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  • Publisher Correction: Targeting hepatic glutaminase activity to ameliorate hyperglycemia
    Nat. Med. (IF 29.886) Pub Date : 2018-06-12
    Russell A. Miller, Yuji Shi, Wenyun Lu, David A. Pirman, Aditi Jatkar, Matthew Blatnik, Hong Wu, César Cárdenas, Min Wan, J. Kevin Foskett, Junyoung O. Park, Yiyi Zhang, William L. Holland, Joshua D. Rabinowitz, Morris J. Birnbaum

    Publisher Correction: Targeting hepatic glutaminase activity to ameliorate hyperglycemia Publisher Correction: Targeting hepatic glutaminase activity to ameliorate hyperglycemia, Published online: 12 June 2018; doi:10.1038/s41591-018-0047-1 Publisher Correction: Targeting hepatic glutaminase activity to ameliorate hyperglycemia

    更新日期:2018-06-12
  • p53 inhibits CRISPR–Cas9 engineering in human pluripotent stem cells
    Nat. Med. (IF 29.886) Pub Date : 2018-06-11
    Robert J. Ihry, Kathleen A. Worringer, Max R. Salick, Elizabeth Frias, Daniel Ho, Kraig Theriault, Sravya Kommineni, Julie Chen, Marie Sondey, Chaoyang Ye, Ranjit Randhawa, Tripti Kulkarni, Zinger Yang, Gregory McAllister, Carsten Russ, John Reece-Hoyes, William Forrester, Gregory R. Hoffman, Ricardo Dolmetsch, Ajamete Kaykas

    CRISPR/Cas9 has revolutionized our ability to engineer genomes and conduct genome-wide screens in human cells1,2,3. Whereas some cell types are amenable to genome engineering, genomes of human pluripotent stem cells (hPSCs) have been difficult to engineer, with reduced efficiencies relative to tumour cell lines or mouse embryonic stem cells3,4,5,6,7,8,9,10,11,12,13. Here, using hPSC lines with stable integration of Cas9 or transient delivery of Cas9-ribonucleoproteins (RNPs), we achieved an average insertion or deletion (indel) efficiency greater than 80%. This high efficiency of indel generation revealed that double-strand breaks (DSBs) induced by Cas9 are toxic and kill most hPSCs. In previous studies, the toxicity of Cas9 in hPSCs was less apparent because of low transfection efficiency and subsequently low DSB induction3. The toxic response to DSBs was P53/TP53-dependent, such that the efficiency of precise genome engineering in hPSCs with a wild-type P53 gene was severely reduced. Our results indicate that Cas9 toxicity creates an obstacle to the high-throughput use of CRISPR/Cas9 for genome engineering and screening in hPSCs. Moreover, as hPSCs can acquire P53 mutations14, cell replacement therapies using CRISPR/Cas9-enginereed hPSCs should proceed with caution, and such engineered hPSCs should be monitored for P53 function.

    更新日期:2018-06-12
  • Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure
    Nat. Med. (IF 29.886) Pub Date : 2018-06-11
    Christina Yingxian Chen, Matthew A. Caporizzo, Kenneth Bedi, Alexia Vite, Alexey I. Bogush, Patrick Robison, Julie G. Heffler, Alex K. Salomon, Neil A. Kelly, Apoorva Babu, Michael P. Morley, Kenneth B. Margulies, Benjamin L. Prosser

    Detyrosinated microtubules provide mechanical resistance that can impede the motion of contracting cardiomyocytes. However, the functional effects of microtubule detyrosination in heart failure or in human hearts have not previously been studied. Here, we utilize mass spectrometry and single-myocyte mechanical assays to characterize changes to the cardiomyocyte cytoskeleton and their functional consequences in human heart failure. Proteomic analysis of left ventricle tissue reveals a consistent upregulation and stabilization of intermediate filaments and microtubules in failing human hearts. As revealed by super-resolution imaging, failing cardiomyocytes are characterized by a dense, heavily detyrosinated microtubule network, which is associated with increased myocyte stiffness and impaired contractility. Pharmacological suppression of detyrosinated microtubules lowers the viscoelasticity of failing myocytes and restores 40–50% of lost contractile function; reduction of microtubule detyrosination using a genetic approach also softens cardiomyocytes and improves contractile kinetics. Together, these data demonstrate that a modified cytoskeletal network impedes contractile function in cardiomyocytes from failing human hearts and that targeting detyrosinated microtubules could represent a new inotropic strategy for improving cardiac function.

    更新日期:2018-06-12
  • STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis
    Nat. Med. (IF 29.886) Pub Date : 2018-06-11
    Neibla Priego, Lucía Zhu, Cátia Monteiro, Manon Mulders, David Wasilewski, Wendy Bindeman, Laura Doglio, Liliana Martínez, Elena Martínez-Saez, Santiago Ramón y Cajal, Diego Megías, Elena Hernández-Encinas, Carmen Blanco-Aparicio, Lola Martínez, Eduardo Zarzuela, Javier Muñoz, Coral Fustero-Torres, Elena Pineiro, Aurelio Hernández-Laín, Luca Bertero, Valeria Poli, Melchor Sánchez-Martínez, Javier A. Menendez, Riccardo Soffietti, Joaquim Bosch-Barrera, Manuel Valiente

    The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.

    更新日期:2018-06-12
  • CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response
    Nat. Med. (IF 29.886) Pub Date : 2018-06-11
    Emma Haapaniemi, Sandeep Botla, Jenna Persson, Bernhard Schmierer, Jussi Taipale

    Here, we report that genome editing by CRISPR–Cas9 induces a p53-mediated DNA damage response and cell cycle arrest in immortalized human retinal pigment epithelial cells, leading to a selection against cells with a functional p53 pathway. Inhibition of p53 prevents the damage response and increases the rate of homologous recombination from a donor template. These results suggest that p53 inhibition may improve the efficiency of genome editing of untransformed cells and that p53 function should be monitored when developing cell-based therapies utilizing CRISPR–Cas9.

    更新日期:2018-06-12
  • Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease
    Nat. Med. (IF 29.886) Pub Date : 2018-06-11
    Seung Pil Yun, Tae-In Kam, Nikhil Panicker, SangMin Kim, Yumin Oh, Jong-Sung Park, Seung-Hwan Kwon, Yong Joo Park, Senthilkumar S. Karuppagounder, Hyejin Park, Sangjune Kim, Nayeon Oh, Nayoung Alice Kim, Saebom Lee, Saurav Brahmachari, Xiaobo Mao, Jun Hee Lee, Manoj Kumar, Daniel An, Sung-Ung Kang, Yunjong Lee, Kang Choon Lee, Dong Hee Na, Donghoon Kim, Sang Hun Lee, Viktor V. Roschke, Shane A. Liddelow, Zoltan Mari, Ben A. Barres, Valina L. Dawson, Seulki Lee, Ted M. Dawson, Han Seok Ko

    Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases1,2. Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat these diseases for which there are no disease-modifying therapies. Glucagon-like peptide-1 receptor (GLP1R) agonists have been indicated as potential neuroprotective agents for neurologic disorders such as Alzheimer’s disease and Parkinson’s disease3,4,5,6,7,8,9,10,11,12,13. The mechanisms by which GLP1R agonists are neuroprotective are not known. Here we show that a potent, brain-penetrant long-acting GLP1R agonist, NLY01, protects against the loss of dopaminergic neurons and behavioral deficits in the α-synuclein preformed fibril (α-syn PFF) mouse model of sporadic Parkinson’s disease14,15. NLY01 also prolongs the life and reduces the behavioral deficits and neuropathological abnormalities in the human A53T α-synuclein (hA53T) transgenic mouse model of α-synucleinopathy-induced neurodegeneration16. We found that NLY01 is a potent GLP1R agonist with favorable properties that is neuroprotective through the direct prevention of microglial-mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of its favorable properties, NLY01 should be evaluated in the treatment of Parkinson’s disease and related neurologic disorders characterized by microglial activation.

    更新日期:2018-06-12
  • The human heart contains distinct macrophage subsets with divergent origins and functions
    Nat. Med. (IF 29.886) Pub Date : 2018-06-11
    Geetika Bajpai, Caralin Schneider, Nicole Wong, Andrea Bredemeyer, Maarten Hulsmans, Matthias Nahrendorf, Slava Epelman, Daniel Kreisel, Yongjian Liu, Akinobu Itoh, Thirupura S. Shankar, Craig H. Selzman, Stavros G. Drakos, Kory J. Lavine

    Paradigm-shifting studies in the mouse have identified tissue macrophage heterogeneity as a critical determinant of immune responses. In contrast, surprisingly little is known regarding macrophage heterogeneity in humans. Macrophages within the mouse heart are partitioned into CCR2− and CCR2+ subsets with divergent origins, repopulation mechanisms, and functions. Here, we demonstrate that the human myocardium also contains distinct subsets of CCR2− and CCR2+ macrophages. Analysis of sex-mismatched heart transplant recipients revealed that CCR2− macrophages are a tissue-resident population exclusively replenished through local proliferation, whereas CCR2+ macrophages are maintained through monocyte recruitment and proliferation. Moreover, CCR2− and CCR2+ macrophages have distinct functional properties, analogous to reparative CCR2− and inflammatory CCR2+ macrophages in the mouse heart. Clinically, CCR2+ macrophage abundance is associated with left ventricular remodeling and systolic function in heart failure patients. Collectively, these observations provide initial evidence for the functional importance of macrophage heterogeneity in the human heart.

    更新日期:2018-06-12
  • Rapid HIV RNA rebound after antiretroviral treatment interruption in persons durably suppressed in Fiebig I acute HIV infection
    Nat. Med. (IF 29.886) Pub Date : 2018-06-11
    Donn J. Colby, Lydie Trautmann, Suteeraporn Pinyakorn, Louise Leyre, Amélie Pagliuzza, Eugène Kroon, Morgane Rolland, Hiroshi Takata, Supranee Buranapraditkun, Jintana Intasan, Nitiya Chomchey, Roshell Muir, Elias K. Haddad, Sodsai Tovanabutra, Sasiwimol Ubolyam, Diane L. Bolton, Brandie A. Fullmer, Robert J. Gorelick, Lawrence Fox, Trevor A. Crowell, Rapee Trichavaroj, Robert O’Connell, Nicolas Chomont, Jerome H. Kim, Nelson L. Michael, Merlin L. Robb, Nittaya Phanuphak, Jintanat Ananworanich

    Antiretroviral therapy during the earliest stage of acute HIV infection (Fiebig I) might minimize establishment of a latent HIV reservoir and thereby facilitate viremic control after analytical treatment interruption. We show that 8 participants, who initiated treatment during Fiebig I and were treated for a median of 2.8 years, all experienced rapid viral load rebound following analytical treatment interruption, indicating that additional strategies are required to control or eradicate HIV.

    更新日期:2018-06-12
  • An inhibitor of oxidative phosphorylation exploits cancer vulnerability
    Nat. Med. (IF 29.886) Pub Date : 2018-06-11
    Jennifer R. Molina, Yuting Sun, Marina Protopopova, Sonal Gera, Madhavi Bandi, Christopher Bristow, Timothy McAfoos, Pietro Morlacchi, Jeffrey Ackroyd, Ahmed-Noor A. Agip, Gheath Al-Atrash, John Asara, Jennifer Bardenhagen, Caroline C. Carrillo, Christopher Carroll, Edward Chang, Stefan Ciurea, Jason B. Cross, Barbara Czako, Angela Deem, Naval Daver, John Frederick de Groot, Jian-Wen Dong, Ningping Feng, Guang Gao, Jason Gay, Mary Geck Do, Jennifer Greer, Virginia Giuliani, Jing Han, Lina Han, Verlene K. Henry, Judy Hirst, Sha Huang, Yongying Jiang, Zhijun Kang, Tin Khor, Sergej Konoplev, Yu-Hsi Lin, Gang Liu, Alessia Lodi, Timothy Lofton, Helen Ma, Mikhila Mahendra, Polina Matre, Robert Mullinax, Michael Peoples, Alessia Petrocchi, Jaime Rodriguez-Canale, Riccardo Serreli, Thomas Shi, Melinda Smith, Yoko Tabe, Jay Theroff, Stefano Tiziani, Quanyun Xu, Qi Zhang, Florian Muller, Ronald A. DePinho, Carlo Toniatti, Giulio F. Draetta, Timothy P. Heffernan, Marina Konopleva, Phili..

    Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.

    更新日期:2018-06-12
  • Reducing diabetes risk at an early age
    Nat. Med. (IF 29.886) Pub Date : 2018-06-06
    Daniel S. Hsia, Steven B. Heymsfield

    Reducing diabetes risk at an early ageReducing diabetes risk at an early age, Published online: 06 June 2018; doi:10.1038/s41591-018-0067-xA large retrospective study involving 62,565 Danish men shows that those who have been overweight in childhood have a lower risk of having type 2 diabetes in adulthood if they had remission of overweight before 13 years of age.

    更新日期:2018-06-07
  • Tracing clear cell renal carcinoma evolution
    Nat. Med. (IF 29.886) Pub Date : 2018-06-06
    Hannah Stower

    Tracing clear cell renal carcinoma evolutionTracing clear cell renal carcinoma evolution, Published online: 06 June 2018; doi:10.1038/s41591-018-0074-yTracing clear cell renal carcinoma evolution

    更新日期:2018-06-07
  • Potential and ethics
    Nat. Med. (IF 29.886) Pub Date : 2018-06-06

    Potential and ethicsPotential and ethics, Published online: 06 June 2018; doi:10.1038/s41591-018-0072-0With the ongoing demand for assisted reproduction, the need and ability to study the fundamentals of human reproduction at a cellular level have never been greater. At this juncture, we join other Nature Research Journals in formalizing our ethical guidelines for papers in this growing field.

    更新日期:2018-06-07
  • About time
    Nat. Med. (IF 29.886) Pub Date : 2018-06-06
    Shraddha Chakradhar

    About timeAbout time, Published online: 06 June 2018; doi:10.1038/s41591-018-0069-8Chronotherapy looks beyond to treating more than just cancer

    更新日期:2018-06-07
  • Training neuropathology
    Nat. Med. (IF 29.886) Pub Date : 2018-06-06
    Hannah Stower

    Training neuropathologyTraining neuropathology, Published online: 06 June 2018; doi:10.1038/s41591-018-0076-9Training neuropathology

    更新日期:2018-06-07
  • Zika virus shedding in semen
    Nat. Med. (IF 29.886) Pub Date : 2018-06-06
    Hannah Stower

    Zika virus shedding in semenZika virus shedding in semen, Published online: 06 June 2018; doi:10.1038/s41591-018-0075-xZika virus shedding in semen

    更新日期:2018-06-07
  • Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle
    Nat. Med. (IF 29.886) Pub Date : 2018-06-06
    Gang Wang, Anup K. Biswas, Wanchao Ma, Manoj Kandpal, Courtney Coker, Paul M. Grandgenett, Michael A. Hollingsworth, Rinku Jain, Kurenai Tanji, Sara Lόpez-Pintado, Alain Borczuk, Doreen Hebert, Supak Jenkitkasemwong, Shintaro Hojyo, Ramana V. Davuluri, Mitchell D. Knutson, Toshiyuki Fukada, Swarnali Acharyya

    Patients with metastatic cancer experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in patients with cancer, yet its underlying mechanisms remain poorly understood. Here, we identify the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14) as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles of mice and in patients with metastatic cancer and can be induced by TNF-α and TGF-β cytokines. Strikingly, germline ablation or muscle-specific depletion of Zip14 markedly reduces muscle atrophy in metastatic cancer models. We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expression of MyoD and Mef2c and blocks muscle-cell differentiation. Importantly, ZIP14-mediated zinc accumulation in differentiated muscle cells induces myosin heavy chain loss. These results highlight a previously unrecognized role for altered zinc homeostasis in metastatic cancer–induced muscle wasting and implicate ZIP14 as a therapeutic target for its treatment.

    更新日期:2018-06-07
  • Intersection of schizophrenia genetics and placental complications
    Nat. Med. (IF 29.886) Pub Date : 2018-06-06
    Margaret M. McCarthy

    Intersection of schizophrenia genetics and placental complicationsIntersection of schizophrenia genetics and placental complications, Published online: 06 June 2018; doi:10.1038/s41591-018-0066-yGenetic risk scores in schizophrenia are influenced by pregnancy complications that compromise the placenta, enhancing association of genes involved in metabolism and cellular stress with schizophrenia risk.

    更新日期:2018-06-07
  • Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma
    Nat. Med. (IF 29.886) Pub Date : 2018-06-04
    David F. McDermott, Mahrukh A. Huseni, Michael B. Atkins, Robert J. Motzer, Brian I. Rini, Bernard Escudier, Lawrence Fong, Richard W. Joseph, Sumanta K. Pal, James A. Reeves, Mario Sznol, John Hainsworth, W. Kimryn Rathmell, Walter M. Stadler, Thomas Hutson, Martin E. Gore, Alain Ravaud, Sergio Bracarda, Cristina Suárez, Riccardo Danielli, Viktor Gruenwald, Toni K. Choueiri, Dorothee Nickles, Suchit Jhunjhunwala, Elisabeth Piault-Louis, Alpa Thobhani, Jiaheng Qiu, Daniel S. Chen, Priti S. Hegde, Christina Schiff, Gregg D. Fine, Thomas Powles

    We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69–1.45) and 1.19 (95% CI, 0.82–1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38–1.08) and 1.03 (95% CI, 0.63–1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.

    更新日期:2018-06-05
  • Targeting the cancer mutanome of breast cancer
    Nat. Med. (IF 29.886) Pub Date : 2018-06-04
    Laszlo G. Radvanyi

    Targeting the cancer mutanome of breast cancerTargeting the cancer mutanome of breast cancer, Published online: 04 June 2018; doi:10.1038/s41591-018-0065-zA metastatic hormone receptor–positive breast cancer, usually resistant to immunotherapy, is successfully treated with tumor-infiltrating lymphocytes enriched for neoantigen reactivity, underscoring the broad potential of this immunotherapeutic approach.

    更新日期:2018-06-05
  • Therapeutic and protective efficacy of a dengue antibody against Zika infection in rhesus monkeys
    Nat. Med. (IF 29.886) Pub Date : 2018-06-04
    Peter Abbink, Rafael A. Larocca, Wanwisa Dejnirattisai, Rebecca Peterson, Joseph P. Nkolola, Erica N. Borducchi, Piyada Supasa, Juthathip Mongkolsapaya, Gavin R. Screaton, Dan H. Barouch

    Strategies to treat Zika virus (ZIKV) infection in dengue virus (DENV)-endemic areas are urgently needed. Here we show that a DENV-specific antibody against the E-dimer epitope (EDE) potently cross-neutralizes ZIKV and provides robust therapeutic efficacy as well as prophylactic efficacy against ZIKV in rhesus monkeys. Viral escape was not detected, suggesting a relatively high bar to escape. These data demonstrate the potential for antibody-based therapy and prevention of ZIKV.

    更新日期:2018-06-05
  • Wang et al. reply
    Nat. Med. (IF 29.886) Pub Date : 2018-06-04
    Pi-Xiao Wang, Guang-Nian Zhao, Yan-Xiao Ji, Peng Zhang, Xiao-Jing Zhang, Jun Gong, Ling-Ping Zhao, Zhen-Zhen Yan, Miao Yin, Zhou Jiang, Li-Jun Shen, Xia Yang, Jing Fang, Song Tian, Jingjing Tong, Yutao Wang, Xue-Yong Zhu, Xin Zhang, Qiao-Fang Wei, Yong Wang, Qingguo Xie, Jing Li, Lu Wan, Zhi-Gang She, Zhihua Wang, Zan Huang, Hongliang Li

    Wang et al. replyWang et al. reply, Published online: 04 June 2018; doi:10.1038/s41591-018-0063-1Wang et al. reply

    更新日期:2018-06-05
  • Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1
    Nat. Med. (IF 29.886) Pub Date : 2018-06-04
    Kai Xu, Priyamvada Acharya, Rui Kong, Cheng Cheng, Gwo-Yu Chuang, Kevin Liu, Mark K. Louder, Sijy O’Dell, Reda Rawi, Mallika Sastry, Chen-Hsiang Shen, Baoshan Zhang, Tongqing Zhou, Mangaiarkarasi Asokan, Robert T. Bailer, Michael Chambers, Xuejun Chen, Chang W. Choi, Venkata P. Dandey, Nicole A. Doria-Rose, Aliaksandr Druz, Edward T. Eng, S. Katie Farney, Kathryn E. Foulds, Hui Geng, Ivelin S. Georgiev, Jason Gorman, Kurt R. Hill, Alexander J. Jafari, Young D. Kwon, Yen-Ting Lai, Thomas Lemmin, Krisha McKee, Tiffany Y. Ohr, Li Ou, Dongjun Peng, Ariana P. Rowshan, Zizhang Sheng, John-Paul Todd, Yaroslav Tsybovsky, Elise G. Viox, Yiran Wang, Hui Wei, Yongping Yang, Amy F. Zhou, Rui Chen, Lu Yang, Diana G. Scorpio, Adrian B. McDermott, Lawrence Shapiro, Bridget Carragher, Clinton S. Potter, John R. Mascola, Peter D. Kwong

    A central goal of HIV-1 vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N-terminal residues of the fusion peptide, a critical component of the viral entry machinery and the epitope of antibodies elicited by HIV-1 infection, through immunization with fusion peptide-coupled carriers and prefusion stabilized envelope trimers, induces cross-clade neutralizing responses. In mice, these immunogens elicited monoclonal antibodies capable of neutralizing up to 31% of a cross-clade panel of 208 HIV-1 strains. Crystal and cryoelectron microscopy structures of these antibodies revealed fusion peptide conformational diversity as a molecular explanation for the cross-clade neutralization. Immunization of guinea pigs and rhesus macaques induced similarly broad fusion peptide-directed neutralizing responses, suggesting translatability. The N terminus of the HIV-1 fusion peptide is thus a promising target of vaccine efforts aimed at eliciting broadly neutralizing antibodies.

    更新日期:2018-06-05
  • Myeloid cell contributions to cardiovascular health and disease
    Nat. Med. (IF 29.886) Pub Date : 2018-06-04
    Matthias Nahrendorf

    Recent advances in cell tracing and sequencing technologies have expanded our knowledge on leukocyte behavior. As a consequence, inflammatory cells, such as monocyte-derived macrophages, and their actions and products are increasingly being considered as potential drug targets for treatment of atherosclerosis, myocardial infarction and heart failure. Particularly promising developments are the identification of harmful arterial and cardiac macrophage subsets, the cells’ altered, sometimes even clonal production in hematopoietic organs, and epigenetically entrained memories of myeloid progenitors and macrophages in the setting of cardiovascular disease. Given the roles of monocytes and macrophages in host defense, intricately understanding the involved cellular subsets, sources and functions is essential for the design of precision therapeutics that preserve protective innate immunity. Here I review how new clinical and preclinical data, often linking the cardiovascular, immune and other organ systems, propel conceptual advances to a point where cardiovascular immunotherapy appears within reach.

    更新日期:2018-06-05
  • Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer
    Nat. Med. (IF 29.886) Pub Date : 2018-06-04
    Nikolaos Zacharakis, Harshini Chinnasamy, Mary Black, Hui Xu, Yong-Chen Lu, Zhili Zheng, Anna Pasetto, Michelle Langhan, Thomas Shelton, Todd Prickett, Jared Gartner, Li Jia, Katarzyna Trebska-McGowan, Robert P. Somerville, Paul F. Robbins, Steven A. Rosenberg, Stephanie L. Goff, Steven A. Feldman

    Immunotherapy using either checkpoint blockade or the adoptive transfer of antitumor lymphocytes has shown effectiveness in treating cancers with high levels of somatic mutations—such as melanoma, smoking-induced lung cancers and bladder cancer—with little effect in other common epithelial cancers that have lower mutation rates, such as those arising in the gastrointestinal tract, breast and ovary1,2,3,4,5,6,7. Adoptive transfer of autologous lymphocytes that specifically target proteins encoded by somatically mutated genes has mediated substantial objective clinical regressions in patients with metastatic bile duct, colon and cervical cancers8,9,10,11. We present a patient with chemorefractory hormone receptor (HR)-positive metastatic breast cancer who was treated with tumor-infiltrating lymphocytes (TILs) reactive against mutant versions of four proteins—SLC3A2, KIAA0368, CADPS2 and CTSB. Adoptive transfer of these mutant-protein-specific TILs in conjunction with interleukin (IL)-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer, which is now ongoing for >22 months, and it represents a new immunotherapy approach for the treatment of these patients.

    更新日期:2018-06-05
  • Inactivating hepatic follistatin alleviates hyperglycemia
    Nat. Med. (IF 29.886) Pub Date : 2018-06-04
    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

    Unsuppressed hepatic glucose production (HGP) contributes substantially to glucose intolerance and diabetes, which can be modeled by the genetic inactivation of hepatic insulin receptor substrate 1 (Irs1) and Irs2 (LDKO mice). We previously showed that glucose intolerance in LDKO mice is resolved by hepatic inactivation of the transcription factor FoxO1 (that is, LTKO mice)—even though the liver remains insensitive to insulin. Here, we report that insulin sensitivity in the white adipose tissue of LDKO mice is also impaired but is restored in LTKO mice in conjunction with normal suppression of HGP by insulin. To establish the mechanism by which white adipose tissue insulin signaling and HGP was regulated by hepatic FoxO1, we identified putative hepatokines—including excess follistatin (Fst)—that were dysregulated in LDKO mice but normalized in LTKO mice. Knockdown of hepatic Fst in the LDKO mouse liver restored glucose tolerance, white adipose tissue insulin signaling and the suppression of HGP by insulin; however, the expression of Fst in the liver of healthy LTKO mice had the opposite effect. Of potential clinical significance, knockdown of Fst also improved glucose tolerance in high-fat-fed obese mice, and the level of serum Fst was reduced in parallel with glycated hemoglobin in obese individuals with diabetes who underwent therapeutic gastric bypass surgery. We conclude that Fst is a pathological hepatokine that might be targeted for diabetes therapy during hepatic insulin resistance.

    更新日期:2018-06-05
  • Modeling cytokine release syndrome
    Nat. Med. (IF 29.886) Pub Date : 2018-05-28
    Cliona Rooney, Tim Sauer

    Modeling cytokine release syndrome Modeling cytokine release syndrome, Published online: 28 May 2018; doi:10.1038/s41591-018-0068-9 Complete leukemic responses to chimeric antigen receptor–modified T cells are invariably accompanied by severe toxicity. Recently developed animal models allow mechanistic dissection and prevention of toxicity without loss of therapeutic benefit.

    更新日期:2018-05-29
  • Convergence of placenta biology and genetic risk for schizophrenia
    Nat. Med. (IF 29.886) Pub Date : 2018-05-28
    Gianluca Ursini, Giovanna Punzi, Qiang Chen, Stefano Marenco, Joshua F. Robinson, Annamaria Porcelli, Emily G. Hamilton, Marina Mitjans, Giancarlo Maddalena, Martin Begemann, Jan Seidel, Hidenaga Yanamori, Andrew E. Jaffe, Karen F. Berman, Michael F. Egan, Richard E. Straub, Carlo Colantuoni, Giuseppe Blasi, Ryota Hashimoto, Dan Rujescu, Hannelore Ehrenreich, Alessandro Bertolino, Daniel R. Weinberger

    Defining the environmental context in which genes enhance disease susceptibility can provide insight into the pathogenesis of complex disorders. We report that the intra-uterine environment modulates the association of schizophrenia with genomic risk (in this study, genome-wide association study–derived polygenic risk scores (PRSs)). In independent samples from the United States, Italy, and Germany, the liability of schizophrenia explained by PRS is more than five times greater in the presence of early-life complications (ELCs) compared with their absence. Patients with ELC histories have significantly higher PRS than patients without ELC histories, which is confirmed in additional samples from Germany and Japan. The gene set composed of schizophrenia loci that interact with ELCs is highly expressed in placenta, is differentially expressed in placentae from complicated in comparison with normal pregnancies, and is differentially upregulated in placentae from male compared with female offspring. Pathway analyses reveal that genes driving the PRS-ELC interaction are involved in cellular stress response; genes that do not drive such interaction implicate orthogonal biological processes (for example, synaptic function). We conclude that a subset of the most significant genetic variants associated with schizophrenia converge on a developmental trajectory sensitive to events that affect the placental response to stress, which may offer insights into sex biases and primary prevention.

    更新日期:2018-05-29
  • CAR T cell–induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade
    Nat. Med. (IF 29.886) Pub Date : 2018-05-28
    Theodoros Giavridis, Sjoukje J. C. van der Stegen, Justin Eyquem, Mohamad Hamieh, Alessandra Piersigilli, Michel Sadelain

    Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL)1. Although a majority of patients will achieve a complete response following a single infusion of CD19-targeted CAR-modified T cells (CD19 CAR T cells)2,3,4, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterized by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines, including interleukin-6 (IL-6)2,5. CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumor burden2,3,4. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity2,3,4,5,6,7,8,9. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. Here we report a murine model of CRS that develops within 2–3 d of CAR T cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell–derived cytokines, but by IL-6, IL-1 and nitric oxide (NO) produced by recipient macrophages, which enables new therapeutic interventions.

    更新日期:2018-05-29
  • SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo
    Nat. Med. (IF 29.886) Pub Date : 2018-05-28
    Sara Mainardi, Antonio Mulero-Sánchez, Anirudh Prahallad, Giovanni Germano, Astrid Bosma, Paul Krimpenfort, Cor Lieftink, Jeffrey D. Steinberg, Niels de Wit, Samuel Gonçalves-Ribeiro, Ernest Nadal, Alberto Bardelli, Alberto Villanueva, Rene Bernards

    RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs)1,2,3. Inhibition of the RAS oncoproteins has proven difficult4, and attempts to target downstream effectors5,6,7 have been hampered by the activation of compensatory resistance mechanisms8. It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers9,10. Consistently, inhibition of SHP2 (also known as PTPN11), which links receptor tyrosine kinase signaling to the RAS–RAF–MEK–ERK pathway11,12, was shown to be ineffective in KRAS-mutant or BRAF-mutant cancer cell lines13. Our data also indicate that SHP2 inhibition in KRAS-mutant NSCLC cells under normal cell culture conditions has little effect. By contrast, SHP2 inhibition under growth factor–limiting conditions in vitro results in a senescence response. In vivo, inhibition of SHP2 in KRAS-mutant NSCLC also provokes a senescence response, which is exacerbated by MEK inhibition. Our data identify SHP2 inhibition as an unexpected vulnerability of KRAS-mutant NSCLC cells that remains undetected in cell culture and can be exploited therapeutically.

    更新日期:2018-05-29
  • Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition
    Nat. Med. (IF 29.886) Pub Date : 2018-05-28
    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

    The role of KRAS, when activated through canonical mutations, has been well established in cancer1. Here we explore a secondary means of KRAS activation in cancer: focal high-level amplification of the KRAS gene in the absence of coding mutations. These amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas2,3,4. KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to their capacity to adaptively respond by rapidly increasing KRAS–GTP levels. Here we demonstrate that inhibition of the guanine-exchange factors SOS1 and SOS2 or the protein tyrosine phosphatase SHP2 can attenuate this adaptive process and that targeting these factors, both genetically and pharmacologically, can enhance the sensitivity of KRAS-amplified models to MEK inhibition in both in vitro and in vivo settings. These data demonstrate the relevance of copy-number amplification as a mechanism of KRAS activation, and uncover the therapeutic potential for targeting of these tumors through combined SHP2 and MEK inhibition.

    更新日期:2018-05-29
  • Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells
    Nat. Med. (IF 29.886) Pub Date : 2018-05-28
    Margherita Norelli, Barbara Camisa, Giulia Barbiera, Laura Falcone, Ayurzana Purevdorj, Marco Genua, Francesca Sanvito, Maurilio Ponzoni, Claudio Doglioni, Patrizia Cristofori, Catia Traversari, Claudio Bordignon, Fabio Ciceri, Renato Ostuni, Chiara Bonini, Monica Casucci, Attilio Bondanza

    In the clinic, chimeric antigen receptor–modified T (CAR T) cell therapy is frequently associated with life-threatening cytokine-release syndrome (CRS) and neurotoxicity. Understanding the nature of these pathologies and developing treatments for them are hampered by the lack of appropriate animal models. Herein, we describe a mouse model recapitulating key features of CRS and neurotoxicity. In humanized mice with high leukemia burden, CAR T cell–mediated clearance of cancer triggered high fever and elevated IL-6 levels, which are hallmarks of CRS. Human monocytes were the major source of IL-1 and IL-6 during CRS. Accordingly, the syndrome was prevented by monocyte depletion or by blocking IL-6 receptor with tocilizumab. Nonetheless, tocilizumab failed to protect mice from delayed lethal neurotoxicity, characterized by meningeal inflammation. Instead, the IL-1 receptor antagonist anakinra abolished both CRS and neurotoxicity, resulting in substantially extended leukemia-free survival. These findings offer a therapeutic strategy to tackle neurotoxicity and open new avenues to safer CAR T cell therapies.

    更新日期:2018-05-29
  • Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase
    Nat. Med. (IF 29.886) Pub Date : 2018-05-28
    Dietrich A. Ruess, Guus J. Heynen, Katrin J. Ciecielski, Jiaoyu Ai, Alexandra Berninger, Derya Kabacaoglu, Kivanc Görgülü, Zahra Dantes, Sonja M. Wörmann, Kalliope N. Diakopoulos, Angeliki F. Karpathaki, Marlena Kowalska, Ezgi Kaya-Aksoy, Liang Song, Eveline A. Zeeuw van der Laan, María P. López-Alberca, Marc Nazaré, Maximilian Reichert, Dieter Saur, Mert M. Erkan, Ulrich T. Hopt, Bruno Sainz Jr, Walter Birchmeier, Roland M. Schmid, Marina Lesina, Hana Algül

    The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors1. Its requirement for complete RAS–MAPK activation and its role as a negative regulator of JAK–STAT signaling have established SHP2 as an essential player in oncogenic signaling pathways1,2,3,4,5,6,7. Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro8. Here, we report a central and indispensable role for SHP2 in oncogenic KRAS-driven tumors. Genetic deletion of Ptpn11 profoundly inhibited tumor development in mutant KRAS-driven murine models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. We provide evidence for a critical dependence of mutant KRAS on SHP2 during carcinogenesis. Deletion or inhibition of SHP2 in established tumors delayed tumor progression but was not sufficient to achieve tumor regression. However, SHP2 was necessary for resistance mechanisms upon blockade of MEK. Synergy was observed when both SHP2 and MEK were targeted, resulting in sustained tumor growth control in murine and human patient-derived organoids and xenograft models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. Our data indicate the clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS-mutant cancers.

    更新日期:2018-05-29
  • Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy
    Nat. Med. (IF 29.886) Pub Date : 2018-05-21
    Lu Wang, Zibo Zhao, Patrick A. Ozark, Damiano Fantini, Stacy A. Marshall, Emily J. Rendleman, Kira A. Cozzolino, Nundia Louis, Xingyao He, Marc A. Morgan, Yoh-hei Takahashi, Clayton K. Collings, Edwin R. Smith, Panagiotis Ntziachristos, Jeffrey N. Savas, Lihua Zou, Rintaro Hashizume, Joshua J. Meeks, Ali Shilatifard

    The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point mutations across a range of human tumor types, but precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within the region encoding its plant homeodomain (PHD) repeats and demonstrate that this domain mediates association of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1. Cancer-associated mutations in the sequence encoding the MLL3 PHD repeats disrupt the interaction between MLL3 and BAP1 and correlate with poor patient survival. Cancer cells that had PHD-associated MLL3 mutations or lacked BAP1 showed reduced recruitment of MLL3 and the H3K27 demethylase KDM6A (also known as UTX) to gene enhancers. As a result, inhibition of the H3K27 methyltransferase activity of the Polycomb repressive complex 2 (PRC2) in tumor cells harboring BAP1 or MLL3 mutations restored normal gene expression patterns and impaired cell proliferation in vivo. This study provides mechanistic insight into the oncogenic effects of PHD-associated mutations in MLL3 and suggests that restoration of a balanced state of Polycomb–COMPASS activity may have therapeutic efficacy in tumors that bear mutations in the genes encoding these epigenetic factors.

    更新日期:2018-05-22
  • Targeting G-quadruplex DNA as cognitive function therapy for ATR-X syndrome
    Nat. Med. (IF 29.886) Pub Date : 2018-05-21
    Norifumi Shioda, Yasushi Yabuki, Kouya Yamaguchi, Misaki Onozato, Yue Li, Kenji Kurosawa, Hideyuki Tanabe, Nobuhiko Okamoto, Takumi Era, Hiroshi Sugiyama, Takahito Wada, Kohji Fukunaga

    Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is caused by mutations in ATRX, which encodes a chromatin-remodeling protein. Genome-wide analyses in mouse and human cells indicate that ATRX tends to bind to G-rich sequences with a high potential to form G-quadruplexes. Here, we report that Atrx mutation induces aberrant upregulation of Xlr3b expression in the mouse brain, an outcome associated with neuronal pathogenesis displayed by ATR-X model mice. We show that ATRX normally binds to G-quadruplexes in CpG islands of the imprinted Xlr3b gene, regulating its expression by recruiting DNA methyltransferases. Xlr3b binds to dendritic mRNAs, and its overexpression inhibits dendritic transport of the mRNA encoding CaMKII-α, promoting synaptic dysfunction. Notably, treatment with 5-ALA, which is converted into G-quadruplex-binding metabolites, reduces RNA polymerase II recruitment and represses Xlr3b transcription in ATR-X model mice. 5-ALA treatment also rescues decreased synaptic plasticity and cognitive deficits seen in ATR-X model mice. Our findings suggest a potential therapeutic strategy to target G-quadruplexes and decrease cognitive impairment associated with ATR-X syndrome.

    更新日期:2018-05-22
  • HIV vaccine candidate activation of hypoxia and the inflammasome in CD14+ monocytes is associated with a decreased risk of SIVmac251 acquisition
    Nat. Med. (IF 29.886) Pub Date : 2018-05-21
    Monica Vaccari, Slim Fourati, Shari N. Gordon, Dallas R. Brown, Massimilano Bissa, Luca Schifanella, Isabela Silva de Castro, Melvin N. Doster, Veronica Galli, Maria Omsland, Dai Fujikawa, Giacomo Gorini, Namal P. M. Liyanage, Hung V. Trinh, Katherine M. McKinnon, Kathryn E. Foulds, Brandon F. Keele, Mario Roederer, Richard A. Koup, Xiaoying Shen, Georgia D. Tomaras, Marcus P. Wong, Karissa J. Munoz, Johannes S. Gach, Donald N. Forthal, David C. Montefiori, David J. Venzon, Barbara K. Felber, Margherita Rosati, George N. Pavlakis, Mangala Rao, Rafick-Pierre Sekaly, Genoveffa Franchini

    Qualitative differences in the innate and adaptive responses elicited by different HIV vaccine candidates have not been thoroughly investigated. We tested the ability of the Aventis Pasteur live recombinant canarypox vector (ALVAC)–SIV, DNA–SIV and Ad26–SIV vaccine prime modalities together with two ALVAC–SIV + gp120 protein boosts to reduce the risk of SIVmac251 acquisition in rhesus macaques. We found that the DNA and ALVAC prime regimens were effective, but the Ad26 prime was not. The activation of hypoxia and the inflammasome in CD14+CD16− monocytes, gut-homing CCR5-negative CD4+ T helper 2 (TH2) cells and antibodies to variable region 2 correlated with a decreased risk of SIVmac251 acquisition. By contrast, signal transducer and activator of transcription 3 activation in CD16+ monocytes was associated with an increased risk of virus acquisition. The Ad26 prime regimen induced the accumulation of CX3CR1+CD163+ macrophages in lymph nodes and of long-lasting CD4+ TH17 cells in the gut and lungs. Our data indicate that the selective engagement of monocyte subsets following a vaccine prime influences long-term immunity, uncovering an unexpected association of CD14+ innate monocytes with a reduced risk of SIVmac251 acquisition.

    更新日期:2018-05-22
  • An immune-beige adipocyte communication via nicotinic acetylcholine receptor signaling
    Nat. Med. (IF 29.886) Pub Date : 2018-05-21
    Heejin Jun, Hui Yu, Jianke Gong, Juan Jiang, Xiaona Qiao, Eric Perkey, Dong-il Kim, Margo P. Emont, Alexander G. Zestos, Jung-Sun Cho, Jianfeng Liu, Robert T. Kennedy, Ivan Maillard, X. Z. Shawn Xu, Jun Wu

    Beige adipocytes have recently been shown to regulate energy dissipation when activated and help organisms defend against hypothermia and obesity. Prior reports indicate that beige-like adipocytes exist in adult humans and that they may present novel opportunities to curb the global epidemic in obesity and metabolic illnesses. In an effort to identify unique features of activated beige adipocytes, we found that expression of the cholinergic receptor nicotinic alpha 2 subunit (Chrna2) was induced in subcutaneous fat during the activation of these cells and that acetylcholine-producing immune cells within this tissue regulated this signaling pathway via paracrine mechanisms. CHRNA2 functioned selectively in uncoupling protein 1 (Ucp1)-positive beige adipocytes, increasing thermogenesis through a cAMP- and protein kinase A-dependent pathway. Furthermore, this signaling via CHRNA2 was conserved and present in human subcutaneous adipocytes. Inactivation of Chrna2 in mice compromised the cold-induced thermogenic response selectively in subcutaneous fat and exacerbated high-fat diet-induced obesity and associated metabolic disorders, indicating that even partial loss of beige fat regulation in vivo had detrimental consequences. Our results reveal a beige-selective immune–adipose interaction mediated through CHRNA2 and identify a novel function of nicotinic acetylcholine receptors in energy metabolism. These findings may lead to identification of therapeutic targets to counteract human obesity.

    更新日期:2018-05-22
  • The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia
    Nat. Med. (IF 29.886) Pub Date : 2018-05-21
    Renée Beekman, Vicente Chapaprieta, Núria Russiñol, Roser Vilarrasa-Blasi, Núria Verdaguer-Dot, Joost H. A. Martens, Martí Duran-Ferrer, Marta Kulis, François Serra, Biola M. Javierre, Steven W. Wingett, Guillem Clot, Ana C. Queirós, Giancarlo Castellano, Julie Blanc, Marta Gut, Angelika Merkel, Simon Heath, Anna Vlasova, Sebastian Ullrich, Emilio Palumbo, Anna Enjuanes, David Martín-García, Sílvia Beà, Magda Pinyol, Marta Aymerich, Romina Royo, Montserrat Puiggros, David Torrents, Avik Datta, Ernesto Lowy, Myrto Kostadima, Maša Roller, Laura Clarke, Paul Flicek, Xabier Agirre, Felipe Prosper, Tycho Baumann, Julio Delgado, Armando López-Guillermo, Peter Fraser, Marie-Laure Yaspo, Roderic Guigó, Reiner Siebert, Marc A. Martí-Renom, Xose S. Puente, Carlos López-Otín, Ivo Gut, Hendrik G. Stunnenberg, Elias Campo, Jose I. Martin-Subero

    Chronic lymphocytic leukemia (CLL) is a frequent hematological neoplasm in which underlying epigenetic alterations are only partially understood. Here, we analyze the reference epigenome of seven primary CLLs and the regulatory chromatin landscape of 107 primary cases in the context of normal B cell differentiation. We identify that the CLL chromatin landscape is largely influenced by distinct dynamics during normal B cell maturation. Beyond this, we define extensive catalogues of regulatory elements de novo reprogrammed in CLL as a whole and in its major clinico-biological subtypes classified by IGHV somatic hypermutation levels. We uncover that IGHV-unmutated CLLs harbor more active and open chromatin than IGHV-mutated cases. Furthermore, we show that de novo active regions in CLL are enriched for NFAT, FOX and TCF/LEF transcription factor family binding sites. Although most genetic alterations are not associated with consistent epigenetic profiles, CLLs with MYD88 mutations and trisomy 12 show distinct chromatin configurations. Furthermore, we observe that non-coding mutations in IGHV-mutated CLLs are enriched in H3K27ac-associated regulatory elements outside accessible chromatin. Overall, this study provides an integrative portrait of the CLL epigenome, identifies extensive networks of altered regulatory elements and sheds light on the relationship between the genetic and epigenetic architecture of the disease.

    更新日期:2018-05-22
  • Targeting skeletal endothelium to ameliorate bone loss
    Nat. Med. (IF 29.886) Pub Date : 2018-05-21
    Ren Xu, Alisha Yallowitz, An Qin, Zhuhao Wu, Dong Yeon Shin, Jung-Min Kim, Shawon Debnath, Gang Ji, Mathias P. Bostrom, Xu Yang, Chao Zhang, Han Dong, Pouneh Kermani, Sarfaraz Lalani, Na Li, Yifang Liu, Michael G. Poulos, Amanda Wach, Yi Zhang, Kazuki Inoue, Annarita Di Lorenzo, Baohong Zhao, Jason M. Butler, Jae-Hyuck Shim, Laurie H. Glimcher, Matthew B. Greenblatt

    Recent studies have identified a specialized subset of CD31hiendomucinhi (CD31hiEMCNhi) vascular endothelium that positively regulates bone formation. However, it remains unclear how CD31hiEMCNhi endothelium levels are coupled to anabolic bone formation. Mice with an osteoblast-specific deletion of Shn3, which have markedly elevated bone formation, demonstrated an increase in CD31hiEMCNhi endothelium. Transcriptomic analysis identified SLIT3 as an osteoblast-derived, SHN3-regulated proangiogenic factor. Genetic deletion of Slit3 reduced skeletal CD31hiEMCNhi endothelium, resulted in low bone mass because of impaired bone formation and partially reversed the high bone mass phenotype of Shn3−/− mice. This coupling between osteoblasts and CD31hiEMCNhi endothelium is essential for bone healing, as shown by defective fracture repair in SLIT3-mutant mice and enhanced fracture repair in SHN3-mutant mice. Finally, administration of recombinant SLIT3 both enhanced bone fracture healing and counteracted bone loss in a mouse model of postmenopausal osteoporosis. Thus, drugs that target the SLIT3 pathway may represent a new approach for vascular-targeted osteoanabolic therapy to treat bone loss.

    更新日期:2018-05-22
  • Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood
    Nat. Med. (IF 29.886) Pub Date : 2018-05-14
    Brooke Tata, Nour El Houda Mimouni, Anne-Laure Barbotin, Samuel A. Malone, Anne Loyens, Pascal Pigny, Didier Dewailly, Sophie Catteau-Jonard, Inger Sundström-Poromaa, Terhi T. Piltonen, Federica Dal Bello, Claudio Medana, Vincent Prevot, Jerome Clasadonte, Paolo Giacobini

    Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and anti-Müllerian hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility, it was unclear whether their levels were also elevated in pregnant women with PCOS. Here we measured AMH in a cohort of pregnant women with PCOS and control pregnant women and found that AMH is significantly more elevated in the former group versus the latter. To determine whether the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modeled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood.

    更新日期:2018-05-15
  • CAR T cells for childhood diffuse midline gliomas
    Nat. Med. (IF 29.886) Pub Date : 2018-05-07
    Vijay Ramaswamy, Michael D Taylor

    CAR T cells for childhood diffuse midline gliomas CAR T cells for childhood diffuse midline gliomas, Published online: 07 May 2018; doi:10.1038/s41591-018-0031-9 Anti-GD2 chimeric antigen receptor (CAR)-modified T cells may be a new and innovative approach for the treatment of pediatric H3-K27M-mutant diffuse midline gliomas.

    更新日期:2018-05-08
  • Sleeper cells
    Nat. Med. (IF 29.886) Pub Date : 2018-05-07
    Shraddha Chakradhar

    Sleeper cells Sleeper cells, Published online: 07 May 2018; doi:10.1038/s41591-018-0039-1 New studies question how HIV persists in the body

    更新日期:2018-05-08
  • Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche
    Nat. Med. (IF 29.886) Pub Date : 2018-05-07
    Maria Maryanovich, Ali H. Zahalka, Halley Pierce, Sandra Pinho, Fumio Nakahara, Noboru Asada, Qiaozhi Wei, Xizhe Wang, Paul Ciero, Jianing Xu, Avigdor Leftin, Paul S. Frenette

    Aging of hematopoietic stem cells (HSCs) is associated with a decline in their regenerative capacity and multilineage differentiation potential, contributing to the development of blood disorders. The bone marrow microenvironment has recently been suggested to influence HSC aging, but the underlying mechanisms remain largely unknown. Here we show that HSC aging critically depends on bone marrow innervation by the sympathetic nervous system (SNS), as loss of SNS nerves or adrenoreceptor β3 signaling in the bone marrow microenvironment of young mice led to premature HSC aging, as evidenced by appearance of HSC phenotypes reminiscent of physiological aging. Strikingly, supplementation of a sympathomimetic acting selectively on adrenoreceptor β3 to old mice significantly rejuvenated the in vivo function of aged HSCs, suggesting that the preservation or restitution of bone marrow SNS innervation during aging may hold the potential for new HSC rejuvenation strategies.

    更新日期:2018-05-08
  • Targeting metabolism to treat psoriasis
    Nat. Med. (IF 29.886) Pub Date : 2018-05-07
    Paul Hiebert, Sabine Werner

    Targeting metabolism to treat psoriasis Targeting metabolism to treat psoriasis, Published online: 07 May 2018; doi:10.1038/s41591-018-0027-5 A crucial role for glucose metabolism has been identified in wound repair and in the pathogenesis of chronic inflammatory skin diseases, indicating that targeting metabolism is an approach for treating psoriasis.

    更新日期:2018-05-08
  • MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency
    Nat. Med. (IF 29.886) Pub Date : 2018-05-07
    Karine Clément, Heike Biebermann, I. Sadaf Farooqi, Lex Van der Ploeg, Barbara Wolters, Christine Poitou, Lia Puder, Fred Fiedorek, Keith Gottesdiener, Gunnar Kleinau, Nicolas Heyder, Patrick Scheerer, Ulrike Blume-Peytavi, Irina Jahnke, Shubh Sharma, Jacek Mokrosinski, Susanna Wiegand, Anne Müller, Katja Weiß, Knut Mai, Joachim Spranger, Annette Grüters, Oliver Blankenstein, Heiko Krude, Peter Kühnen

    Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45–61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies.

    更新日期:2018-05-08
  • Redefining Medicine
    Nat. Med. (IF 29.886) Pub Date : 2018-05-07

    Redefining Medicine Redefining Medicine, Published online: 07 May 2018; doi:10.1038/s41591-018-0037-3 For more than two decades, Nature Medicine has been the prime venue for publication of outstanding work in the translational space. Now the journal’s scope is evolving to embrace the clinical research that meets the challenges and complexities of contemporary medicine.

    更新日期:2018-05-08
  • ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade
    Nat. Med. (IF 29.886) Pub Date : 2018-05-07
    Jianfeng Shen, Zhenlin Ju, Wei Zhao, Lulu Wang, Yang Peng, Zhongqi Ge, Zachary D. Nagel, Jun Zou, Chen Wang, Prabodh Kapoor, Xiangyi Ma, Ding Ma, Jiyong Liang, Shumei Song, Jinsong Liu, Leona D. Samson, Jaffer A. Ajani, Guo-Min Li, Han Liang, Xuetong Shen, Gordon B. Mills, Guang Peng

    ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer1,2. The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression3, which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Tumors formed by an ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Notably, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A-deficient but not ARID1A-wild-type ovarian tumors. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy.

    更新日期:2018-05-08
  • The best Cas scenario
    Nat. Med. (IF 29.886) Pub Date : 2018-05-07
    Peter Andrey Smith

    The best Cas scenario The best Cas scenario, Published online: 07 May 2018; doi:10.1038/s41591-018-0038-2 Finding poetry in gene editing and ways to improve it

    更新日期:2018-05-08
  • Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial
    Nat. Med. (IF 29.886) Pub Date : 2018-04-30
    Andrew Tutt, Holly Tovey, Maggie Chon U. Cheang, Sarah Kernaghan, Lucy Kilburn, Patrycja Gazinska, Julie Owen, Jacinta Abraham, Sophie Barrett, Peter Barrett-Lee, Robert Brown, Stephen Chan, Mitchell Dowsett, James M Flanagan, Lisa Fox, Anita Grigoriadis, Alexander Gutin, Catherine Harper-Wynne, Matthew Q. Hatton, Katherine A. Hoadley, Jyoti Parikh, Peter Parker, Charles M. Perou, Rebecca Roylance, Vandna Shah, Adam Shaw, Ian E. Smith, Kirsten M. Timms, Andrew M. Wardley, Gregory Wilson, Cheryl Gillett, Jerry S. Lanchbury, Alan Ashworth, Nazneen Rahman, Mark Harries, Paul Ellis, Sarah E. Pinder, Judith M. Bliss

    Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative ‘BRCAness’ subgroups—tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes—may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker–treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection.

    更新日期:2018-04-30
  • Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia
    Nat. Med. (IF 29.886) Pub Date : 2018-04-30
    Joseph A. Fraietta, Simon F. Lacey, Elena J. Orlando, Iulian Pruteanu-Malinici, Mercy Gohil, Stefan Lundh, Alina C. Boesteanu, Yan Wang, Roddy S. O’Connor, Wei-Ting Hwang, Edward Pequignot, David E. Ambrose, Changfeng Zhang, Nicholas Wilcox, Felipe Bedoya, Corin Dorfmeier, Fang Chen, Lifeng Tian, Harit Parakandi, Minnal Gupta, Regina M. Young, F. Brad Johnson, Irina Kulikovskaya, Li Liu, Jun Xu, Sadik H. Kassim, Megan M. Davis, Bruce L. Levine, Noelle V. Frey, Donald L. Siegel, Alexander C. Huang, E. John Wherry, Hans Bitter, Jennifer L. Brogdon, David L. Porter, Carl H. June, J. Joseph Melenhorst

    Tolerance to self-antigens prevents the elimination of cancer by the immune system1,2. We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cells from complete-responding patients with CLL were enriched in memory-related genes, including IL-6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27+CD45RO–CD8+ T cells before CAR T cell generation, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cells from patients produced STAT3-related cytokines, and serum IL-6 correlated with CAR T cell expansion. IL-6/STAT3 blockade diminished CAR T cell proliferation. Furthermore, a mechanistically relevant population of CD27+PD-1–CD8+ CAR T cells expressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cell biology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies.

    更新日期:2018-04-30
  • Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes
    Nat. Med. (IF 29.886) Pub Date : 2018-04-30
    Bjoern Chapuy, Chip Stewart, Andrew J. Dunford, Jaegil Kim, Atanas Kamburov, Robert A. Redd, Mike S. Lawrence, Margaretha G. M. Roemer, Amy J. Li, Marita Ziepert, Annette M. Staiger, Jeremiah A. Wala, Matthew D. Ducar, Ignaty Leshchiner, Ester Rheinbay, Amaro Taylor-Weiner, Caroline A. Coughlin, Julian M. Hess, Chandra S. Pedamallu, Dimitri Livitz, Daniel Rosebrock, Mara Rosenberg, Adam A. Tracy, Heike Horn, Paul van Hummelen, Andrew L. Feldman, Brian K. Link, Anne J. Novak, James R. Cerhan, Thomas M. Habermann, Reiner Siebert, Andreas Rosenwald, Aaron R. Thorner, Matthew L. Meyerson, Todd R. Golub, Rameen Beroukhim, Gerald G. Wulf, German Ott, Scott J. Rodig, Stefano Monti, Donna S. Neuberg, Markus Loeffler, Michael Pfreundschuh, Lorenz Trümper, Gad Getz, Margaret A. Shipp

    Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.

    更新日期:2018-04-30
  • Transcript-indexed ATAC-seq for precision immune profiling
    Nat. Med. (IF 29.886) Pub Date : 2018-04-23
    Ansuman T. Satpathy, Naresha Saligrama, Jason D. Buenrostro, Yuning Wei, Beijing Wu, Adam J. Rubin, Jeffrey M. Granja, Caleb A. Lareau, Rui Li, Yanyan Qi, Kevin R. Parker, Maxwell R. Mumbach, William S. Serratelli, David G. Gennert, Alicia N. Schep, M. Ryan Corces, Michael S. Khodadoust, Youn H. Kim, Paul A. Khavari, William J. Greenleaf, Mark M. Davis, Howard Y. Chang

    T cells create vast amounts of diversity in the genes that encode their T cell receptors (TCRs), which enables individual clones to recognize specific peptide–major histocompatibility complex (MHC) ligands. Here we combined sequencing of the TCR-encoding genes with assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis at the single-cell level to provide information on the TCR specificity and epigenomic state of individual T cells. By using this approach, termed transcript-indexed ATAC-seq (T-ATAC-seq), we identified epigenomic signatures in immortalized leukemic T cells, primary human T cells from healthy volunteers and primary leukemic T cells from patient samples. In peripheral blood CD4+ T cells from healthy individuals, we identified cis and trans regulators of naive and memory T cell states and found substantial heterogeneity in surface-marker-defined T cell populations. In patients with a leukemic form of cutaneous T cell lymphoma, T-ATAC-seq enabled identification of leukemic and nonleukemic regulatory pathways in T cells from the same individual by allowing separation of the signals that arose from the malignant clone from the background T cell noise. Thus, T-ATAC-seq is a new tool that enables analysis of epigenomic landscapes in clonal T cells and should be valuable for studies of T cell malignancy, immunity and immunotherapy.

    更新日期:2018-04-23
  • Understanding the tumor immune microenvironment (TIME) for effective therapy
    Nat. Med. (IF 29.886) Pub Date : 2018-04-23
    Mikhail Binnewies, Edward W. Roberts, Kelly Kersten, Vincent Chan, Douglas F. Fearon, Miriam Merad, Lisa M. Coussens, Dmitry I. Gabrilovich, Suzanne Ostrand-Rosenberg, Catherine C. Hedrick, Robert H. Vonderheide, Mikael J. Pittet, Rakesh K. Jain, Weiping Zou, T. Kevin Howcroft, Elisa C. Woodhouse, Robert A. Weinberg, Matthew F. Krummel

    The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient’s tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.

    更新日期:2018-04-23
  • Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer
    Nat. Med. (IF 29.886) Pub Date : 2018-04-23
    Jacqulyne P. Robichaux, Yasir Y. Elamin, Zhi Tan, Brett W. Carter, Shuxing Zhang, Shengwu Liu, Shuai Li, Ting Chen, Alissa Poteete, Adriana Estrada-Bernal, Anh T. Le, Anna Truini, Monique B. Nilsson, Huiying Sun, Emily Roarty, Sarah B. Goldberg, Julie R. Brahmer, Mehmet Altan, Charles Lu, Vassiliki Papadimitrakopoulou, Katerina Politi, Robert C. Doebele, Kwok-Kin Wong, John V. Heymach

    Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.

    更新日期:2018-04-23
  • Clonal CD4+ T cells in the HIV-1 latent reservoir display a distinct gene profile upon reactivation
    Nat. Med. (IF 29.886) Pub Date : 2018-04-23
    Lillian B. Cohn, Israel T. da Silva, Renan Valieris, Amy S. Huang, Julio C. C. Lorenzi, Yehuda Z. Cohen, Joy A. Pai, Allison L. Butler, Marina Caskey, Mila Jankovic, Michel C. Nussenzweig

    Despite suppressive combination antiretroviral therapy (ART), latent HIV-1 proviruses persist in patients. This latent reservoir is established within 48–72 h after infection, has a long half-life1,2, enables viral rebound when ART is interrupted, and is the major barrier to a cure for HIV-13. Latent cells are exceedingly rare in blood (∼1 per 1 × 106 CD4+ T cells) and are typically enumerated by indirect means, such as viral outgrowth assays4,5. We report a new strategy to purify and characterize single reactivated latent cells from HIV-1-infected individuals on suppressive ART. Surface expression of viral envelope protein was used to enrich reactivated latent T cells producing HIV RNA, and single-cell analysis was performed to identify intact virus. Reactivated latent cells produce full-length viruses that are identical to those found in viral outgrowth cultures and represent clones of in vivo expanded T cells, as determined by their T cell receptor sequence. Gene-expression analysis revealed that these cells share a transcriptional profile that includes expression of genes implicated in silencing the virus. We conclude that reactivated latent T cells isolated from blood can share a gene-expression program that allows for cell division without activation of the cell death pathways that are normally triggered by HIV-1 replication.

    更新日期:2018-04-23
  • Stimulation of entorhinal cortex–dentate gyrus circuitry is antidepressive
    Nat. Med. (IF 29.886) Pub Date : 2018-04-16
    Sanghee Yun, Ryan P. Reynolds, Iraklis Petrof, Alicia White, Phillip D. Rivera, Amir Segev, Adam D. Gibson, Maiko Suarez, Matthew J. DeSalle, Naoki Ito, Shibani Mukherjee, Devon R. Richardson, Catherine E. Kang, Rebecca C. Ahrens-Nicklas, Ivan Soler, Dane M. Chetkovich, Saïd Kourrich, Douglas A. Coulter, Amelia J. Eisch

    Major depressive disorder (MDD) is considered a ‘circuitopathy’, and brain stimulation therapies hold promise for ameliorating MDD symptoms, including hippocampal dysfunction. It is unknown whether stimulation of upstream hippocampal circuitry, such as the entorhinal cortex (Ent), is antidepressive, although Ent stimulation improves learning and memory in mice and humans. Here we show that molecular targeting (Ent-specific knockdown of a psychosocial stress-induced protein) and chemogenetic stimulation of Ent neurons induce antidepressive-like effects in mice. Mechanistically, we show that Ent-stimulation-induced antidepressive-like behavior relies on the generation of new hippocampal neurons. Thus, controlled stimulation of Ent hippocampal afferents is antidepressive via increased hippocampal neurogenesis. These findings emphasize the power and potential of Ent glutamatergic afferent stimulation—previously well-known for its ability to influence learning and memory—for MDD treatment.

    更新日期:2018-04-16
  • Targeting sphingosine-1-phosphate lyase as an anabolic therapy for bone loss
    Nat. Med. (IF 29.886) Pub Date : 2018-04-16
    Sarah Weske, Mithila Vaidya, Alina Reese, Karin von Wnuck Lipinski, Petra Keul, Julia K Bayer, Jens W Fischer, Ulrich Flögel, Jens Nelsen, Matthias Epple, Marta Scatena, Edzard Schwedhelm, Marcus Dörr, Henry Völzke, Eileen Moritz, Anke Hannemann, Bernhard H Rauch, Markus H Gräler, Gerd Heusch, Bodo Levkau

    Sphingosine-1-phosphate (S1P) signaling influences bone metabolism, but its therapeutic potential in bone disorders has remained unexplored. We show that raising S1P levels in adult mice through conditionally deleting or pharmacologically inhibiting S1P lyase, the sole enzyme responsible for irreversibly degrading S1P, markedly increased bone formation, mass and strength and substantially decreased white adipose tissue. S1P signaling through S1P2 potently stimulated osteoblastogenesis at the expense of adipogenesis by inversely regulating osterix and PPAR-γ, and it simultaneously inhibited osteoclastogenesis by inducing osteoprotegerin through newly discovered p38–GSK3β–β-catenin and WNT5A–LRP5 pathways. Accordingly, S1P2-deficient mice were osteopenic and obese. In ovariectomy-induced osteopenia, S1P lyase inhibition was as effective as intermittent parathyroid hormone (iPTH) treatment in increasing bone mass and was superior to iPTH in enhancing bone strength. Furthermore, lyase inhibition in mice successfully corrected severe genetic osteoporosis caused by osteoprotegerin deficiency. Human data from 4,091 participants of the SHIP-Trend population-based study revealed a positive association between serum levels of S1P and bone formation markers, but not resorption markers. Furthermore, serum S1P levels were positively associated with serum calcium , negatively with PTH , and curvilinearly with body mass index. Bone stiffness, as determined through quantitative ultrasound, was inversely related to levels of both S1P and the bone formation marker PINP, suggesting that S1P stimulates osteoanabolic activity to counteract decreasing bone quality. S1P-based drugs should be considered as a promising therapeutic avenue for the treatment of osteoporotic diseases.

    更新日期:2018-04-16
  • Differential glucose requirement in skin homeostasis and injury identifies a therapeutic target for psoriasis
    Nat. Med. (IF 29.886) Pub Date : 2018-04-16
    Zhuzhen Zhang, Zhenzhen Zi, Eunice E. Lee, Jiawei Zhao, Diana C. Contreras, Andrew P. South, E. Dale Abel, Benjamin F. Chong, Travis Vandergriff, Gregory A. Hosler, Philipp E. Scherer, Marcel Mettlen, Jeffrey C. Rathmell, Ralph J. DeBerardinis, Richard C. Wang

    Proliferating cells, compared with quiescent cells, are more dependent on glucose for their growth. Although glucose transport in keratinocytes is mediated largely by the Glut1 facilitative transporter, we found that keratinocyte-specific ablation of Glut1 did not compromise mouse skin development and homeostasis. Ex vivo metabolic profiling revealed altered sphingolipid, hexose, amino acid, and nucleotide metabolism in Glut1-deficient keratinocytes, thus suggesting metabolic adaptation. However, cultured Glut1-deficient keratinocytes displayed metabolic and oxidative stress and impaired proliferation. Similarly, Glut1 deficiency impaired in vivo keratinocyte proliferation and migration within wounded or UV-damaged mouse skin. Notably, both genetic and pharmacological Glut1 inactivation decreased hyperplasia in mouse models of psoriasis-like disease. Topical application of a Glut1 inhibitor also decreased inflammation in these models. Glut1 inhibition decreased the expression of pathology-associated genes in human psoriatic skin organoids. Thus, Glut1 is selectively required for injury- and inflammation-associated keratinocyte proliferation, and its inhibition offers a novel treatment strategy for psoriasis.

    更新日期:2018-04-16
  • A single injection of crystallizable fragment domain–modified antibodies elicits durable protection from SHIV infection
    Nat. Med. (IF 29.886) Pub Date : 2018-04-16
    Rajeev Gautam, Yoshiaki Nishimura, Natalie Gaughan, Anna Gazumyan, Till Schoofs, Alicia Buckler-White, Michael S. Seaman, Bruce J. Swihart, Dean A. Follmann, Michel C. Nussenzweig, Malcolm A. Martin

    In the absence of an effective and safe vaccine against HIV-1, the administration of broadly neutralizing antibodies (bNAbs) represents a logical alternative approach to prevent virus transmission. Here, we introduced two mutations encoding amino acid substitutions (M428L and N434S, collectively referred to as ‘LS’) into the genes encoding the crystallizable fragment domains of the highly potent HIV-specific 3BNC117 and 10-1074 bNAbs to increase their half-lives and evaluated their efficacy in blocking infection following repeated low-dose mucosal challenges of rhesus macaques (Macaca mulatta) with the tier 2 SHIVAD8-EO. A single intravenous infusion of 10-1074-LS monoclonal antibodies markedly delayed virus acquisition for 18 to 37 weeks (median, 27 weeks), whereas the protective effect of the 3BNC117-LS bNAb was more modest (provided protection for 11–23 weeks; median, 17 weeks). Serum concentrations of the 10-1074-LS monoclonal antibody gradually declined and became undetectable in all recipients between weeks 26 and 41, whereas the 3BNC117-LS bNAb exhibited a shorter half-life. To model immunoprophylaxis against genetically diverse and/or neutralization-resistant HIV-1 strains, a combination of the 3BNC117-LS plus 10-1074-LS monoclonal antibodies was injected into macaques via the more clinically relevant subcutaneous route. Even though the administered mixture contained an amount of each bNAb that was nearly threefold less than the quantity of the single monoclonal antibody in the intravenous injections, the monoclonal antibody combination still protected macaques for a median of 20 weeks. The extended period of protection observed in macaques for the 3BNC117-LS plus 10-1074-LS combination could translate into an effective semiannual or annual immunoprophylaxis regimen for preventing HIV-1 infections in humans.

    更新日期:2018-04-16
  • Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas
    Nat. Med. (IF 29.886) Pub Date : 2018-04-16
    Christopher W. Mount, Robbie G. Majzner, Shree Sundaresh, Evan P. Arnold, Meena Kadapakkam, Samuel Haile, Louai Labanieh, Esther Hulleman, Pamelyn J. Woo, Skyler P. Rietberg, Hannes Vogel, Michelle Monje, Crystal L. Mackall

    Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1,2,3,4,5 are aggressive and universally fatal pediatric brain cancers6. Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7,8,9,10, and recent results suggest benefit in central nervous system malignancies11,12,13. Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2. Anti-GD2 CAR T cells incorporating a 4-1BBz costimulatory domain14 demonstrated robust antigen-dependent cytokine generation and killing of DMG cells in vitro. In five independent patient-derived H3-K27M+ DMG orthotopic xenograft models, systemic administration of GD2-targeted CAR T cells cleared engrafted tumors except for a small number of residual GD2lo glioma cells. To date, GD2-targeted CAR T cells have been well tolerated in clinical trials15,16,17. Although GD2-targeted CAR T cell administration was tolerated in the majority of mice bearing orthotopic xenografts, peritumoral neuroinflammation during the acute phase of antitumor activity resulted in hydrocephalus that was lethal in a fraction of animals. Given the precarious neuroanatomical location of midline gliomas, careful monitoring and aggressive neurointensive care management will be required for human translation. With a cautious multidisciplinary clinical approach, GD2-targeted CAR T cell therapy for H3-K27M+ diffuse gliomas of pons, thalamus and spinal cord could prove transformative for these lethal childhood cancers.

    更新日期:2018-04-16
  • Corrigendum: Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury
    Nat. Med. (IF 29.886) Pub Date : 2018-04-10
    Enrico Velardi, Jennifer J Tsai, Stefan Radtke, Kirsten Cooper, Kimon V Argyropoulos, Shieh Jae-Hung, Lauren F Young, Amina Lazrak, Odette M Smith, Sophie Lieberman, Fabiana Kreines, Yusuke Shono, Tobias Wertheimer, Robert R Jenq, Alan M Hanash, Prema Narayan, Zhenmin Lei, Malcolm A Moore, Hans-Peter Kiem, Marcel R M van den Brink, Jarrod A Dudakov

    Corrigendum: Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury Corrigendum: Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury, Published online: 10 April 2018; doi:10.1038/nm0418-525b Corrigendum: Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury

    更新日期:2018-04-11
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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