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  • Granulocyte-derived TNFα promotes vascular and hematopoietic regeneration in the bone marrow
    Nat. Med. (IF 29.886) Pub Date : 2017-11-20
    Emily Bowers, Anastasiya Slaughter, Paul S Frenette, Rork Kuick, Oscar M Pello, Daniel Lucas

    Granulocyte-derived TNFα promotes vascular and hematopoietic regeneration in the bone marrow Granulocyte-derived TNFα promotes vascular and hematopoietic regeneration in the bone marrow, Published online: 20 November 2017; doi:10.1038/nm.4448 In the bone marrow, granulocyte-derived TNFα acts on endothelial cells to maintain the vasculature under steady-state conditions and to promote its regeneration after injury or transplantation.

    更新日期:2017-11-21
  • CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy
    Nat. Med. (IF 29.886) Pub Date : 2017-11-20
    Terry J Fry, Nirali N Shah, Rimas J Orentas, Maryalice Stetler-Stevenson, Constance M Yuan, Sneha Ramakrishna, Pamela Wolters, Staci Martin, Cindy Delbrook, Bonnie Yates, Haneen Shalabi, Thomas J Fountaine, Jack F Shern, Robbie G Majzner, David F Stroncek, Marianna Sabatino, Yang Feng, Dimiter S Dimitrov, Ling Zhang, Sang Nguyen, Haiying Qin, Boro Dropulic, Daniel W Lee, Crystal L Mackall

    CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy, Published online: 20 November 2017; doi:10.1038/nm.4441 Fry et al. report the first results from a human trial of a CD22-directed chimeric antigen receptor (CAR) T cell therapy providing evidence of efficacy in the treatment of pre–B cell acute lymphoblastic leukemia that is immunotherapy-naive or resistant to CD19-directed CAR T cells.

    更新日期:2017-11-21
  • Granulocyte-derived TNFα promotes vascular and hematopoietic regeneration in the bone marrow
    Nat. Med. (IF 29.886) Pub Date : 2017-11-20
    Emily Bowers, Anastasiya Slaughter, Paul S Frenette, Rork Kuick, Oscar M Pello, Daniel Lucas

    Granulocyte-derived TNFα promotes vascular and hematopoietic regeneration in the bone marrow Granulocyte-derived TNFα promotes vascular and hematopoietic regeneration in the bone marrow, Published online: 20 November 2017; doi:10.1038/nm.4448 In the bone marrow, granulocyte-derived TNFα acts on endothelial cells to maintain the vasculature under steady-state conditions and to promote its regeneration after injury or transplantation.

    更新日期:2017-11-21
  • CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy
    Nat. Med. (IF 29.886) Pub Date : 2017-11-20
    Terry J Fry, Nirali N Shah, Rimas J Orentas, Maryalice Stetler-Stevenson, Constance M Yuan, Sneha Ramakrishna, Pamela Wolters, Staci Martin, Cindy Delbrook, Bonnie Yates, Haneen Shalabi, Thomas J Fountaine, Jack F Shern, Robbie G Majzner, David F Stroncek, Marianna Sabatino, Yang Feng, Dimiter S Dimitrov, Ling Zhang, Sang Nguyen, Haiying Qin, Boro Dropulic, Daniel W Lee, Crystal L Mackall

    CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy, Published online: 20 November 2017; doi:10.1038/nm.4441 Fry et al. report the first results from a human trial of a CD22-directed chimeric antigen receptor (CAR) T cell therapy providing evidence of efficacy in the treatment of pre–B cell acute lymphoblastic leukemia that is immunotherapy-naive or resistant to CD19-directed CAR T cells.

    更新日期:2017-11-21
  • Human primary liver cancer–derived organoid cultures for disease modeling and drug screening
    Nat. Med. (IF 29.886) Pub Date : 2017-11-13
    Laura Broutier, Gianmarco Mastrogiovanni, Monique MA Verstegen, Hayley E Francies, Lena Morrill Gavarró, Charles R Bradshaw, George E Allen, Robert Arnes-Benito, Olga Sidorova, Marcia P Gaspersz, Nikitas Georgakopoulos, Bon-Kyoung Koo, Sabine Dietmann, Susan E Davies, Raaj K Praseedom, Ruby Lieshout, Jan N M IJzermans, Stephen J Wigmore, Kourosh Saeb-Parsy, Mathew J Garnett, Luc JW van der Laan, Meritxell Huch

    Human primary liver cancer–derived organoid cultures for disease modeling and drug screening Human primary liver cancer–derived organoid cultures for disease modeling and drug screening, Published online: 13 November 2017; doi:10.1038/nm.4438 NatureArticleSnippet(type=short-summary, markup= Tumor organoids derived from the most common subtypes of primary liver cancer recapitulate the histologic and molecular features of the tissues of origin, even after long-term culture. These in vitro models, as well as those for colorectal cancer reported in Crespo et al. in a previous issue, are amenable for drug screening and allow the identification of therapeutic approaches with potential for cancer treatment. , isJats=true)

    更新日期:2017-11-13
  • Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies
    Nat. Med. (IF 29.886) Pub Date : 2017-11-13
    Paul M Maciocia, Patrycja A Wawrzyniecka, Brian Philip, Ida Ricciardelli, Ayse U Akarca, Shimobi C Onuoha, Mateusz Legut, David K Cole, Andrew K Sewell, Giuseppe Gritti, Joan Somja, Miguel A Piris, Karl S Peggs, David C Linch, Teresa Marafioti, Martin A Pule

    Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies, Published online: 13 November 2017; doi:10.1038/nm.4444 NatureArticleSnippet(type=short-summary, markup= Pule and colleagues identify the TCR β-chain constant region as a new target for chimeric antigen receptor (CAR) T cells in treatment of T cell cancers while potentially preserving a healthy T cell repertoire. They demonstrate that anti-TCRB1 CAR T cells eliminate cancerous TCRB1+ T cells while sparing nearly one-third of normal TCRB2+ T cells. , isJats=true)

    更新日期:2017-11-13
  • UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis
    Nat. Med. (IF 29.886) Pub Date : 2017-11-13
    Kenji Ikeda, Qianqian Kang, Takeshi Yoneshiro, Joao Paulo Camporez, Hiroko Maki, Mayu Homma, Kosaku Shinoda, Yong Chen, Xiaodan Lu, Pema Maretich, Kazuki Tajima, Kolapo M Ajuwon, Tomoyoshi Soga, Shingo Kajimura

    UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis, Published online: 13 November 2017; doi:10.1038/nm.4429 NatureArticleSnippet(type=short-summary, markup= Calcium cycling induced by the SERCA2b–RyR2 pathway in beige fat cells allows for thermogenic activity independent of UCP1. , isJats=true)

    更新日期:2017-11-13
  • Enhancing the precision of genetic lineage tracing using dual recombinases
    Nat. Med. (IF 29.886) Pub Date : 2017-11-13
    Lingjuan He, Yan Li, Yi Li, Wenjuan Pu, Xiuzhen Huang, Xueying Tian, Yue Wang, Hui Zhang, Qiaozhen Liu, Libo Zhang, Huan Zhao, Juan Tang, Hongbin Ji, Dongqing Cai, Zhibo Han, Zhongchao Han, Yu Nie, Shengshou Hu, Qing-Dong Wang, Ruilin Sun, Jian Fei, Fengchao Wang, Ting Chen, Yan Yan, Hefeng Huang, William T Pu, Bin Zhou

    Enhancing the precision of genetic lineage tracing using dual recombinases Enhancing the precision of genetic lineage tracing using dual recombinases, Published online: 13 November 2017; doi:10.1038/nm.4437 NatureArticleSnippet(type=short-summary, markup= Genetic cell-lineage tracing studies in mice are crucial for delineating the contribution of stem and progenitor cells to different cell types, both in disease states and after regenerative therapy. He et al. have developed new genetic lineage-tracing systems that provide more definitive results than the commonly used Cre-based system and show that this new technology can resolve current controversies in the field, as demonstrated by lineage-tracing studies in the heart and liver. , isJats=true)

    更新日期:2017-11-13
  • Human primary liver cancer–derived organoid cultures for disease modeling and drug screening
    Nat. Med. (IF 29.886) Pub Date : 
    Laura Broutier, Gianmarco Mastrogiovanni, Monique MA Verstegen, Hayley E Francies, Lena Morrill Gavarró, Charles R Bradshaw, George E Allen, Robert Arnes-Benito, Olga Sidorova, Marcia P Gaspersz, Nikitas Georgakopoulos, Bon-Kyoung Koo, Sabine Dietmann, Susan E Davies, Raaj K Praseedom, Ruby Lieshout, Jan N M IJzermans, Stephen J Wigmore, Kourosh Saeb-Parsy, Mathew J Garnett, Luc JW van der Laan, Meritxell Huch

    Human primary liver cancer–derived organoid cultures for disease modeling and drug screening Human primary liver cancer–derived organoid cultures for disease modeling and drug screening, Published online: 13 November 2017; doi:10.1038/nm.4438 NatureArticleSnippet(type=short-summary, markup= Tumor organoids derived from the most common subtypes of primary liver cancer recapitulate the histologic and molecular features of the tissues of origin, even after long-term culture. These in vitro models, as well as those for colorectal cancer reported in Crespo et al. in a previous issue, are amenable for drug screening and allow the identification of therapeutic approaches with potential for cancer treatment. , isJats=true)

    更新日期:2017-11-13
  • Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies
    Nat. Med. (IF 29.886) Pub Date : 
    Paul M Maciocia, Patrycja A Wawrzyniecka, Brian Philip, Ida Ricciardelli, Ayse U Akarca, Shimobi C Onuoha, Mateusz Legut, David K Cole, Andrew K Sewell, Giuseppe Gritti, Joan Somja, Miguel A Piris, Karl S Peggs, David C Linch, Teresa Marafioti, Martin A Pule

    Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies, Published online: 13 November 2017; doi:10.1038/nm.4444 NatureArticleSnippet(type=short-summary, markup= Pule and colleagues identify the TCR β-chain constant region as a new target for chimeric antigen receptor (CAR) T cells in treatment of T cell cancers while potentially preserving a healthy T cell repertoire. They demonstrate that anti-TCRB1 CAR T cells eliminate cancerous TCRB1+ T cells while sparing nearly one-third of normal TCRB2+ T cells. , isJats=true)

    更新日期:2017-11-13
  • UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis
    Nat. Med. (IF 29.886) Pub Date : 
    Kenji Ikeda, Qianqian Kang, Takeshi Yoneshiro, Joao Paulo Camporez, Hiroko Maki, Mayu Homma, Kosaku Shinoda, Yong Chen, Xiaodan Lu, Pema Maretich, Kazuki Tajima, Kolapo M Ajuwon, Tomoyoshi Soga, Shingo Kajimura

    UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis, Published online: 13 November 2017; doi:10.1038/nm.4429 NatureArticleSnippet(type=short-summary, markup= Calcium cycling induced by the SERCA2b–RyR2 pathway in beige fat cells allows for thermogenic activity independent of UCP1. , isJats=true)

    更新日期:2017-11-13
  • Enhancing the precision of genetic lineage tracing using dual recombinases
    Nat. Med. (IF 29.886) Pub Date : 
    Lingjuan He, Yan Li, Yi Li, Wenjuan Pu, Xiuzhen Huang, Xueying Tian, Yue Wang, Hui Zhang, Qiaozhen Liu, Libo Zhang, Huan Zhao, Juan Tang, Hongbin Ji, Dongqing Cai, Zhibo Han, Zhongchao Han, Yu Nie, Shengshou Hu, Qing-Dong Wang, Ruilin Sun, Jian Fei, Fengchao Wang, Ting Chen, Yan Yan, Hefeng Huang, William T Pu, Bin Zhou

    Enhancing the precision of genetic lineage tracing using dual recombinases Enhancing the precision of genetic lineage tracing using dual recombinases, Published online: 13 November 2017; doi:10.1038/nm.4437 NatureArticleSnippet(type=short-summary, markup= Genetic cell-lineage tracing studies in mice are crucial for delineating the contribution of stem and progenitor cells to different cell types, both in disease states and after regenerative therapy. He et al. have developed new genetic lineage-tracing systems that provide more definitive results than the commonly used Cre-based system and show that this new technology can resolve current controversies in the field, as demonstrated by lineage-tracing studies in the heart and liver. , isJats=true)

    更新日期:2017-11-13
  • Corrigendum: Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    Marie Toussaint, David J Jackson, Dawid Swieboda, Anabel Guedán, Theodora-Dorita Tsourouktsoglou, Yee Man Ching, Coraline Radermecker, Heidi Makrinioti, Julia Aniscenko, Michael R Edwards, Roberto Solari, Frédéric Farnir, Venizelos Papayannopoulos, Fabrice Bureau, Thomas Marichal, Sebastian L Johnston

    Corrigendum: Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation Corrigendum: Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation, Published online: 07 November 2017; doi:10.1038/nm1117-1384a

    更新日期:2017-11-08
  • Corrigendum: Targeting cellular senescence prevents age-related bone loss in mice
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    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

    Corrigendum: Targeting cellular senescence prevents age-related bone loss in mice Corrigendum: Targeting cellular senescence prevents age-related bone loss in mice, Published online: 07 November 2017; doi:10.1038/nm1117-1384c

    更新日期:2017-11-08
  • Barrier-tissue macrophages: functional adaptation to environmental challenges
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    Allan McI Mowat, Charlotte L Scott, Calum C Bain

    Barrier-tissue macrophages: functional adaptation to environmental challenges Barrier-tissue macrophages: functional adaptation to environmental challenges, Published online: 07 November 2017; doi:10.1038/nm.4430 NatureArticleSnippet(type=short-summary, markup= Mowat, Scott and Bain discuss the functions of barrier-tissue macrophages in homeostasis and disease, and how these are shaped by their local environment. , isJats=true)

    更新日期:2017-11-08
  • Can NK cells purge HIV sanctuaries?
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    Madeleine J Bunders, Marcus Altfeld

    Can NK cells purge HIV sanctuaries? Can NK cells purge HIV sanctuaries?, Published online: 07 November 2017; doi:10.1038/nm.4434 NatureArticleSnippet(type=standfirst, markup= A recent study identifies a population of CXCR5+ natural killer (NK) cells patrolling B cell follicles in simian immunodeficiency virus (SIV)-infected African green monkeys that might contribute to the lack of disease progression in this nonpathogenic model. , isJats=true)

    更新日期:2017-11-08
  • Long-range hypoxia signaling in NAFLD
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    Edward L LaGory, Amato J Giaccia

    Long-range hypoxia signaling in NAFLD Long-range hypoxia signaling in NAFLD, Published online: 07 November 2017; doi:10.1038/nm.4436 NatureArticleSnippet(type=standfirst, markup= A recent study describes a role for hypoxic signaling in the small intestine in the etiology of nonalcoholic fatty liver disease (NAFLD) and suggests that HIF-2α inhibitors may be an effective option for the treatment of this disease. , isJats=true)

    更新日期:2017-11-08
  • Macrophages dispose of catecholamines in adipose tissue
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    Michael P Czech

    Macrophages dispose of catecholamines in adipose tissue Macrophages dispose of catecholamines in adipose tissue, Published online: 07 November 2017; doi:10.1038/nm.4440 NatureArticleSnippet(type=standfirst, markup= Recent research has identified sympathetic neuron–associated macrophages in adipose tissue that take up and degrade catecholamines released from neurons. Obesity and aging enhance this system, decreasing responses to cold stress and starvation. , isJats=true)

    更新日期:2017-11-08
  • Predictable response: Finding optimal drugs and doses using artificial intelligence
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    Shraddha Chakradhar

    Predictable response: Finding optimal drugs and doses using artificial intelligence Predictable response: Finding optimal drugs and doses using artificial intelligence, Published online: 07 November 2017; doi:10.1038/nm1117-1244

    更新日期:2017-11-08
  • Stalking new vaccines: Methods that target the stems of viral proteins could put universal vaccines within reach
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    Carrie Arnold

    Stalking new vaccines: Methods that target the stems of viral proteins could put universal vaccines within reach Stalking new vaccines: Methods that target the stems of viral proteins could put universal vaccines within reach, Published online: 07 November 2017; doi:10.1038/nm1117-1248

    更新日期:2017-11-08
  • Corrigendum: Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    Marie Toussaint, David J Jackson, Dawid Swieboda, Anabel Guedán, Theodora-Dorita Tsourouktsoglou, Yee Man Ching, Coraline Radermecker, Heidi Makrinioti, Julia Aniscenko, Michael R Edwards, Roberto Solari, Frédéric Farnir, Venizelos Papayannopoulos, Fabrice Bureau, Thomas Marichal, Sebastian L Johnston

    Corrigendum: Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation Corrigendum: Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation, Published online: 07 November 2017; doi:10.1038/nm1117-1384a

    更新日期:2017-11-08
  • Corrigendum: Targeting cellular senescence prevents age-related bone loss in mice
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    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

    Corrigendum: Targeting cellular senescence prevents age-related bone loss in mice Corrigendum: Targeting cellular senescence prevents age-related bone loss in mice, Published online: 07 November 2017; doi:10.1038/nm1117-1384c

    更新日期:2017-11-08
  • Barrier-tissue macrophages: functional adaptation to environmental challenges
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    Allan McI Mowat, Charlotte L Scott, Calum C Bain

    Barrier-tissue macrophages: functional adaptation to environmental challenges Barrier-tissue macrophages: functional adaptation to environmental challenges, Published online: 07 November 2017; doi:10.1038/nm.4430 NatureArticleSnippet(type=short-summary, markup= Mowat, Scott and Bain discuss the functions of barrier-tissue macrophages in homeostasis and disease, and how these are shaped by their local environment. , isJats=true)

    更新日期:2017-11-08
  • Can NK cells purge HIV sanctuaries?
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    Madeleine J Bunders, Marcus Altfeld

    Can NK cells purge HIV sanctuaries? Can NK cells purge HIV sanctuaries?, Published online: 07 November 2017; doi:10.1038/nm.4434 NatureArticleSnippet(type=standfirst, markup= A recent study identifies a population of CXCR5+ natural killer (NK) cells patrolling B cell follicles in simian immunodeficiency virus (SIV)-infected African green monkeys that might contribute to the lack of disease progression in this nonpathogenic model. , isJats=true)

    更新日期:2017-11-08
  • Long-range hypoxia signaling in NAFLD
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    Edward L LaGory, Amato J Giaccia

    Long-range hypoxia signaling in NAFLD Long-range hypoxia signaling in NAFLD, Published online: 07 November 2017; doi:10.1038/nm.4436 NatureArticleSnippet(type=standfirst, markup= A recent study describes a role for hypoxic signaling in the small intestine in the etiology of nonalcoholic fatty liver disease (NAFLD) and suggests that HIF-2α inhibitors may be an effective option for the treatment of this disease. , isJats=true)

    更新日期:2017-11-08
  • Macrophages dispose of catecholamines in adipose tissue
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    Michael P Czech

    Macrophages dispose of catecholamines in adipose tissue Macrophages dispose of catecholamines in adipose tissue, Published online: 07 November 2017; doi:10.1038/nm.4440 NatureArticleSnippet(type=standfirst, markup= Recent research has identified sympathetic neuron–associated macrophages in adipose tissue that take up and degrade catecholamines released from neurons. Obesity and aging enhance this system, decreasing responses to cold stress and starvation. , isJats=true)

    更新日期:2017-11-08
  • Predictable response: Finding optimal drugs and doses using artificial intelligence
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    Shraddha Chakradhar

    Predictable response: Finding optimal drugs and doses using artificial intelligence Predictable response: Finding optimal drugs and doses using artificial intelligence, Published online: 07 November 2017; doi:10.1038/nm1117-1244

    更新日期:2017-11-08
  • Stalking new vaccines: Methods that target the stems of viral proteins could put universal vaccines within reach
    Nat. Med. (IF 29.886) Pub Date : 2017-11-07
    Carrie Arnold

    Stalking new vaccines: Methods that target the stems of viral proteins could put universal vaccines within reach Stalking new vaccines: Methods that target the stems of viral proteins could put universal vaccines within reach, Published online: 07 November 2017; doi:10.1038/nm1117-1248

    更新日期:2017-11-08
  • A microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscle
    Nat. Med. (IF 29.886) Pub Date : 2017-11-06
    Motoharu Awazawa, Paula Gabel, Eva Tsaousidou, Hendrik Nolte, Marcus Krüger, Joel Schmitz, P Justus Ackermann, Claus Brandt, Janine Altmüller, Susanne Motameny, F Thomas Wunderlich, Jan-Wilhelm Kornfeld, Matthias Blüher, Jens C Brüning

    A microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscleA microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscle, Published online: 06 November 2017; doi:10.1038/nm.4420NatureArticleSnippet(type=short-summary, markup=Screening reveals that obesity induces the expression of liver ectodysplasin A, which acts on the muscle to induce insulin resistance., isJats=true)

    更新日期:2017-11-06
  • IRF3 and type I interferons fuel a fatal response to myocardial infarction
    Nat. Med. (IF 29.886) Pub Date : 2017-11-06
    Kevin R King, Aaron D Aguirre, Yu-Xiang Ye, Yuan Sun, Jason D Roh, Richard P Ng Jr, Rainer H Kohler, Sean P Arlauckas, Yoshiko Iwamoto, Andrej Savol, Ruslan I Sadreyev, Mark Kelly, Timothy P Fitzgibbons, Katherine A Fitzgerald, Timothy Mitchison, Peter Libby, Matthias Nahrendorf, Ralph Weissleder

    IRF3 and type I interferons fuel a fatal response to myocardial infarctionIRF3 and type I interferons fuel a fatal response to myocardial infarction, Published online: 06 November 2017; doi:10.1038/nm.4428NatureArticleSnippet(type=short-summary, markup=The massive cell death that occurs during myocardial infarction releases self-DNA and triggers an interferon response in infiltrating leukocytes via a cGAS–STING–IRF3 pathway. Interference with this response—either by genetic disruption of the pathway or antibody blockade of the type I interferon receptor—is beneficial in mice subjected to myocardial infarction., isJats=true)

    更新日期:2017-11-06
  • Asprosin is a centrally acting orexigenic hormone
    Nat. Med. (IF 29.886) Pub Date : 2017-11-06
    Clemens Duerrschmid, Yanlin He, Chunmei Wang, Chia Li, Juan C Bournat, Chase Romere, Pradip K Saha, Mark E Lee, Kevin J Phillips, Mahim Jain, Peilin Jia, Zhongming Zhao, Monica Farias, Qi Wu, Dianna M Milewicz, V Reid Sutton, David D Moore, Nancy F Butte, Michael J Krashes, Yong Xu, Atul R Chopra

    Asprosin is a centrally acting orexigenic hormoneAsprosin is a centrally acting orexigenic hormone, Published online: 06 November 2017; doi:10.1038/nm.4432NatureArticleSnippet(type=short-summary, markup=Asprosin, a recently identified secreted hormone from adipose tissue, acts centrally to promote food intake., isJats=true)

    更新日期:2017-11-06
  • The activated conformation of integrin β7 is a novel multiple myeloma–specific target for CAR T cell therapy
    Nat. Med. (IF 29.886) Pub Date : 2017-11-06
    Naoki Hosen, Yukiko Matsunaga, Kana Hasegawa, Hiroshi Matsuno, Yuki Nakamura, Mio Makita, Kouki Watanabe, Mikako Yoshida, Kei Satoh, Soyoko Morimoto, Fumihiro Fujiki, Hiroko Nakajima, Jun Nakata, Sumiyuki Nishida, Akihiro Tsuboi, Yoshihiro Oka, Masahiro Manabe, Hiroyoshi Ichihara, Yasutaka Aoyama, Atsuko Mugitani, Takafumi Nakao, Masayuki Hino, Ryosuke Uchibori, Keiya Ozawa, Yoshihiro Baba, Seitaro Terakura, Naoki Wada, Eiichi Morii, Junichi Nishimura, Kiyoshi Takeda, Yusuke Oji, Haruo Sugiyama, Junichi Takagi, Atsushi Kumanogoh

    The activated conformation of integrin β7 is a novel multiple myeloma–specific target for CAR T cell therapyThe activated conformation of integrin β<sub>7</sub> is a novel multiple myeloma–specific target for CAR T cell therapy, Published online: 06 November 2017; doi:10.1038/nm.4431NatureArticleSnippet(type=short-summary, markup=Hosen et al. identify an active conformation of integrin beta-7 as a cancer-associated antigen in multiple myeloma, and engineer a CAR-T cell that shows efficacy against MM in a mouse model. These findings describe the first conformation-specific CAR-T cell and highlight the potential of conformational targets in cancer immunotherapy., isJats=true)

    更新日期:2017-11-06
  • Selective neuronal lapses precede human cognitive lapses following sleep deprivation
    Nat. Med. (IF 29.886) Pub Date : 2017-11-06
    Yuval Nir, Thomas Andrillon, Amit Marmelshtein, Nanthia Suthana, Chiara Cirelli, Giulio Tononi, Itzhak Fried

    Selective neuronal lapses precede human cognitive lapses following sleep deprivationSelective neuronal lapses precede human cognitive lapses following sleep deprivation, Published online: 06 November 2017; doi:10.1038/nm.4433NatureArticleSnippet(type=short-summary, markup=In humans, a full night of sleep deprivation causes attenuated and delayed neuronal responses that correlate with impaired cognitive performance., isJats=true)

    更新日期:2017-11-06
  • A microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscle
    Nat. Med. (IF 29.886) Pub Date : 2017-11-06
    Motoharu Awazawa, Paula Gabel, Eva Tsaousidou, Hendrik Nolte, Marcus Krüger, Joel Schmitz, P Justus Ackermann, Claus Brandt, Janine Altmüller, Susanne Motameny, F Thomas Wunderlich, Jan-Wilhelm Kornfeld, Matthias Blüher, Jens C Brüning

    A microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscleA microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscle, Published online: 06 November 2017; doi:10.1038/nm.4420NatureArticleSnippet(type=short-summary, markup=Screening reveals that obesity induces the expression of liver ectodysplasin A, which acts on the muscle to induce insulin resistance., isJats=true)

    更新日期:2017-11-06
  • IRF3 and type I interferons fuel a fatal response to myocardial infarction
    Nat. Med. (IF 29.886) Pub Date : 2017-11-06
    Kevin R King, Aaron D Aguirre, Yu-Xiang Ye, Yuan Sun, Jason D Roh, Richard P Ng Jr, Rainer H Kohler, Sean P Arlauckas, Yoshiko Iwamoto, Andrej Savol, Ruslan I Sadreyev, Mark Kelly, Timothy P Fitzgibbons, Katherine A Fitzgerald, Timothy Mitchison, Peter Libby, Matthias Nahrendorf, Ralph Weissleder

    IRF3 and type I interferons fuel a fatal response to myocardial infarctionIRF3 and type I interferons fuel a fatal response to myocardial infarction, Published online: 06 November 2017; doi:10.1038/nm.4428NatureArticleSnippet(type=short-summary, markup=The massive cell death that occurs during myocardial infarction releases self-DNA and triggers an interferon response in infiltrating leukocytes via a cGAS–STING–IRF3 pathway. Interference with this response—either by genetic disruption of the pathway or antibody blockade of the type I interferon receptor—is beneficial in mice subjected to myocardial infarction., isJats=true)

    更新日期:2017-11-06
  • Asprosin is a centrally acting orexigenic hormone
    Nat. Med. (IF 29.886) Pub Date : 2017-11-06
    Clemens Duerrschmid, Yanlin He, Chunmei Wang, Chia Li, Juan C Bournat, Chase Romere, Pradip K Saha, Mark E Lee, Kevin J Phillips, Mahim Jain, Peilin Jia, Zhongming Zhao, Monica Farias, Qi Wu, Dianna M Milewicz, V Reid Sutton, David D Moore, Nancy F Butte, Michael J Krashes, Yong Xu, Atul R Chopra

    Asprosin is a centrally acting orexigenic hormoneAsprosin is a centrally acting orexigenic hormone, Published online: 06 November 2017; doi:10.1038/nm.4432NatureArticleSnippet(type=short-summary, markup=Asprosin, a recently identified secreted hormone from adipose tissue, acts centrally to promote food intake., isJats=true)

    更新日期:2017-11-06
  • The activated conformation of integrin β7 is a novel multiple myeloma–specific target for CAR T cell therapy
    Nat. Med. (IF 29.886) Pub Date : 2017-11-06
    Naoki Hosen, Yukiko Matsunaga, Kana Hasegawa, Hiroshi Matsuno, Yuki Nakamura, Mio Makita, Kouki Watanabe, Mikako Yoshida, Kei Satoh, Soyoko Morimoto, Fumihiro Fujiki, Hiroko Nakajima, Jun Nakata, Sumiyuki Nishida, Akihiro Tsuboi, Yoshihiro Oka, Masahiro Manabe, Hiroyoshi Ichihara, Yasutaka Aoyama, Atsuko Mugitani, Takafumi Nakao, Masayuki Hino, Ryosuke Uchibori, Keiya Ozawa, Yoshihiro Baba, Seitaro Terakura, Naoki Wada, Eiichi Morii, Junichi Nishimura, Kiyoshi Takeda, Yusuke Oji, Haruo Sugiyama, Junichi Takagi, Atsushi Kumanogoh

    The activated conformation of integrin β7 is a novel multiple myeloma–specific target for CAR T cell therapyThe activated conformation of integrin β<sub>7</sub> is a novel multiple myeloma–specific target for CAR T cell therapy, Published online: 06 November 2017; doi:10.1038/nm.4431NatureArticleSnippet(type=short-summary, markup=Hosen et al. identify an active conformation of integrin beta-7 as a cancer-associated antigen in multiple myeloma, and engineer a CAR-T cell that shows efficacy against MM in a mouse model. These findings describe the first conformation-specific CAR-T cell and highlight the potential of conformational targets in cancer immunotherapy., isJats=true)

    更新日期:2017-11-06
  • Selective neuronal lapses precede human cognitive lapses following sleep deprivation
    Nat. Med. (IF 29.886) Pub Date : 2017-11-06
    Yuval Nir, Thomas Andrillon, Amit Marmelshtein, Nanthia Suthana, Chiara Cirelli, Giulio Tononi, Itzhak Fried

    Selective neuronal lapses precede human cognitive lapses following sleep deprivationSelective neuronal lapses precede human cognitive lapses following sleep deprivation, Published online: 06 November 2017; doi:10.1038/nm.4433NatureArticleSnippet(type=short-summary, markup=In humans, a full night of sleep deprivation causes attenuated and delayed neuronal responses that correlate with impaired cognitive performance., isJats=true)

    更新日期:2017-11-06
  • ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis
    Nat. Med. (IF 29.886) Pub Date : 2017-10-23
    David Lagares, Parisa Ghassemi-Kakroodi, Caroline Tremblay, Alba Santos, Clemens K Probst, Alicia Franklin, Daniela M Santos, Paula Grasberger, Neil Ahluwalia, Sydney B Montesi, Barry S Shea, Katharine E Black, Rachel Knipe, Meryem Blati, Murray Baron, Brian Wu, Hassan Fahmi, Rajiv Gandhi, Annie Pardo, Moisés Selman, Jiangping Wu, Jean-Pierre Pelletier, Johanne Martel-Pelletier, Andrew M Tager, Mohit Kapoor

    ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis Nature Medicine, Published online: 23 October 2017; doi:10.1038/nm.4419 TGF-β induces expression of ADAM10, which results in greater shedding of ephrin-B2. This shedding promotes the chemotaxis and activation of myofibroblasts and thus the progression of organ fibrosis.

    更新日期:2017-10-25
  • ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis
    Nat. Med. (IF 29.886) Pub Date : 2017-10-23
    David Lagares, Parisa Ghassemi-Kakroodi, Caroline Tremblay, Alba Santos, Clemens K Probst, Alicia Franklin, Daniela M Santos, Paula Grasberger, Neil Ahluwalia, Sydney B Montesi, Barry S Shea, Katharine E Black, Rachel Knipe, Meryem Blati, Murray Baron, Brian Wu, Hassan Fahmi, Rajiv Gandhi, Annie Pardo, Moisés Selman, Jiangping Wu, Jean-Pierre Pelletier, Johanne Martel-Pelletier, Andrew M Tager, Mohit Kapoor

    ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis Nature Medicine, Published online: 23 October 2017; doi:10.1038/nm.4419 TGF-β induces expression of ADAM10, which results in greater shedding of ephrin-B2. This shedding promotes the chemotaxis and activation of myofibroblasts and thus the progression of organ fibrosis.

    更新日期:2017-10-25
  • lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling
    Nat. Med. (IF 29.886) Pub Date : 2017-10-16
    Yuanyuan Lu, Xiaodi Zhao, Qi Liu, Cunxi Li, Ramona Graves-Deal, Zheng Cao, Bhuminder Singh, Jeffrey L Franklin, Jing Wang, Huaying Hu, Tianying Wei, Mingli Yang, Timothy J Yeatman, Ethan Lee, Kenyi Saito-Diaz, Scott Hinger, James G Patton, Christine H Chung, Stephan Emmrich, Jan-Henning Klusmann, Daiming Fan, Robert J Coffey

    lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling Nature Medicine, Published online: 16 October 2017; doi:10.1038/nm.4424 Concomitant overexpression of microRNAs miR-100 and miR-125b-1 within the host long non-coding RNA MIR100HG induces cetuximab resistance in cancer in the absence of previously associated genetic alterations. miR-100 and miR-125b target negative regulators of Wnt/β-catenin signaling and sustain drug resistance through feedback inhibition of GATA6 expression and this resistance can be overcome by pharmacological inhibition of Wnt activity. These findings, together with those by Tan et al. in the previous issue, highlight the emerging functional role of non-coding RNAs in modulating the response to anti-cancer therapies.

    更新日期:2017-10-25
  • Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits
    Nat. Med. (IF 29.886) Pub Date : 2017-10-16
    Jason C You, Kavitha Muralidharan, Jin W Park, Iraklis Petrof, Mark S Pyfer, Brian F Corbett, John J LaFrancois, Yi Zheng, Xiaohong Zhang, Carrie A Mohila, Daniel Yoshor, Robert A Rissman, Eric J Nestler, Helen E Scharfman, Jeannie Chin

    Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits Nature Medicine, Published online: 16 October 2017; doi:10.1038/nm.4413 In rodent models of Alzheimer's disease (AD) and epilepsy, seizure-dependent induction of ΔFosB results in epigenetic silencing of calbindin. Hippocampal inhibition of ΔFosB or elevation of calbindin rescues spatial memory deficits in mouse models of AD.

    更新日期:2017-10-25
  • Natural killer cells migrate into and control simian immunodeficiency virus replication in lymph node follicles in African green monkeys
    Nat. Med. (IF 29.886) Pub Date : 2017-10-16
    Nicolas Huot, Beatrice Jacquelin, Thalia Garcia-Tellez, Philippe Rascle, Mickaël J Ploquin, Yoann Madec, R Keith Reeves, Nathalie Derreudre-Bosquet, Michaela Müller-Trutwin

    Natural killer cells migrate into and control simian immunodeficiency virus replication in lymph node follicles in African green monkeys Nature Medicine, Published online: 16 October 2017; doi:10.1038/nm.4421 Huot et al. investigate the differences in natural killer (NK) cells in lymph nodes during pathogenic and nonpathogenic simian immunodeficiency virus (SIV) infection of cynomolgus macaques and African green monkeys (AGMs), respectively. Their findings suggest that NK cells are specifically recruited to follicles in AGMs and regulate SIV replication in the lymph node.

    更新日期:2017-10-25
  • Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma
    Nat. Med. (IF 29.886) Pub Date : 2017-10-09
    Wilson X Mai, Laura Gosa, Veerle W Daniels, Lisa Ta, Jonathan E Tsang, Brian Higgins, W Blake Gilmore, Nicholas A Bayley, Mitra Dehghan Harati, Jason T Lee, William H Yong, Harley I Kornblum, Steven J Bensinger, Paul S Mischel, P Nagesh Rao, Peter M Clark, Timothy F Cloughesy, Anthony Letai, David A Nathanson

    Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma Nature Medicine, Published online: 9 October 2017; doi:10.1038/nm.4418 Combined inhibition of oncogene-driven glucose uptake and induction of cytoplasmic-p53 activity induces apoptosis in a subset of glioblastoma samples. In mice, PET imaging of glucose uptake predicts glioblastoma response to this combination therapy.

    更新日期:2017-10-25
  • Sympathetic neuron–associated macrophages contribute to obesity by importing and metabolizing norepinephrine
    Nat. Med. (IF 29.886) Pub Date : 2017-10-09
    Roksana M Pirzgalska, Elsa Seixas, Jason S Seidman, Verena M Link, Noelia Martínez Sánchez, Inês Mahú, Raquel Mendes, Vitka Gres, Nadiya Kubasova, Imogen Morris, Bernardo A Arús, Chelsea M Larabee, Miguel Vasques, Francisco Tortosa, Ana L Sousa, Sathyavathy Anandan, Erin Tranfield, Maureen K Hahn, Matteo Iannacone, Nathanael J Spann, Christopher K Glass, Ana I Domingos

    Sympathetic neuron–associated macrophages contribute to obesity by importing and metabolizing norepinephrine Nature Medicine, Published online: 9 October 2017; doi:10.1038/nm.4422 Sympathetic neuron–associated macrophages act as a local sink for norepinephrine, leading to reduced thermogenesis and increased obesity.

    更新日期:2017-10-25
  • Targeting glioma stem cells through combined BMI1 and EZH2 inhibition
    Nat. Med. (IF 29.886) Pub Date : 2017-10-09
    Xun Jin, Leo J Y Kim, Qiulian Wu, Lisa C Wallace, Briana C Prager, Tanwarat Sanvoranart, Ryan C Gimple, Xiuxing Wang, Stephen C Mack, Tyler E Miller, Ping Huang, Claudia L Valentim, Qi-gang Zhou, Jill S Barnholtz-Sloan, Shideng Bao, Andrew E Sloan, Jeremy N Rich

    Targeting glioma stem cells through combined BMI1 and EZH2 inhibition Nature Medicine, Published online: 9 October 2017; doi:10.1038/nm.4415 Microenvironmental pressures in glioblastoma select for glioma stem cells (GSCs) subpopulations that are maintained through preferential activation of BMI1 and EZH2 in different niches. Given the high degree of intratumor heterogeneity, combined pharmacological inhibition of Polycomb repressive complexes targets proneural and mesenchynmal GSCs and expands lifespan in mice, warranting the therapeutic evaluation of this approach in patients with glioblastoma.

    更新日期:2017-10-25
  • Omega-3 fatty acid epoxides are autocrine mediators that control the magnitude of IgE-mediated mast cell activation
    Nat. Med. (IF 29.886) Pub Date : 2017-10-09
    Yuta Shimanaka, Nozomu Kono, Yoshitaka Taketomi, Makoto Arita, Yoshimichi Okayama, Yuki Tanaka, Yasumasa Nishito, Tatsuki Mochizuki, Hiroyuki Kusuhara, Alexander Adibekian, Benjamin F Cravatt, Makoto Murakami, Hiroyuki Arai

    Critical to the function of mast cells in immune responses including allergy is their production of lipid mediators, among which only omega-6 (ω-6) arachidonate–derived eicosanoids have been well characterized. Here, by employing comprehensive lipidomics, we identify omega-3 (ω-3) fatty acid epoxides as new mast cell–derived lipid mediators and show that they are produced by PAF-AH2, an oxidized-phospholipid-selective phospholipase A2. Genetic or pharmacological deletion of PAF-AH2 reduced the steady-state production of ω-3 epoxides, leading to attenuated mast cell activation and anaphylaxis following FcεRI cross-linking. Mechanistically, the ω-3 epoxides promote IgE-mediated activation of mast cells by downregulating Srcin1, a Src-inhibitory protein that counteracts FcεRI signaling, through a pathway involving PPARg. Thus, the PAF-AH2–ω-3 epoxide–Srcin1 axis presents new potential drug targets for allergic diseases.

    更新日期:2017-10-25
  • lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling
    Nat. Med. (IF 29.886) Pub Date : 
    Yuanyuan Lu, Xiaodi Zhao, Qi Liu, Cunxi Li, Ramona Graves-Deal, Zheng Cao, Bhuminder Singh, Jeffrey L Franklin, Jing Wang, Huaying Hu, Tianying Wei, Mingli Yang, Timothy J Yeatman, Ethan Lee, Kenyi Saito-Diaz, Scott Hinger, James G Patton, Christine H Chung, Stephan Emmrich, Jan-Henning Klusmann, Daiming Fan, Robert J Coffey

    De novo and acquired resistance, which are largely attributed to genetic alterations, are barriers to effective anti-epidermal-growth-factor-receptor (EGFR) therapy. To generate cetuximab-resistant cells, we exposed cetuximab-sensitive colorectal cancer cells to cetuximab in three-dimensional culture. Using whole-exome sequencing and transcriptional profiling, we found that the long non-coding RNA MIR100HG and two embedded microRNAs, miR-100 and miR-125b, were overexpressed in the absence of known genetic events linked to cetuximab resistance. MIR100HG, miR-100 and miR-125b overexpression was also observed in cetuximab-resistant colorectal cancer and head and neck squamous cell cancer cell lines and in tumors from colorectal cancer patients that progressed on cetuximab. miR-100 and miR-125b coordinately repressed five Wnt/β-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness. Our results describe a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby GATA6 represses MIR100HG, but this repression is relieved by miR-125b targeting of GATA6. These findings identify a clinically actionable, epigenetic cause of cetuximab resistance.

    更新日期:2017-10-16
  • Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits
    Nat. Med. (IF 29.886) Pub Date : 
    Jason C You, Kavitha Muralidharan, Jin W Park, Iraklis Petrof, Mark S Pyfer, Brian F Corbett, John J LaFrancois, Yi Zheng, Xiaohong Zhang, Carrie A Mohila, Daniel Yoshor, Robert A Rissman, Eric J Nestler, Helen E Scharfman, Jeannie Chin

    Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits Nature Medicine, Published online: 16 October 2017; doi:10.1038/nm.4413 In rodent models of Alzheimer's disease (AD) and epilepsy, seizure-dependent induction of ΔFosB results in epigenetic silencing of calbindin. Hippocampal inhibition of ΔFosB or elevation of calbindin rescues spatial memory deficits in mouse models of AD.

    更新日期:2017-10-16
  • Natural killer cells migrate into and control simian immunodeficiency virus replication in lymph node follicles in African green monkeys
    Nat. Med. (IF 29.886) Pub Date : 
    Nicolas Huot, Beatrice Jacquelin, Thalia Garcia-Tellez, Philippe Rascle, Mickaël J Ploquin, Yoann Madec, R Keith Reeves, Nathalie Derreudre-Bosquet, Michaela Müller-Trutwin

    Natural killer (NK) cells play an essential role in antiviral immunity, but knowledge of their function in secondary lymphoid organs is incomplete. Lymph node follicles constitute a major viral reservoir during infections with HIV-1 and simian immunodeficiency virus of macaques (SIVmac). In contrast, during nonpathogenic infection with SIV from African green monkeys (SIVagm), follicles remain generally virus free. We show that NK cells in secondary lymphoid organs from chronically SIVagm-infected African green monkeys (AGMs) were frequently CXCR5+ and entered and persisted in lymph node follicles throughout the follow-up (240 d post-infection). These follicles were strongly positive for IL-15, which was primarily presented in its membrane-bound form by follicular dendritic cells. NK cell depletion through treatment with anti-IL-15 monoclonal antibody during chronic SIVagm infection resulted in high viral replication rates in follicles and the T cell zone and increased viral DNA in lymph nodes. Our data suggest that, in nonpathogenic SIV infection, NK cells migrate into follicles and play a major role in viral reservoir control in lymph nodes.

    更新日期:2017-10-16
  • Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma
    Nat. Med. (IF 29.886) Pub Date : 
    Wilson X Mai, Laura Gosa, Veerle W Daniels, Lisa Ta, Jonathan E Tsang, Brian Higgins, W Blake Gilmore, Nicholas A Bayley, Mitra Dehghan Harati, Jason T Lee, William H Yong, Harley I Kornblum, Steven J Bensinger, Paul S Mischel, P Nagesh Rao, Peter M Clark, Timothy F Cloughesy, Anthony Letai, David A Nathanson

    Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies.

    更新日期:2017-10-11
  • Sympathetic neuron–associated macrophages contribute to obesity by importing and metabolizing norepinephrine
    Nat. Med. (IF 29.886) Pub Date : 
    Roksana M Pirzgalska, Elsa Seixas, Jason S Seidman, Verena M Link, Noelia Martínez Sánchez, Inês Mahú, Raquel Mendes, Vitka Gres, Nadiya Kubasova, Imogen Morris, Bernardo A Arús, Chelsea M Larabee, Miguel Vasques, Francisco Tortosa, Ana L Sousa, Sathyavathy Anandan, Erin Tranfield, Maureen K Hahn, Matteo Iannacone, Nathanael J Spann, Christopher K Glass, Ana I Domingos

    The cellular mechanism(s) linking macrophages to norepinephrine (NE)-mediated regulation of thermogenesis have been a topic of debate. Here we identify sympathetic neuron–associated macrophages (SAMs) as a population of cells that mediate clearance of NE via expression of solute carrier family 6 member 2 (SLC6A2), an NE transporter, and monoamine oxidase A (MAOA), a degradation enzyme. Optogenetic activation of the sympathetic nervous system (SNS) upregulates NE uptake by SAMs and shifts the SAM profile to a more proinflammatory state. NE uptake by SAMs is prevented by genetic deletion of Slc6a2 or inhibition of the encoded transporter. We also observed an increased proportion of SAMs in the SNS of two mouse models of obesity. Genetic ablation of Slc6a2 in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis, and leads to substantial and sustained weight loss in obese mice. We further show that this pathway is conserved, as human sympathetic ganglia also contain SAMs expressing the analogous molecular machinery for NE clearance, which thus constitutes a potential target for obesity treatment.

    更新日期:2017-10-11
  • Targeting glioma stem cells through combined BMI1 and EZH2 inhibition
    Nat. Med. (IF 29.886) Pub Date : 
    Xun Jin, Leo J Y Kim, Qiulian Wu, Lisa C Wallace, Briana C Prager, Tanwarat Sanvoranart, Ryan C Gimple, Xiuxing Wang, Stephen C Mack, Tyler E Miller, Ping Huang, Claudia L Valentim, Qi-gang Zhou, Jill S Barnholtz-Sloan, Shideng Bao, Andrew E Sloan, Jeremy N Rich

    Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are more sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity.

    更新日期:2017-10-11
  • Omega-3 fatty acid epoxides are autocrine mediators that control the magnitude of IgE-mediated mast cell activation
    Nat. Med. (IF 29.886) Pub Date : 
    Yuta Shimanaka, Nozomu Kono, Yoshitaka Taketomi, Makoto Arita, Yoshimichi Okayama, Yuki Tanaka, Yasumasa Nishito, Tatsuki Mochizuki, Hiroyuki Kusuhara, Alexander Adibekian, Benjamin F Cravatt, Makoto Murakami, Hiroyuki Arai

    Critical to the function of mast cells in immune responses including allergy is their production of lipid mediators, among which only omega-6 (ω-6) arachidonate–derived eicosanoids have been well characterized. Here, by employing comprehensive lipidomics, we identify omega-3 (ω-3) fatty acid epoxides as new mast cell–derived lipid mediators and show that they are produced by PAF-AH2, an oxidized-phospholipid-selective phospholipase A2. Genetic or pharmacological deletion of PAF-AH2 reduced the steady-state production of ω-3 epoxides, leading to attenuated mast cell activation and anaphylaxis following FcεRI cross-linking. Mechanistically, the ω-3 epoxides promote IgE-mediated activation of mast cells by downregulating Srcin1, a Src-inhibitory protein that counteracts FcεRI signaling, through a pathway involving PPARg. Thus, the PAF-AH2–ω-3 epoxide–Srcin1 axis presents new potential drug targets for allergic diseases.

    更新日期:2017-10-11
  • Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis
    Nat. Med. (IF 29.886) Pub Date : 
    Cen Xie, Tomoki Yagai, Yuhong Luo, Xianyi Liang, Tao Chen, Qiong Wang, Dongxue Sun, Jie Zhao, Sadeesh K Ramakrishnan, Lulu Sun, Chunmei Jiang, Xiang Xue, Yuan Tian, Kristopher W Krausz, Andrew D Patterson, Yatrik M Shah, Yue Wu, Changtao Jiang, Frank J Gonzalez

    Nonalcoholic fatty liver disease is becoming the most common chronic liver disease in Western countries, and limited therapeutic options are available. Here we uncovered a role for intestinal hypoxia-inducible factor (HIF) in hepatic steatosis. Human-intestine biopsies from individuals with or without obesity revealed that intestinal HIF-2α signaling was positively correlated with body-mass index and hepatic toxicity. The causality of this correlation was verified in mice with an intestine-specific disruption of Hif2a, in which high-fat-diet-induced hepatic steatosis and obesity were substantially lower as compared to control mice. PT2385, a HIF-2α-specific inhibitor, had preventive and therapeutic effects on metabolic disorders that were dependent on intestine HIF-2α. Intestine HIF-2α inhibition markedly reduced intestine and serum ceramide levels. Mechanistically, intestine HIF-2α regulates ceramide metabolism mainly from the salvage pathway, by positively regulating the expression of Neu3, the gene encoding neuraminidase 3. These results suggest that intestinal HIF-2α could be a viable target for hepatic steatosis therapy.

    更新日期:2017-10-11
  • Angst about exclusivity: The potential cost of incentivizing makers of generic drugs
    Nat. Med. (IF 29.886) Pub Date : 
    Shraddha Chakradhar, Roxanne Khamsi

    Angst about exclusivity: The potential cost of incentivizing makers of generic drugs Nature Medicine, Published online: 6 October 2017; doi:10.1038/nm1017-1114

    更新日期:2017-10-11
  • Clonal evolution in leukemia
    Nat. Med. (IF 29.886) Pub Date : 
    Adolfo A Ferrando, Carlos López-Otín

    Human leukemias are liquid malignancies characterized by diffuse infiltration of the bone marrow by transformed hematopoietic progenitors. The accessibility of tumor cells obtained from peripheral blood or through bone marrow aspirates, together with recent advances in cancer genomics and single-cell molecular analysis, have facilitated the study of clonal populations and their genetic and epigenetic evolution over time with unprecedented detail. The results of these analyses challenge the classic view of leukemia as a clonal homogeneous diffuse tumor and introduce a more complex and dynamic scenario. In this review, we present current concepts on the role of clonal evolution in lymphoid and myeloid leukemia as a driver of tumor initiation, disease progression and relapse. We also discuss the implications of these concepts in our understanding of the evolutionary mechanisms involved in leukemia transformation and therapy resistance.

    更新日期:2017-10-11
  • GDF15 and energy balance: homing in on a mechanism
    Nat. Med. (IF 29.886) Pub Date : 
    Irene Cimino, Anthony P Coll, Giles S H Yeo

    GDF15 and energy balance: homing in on a mechanism Nature Medicine, Published online: 6 October 2017; doi:10.1038/nm.4414 Three recent studies in mice have identified a specific receptor, GFRAL, for the known anorectic peptide GDF15. The finding increases mechanistic understanding of its effect and paves the way for the development of novel anti-obesity therapeutics.

    更新日期:2017-10-11
  • Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence
    Nat. Med. (IF 29.886) Pub Date : 
    Jian Yuan Goh, Min Feng, Wenyu Wang, Gokce Oguz, Siti Maryam J M Yatim, Puay Leng Lee, Yi Bao, Tse Hui Lim, Panpan Wang, Wai Leong Tam, Annette R Kodahl, Maria B Lyng, Suman Sarma, Selena Y Lin, Alexander Lezhava, Yoon Sim Yap, Alvin S T Lim, Dave S B Hoon, Henrik J Ditzel, Soo Chin Lee, Ern Yu Tan, Qiang Yu

    Tumor recurrence remains the main reason for breast cancer–associated mortality, and there are unmet clinical demands for the discovery of new biomarkers and development of treatment solutions to benefit patients with breast cancer at high risk of recurrence. Here we report the identification of chromosomal copy-number amplification at 1q21.3 that is enriched in subpopulations of breast cancer cells bearing characteristics of tumor-initiating cells (TICs) and that strongly associates with breast cancer recurrence. Amplification is present in ~10–30% of primary tumors but in more than 70% of recurrent tumors, regardless of breast cancer subtype. Detection of amplification in cell-free DNA (cfDNA) from blood is strongly associated with early relapse in patients with breast cancer and could also be used to track the emergence of tumor resistance to chemotherapy. We further show that 1q21.3-encoded S100 calcium-binding protein (S100A) family members, mainly S100A7, S100A8, and S100A9 (S100A7/8/9), and IL-1 receptor–associated kinase 1 (IRAK1) establish a reciprocal feedback loop driving tumorsphere growth. Notably, this functional circuitry can be disrupted by the small-molecule kinase inhibitor pacritinib, leading to preferential impairment of the growth of 1q21.3-amplified breast tumors. Our study uncovers the 1q21.3-directed S100A7/8/9–IRAK1 feedback loop as a crucial component of breast cancer recurrence, serving as both a trackable biomarker and an actionable therapeutic target for breast cancer.

    更新日期:2017-09-28
  • 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

    Mutations in MECP2 cause Rett syndrome (RTT), an X-linked neurological disorder characterized by regressive loss of neurodevelopmental milestones and acquired psychomotor deficits. However, the cellular heterogeneity of the brain impedes an understanding of how MECP2 mutations contribute to RTT. Here we developed a Cre-inducible method for cell-type-specific biotin tagging of MeCP2 in mice. Combining this approach with an allelic series of knock-in mice carrying frequent RTT-associated mutations (encoding T158M and R106W) enabled the selective profiling of RTT-associated nuclear transcriptomes in excitatory and inhibitory cortical neurons. We found that most gene-expression changes were largely specific to each RTT-associated mutation and cell type. Lowly expressed cell-type-enriched genes were preferentially disrupted by MeCP2 mutations, with upregulated and downregulated genes reflecting distinct functional categories. Subcellular RNA analysis in MeCP2-mutant neurons further revealed reductions in the nascent transcription of long genes and uncovered widespread post-transcriptional compensation at the cellular level. Finally, we overcame X-linked cellular mosaicism in female RTT models and identified distinct gene-expression changes between neighboring wild-type and mutant neurons, providing contextual insights into RTT etiology that support personalized therapeutic interventions.

    更新日期:2017-09-26
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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