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  • The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells
    Nat. Med. (IF 29.886) Pub Date : 2017-09-18
    Ly P Vu, Brian F Pickering, Yuanming Cheng, Sara Zaccara, Diu Nguyen, Gerard Minuesa, Timothy Chou, Arthur Chow, Yogesh Saletore, Matthew MacKay, Jessica Schulman, Christopher Famulare, Minal Patel, Virginia M Klimek, Francine E Garrett-Bakelman, Ari Melnick, Martin Carroll, Christopher E Mason, Samie R Jaffrey, Michael G Kharas

    N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m6A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m6A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m6A coupled with ribosome profiling reveals that m6A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia.

    更新日期:2017-09-21
  • Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma
    Nat. Med. (IF 29.886) Pub Date : 2017-09-18
    Daniel S W Tan, Fui Teen Chong, Hui Sun Leong, Shen Yon Toh, Dawn P Lau, Xue Lin Kwang, Xiaoqian Zhang, Gopinath M Sundaram, Gek San Tan, Mei Mei Chang, Boon Tin Chua, Wan Teck Lim, Eng Huat Tan, Mei Kim Ang, Tony K H Lim, Prabha Sampath, Balram Chowbay, Anders J Skanderup, Ramanuj DasGupta, N Gopalakrishna Iyer

    Targeting EGFR is a validated approach in the treatment of squamous-cell cancers (SCCs), although there are no established biomarkers for predicting response. We have identified a synonymous mutation in EGFR, c.2361G>A (encoding p.Gln787Gln), in two patients with head and neck SCC (HNSCC) who were exceptional responders to gefitinib, and we showed in patient-derived cultures that the A/A genotype was associated with greater sensitivity to tyrosine kinase inhibitors (TKIs) as compared to the G/A and G/G genotypes. Remarkably, single-copy G>A nucleotide editing in isogenic models conferred a 70-fold increase in sensitivity due to decreased stability of the EGFR-AS1 long noncoding RNA (lncRNA). In the appropriate context, sensitivity could be recapitulated through EGFR-AS1 knockdown in vitro and in vivo, whereas overexpression was sufficient to induce resistance to TKIs. Reduced EGFR-AS1 levels shifted splicing toward EGFR isoform D, leading to ligand-mediated pathway activation. In co-clinical trials involving patients and patient-derived xenograft (PDX) models, tumor shrinkage was most pronounced in the context of the A/A genotype for EGFR-Q787Q, low expression of EGFR-AS1 and high expression of EGFR isoform D. Our study reveals how a 'silent' mutation influences the levels of a lncRNA, resulting in noncanonical EGFR addiction, and delineates a new predictive biomarker suite for response to EGFR TKIs.

    更新日期:2017-09-21
  • KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis
    Nat. Med. (IF 29.886) Pub Date : 2017-09-18
    Meera Murgai, Wei Ju, Matthew Eason, Jessica Kline, Daniel W Beury, Sabina Kaczanowska, Markku M Miettinen, Michael Kruhlak, Haiyan Lei, Jack F Shern, Olga A Cherepanova, Gary K Owens, Rosandra N Kaplan

    A deeper understanding of the metastatic process is required for the development of new therapies that improve patient survival. Metastatic tumor cell growth and survival in distant organs is facilitated by the formation of a pre-metastatic niche that is composed of hematopoietic cells, stromal cells and extracellular matrix (ECM). Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are involved in new vessel formation and in promoting stem cell maintenance and proliferation. Given the well-described plasticity of perivascular cells, we hypothesized that perivascular cells similarly regulate tumor cell fate at metastatic sites. We used perivascular-cell-specific and pericyte-specific lineage-tracing models to trace the fate of perivascular cells in the pre-metastatic and metastatic microenvironments. We show that perivascular cells lose the expression of traditional vSMC and pericyte markers in response to tumor-secreted factors and exhibit increased proliferation, migration and ECM synthesis. Increased expression of the pluripotency gene Klf4 in these phenotypically switched perivascular cells promoted a less differentiated state, characterized by enhanced ECM production, that established a pro-metastatic fibronectin-rich environment. Genetic inactivation of Klf4 in perivascular cells decreased formation of a pre-metastatic niche and metastasis. Our data revealed a previously unidentified role for perivascular cells in pre-metastatic niche formation and uncovered novel strategies for limiting metastasis.

    更新日期:2017-09-21
  • Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells
    Nat. Med. (IF 29.886) Pub Date : 2017-09-18
    Elodie M Kuntz, Pablo Baquero, Alison M Michie, Karen Dunn, Saverio Tardito, Tessa L Holyoake, G Vignir Helgason, Eyal Gottlieb

    Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cellsNature Medicine, Published online: 18 September 2017; doi:10.1038/nm.4399Treatment with tyrosine kinase inhibitors results in a survival benefit in patients with chronic myeloid leukemia (CML). However, relapse due to persistent leukemic stem cells (LSCs) requires additional selective targets for efficient eradication of the disease. Metabolomic analyses on patient-derived CML LSCs reveal that these have an increased dependency on oxidative metabolism that renders them sensitive to treatment with tigecycline, an FDA-approved inhibitor of mitochondrial translation. These findings uncover a new metabolic vulnerability in CML and provide a rational approach for further clinical evaluation.

    更新日期:2017-09-21
  • Biotin tagging of MeCP2 in mice reveals contextual insights into the Rett syndrome transcriptome
    Nat. Med. (IF 29.886) Pub Date : 2017-09-18
    Brian S Johnson, Ying-Tao Zhao, Maria Fasolino, Janine M Lamonica, Yoon Jung Kim, George Georgakilas, Kathleen H Wood, Daniel Bu, Yue Cui, Darren Goffin, Golnaz Vahedi, Tae Hoon Kim, Zhaolan Zhou

    Transcriptomic profiling using a newly-developed cre-inducible method to biotinylate wild-type and mutant MeCP2 protein highlights the cellular heterogeneity of transcriptional changes in rodent models of Rett Syndrome, including cell-type- and subcellular compartment-specific differences in male brains and X-linked mosaicism in female brains.

    更新日期:2017-09-18
  • A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors
    Nat. Med. (IF 29.886) Pub Date : 
    Julia E Neumann, Annika K Wefers, Sander Lambo, Edoardo Bianchi, Marie Bockstaller, Mario M Dorostkar, Valerie Meister, Pia Schindler, Andrey Korshunov, Katja von Hoff, Johannes Nowak, Monika Warmuth-Metz, Marlon R Schneider, Ingrid Renner-Müller, Daniel J Merk, Mehdi Shakarami, Tanvi Sharma, Lukas Chavez, Rainer Glass, Jennifer A Chan, M Mark Taketo, Philipp Neumann, Marcel Kool, Ulrich Schüller

    Embryonal tumors with multilayered rosettes (ETMRs) have recently been described as a new entity of rare pediatric brain tumors with a fatal outcome. We show here that ETMRs are characterized by a parallel activation of Shh and Wnt signaling. Co-activation of these pathways in mouse neural precursors is sufficient to induce ETMR-like tumors in vivo that resemble their human counterparts on the basis of histology and global gene-expression analyses, and that point to apical radial glia cells as the possible tumor cell of origin. Overexpression of LIN28A, which is a hallmark of human ETMRs, augments Sonic-hedgehog (Shh) and Wnt signaling in these precursor cells through the downregulation of let7-miRNA, and LIN28A/let7a interaction with the Shh pathway was detected at the level of Gli mRNA. Finally, human ETMR cells that were transplanted into immunocompromised host mice were responsive to the SHH inhibitor arsenic trioxide (ATO). Our work provides a novel mouse model in which to study this tumor type, demonstrates the driving role of Wnt and Shh activation in the growth of ETMRs and proposes downstream inhibition of Shh signaling as a therapeutic option for patients with ETMRs.

    更新日期:2017-09-12
  • Regulatory T cells impede acute and long-term immunity to blood-stage malaria through CTLA-4
    Nat. Med. (IF 29.886) Pub Date : 
    Samarchith P Kurup, Nyamekye Obeng-Adjei, Scott M Anthony, Boubacar Traore, Ogobara K Doumbo, Noah S Butler, Peter D Crompton, John T Harty

    John Harty and colleagues report that, in mouse models of malaria, regulatory T cells expand, as in humans, and inhibit conventional T cells and germinal center B cells, thereby impairing protective responses against blood-stage disease. Timed blockade of the inhibitory receptor CTLA-4 cured infection in mice and promoted cross-protective blood-stage immunity against a different Plasmodium species.

    更新日期:2017-09-12
  • Sex-specific disease-associated modules for depression
    Nat. Med. (IF 29.886) Pub Date : 
    Ronald S Duman

    Sex-specific disease-associated modules for depression Nature Medicine, Published online: 8 September 2017; doi:10.1038/nm.4391 A recent study reveals sexually dimorphic disease-associated gene-expression modules and hub genes in postmortem brains from female and male individuals with depression. These modules are conserved in mouse models of depression.

    更新日期:2017-09-09
  • Functional precision cancer medicine—moving beyond pure genomics
    Nat. Med. (IF 29.886) Pub Date : 
    Anthony Letai

    Functional precision cancer medicine—moving beyond pure genomics Nature Medicine, Published online: 8 September 2017; doi:10.1038/nm.4389 Anthony Letai proposes wider adoption of functional assays in efforts to match the right drug to the right patient and discusses why these assays might be complementary to existing genomics-based approaches.

    更新日期:2017-09-09
  • Microglia emerge as central players in brain disease
    Nat. Med. (IF 29.886) Pub Date : 
    Michael W Salter, Beth Stevens

    There has been an explosion of new findings recently giving us insights into the involvement of microglia in central nervous system (CNS) disorders. A host of new molecular tools and mouse models of disease are increasingly implicating this enigmatic type of nervous system cell as a key player in conditions ranging from neurodevelopmental disorders such as autism to neurodegenerative disorders such as Alzheimer's disease and chronic pain. Contemporaneously, diverse roles are emerging for microglia in the healthy brain, from sculpting developing neuronal circuits to guiding learning-associated plasticity. Understanding the physiological functions of these cells is crucial to determining their roles in disease. Here we focus on recent developments in our rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS.

    更新日期:2017-09-09
  • Correction
    Nat. Med. (IF 29.886) Pub Date : 

    Correction Nature Medicine, Published online: 8 September 2017; doi:10.1038/nm0917-1011

    更新日期:2017-09-09
  • Children first
    Nat. Med. (IF 29.886) Pub Date : 

    Children first Nature Medicine, Published online: 8 September 2017; doi:10.1038/nm.4404 Drugs administered to children with cancer were typically developed under the assumption that childhood cancers are similar to their tissue-matched adult counterparts. Focusing on identifying and targeting alterations present specifically in childhood tumors will accelerate the development of tailored therapies and improve the prognosis of children with cancer.

    更新日期:2017-09-09
  • Inflammatory illness: Why the next wave of antidepressants may target the immune system
    Nat. Med. (IF 29.886) Pub Date : 
    Nicole Wetsman

    Inflammatory illness: Why the next wave of antidepressants may target the immune system Nature Medicine, Published online: 8 September 2017; doi:10.1038/nm0917-1009

    更新日期:2017-09-09
  • SPOP tips the balance of BETs in cancer
    Nat. Med. (IF 29.886) Pub Date : 
    Katie A Fennell, Mark A Dawson

    SPOP tips the balance of BETs in cancer Nature Medicine, Published online: 8 September 2017; doi:10.1038/nm.4398 Cancer-associated mutations in speckle-type POZ (pox virus and zinc-finger) protein confer neomorphic activity, altering its substrate affinities and its response to bromodomain and extraterminal inhibitors in prostate and endometrial cancer.

    更新日期:2017-09-09
  • Uncovering cancer: How enlisting T cells can boost the power of immunotherapy
    Nat. Med. (IF 29.886) Pub Date : 
    Amanda B. Keener

    Uncovering cancer: How enlisting T cells can boost the power of immunotherapy Nature Medicine, Published online: 8 September 2017; doi:10.1038/nm0917-1006

    更新日期:2017-09-09
  • Children first
    Nat. Med. (IF 29.886) Pub Date : 2017-09-08

    Drugs administered to children with cancer were typically developed under the assumption that childhood cancers are similar to their tissue-matched adult counterparts. Focusing on identifying and targeting alterations present specifically in childhood tumors will accelerate the development of tailored therapies and improve the prognosis of children with cancer.

    更新日期:2017-09-09
  • The enteric virome in hematopoietic stem cell transplantation: ready for its close-up
    Nat. Med. (IF 29.886) Pub Date : 2017-09-08
    Shuichiro Takashima, Alan M Hanash

    A new study highlights dynamic changes in the enteric virome after hematopoietic stem cell transplantation in humans, pointing to a correlation between these changes and graft-versus-host disease.

    更新日期:2017-09-09
  • Microglia emerge as central players in brain disease
    Nat. Med. (IF 29.886) Pub Date : 2017-09-08
    Michael W Salter, Beth Stevens

    There has been an explosion of new findings recently giving us insights into the involvement of microglia in central nervous system (CNS) disorders. A host of new molecular tools and mouse models of disease are increasingly implicating this enigmatic type of nervous system cell as a key player in conditions ranging from neurodevelopmental disorders such as autism to neurodegenerative disorders such as Alzheimer's disease and chronic pain. Contemporaneously, diverse roles are emerging for microglia in the healthy brain, from sculpting developing neuronal circuits to guiding learning-associated plasticity. Understanding the physiological functions of these cells is crucial to determining their roles in disease. Here we focus on recent developments in our rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS.

    更新日期:2017-09-09
  • Sex-specific disease-associated modules for depression
    Nat. Med. (IF 29.886) Pub Date : 2017-09-08
    Ronald S Duman

    A recent study reveals sexually dimorphic disease-associated gene-expression modules and hub genes in postmortem brains from female and male individuals with depression. These modules are conserved in mouse models of depression.

    更新日期:2017-09-09
  • SPOP tips the balance of BETs in cancer
    Nat. Med. (IF 29.886) Pub Date : 2017-09-08
    Katie A Fennell, Mark A Dawson

    Cancer-associated mutations in speckle-type POZ (pox virus and zinc-finger) protein confer neomorphic activity, altering its substrate affinities and its response to bromodomain and extraterminal inhibitors in prostate and endometrial cancer.

    更新日期:2017-09-09
  • D-mannose induces regulatory T cells and suppresses immunopathology
    Nat. Med. (IF 29.886) Pub Date : 2017-07-24
    Dunfang Zhang, Cheryl Chia, Xue Jiao, Wenwen Jin, Shimpei Kasagi, Ruiqing Wu, Joanne E Konkel, Hiroko Nakatsukasa, Peter Zanvit, Nathan Goldberg, Qianming Chen, Lingyun Sun, Zi-Jiang Chen, WanJun Chen

    D-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of D-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of D-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3+ regulatory T cells (Treg cells) in mice. In vitro, D-mannose stimulated Treg cell differentiation in human and mouse cells by promoting TGF-β activation, which in turn was mediated by upregulation of integrin αvβ8 and reactive oxygen species generated by increased fatty acid oxidation. This previously unrecognized immunoregulatory function of D-mannose may have clinical applications for immunopathology.

    更新日期:2017-09-09
  • Functional precision cancer medicine—moving beyond pure genomics
    Nat. Med. (IF 29.886) Pub Date : 2017-09-08
    Anthony Letai

    Anthony Letai proposes wider adoption of functional assays in efforts to match the right drug to the right patient and discusses why these assays might be complementary to existing genomics-based approaches.

    更新日期:2017-09-09
  • Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors
    Nat. Med. (IF 29.886) Pub Date : 2017-08-14
    Hana Janouskova, Geniver El Tekle, Elisa Bellini, Namrata D Udeshi, Anna Rinaldi, Anna Ulbricht, Tiziano Bernasocchi, Gianluca Civenni, Marco Losa, Tanya Svinkina, Craig M Bielski, Gregory V Kryukov, Luciano Cascione, Sara Napoli, Radoslav I Enchev, David G Mutch, Michael E Carney, Andrew Berchuck, Boris J N Winterhoff, Russell R Broaddus, Peter Schraml, Holger Moch, Francesco Bertoni, Carlo V Catapano, Matthias Peter, Steven A Carr, Levi A Garraway, Peter J Wild, Jean-Philippe P Theurillat

    It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer–associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP–CUL3 substrates that are preferentially degraded by endometrial cancer–associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer–specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.

    更新日期:2017-09-09
  • Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT–mTORC1 activation
    Nat. Med. (IF 29.886) Pub Date : 2017-08-14
    Pingzhao Zhang, Dejie Wang, Yu Zhao, Shancheng Ren, Kun Gao, Zhenqing Ye, Shangqian Wang, Chun-Wu Pan, Yasheng Zhu, Yuqian Yan, Yinhui Yang, Di Wu, Yundong He, Jun Zhang, Daru Lu, Xiuping Liu, Long Yu, Shimin Zhao, Yao Li, Dong Lin, Yuzhuo Wang, Liguo Wang, Yu Chen, Yinghao Sun, Chenji Wang, Haojie Huang

    Mutations in SPOP, the gene encoding a component of the E3 ubiquitin ligase complex, impair ubiquitination-dependent degradation of BRD2, BRD3 and BRD4 proteins and result in activation of ATK–mTORC1 signaling and resistance to BET inhibitors. Pharmacological blockade of AKT represents a viable strategy to restore the sensitivity of SPOP-mutant prostate tumors to BET inhibitors. These results, together with findings by Dai et al. and Janouskova et al., uncover a new nongenetic mechanism of resistance to BET inhibition involving cancer-type-specific mutations in SPOP, and support the evaluation of SPOP mutation status to inform the administration of BET inhibitors in the clinic.

    更新日期:2017-09-09
  • Prostate cancer–associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4
    Nat. Med. (IF 29.886) Pub Date : 2017-08-14
    Xiangpeng Dai, Wenjian Gan, Xiaoning Li, Shangqian Wang, Wei Zhang, Ling Huang, Shengwu Liu, Qing Zhong, Jianping Guo, Jinfang Zhang, Ting Chen, Kouhei Shimizu, Francisco Beca, Mirjam Blattner, Divya Vasudevan, Dennis L Buckley, Jun Qi, Lorenz Buser, Pengda Liu, Hiroyuki Inuzuka, Andrew H Beck, Liewei Wang, Peter J Wild, Levi A Garraway, Mark A Rubin, Christopher E Barbieri, Kwok-Kin Wong, Senthil K Muthuswamy, Jiaoti Huang, Yu Chen, James E Bradner, Wenyi Wei

    Recurrent mutations in SPOP-encoding a Cullin 3-based E3 ubiquitin ligase- in prostate cancer disrupt the recognition and degradation of ubiquitination substrates, including BET proteins. Consequently, stability of BET proteins is enhanced and this increases the resistance to BET inhibitors in SPOP-mutant prostate tumors. These results, together with those in Janouskova et al. and Zhang et al., uncover a novel non genetic mechanism of resistance to BET inhibition involving cancer type-specific mutations in SPOP, and support the evaluation of SPOP mutations to inform the administration of BET inhibitors in the clinic.

    更新日期:2017-09-09
  • Targeting cellular senescence prevents age-related bone loss in mice
    Nat. Med. (IF 29.886) Pub Date : 2017-08-21
    Joshua N Farr, Ming Xu, Megan M Weivoda, David G Monroe, Daniel G Fraser, Jennifer L Onken, Brittany A Negley, Jad G Sfeir, Mikolaj B Ogrodnik, Christine M Hachfeld, Nathan K LeBrasseur, Matthew T Drake, Robert J Pignolo, Tamar Pirtskhalava, Tamara Tchkonia, Merry Jo Oursler, James L Kirkland, Sundeep Khosla

    Genetic or pharmacological depletion of senescent cells or inhibition of their function reduces bone loss in aged mice.

    更新日期:2017-09-09
  • The eukaryotic gut virome in hematopoietic stem cell transplantation: new clues in enteric graft-versus-host disease
    Nat. Med. (IF 29.886) Pub Date : 2017-07-31
    Jérôme Legoff, Matthieu Resche-Rigon, Jerome Bouquet, Marie Robin, Samia N Naccache, Séverine Mercier-Delarue, Scot Federman, Erik Samayoa, Clotilde Rousseau, Prescillia Piron, Nathalie Kapel, François Simon, Gérard Socié, Charles Y Chiu

    Charles Chiu and colleagues analyze the gut viromes of recipients of hematopoietic stem cell transplantation and identify characteristics associated with the severity of graft-versus-host disease in the gut.

    更新日期:2017-09-09
  • A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels
    Nat. Med. (IF 29.886) Pub Date : 2017-08-21
    Sumeet A Khetarpal, Xuemei Zeng, John S Millar, Cecilia Vitali, Amritha Varshini Hanasoge Somasundara, Paolo Zanoni, James A Landro, Nicole Barucci, William J Zavadoski, Zhiyuan Sun, Hans de Haard, Ildikó V Toth, Gina M Peloso, Pradeep Natarajan, Marina Cuchel, Sissel Lund-Katz, Michael C Phillips, Alan R Tall, Sekar Kathiresan, Paul DaSilva-Jardine, Nathan A Yates, Daniel J Rader

    On the basis of new mechanistic studies of a mutant form of the apolipoprotein apoC-III that protects against coronary heart disease, Khetarpal et al. have developed therapeutic apoC-III-targeting monoclonal antibodies that lower circulating apoC-III protein and triglyceride levels in mice.

    更新日期:2017-09-09
  • Sex-specific transcriptional signatures in human depression
    Nat. Med. (IF 29.886) Pub Date : 2017-08-21
    Benoit Labonté, Olivia Engmann, Immanuel Purushothaman, Caroline Menard, Junshi Wang, Chunfeng Tan, Joseph R Scarpa, Gregory Moy, Yong-Hwee E Loh, Michael Cahill, Zachary S Lorsch, Peter J Hamilton, Erin S Calipari, Georgia E Hodes, Orna Issler, Hope Kronman, Madeline Pfau, Aleksandar L J Obradovic, Yan Dong, Rachael L Neve, Scott Russo, Andrew Kazarskis, Carol Tamminga, Naguib Mechawar, Gustavo Turecki, Bin Zhang, Li Shen, Eric J Nestler

    Brain-region-specific RNA-seq from humans with major depressive disorder reveals unique transcriptomic profiles in males and females, with little overlap.

    更新日期:2017-09-09
  • Implications of human genetic variation in CRISPR-based therapeutic genome editing
    Nat. Med. (IF 29.886) Pub Date : 2017-07-31
    David A Scott, Feng Zhang

    Analysis of the ExAC and 1000 Genomes data sets estimates the impact of inter-individual variation on the efficacy and safety of therapies based on CRISPR endonucleases.

    更新日期:2017-09-09
  • Human-monoclonal-antibody therapy protects nonhuman primates against advanced Lassa fever
    Nat. Med. (IF 29.886) Pub Date : 
    Chad E Mire, Robert W Cross, Joan B Geisbert, Viktoriya Borisevich, Krystle N Agans, Daniel J Deer, Megan L Heinrich, Megan M Rowland, Augustine Goba, Mambu Momoh, Mathew L Boisen, Donald S Grant, Mohamed Fullah, Sheik Humarr Khan, Karla A Fenton, James E Robinson, Luis M Branco, Robert F Garry, Thomas W Geisbert

    Thomas Geisbert and colleagues show that a cocktail of monoclonal antibodies protects cynomolgus monkeys from lethal Lassa fever virus infection, including when administration is delayed by more than a week after viral challenge.

    更新日期:2017-09-07
  • GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates
    Nat. Med. (IF 29.886) Pub Date : 2017-08-28
    Shannon E Mullican, Xiefan Lin-Schmidt, Chen-Ni Chin, Jose A Chavez, Jennifer L Furman, Anthony A Armstrong, Stephen C Beck, Victoria J South, Thai Q Dinh, Tanesha D Cash-Mason, Cassandre R Cavanaugh, Serena Nelson, Chichi Huang, Michael J Hunter, Shamina M Rangwala

    Growth differentiation factor 15 (GDF15), a distant member of the transforming growth factor (TGF)-β family, is a secreted protein that circulates as a 25-kDa dimer. In humans, elevated GDF15 correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake. The mechanisms through which GDF15 reduces body weight remain poorly understood, because the cognate receptor for GDF15 is unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we find that GDF15 binds with high affinity to GDNF family receptor α–like (GFRAL), a distant relative of receptors for a distinct class of the TGF-β superfamily ligands. Gfral is expressed in neurons of the area postrema and nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a new regulator of body weight and as the bona fide receptor mediating the metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as a potential pharmacotherapy for the treatment of obesity.

    更新日期:2017-09-07
  • GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand
    Nat. Med. (IF 29.886) Pub Date : 2017-08-28
    Linda Yang, Chih-Chuan Chang, Zhe Sun, Dennis Madsen, Haisun Zhu, Søren B Padkjær, Xiaoai Wu, Tao Huang, Karin Hultman, Sarah J Paulsen, Jishu Wang, Anne Bugge, Jane Boesen Frantzen, Per Nørgaard, Jacob Fuglsbjerg Jeppesen, Zhiru Yang, Anna Secher, Haibin Chen, Xun Li, Linu Mary John, Bing Shan, Zhenhua He, Xiang Gao, Jing Su, Kristian T Hansen, Wei Yang, Sebastian Beck Jørgensen

    Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-β superfamily and is associated with body-weight regulation in humans and rodents. However, the cognate receptor of GDF15 is unknown. Here we show that GDF15 binds specifically to GDNF family receptor α-like (GFRAL) with high affinity, and that GFRAL requires association with the coreceptor RET to elicit intracellular signaling in response to GDF15 stimulation. We also found that GDF15-mediated reductions in food intake and body weight of mice with obesity were abolished in GFRAL-knockout mice. We further found that GFRAL expression was limited to hindbrain neurons and not present in peripheral tissues, which suggests that GDF15–GFRAL-mediated regulation of food intake is by a central mechanism. Lastly, given that GDF15 did not increase energy expenditure in treated mice with obesity, the anti-obesity actions of the cytokine are likely driven primarily by a reduction in food intake.

    更新日期:2017-09-07
  • Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors
    Nat. Med. (IF 29.886) Pub Date : 2017-08-14
    Hana Janouskova, Geniver El Tekle, Elisa Bellini, Namrata D Udeshi, Anna Rinaldi, Anna Ulbricht, Tiziano Bernasocchi, Gianluca Civenni, Marco Losa, Tanya Svinkina, Craig M Bielski, Gregory V Kryukov, Luciano Cascione, Sara Napoli, Radoslav I Enchev, David G Mutch, Michael E Carney, Andrew Berchuck, Boris J N Winterhoff, Russell R Broaddus, Peter Schraml, Holger Moch, Francesco Bertoni, Carlo V Catapano, Matthias Peter, Steven A Carr, Levi A Garraway, Peter J Wild, Jean-Philippe P Theurillat

    It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer–associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP–CUL3 substrates that are preferentially degraded by endometrial cancer–associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer–specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.

    更新日期:2017-09-07
  • D-mannose induces regulatory T cells and suppresses immunopathology
    Nat. Med. (IF 29.886) Pub Date : 2017-07-24
    Dunfang Zhang, Cheryl Chia, Xue Jiao, Wenwen Jin, Shimpei Kasagi, Ruiqing Wu, Joanne E Konkel, Hiroko Nakatsukasa, Peter Zanvit, Nathan Goldberg, Qianming Chen, Lingyun Sun, Zi-Jiang Chen, WanJun Chen

    D-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of D-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of D-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3+ regulatory T cells (Treg cells) in mice. In vitro, D-mannose stimulated Treg cell differentiation in human and mouse cells by promoting TGF-β activation, which in turn was mediated by upregulation of integrin αvβ8 and reactive oxygen species generated by increased fatty acid oxidation. This previously unrecognized immunoregulatory function of D-mannose may have clinical applications for immunopathology.

    更新日期:2017-09-07
  • SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans
    Nat. Med. (IF 29.886) Pub Date : 2017-07-17

    Previous studies have reported associations of IFITM3 SNP rs12252 with severe influenza, but evidence of association and the mechanism by which risk is conferred remain controversial. We prioritized SNPs in IFITM3 on the basis of putative biological function and identified rs34481144 in the 5′ UTR. We found evidence of a new association of rs34481144 with severe influenza in three influenza-infected cohorts characterized by different levels of influenza illness severity. We determined a role for rs34481144 as an expression quantitative trait locus (eQTL) for IFITM3, with the risk allele associated with lower mRNA expression. The risk allele was found to have decreased IRF3 binding and increased CTCF binding in promoter-binding assays, and risk allele carriage diminished transcriptional correlations among IFITM3-neighboring genes, indicative of CTCF boundary activity. Furthermore, the risk allele disrupts a CpG site that undergoes differential methylation in CD8+ T cell subsets. Carriers of the risk allele had reduced numbers of CD8+ T cells in their airways during natural influenza infection, consistent with IFITM3 promoting accumulation of CD8+ T cells in airways and indicating that a critical function for IFITM3 may be to promote immune cell persistence at mucosal sites.Our study identifies a new regulator of IFITM3 expression that associates with CD8+ T cell levels in the airways and a spectrum of clinical outcomes.

    更新日期:2017-09-07
  • Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells
    Nat. Med. (IF 29.886) Pub Date : 2017-07-17

    Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as the mediators of a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired ILC2 proliferation and activation of regulatory T (Treg) cells, and resulted in chronic arthritis with excessive cartilage destruction and bone loss. In contrast, treatment with IL-9 promoted ILC2-dependent Treg activation and effectively induced resolution of inflammation and protection of bone. Patients with rheumatoid arthritis in remission exhibited high numbers of IL-9+ ILC2s in joints and the circulation. Hence, fostering IL-9-mediated ILC2 activation may offer a novel therapeutic approach inducing resolution of inflammation rather than suppression of inflammatory responses.

    更新日期:2017-09-07
  • An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer
    Nat. Med. (IF 29.886) Pub Date : 2017-07-17

    The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAFamp) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment. The evolutionary selection of BRAFamp was determined by the fitness threshold, the barrier that subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for inhibitors of ERK signaling, suggesting that sequential monotherapy is ineffective and selects for a progressively higher BRAF copy number. Concurrent targeting of the RAF, MEK and ERK kinases, however, imposed a sufficiently high fitness threshold to prevent the propagation of subclones with high-level BRAFamp. When administered on an intermittent schedule, this treatment inhibited tumor growth in 11/11 PDXs of lung cancer or melanoma without apparent toxicity in mice. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose the highest fitness threshold will likely prevent the evolution of resistance-causing alterations and, thus, merit testing in patients.

    更新日期:2017-09-07
  • Plk1 regulates contraction of postmitotic smooth muscle cells and is required for vascular homeostasis
    Nat. Med. (IF 29.886) Pub Date : 2017-07-10
    Guillermo de Cárcer, Paulina Wachowicz, Sara Martínez-Martínez, Jorge Oller, Nerea Méndez-Barbero, Beatriz Escobar, Alejandra González-Loyola, Tohru Takaki, Aicha El Bakkali, Juan A Cámara, Luis J Jiménez-Borreguero, Xosé R Bustelo, Marta Cañamero, Francisca Mulero, María de los Ángeles Sevilla, María Jose Montero, Juan Miguel Redondo, Marcos Malumbres

    Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo. Mechanistically, we found that Plk1 regulated angiotensin II–dependent activation of RhoA and actomyosin dynamics in VSMCs in a mitosis-independent manner. This regulation depended on Plk1 kinase activity, and the administration of small-molecule Plk1 inhibitors to angiotensin II–treated mice led to reduced arterial fitness and an elevated risk of aneurysm and aortic rupture. We thus conclude that a partial reduction of Plk1 activity that does not block cell division can nevertheless impair aortic homeostasis. Our findings have potentially important implications for current approaches aimed at PLK1 inhibition for cancer therapy.

    更新日期:2017-09-07
  • Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids
    Nat. Med. (IF 29.886) Pub Date : 2017-07-03
    Fotios Sampaziotis, Alexander W Justin, Olivia C Tysoe, Stephen Sawiak, Edmund M Godfrey, Sara S Upponi, Richard L Gieseck, Miguel Cardoso de Brito, Natalie Lie Berntsen, María J Gómez-Vázquez, Daniel Ortmann, Loukia Yiangou, Alexander Ross, Johannes Bargehr, Alessandro Bertero, Mariëlle C F Zonneveld, Marianne T Pedersen, Matthias Pawlowski, Laura Valestrand, Pedro Madrigal, Nikitas Georgakopoulos, Negar Pirmadjid, Gregor M Skeldon, John Casey, Wenmiao Shu, Paulina M Materek, Kirsten E Snijders, Stephanie E Brown, Casey A Rimland, Ingrid Simonic, Susan E Davies, Kim B Jensen, Matthias Zilbauer, William T H Gelson, Graeme J Alexander, Sanjay Sinha, Nicholas R F Hannan, Thomas A Wynn, Tom H Karlsen, Espen Melum, Athina E Markaki, Kourosh Saeb-Parsy, Ludovic Vallier

    The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids in vivo and demonstrate that ECOs self-organize into bile duct–like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded in vitro.

    更新日期:2017-09-07
  • A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease
    Nat. Med. (IF 29.886) Pub Date : 2017-06-26
    Salim S Hayek, Kwi Hye Koh, Morgan E Grams, Changli Wei, Yi-An Ko, Jing Li, Beata Samelko, Hyun Lee, Ranadheer R Dande, Ha Won Lee, Eunsil Hahm, Vasil Peev, Melissa Tracy, Nicholas J Tardi, Vineet Gupta, Mehmet M Altintas, Garrett Garborcauskas, Nikolina Stojanovic, Cheryl A Winkler, Michael S Lipkowitz, Adrienne Tin, Lesley A Inker, Andrew S Levey, Martin Zeier, Barry I Freedman, Jeffrey B Kopp, Karl Skorecki, Josef Coresh, Arshed A Quyyumi, Sanja Sever, Jochen Reiser

    Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and αvβ3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments αvβ3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on αvβ3 integrin activation is a mechanism for CKD.

    更新日期:2017-09-07
  • Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas
    Nat. Med. (IF 29.886) Pub Date : 
    Elodie Bal, Hyun-Sook Park, Zakia Belaid-Choucair, Hülya Kayserili, Magali Naville, Marine Madrange, Elena Chiticariu, Smail Hadj-Rabia, Nicolas Cagnard, Francois Kuonen, Daniel Bachmann, Marcel Huber, Cindy Le Gall, Francine Côté, Sylvain Hanein, Rasim Özgür Rosti, Ayca Dilruba Aslanger, Quinten Waisfisz, Christine Bodemer, Olivier Hermine, Fanny Morice-Picard, Bruno Labeille, Frédéric Caux, Juliette Mazereeuw-Hautier, Nicole Philip, Nicolas Levy, Alain Taieb, Marie-Françoise Avril, Denis J Headon, Gabor Gyapay, Thierry Magnaldo, Sylvie Fraitag, Hugues Roest Crollius, Pierre Vabres, Daniel Hohl, Arnold Munnich, Asma Smahi

    Inactivating mutations in ACTRT1 or surrounding noncoding sequences transcribed into functional enhancer RNAs cause aberrant activation of Hedgehog signaling in both sporadic and inherited forms, such as Bazex–Dupré–Christol syndrome, of basal cell carcinoma. These findings identify a new tumor-suppressor gene and underscore the functional relevance of genomic alterations in noncoding transcribed regions in tumor development.

    更新日期:2017-09-07
  • The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL
    Nat. Med. (IF 29.886) Pub Date : 2017-08-28
    Paul J Emmerson, Feng Wang, Yong Du, Qian Liu, Richard T Pickard, Malgorzata D Gonciarz, Tamer Coskun, Matthew J Hamang, Dana K Sindelar, Kimberly K Ballman, Lisa A Foltz, Avinash Muppidi, Jorge Alsina-Fernandez, Gavin C Barnard, Jason X Tang, Xilin Liu, Xudong Mao, Robert Siegel, John H Sloan, Pamela J Mitchell, Bei B Zhang, Ruth E Gimeno, Bei Shan, Xinle Wu

    GDF15 has potent anti-obesity effects, but its receptor was previously unknown. GFRAL has now been identified as the receptor for GDF15, and it mediates the effects of GDF15 via central actions in the hindbrain.

    更新日期:2017-09-07
  • Targeting cellular senescence prevents age-related bone loss in mice
    Nat. Med. (IF 29.886) Pub Date : 2017-08-21
    Joshua N Farr, Ming Xu, Megan M Weivoda, David G Monroe, Daniel G Fraser, Jennifer L Onken, Brittany A Negley, Jad G Sfeir, Mikolaj B Ogrodnik, Christine M Hachfeld, Nathan K LeBrasseur, Matthew T Drake, Robert J Pignolo, Tamar Pirtskhalava, Tamara Tchkonia, Merry Jo Oursler, James L Kirkland, Sundeep Khosla

    Genetic or pharmacological depletion of senescent cells or inhibition of their function reduces bone loss in aged mice.

    更新日期:2017-09-07
  • A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels
    Nat. Med. (IF 29.886) Pub Date : 2017-08-21
    Sumeet A Khetarpal, Xuemei Zeng, John S Millar, Cecilia Vitali, Amritha Varshini Hanasoge Somasundara, Paolo Zanoni, James A Landro, Nicole Barucci, William J Zavadoski, Zhiyuan Sun, Hans de Haard, Ildikó V Toth, Gina M Peloso, Pradeep Natarajan, Marina Cuchel, Sissel Lund-Katz, Michael C Phillips, Alan R Tall, Sekar Kathiresan, Paul DaSilva-Jardine, Nathan A Yates, Daniel J Rader

    On the basis of new mechanistic studies of a mutant form of the apolipoprotein apoC-III that protects against coronary heart disease, Khetarpal et al. have developed therapeutic apoC-III-targeting monoclonal antibodies that lower circulating apoC-III protein and triglyceride levels in mice.

    更新日期:2017-09-07
  • Prostate cancer–associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4
    Nat. Med. (IF 29.886) Pub Date : 2017-08-14
    Xiangpeng Dai, Wenjian Gan, Xiaoning Li, Shangqian Wang, Wei Zhang, Ling Huang, Shengwu Liu, Qing Zhong, Jianping Guo, Jinfang Zhang, Ting Chen, Kouhei Shimizu, Francisco Beca, Mirjam Blattner, Divya Vasudevan, Dennis L Buckley, Jun Qi, Lorenz Buser, Pengda Liu, Hiroyuki Inuzuka, Andrew H Beck, Liewei Wang, Peter J Wild, Levi A Garraway, Mark A Rubin, Christopher E Barbieri, Kwok-Kin Wong, Senthil K Muthuswamy, Jiaoti Huang, Yu Chen, James E Bradner, Wenyi Wei

    Recurrent mutations in SPOP-encoding a Cullin 3-based E3 ubiquitin ligase- in prostate cancer disrupt the recognition and degradation of ubiquitination substrates, including BET proteins. Consequently, stability of BET proteins is enhanced and this increases the resistance to BET inhibitors in SPOP-mutant prostate tumors. These results, together with those in Janouskova et al. and Zhang et al., uncover a novel non genetic mechanism of resistance to BET inhibition involving cancer type-specific mutations in SPOP, and support the evaluation of SPOP mutations to inform the administration of BET inhibitors in the clinic.

    更新日期:2017-09-07
  • Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT–mTORC1 activation
    Nat. Med. (IF 29.886) Pub Date : 2017-08-14
    Pingzhao Zhang, Dejie Wang, Yu Zhao, Shancheng Ren, Kun Gao, Zhenqing Ye, Shangqian Wang, Chun-Wu Pan, Yasheng Zhu, Yuqian Yan, Yinhui Yang, Di Wu, Yundong He, Jun Zhang, Daru Lu, Xiuping Liu, Long Yu, Shimin Zhao, Yao Li, Dong Lin, Yuzhuo Wang, Liguo Wang, Yu Chen, Yinghao Sun, Chenji Wang, Haojie Huang

    Mutations in SPOP, the gene encoding a component of the E3 ubiquitin ligase complex, impair ubiquitination-dependent degradation of BRD2, BRD3 and BRD4 proteins and result in activation of ATK–mTORC1 signaling and resistance to BET inhibitors. Pharmacological blockade of AKT represents a viable strategy to restore the sensitivity of SPOP-mutant prostate tumors to BET inhibitors. These results, together with findings by Dai et al. and Janouskova et al., uncover a new nongenetic mechanism of resistance to BET inhibition involving cancer-type-specific mutations in SPOP, and support the evaluation of SPOP mutation status to inform the administration of BET inhibitors in the clinic.

    更新日期:2017-09-07
  • The eukaryotic gut virome in hematopoietic stem cell transplantation: new clues in enteric graft-versus-host disease
    Nat. Med. (IF 29.886) Pub Date : 2017-07-31
    Jérôme Legoff, Matthieu Resche-Rigon, Jerome Bouquet, Marie Robin, Samia N Naccache, Séverine Mercier-Delarue, Scot Federman, Erik Samayoa, Clotilde Rousseau, Prescillia Piron, Nathalie Kapel, François Simon, Gérard Socié, Charles Y Chiu

    Charles Chiu and colleagues analyze the gut viromes of recipients of hematopoietic stem cell transplantation and identify characteristics associated with the severity of graft-versus-host disease in the gut.

    更新日期:2017-09-07
  • Correction of a splicing defect in a mouse model of congenital muscular dystrophy type 1A using a homology-directed-repair-independent mechanism
    Nat. Med. (IF 29.886) Pub Date : 2017-07-17

    An HDR-independent therapeutic genome-editing approach corrected the splice-site mutation in Lama2 in a mouse model of congenital muscular dystrophy type 1A, and may be applied more broadly to correct splice-site mutations associated with other diseases.

    更新日期:2017-09-07
  • Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus
    Nat. Med. (IF 29.886) Pub Date : 2017-07-10
    Jason K Karimy, Jinwei Zhang, David B Kurland, Brianna Carusillo Theriault, Daniel Duran, Jesse A Stokum, Charuta Gavankar Furey, Xu Zhou, M Shahid Mansuri, Julio Montejo, Alberto Vera, Michael L DiLuna, Eric Delpire, Seth L Alper, Murat Gunel, Volodymyr Gerzanich, Ruslan Medzhitov, J Marc Simard, Kristopher T Kahle

    In a rat model of hydrocephalus triggered by intraventricular hemorrhage, Kristopher Kahle and colleagues show that TLR4–NF-κB-dependent inflammatory signaling in the choroid plexus causes hypersecretion of cerebrospinal fluid that drives hydrocephalus. Targeting TLR4–NF-κB-mediated signaling or the NKCC1–SPAK complex ameliorates hydrocephalus.

    更新日期:2017-09-07
  • Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice
    Nat. Med. (IF 29.886) Pub Date : 2017-06-26
    Bérengère Benoit, Emmanuelle Meugnier, Martina Castelli, Stéphanie Chanon, Aurélie Vieille-Marchiset, Christine Durand, Nadia Bendridi, Sandra Pesenti, Pierre-Axel Monternier, Anne-Cécile Durieux, Damien Freyssenet, Jennifer Rieusset, Etienne Lefai, Hubert Vidal, Jérôme Ruzzin

    FGF19 acts directly on skeletal muscle to increase its mass, and treatment with the hormone ameliorates muscle atrophy in three mouse models.

    更新日期:2017-09-07
  • Implications of human genetic variation in CRISPR-based therapeutic genome editing
    Nat. Med. (IF 29.886) Pub Date : 2017-07-31
    David A Scott, Feng Zhang

    Analysis of the ExAC and 1000 Genomes data sets estimates the impact of inter-individual variation on the efficacy and safety of therapies based on CRISPR endonucleases.

    更新日期:2017-09-07
  • Sex-specific transcriptional signatures in human depression
    Nat. Med. (IF 29.886) Pub Date : 2017-08-21
    Benoit Labonté, Olivia Engmann, Immanuel Purushothaman, Caroline Menard, Junshi Wang, Chunfeng Tan, Joseph R Scarpa, Gregory Moy, Yong-Hwee E Loh, Michael Cahill, Zachary S Lorsch, Peter J Hamilton, Erin S Calipari, Georgia E Hodes, Orna Issler, Hope Kronman, Madeline Pfau, Aleksandar L J Obradovic, Yan Dong, Rachael L Neve, Scott Russo, Andrew Kazarskis, Carol Tamminga, Naguib Mechawar, Gustavo Turecki, Bin Zhang, Li Shen, Eric J Nestler

    Brain-region-specific RNA-seq from humans with major depressive disorder reveals unique transcriptomic profiles in males and females, with little overlap.

    更新日期:2017-09-07
  • Calculated risk: a new single-nucleotide polymorphism linked to severe influenza disease
    Nat. Med. (IF 29.886) Pub Date : 2017-08-04
    Amie J Eisfeld, Yoshihiro Kawaoka

    Clear links between human genes and susceptibility to influenza disease are scarce. A recent study uncovers a gene variant coupled to severe influenza, and shows how it hampers the expression of an antiviral gene that is key to immune cell survival.

    更新日期:2017-08-05
  • A three-drug combination to treat BRAF-mutant cancers
    Nat. Med. (IF 29.886) Pub Date : 2017-08-04
    Ari J Firestone, Jeff Settleman

    A new study that uses a triple-drug combination to overcome a major mechanism of drug resistance in cancer provides insights into the evolutionary paths taken by tumors in the face of selective pressure.

    更新日期:2017-08-05
  • Resolving a chronic inflammation mystery
    Nat. Med. (IF 29.886) Pub Date : 2017-08-04
    Ben Roediger, Wolfgang Weninger

    Using interleukin (IL)-9-deficient mice, Rauber and colleagues unveil a crucial role for group 2 innate lymphoid cells (ILC2s) in the resolution phase of arthritic inflammation, opening up new therapeutic avenues for chronic inflammatory disease.

    更新日期:2017-08-05
  • Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic
    Nat. Med. (IF 29.886) Pub Date : 2017-08-04
    Benjamin Blasco, Didier Leroy, David A Fidock

    The global adoption of artemisinin-based combination therapies (ACTs) in the early 2000s heralded a new era in effectively treating drug-resistant Plasmodium falciparum malaria. However, several Southeast Asian countries have now reported the emergence of parasites that have decreased susceptibility to artemisinin (ART) derivatives and ACT partner drugs, resulting in increasing rates of treatment failures. Here we review recent advances in understanding how antimalarials act and how resistance develops, and discuss new strategies for effectively combatting resistance, optimizing treatment and advancing the global campaign to eliminate malaria.

    更新日期:2017-08-05
  • An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer
    Nat. Med. (IF 29.886) Pub Date : 2017-07-17
    Yaohua Xue, Luciano Martelotto, Timour Baslan, Alberto Vides, Martha Solomon, Trang Thi Mai, Neelam Chaudhary, Greg J Riely, Bob T Li, Kerry Scott, Fabiola Cechhi, Ulrika Stierner, Kalyani Chadalavada, Elisa de Stanchina, Sarit Schwartz, Todd Hembrough, Gouri Nanjangud, Michael F Berger, Jonas Nilsson, Scott W Lowe, Jorge S Reis-Filho, Neal Rosen, Piro Lito

    The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAFamp) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment. The evolutionary selection of BRAFamp was determined by the fitness threshold, the barrier that subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for inhibitors of ERK signaling, suggesting that sequential monotherapy is ineffective and selects for a progressively higher BRAF copy number. Concurrent targeting of the RAF, MEK and ERK kinases, however, imposed a sufficiently high fitness threshold to prevent the propagation of subclones with high-level BRAFamp. When administered on an intermittent schedule, this treatment inhibited tumor growth in 11/11 PDXs of lung cancer or melanoma without apparent toxicity in mice. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose the highest fitness threshold will likely prevent the evolution of resistance-causing alterations and, thus, merit testing in patients.

    更新日期:2017-08-05
  • Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells
    Nat. Med. (IF 29.886) Pub Date : 2017-07-17
    Simon Rauber, Markus Luber, Stefanie Weber, Lisa Maul, Alina Soare, Thomas Wohlfahrt, Neng-Yu Lin, Katharina Dietel, Aline Bozec, Martin Herrmann, Mark H Kaplan, Benno Weigmann, Mario M Zaiss, Ursula Fearon, Douglas J Veale, Juan D Cañete, Oliver Distler, Felice Rivellese, Costantino Pitzalis, Markus F Neurath, Andrew N J McKenzie, Stefan Wirtz, Georg Schett, Jörg H W Distler, Andreas Ramming

    Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as the mediators of a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired ILC2 proliferation and activation of regulatory T (Treg) cells, and resulted in chronic arthritis with excessive cartilage destruction and bone loss. In contrast, treatment with IL-9 promoted ILC2-dependent Treg activation and effectively induced resolution of inflammation and protection of bone. Patients with rheumatoid arthritis in remission exhibited high numbers of IL-9+ ILC2s in joints and the circulation. Hence, fostering IL-9-mediated ILC2 activation may offer a novel therapeutic approach inducing resolution of inflammation rather than suppression of inflammatory responses.

    更新日期:2017-08-05
  • A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease
    Nat. Med. (IF 29.886) Pub Date : 2017-06-26
    Salim S Hayek, Kwi Hye Koh, Morgan E Grams, Changli Wei, Yi-An Ko, Jing Li, Beata Samelko, Hyun Lee, Ranadheer R Dande, Ha Won Lee, Eunsil Hahm, Vasil Peev, Melissa Tracy, Nicholas J Tardi, Vineet Gupta, Mehmet M Altintas, Garrett Garborcauskas, Nikolina Stojanovic, Cheryl A Winkler, Michael S Lipkowitz, Adrienne Tin, Lesley A Inker, Andrew S Levey, Martin Zeier, Barry I Freedman, Jeffrey B Kopp, Karl Skorecki, Josef Coresh, Arshed A Quyyumi, Sanja Sever, Jochen Reiser

    Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and αvβ3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments αvβ3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on αvβ3 integrin activation is a mechanism for CKD.

    更新日期:2017-08-05
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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