CRISPR gene editing have emerged to varying degrees with the advent of the technology. As new therapies move from bench to bedside, scientists need to redouble their efforts to document the spectrum of these off-target effects while also acknowledging the reality that a certain degree of risk is embedded in many promising and successful medical therapies.
Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab Nat. Med. (IF 32.621) Pub Date : 2018-08-06 David R. Gandara, Sarah M. Paul, Marcin Kowanetz, Erica Schleifman, Wei Zou, Yan Li, Achim Rittmeyer, Louis Fehrenbacher, Geoff Otto, Christine Malboeuf, Daniel S. Lieber, Doron Lipson, Jacob Silterra, Lukas Amler, Todd Riehl, Craig A. Cummings, Priti S. Hegde, Alan Sandler, Marcus Ballinger, David Fabrizio, Tony Mok, David S. Shames
Although programmed death-ligand 1–programmed death 1 (PD-L1–PD-1) inhibitors are broadly efficacious, improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden (TMB). PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung cancer (NSCLC). However, obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging. Thus, an unmet medical need exists for diagnostic approaches that do not require tissue to identify patients who may benefit from immunotherapy. Here, we describe a novel, technically robust, blood-based assay to measure TMB in plasma (bTMB) that is distinct from tissue-based approaches. Using a retrospective analysis of two large randomized trials as test and validation studies, we show that bTMB reproducibly identifies patients who derive clinically significant improvements in progression-free survival from atezolizumab (an anti-PD-L1) in second-line and higher NSCLC. Collectively, our data show that high bTMB is a clinically actionable biomarker for atezolizumab in NSCLC.
Pondering privatization Nat. Med. (IF 32.621) Pub Date : 2018-07-30 Katharine Gammon
Pondering privatizationPondering privatization, Published online: 30 July 2018; doi:10.1038/s41591-018-0148-xResearchers hope the Veterans Affairs’ research agenda won’t change much if it integrates more private care.
The exerkine apelin reverses age-associated sarcopenia Nat. Med. (IF 32.621) Pub Date : 2018-07-30 Claire Vinel, Laura Lukjanenko, Aurelie Batut, Simon Deleruyelle, Jean-Philippe Pradère, Sophie Le Gonidec, Alizée Dortignac, Nancy Geoffre, Ophelie Pereira, Sonia Karaz, Umji Lee, Mylène Camus, Karima Chaoui, Etienne Mouisel, Anne Bigot, Vincent Mouly, Mathieu Vigneau, Allan F. Pagano, Angèle Chopard, Fabien Pillard, Sophie Guyonnet, Matteo Cesari, Odile Burlet-Schiltz, Marco Pahor, Jerome N. Feige, Bruno Vellas, Philippe Valet, Cedric Dray
Sarcopenia, the degenerative loss of skeletal muscle mass, quality and strength, lacks early diagnostic tools and new therapeutic strategies to prevent the frailty-to-disability transition often responsible for the medical institutionalization of elderly individuals. Herein we report that production of the endogenous peptide apelin, induced by muscle contraction, is reduced in an age-dependent manner in humans and rodents and is positively associated with the beneficial effects of exercise in older persons. Mice deficient in either apelin or its receptor (APLNR) presented dramatic alterations in muscle function with increasing age. Various strategies that restored apelin signaling during aging further demonstrated that this peptide considerably enhanced muscle function by triggering mitochondriogenesis, autophagy and anti-inflammatory pathways in myofibers as well as enhancing the regenerative capacity by targeting muscle stem cells. Taken together, these findings revealed positive regulatory feedback between physical activity, apelin and muscle function and identified apelin both as a tool for diagnosis of early sarcopenia and as the target of an innovative pharmacological strategy to prevent age-associated muscle weakness and restore physical autonomy.
Experimental microbial dysbiosis does not promote disease progression in SIV-infected macaques Nat. Med. (IF 32.621) Pub Date : 2018-07-30 Alexandra M. Ortiz, Jacob K. Flynn, Sarah R. DiNapoli, Ivan Vujkovic-Cvijin, Carly E. Starke, Stephen H. Lai, MacKenzie E. Long, Ornella Sortino, Carol L. Vinton, Joseph C. Mudd, Leslie Johnston, Kathleen Busman-Sahay, Yasmine Belkaid, Jacob D. Estes, Jason M. Brenchley
Intestinal microbial dysbiosis has been described in individuals with an HIV-1 infection and may underlie persistent inflammation in chronic infection, thereby contributing to disease progression. Herein, we induced an HIV-1-like intestinal dysbiosis in rhesus macaques (Macaca mulatta) with vancomycin treatment and assessed the contribution of dysbiosis to SIV disease progression. Dysbiotic and control animals had similar disease progression, indicating that intestinal microbial dysbiosis similar to that observed in individuals with HIV is not sufficient to accelerate untreated lentiviral disease progression.
Cytotoxic CD8+ T cells recognize and kill Plasmodium vivax–infected reticulocytes Nat. Med. (IF 32.621) Pub Date : 2018-07-23 Caroline Junqueira, Camila R. R. Barbosa, Pedro A. C. Costa, Andréa Teixeira-Carvalho, Guilherme Castro, Sumit Sen Santara, Rafael P. Barbosa, Farokh Dotiwala, Dhelio B. Pereira, Lis R. Antonelli, Judy Lieberman, Ricardo T. Gazzinelli
Plasmodium vivax causes approximately 100 million clinical malaria cases yearly1,2. The basis of protective immunity is poorly understood and thought to be mediated by antibodies3,4. Cytotoxic CD8+ T cells protect against other intracellular parasites by detecting parasite peptides presented by human leukocyte antigen class I on host cells. Cytotoxic CD8+ T cells kill parasite-infected mammalian cells and intracellular parasites by releasing their cytotoxic granules5,6. Perforin delivers the antimicrobial peptide granulysin and death-inducing granzymes into the host cell, and granulysin then delivers granzymes into the parasite. Cytotoxic CD8+ T cells were thought to have no role against Plasmodium spp. blood stages because red blood cells generally do not express human leukocyte antigen class I7. However, P. vivax infects reticulocytes that retain the protein translation machinery. Here we show that P. vivax–infected reticulocytes express human leukocyte antigen class I. Infected patient circulating CD8+ T cells highly express cytotoxic proteins and recognize and form immunological synapses with P. vivax–infected reticulocytes in a human leukocyte antigen–dependent manner, releasing their cytotoxic granules to kill both host cell and intracellular parasite, preventing reinvasion. P. vivax–infected reticulocytes and parasite killing is perforin independent, but depends on granulysin, which generally efficiently forms pores only in microbial membranes8. We find that P. vivax depletes cholesterol from the P. vivax–infected reticulocyte cell membrane, rendering it granulysin-susceptible. This unexpected T cell defense might be mobilized to improve P. vivax vaccine efficacy.
Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia Nat. Med. (IF 32.621) Pub Date : 2018-07-23 Nikos Kourtis, Charalampos Lazaris, Kathryn Hockemeyer, Juan Carlos Balandrán, Alejandra R. Jimenez, Jasper Mullenders, Yixiao Gong, Thomas Trimarchi, Kamala Bhatt, Hai Hu, Liza Shrestha, Alberto Ambesi-Impiombato, Michelle Kelliher, Elisabeth Paietta, Gabriela Chiosis, Monica L. Guzman, Adolfo A. Ferrando, Aristotelis Tsirigos, Iannis Aifantis
Cellular transformation is accompanied by extensive rewiring of many biological processes leading to augmented levels of distinct types of cellular stress, including proteotoxic stress. Cancer cells critically depend on stress-relief pathways for their survival. However, the mechanisms underlying the transcriptional initiation and maintenance of the oncogenic stress response remain elusive. Here, we show that the expression of heat shock transcription factor 1 (HSF1) and the downstream mediators of the heat shock response is transcriptionally upregulated in T cell acute lymphoblastic leukemia (T-ALL). Hsf1 ablation suppresses the growth of human T-ALL and eradicates leukemia in mouse models of T-ALL, while sparing normal hematopoiesis. HSF1 drives a compact transcriptional program and among the direct HSF1 targets, specific chaperones and co-chaperones mediate its critical role in T-ALL. Notably, we demonstrate that the central T-ALL oncogene NOTCH1 hijacks the cellular stress response machinery by inducing the expression of HSF1 and its downstream effectors. The NOTCH1 signaling status controls the levels of chaperone/co-chaperone complexes and predicts the response of T-ALL patient samples to HSP90 inhibition. Our data demonstrate an integral crosstalk between mediators of oncogene and non-oncogene addiction and reveal critical nodes of the heat shock response pathway that can be targeted therapeutically.
Interleukin-1β has atheroprotective effects in advanced atherosclerotic lesions of mice Nat. Med. (IF 32.621) Pub Date : 2018-07-23 Delphine Gomez, Richard A. Baylis, Brittany G. Durgin, Alexandra A. C. Newman, Gabriel F. Alencar, Sidney Mahan, Cynthia St. Hilaire, Werner Müller, Ari Waisman, Sheila E. Francis, Emmanuel Pinteaux, Gwendalyn J. Randolph, Hermann Gram, Gary K. Owens
Despite decades of research, our understanding of the processes controlling late-stage atherosclerotic plaque stability remains poor. A prevailing hypothesis is that reducing inflammation may improve advanced plaque stability, as recently tested in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial, in which post-myocardial infarction subjects were treated with an IL-1β antibody. Here, we performed intervention studies in which smooth muscle cell (SMC) lineage-tracing Apoe-/- mice with advanced atherosclerosis were treated with anti-IL-1β or IgG control antibodies. Surprisingly, we found that IL-1β antibody treatment between 18 and 26 weeks of Western diet feeding induced a marked reduction in SMC and collagen content, but increased macrophage numbers in the fibrous cap. Moreover, although IL-1β antibody treatment had no effect on lesion size, it completely inhibited beneficial outward remodeling. We also found that SMC-specific knockout of Il1r1 (encoding IL-1 receptor type 1) resulted in smaller lesions nearly devoid of SMCs and lacking a fibrous cap, whereas macrophage-selective loss of IL-1R1 had no effect on lesion size or composition. Taken together, these results show that IL-1β has multiple beneficial effects in late-stage murine atherosclerosis, including promotion of outward remodeling and formation and maintenance of an SMC- and collagen-rich fibrous cap.
Enhancer mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer Nat. Med. (IF 32.621) Pub Date : 2018-07-23 Darren K. Patten, Giacomo Corleone, Balázs Győrffy, Ylenia Perone, Neil Slaven, Iros Barozzi, Edina Erdős, Alina Saiakhova, Kate Goddard, Andrea Vingiani, Sami Shousha, Lőrinc Sándor Pongor, Dimitri J. Hadjiminas, Gaia Schiavon, Peter Barry, Carlo Palmieri, Raul C. Coombes, Peter Scacheri, Giancarlo Pruneri, Luca Magnani
The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumor evolution is poorly understood. Phenotypic drifts can be transmitted via inheritable transcriptional programs. Cell-type specific transcription is maintained through the activation of epigenetically defined regulatory regions including promoters and enhancers. Here we have annotated the epigenome of 47 primary and metastatic estrogen-receptor (ERα)-positive breast cancer clinical specimens and inferred phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Shared regions contain a unique set of regulatory information including the motif for transcription factor YY1. We identify YY1 as a critical determinant of ERα transcriptional activity promoting tumor growth in most luminal patients. YY1 also contributes to the expression of genes mediating resistance to endocrine treatment. Finally, we used H3K27ac levels at active enhancer elements as a surrogate of intra-tumor phenotypic heterogeneity to track the expansion and contraction of phenotypic subpopulations throughout breast cancer progression. By tracking the clonality of SLC9A3R1-positive cells, a bona fide YY1-ERα-regulated gene, we show that endocrine therapies select for phenotypic clones under-represented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.
Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo Nat. Med. (IF 32.621) Pub Date : 2018-07-23 Anila K. Madiraju, Yang Qiu, Rachel J. Perry, Yasmeen Rahimi, Xian-Man Zhang, Dongyan Zhang, João-Paulo G. Camporez, Gary W. Cline, Gina M. Butrico, Bruce E. Kemp, Gregori Casals, Gregory R. Steinberg, Daniel F. Vatner, Kitt F. Petersen, Gerald I. Shulman
Metformin, the universal first-line treatment for type 2 diabetes, exerts its therapeutic glucose-lowering effects by inhibiting hepatic gluconeogenesis. However, the primary molecular mechanism of this biguanide remains unclear, though it has been suggested to act, at least partially, by mitochondrial complex I inhibition. Here we show that clinically relevant concentrations of plasma metformin achieved by acute intravenous, acute intraportal or chronic oral administration in awake normal and diabetic rats inhibit gluconeogenesis from lactate and glycerol but not from pyruvate and alanine, implicating an increased cytosolic redox state in mediating metformin’s antihyperglycemic effect. All of these effects occurred independently of complex I inhibition, evidenced by unaltered hepatic energy charge and citrate synthase flux. Normalizing the cytosolic redox state by infusion of methylene blue or substrates that contribute to gluconeogenesis independently of the cytosolic redox state abrogated metformin-mediated inhibition of gluconeogenesis in vivo. Additionally, in mice expressing constitutively active acetyl-CoA carboxylase, metformin acutely decreased hepatic glucose production and increased the hepatic cytosolic redox state without altering hepatic triglyceride content or gluconeogenic enzyme expression. These studies demonstrate that metformin, at clinically relevant plasma concentrations, inhibits hepatic gluconeogenesis in a redox-dependent manner independently of reductions in citrate synthase flux, hepatic nucleotide concentrations, acetyl-CoA carboxylase activity, or gluconeogenic enzyme protein expression.
Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses Nat. Med. (IF 32.621) Pub Date : 2018-07-23 Israel Cañadas, Rohit Thummalapalli, Jong Wook Kim, Shunsuke Kitajima, Russell William Jenkins, Camilla Laulund Christensen, Marco Campisi, Yanan Kuang, Yanxi Zhang, Evisa Gjini, Gao Zhang, Tian Tian, Debattama Rai. Sen, Diana Miao, Yu Imamura, Tran Thai, Brandon Piel, Hideki Terai, Amir Reza Aref, Timothy Hagan, Shohei Koyama, Masayuki Watanabe, Hideo Baba, Anika Elise Adeni, Christine Anne Lydon, Pablo Tamayo, Zhi Wei, Meenhard Herlyn, Thanh Uyen Barbie, Ravindra Uppaluri, Lynnette Marie Sholl, Ewa Sicinska, Jacob Sands, Scott Rodig, Kwok Kin Wong, Cloud Peter Paweletz, Hideo Watanabe, David Allen Barbie
Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1,2,3,4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5,6,7,8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3′ untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5′ long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy.
Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer Nat. Med. (IF 32.621) Pub Date : 2018-07-16 Seung Tae Kim, Razvan Cristescu, Adam J. Bass, Kyoung-Mee Kim, Justin I. Odegaard, Kyung Kim, Xiao Qiao Liu, Xinwei Sher, Hun Jung, Mijin Lee, Sujin Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Hyuk Lee, Mingew Choi, AmirAli Talasaz, Peter Soonmo Kang, Jonathan Cheng, Andrey Loboda, Jeeyun Lee, Won Ki Kang
Clinical studies support the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic gastric cancer (mGC). With the goal of identifying determinants of response, we performed molecular characterization of tissues and circulating tumor DNA (ctDNA) from 61 patients with mGC who were treated with pembrolizumab as salvage treatment in a prospective phase 2 clinical trial. In patients with microsatellite instability-high and Epstein–Barr virus-positive tumors, which are mutually exclusive, dramatic responses to pembrolizumab were observed (overall response rate (ORR) 85.7% in microsatellite instability-high mGC and ORR 100% in Epstein–Barr virus-positive mGC). For the 55 patients for whom programmed death-ligand 1 (PD-L1) combined positive score positivity was available (combined positive score cut-off value ≥1%), ORR was significantly higher in PD-L1(+) gastric cancer when compared to PD-L1(−) tumors (50.0% versus 0.0%, P value <0.001). Changes in ctDNA levels at six weeks post-treatment predicted response and progression-free survival, and decreased ctDNA was associated with improved outcomes. Our findings provide insight into the molecular features associated with response to pembrolizumab in patients with mGC and provide biomarkers potentially relevant for the selection of patients who may derive greater benefit from PD-1 inhibition.
Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib Nat. Med. (IF 32.621) Pub Date : 2018-07-16 Lynn Quek, Muriel D. David, Alison Kennedy, Marlen Metzner, Michael Amatangelo, Alan Shih, Bilyana Stoilova, Cyril Quivoron, Maël Heiblig, Christophe Willekens, Véronique Saada, Samar Alsafadi, M. S. Vijayabaskar, Andy Peniket, Oliver A. Bernard, Sam Agresta, Katharine Yen, Kyle MacBeth, Eytan Stein, George S. Vassiliou, Ross Levine, Stephane De Botton, Anjan Thakurta, Virginie Penard-Lacronique, Paresh Vyas
Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clonal structure in cell populations at different stages of differentiation can reveal the response and evolution of clones during treatment response and relapse.
Fetal gene therapy for neurodegenerative disease of infants Nat. Med. (IF 32.621) Pub Date : 2018-07-16 Giulia Massaro, Citra N. Z. Mattar, Andrew M. S. Wong, Ernestas Sirka, Suzanne M. K. Buckley, Bronwen R. Herbert, Stefan Karlsson, Dany P. Perocheau, Derek Burke, Simon Heales, Angela Richard-Londt, Sebastian Brandner, Mylene Huebecker, David A. Priestman, Frances M. Platt, Kevin Mills, Arijit Biswas, Jonathan D. Cooper, Jerry K. Y. Chan, Seng H. Cheng, Simon N. Waddington, Ahad A. Rahim
For inherited genetic diseases, fetal gene therapy offers the potential of prophylaxis against early, irreversible and lethal pathological change. To explore this, we studied neuronopathic Gaucher disease (nGD), caused by mutations in GBA. In adult patients, the milder form presents with hepatomegaly, splenomegaly and occasional lung and bone disease; this is managed, symptomatically, by enzyme replacement therapy. The acute childhood lethal form of nGD is untreatable since enzyme cannot cross the blood–brain barrier. Patients with nGD exhibit signs consistent with hindbrain neurodegeneration, including neck hyperextension, strabismus and, often, fatal apnea1. We selected a mouse model of nGD carrying a loxP-flanked neomycin disruption of Gba plus Cre recombinase regulated by the keratinocyte-specific K14 promoter. Exclusive skin expression of Gba prevents fatal neonatal dehydration. Instead, mice develop fatal neurodegeneration within 15 days2. Using this model, fetal intracranial injection of adeno-associated virus (AAV) vector reconstituted neuronal glucocerebrosidase expression. Mice lived for up to at least 18 weeks, were fertile and fully mobile. Neurodegeneration was abolished and neuroinflammation ameliorated. Neonatal intervention also rescued mice but less effectively. As the next step to clinical translation, we also demonstrated the feasibility of ultrasound-guided global AAV gene transfer to fetal macaque brains.
Author Correction: Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia Nat. Med. (IF 32.621) Pub Date : 2018-07-16 Pankaj Baral, Benjamin D Umans, Lu Li, Antonia Wallrapp, Meghna Bist, Talia Kirschbaum, Yibing Wei, Yan Zhou, Vijay K Kuchroo, Patrick R Burkett, Bryan G Yipp, Stephen D Liberles, Isaac M Chiu
Author Correction: Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia Author Correction: Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia, Published online: 16 July 2018; doi:10.1038/s41591-018-0093-8 Author Correction: Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia
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