样式: 排序: IF: - GO 导出 标记为已读
-
Comparison of the immunogenicity and protective efficacy of ACAM2000, MVA, and vectored subunit vaccines for Mpox in rhesus macaques Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-27 Catherine Jacob-Dolan, Darren Ty, David Hope, Katherine McMahan, Jinyan Liu, Olivia C. Powers, Catherine A. Cotter, Michela Sciacca, Cindy Wu, Erica Borducchi, Emily Bouffard, Hannah Richter, Jason Velasco, Elyse Teow, Mona Boursiquot, Anthony Cook, Karen Feliciano, Jake Yalley-Ogunro, Michael S. Seaman, Laurent Pessiant, Mark G. Lewis, Hanne Andersen, Bernard Moss, Dan H. Barouch
The 2022–2023 mpox outbreak triggered vaccination efforts using smallpox vaccines that were approved for mpox, including modified vaccinia Ankara (MVA; JYNNEOS), which is a safer alternative to live replicating vaccinia virus (ACAM2000). Here, we compare the immunogenicity and protective efficacy of JYNNEOS by the subcutaneous or intradermal routes, ACAM2000 by the percutaneous route, and subunit Ad35
-
Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-27 Minrui Liang, Nicholas Dickel, Andrea-Hermina Györfi, Bilgesu SafakTümerdem, Yi-Nan Li, Aleix Rius Rigau, Chunguang Liang, Xuezhi Hong, Lichong Shen, Alexandru-Emil Matei, Thuong Trinh-Minh, Cuong Tran-Manh, Xiang Zhou, Ariella Zehender, Alexander Kreuter, Hejian Zou, Georg Schett, Meik Kunz, Jörg H. W. Distler
Fibrotic diseases impose a major socioeconomic challenge on modern societies and have limited treatment options. Adropin, a peptide hormone encoded by the energy homeostasis–associated ( ENHO ) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and
-
The gut microbiota posttranslationally modifies IgA1 in autoimmune glomerulonephritis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-27 Patrick J. Gleeson, Nicolas Benech, Jonathan Chemouny, Eleftheria Metallinou, Laureline Berthelot, Jennifer da Silva, Julie Bex-Coudrat, Erwan Boedec, Fanny Canesi, Carine Bounaix, Willy Morelle, Maryse Moya-Nilges, John Kenny, Liam O’Mahony, Loredana Saveanu, Bertrand Arnulf, Aurélie Sannier, Eric Daugas, François Vrtovsnik, Patricia Lepage, Harry Sokol, Renato C. Monteiro
Mechanisms underlying the disruption of self-tolerance in acquired autoimmunity remain unclear. Immunoglobulin A (IgA) nephropathy is an acquired autoimmune disease where deglycosylated IgA1 (IgA subclass 1) auto-antigens are recognized by IgG auto-antibodies, forming immune complexes that are deposited in the kidneys, leading to glomerulonephritis. In the intestinal microbiota of patients with IgA
-
A tough bioadhesive hydrogel supports sutureless sealing of the dural membrane in porcine and ex vivo human tissue Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Kyle C. Wu, Benjamin R. Freedman, Phoebe S. Kwon, Matthew Torre, Daniel O. Kent, Wenya Linda Bi, David J. Mooney
Complete sequestration of central nervous system tissue and cerebrospinal fluid by the dural membrane is fundamental to maintaining homeostasis and proper organ function, making reconstruction of this layer an essential step during neurosurgery. Primary closure of the dura by suture repair is the current standard, despite facing technical, microenvironmental, and anatomic challenges. Here, we apply
-
An anti–TNF–glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Michael J. McPherson, Adrian D. Hobson, Axel HernandezJr., Christopher C. Marvin, Wendy Waegell, Christian Goess, Jason Z. Oh, Dan Shi, Martin E. Hayes, Lu Wang, Lu Wang, Diana Schmidt, Zhi Wang, Victoria Pitney, Kimberley McCarthy, Ying Jia, Ce Wang, Bit Na Kang, Shaughn Bryant, Suzanne Mathieu, Melanie Ruzek, Julie Parmentier, Ronilda R. D’Cunha, Yinuo Pang, Lucy Phillips, Nathan J. Brown, Jianwen
Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti–tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore
-
The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Martin Skov, Titia Q. Ruijs, Thomas S. Grønnebæk, Marianne Skals, Anders Riisager, Jeppe Blichfeldt Winther, Kamilla Løhde Tordrup Dybdahl, Anders Findsen, Jeanette J. Morgen, Nete Huus, Martin Broch-Lips, Ole B. Nielsen, Catherine M.K.E. de Cuba, Jules A.A.C. Heuberger, Marieke L. de Kam, Martijn Tannemaat, Jan J. G. M. Verschuuren, Lars J. S. Knutsen, Nicholas M. Kelly, Klaus G. Jensen, William D
Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl−) ion channel that plays
-
Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Jianxing Yin, Xin Ge, Fangshu Ding, Liuguijie He, Keying Song, Zhumei Shi, Zehe Ge, Junxia Zhang, Jing Ji, Xiefeng Wang, Ningwei Zhao, Chuanjun Shu, Fan Lin, Qianghu Wang, Qigang Zhou, Yuandong Cao, Wentao Liu, Dan Ye, Jeremy N. Rich, Xiuxing Wang, Yongping You, Xu Qian
Glioblastoma, the most lethal primary brain tumor, harbors glioma stem cells (GSCs) that not only initiate and maintain malignant phenotypes but also enhance therapeutic resistance. Although frequently mutated in glioblastomas, the function and regulation of PTEN in PTEN-intact GSCs are unknown. Here, we found that PTEN directly interacted with MMS19 and competitively disrupted MMS19-based cytosolic
-
Apelin stimulation of the vascular skeletal muscle stem cell niche enhances endogenous repair in dystrophic mice Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Emmeran Le Moal, Yuguo Liu, Jasmin Collerette-Tremblay, Simon Dumontier, Paul Fabre, Thomas Molina, Junio Dort, Zakaria Orfi, Nicolas Denault, Joël Boutin, Joris Michaud, Hugo Giguère, Alexandre Desroches, Kien Trân, Benjamin Ellezam, François Vézina, Sonia Bedard, Catherine Raynaud, Frederic Balg, Philippe Sarret, Pierre-Luc Boudreault, Michelle S. Scott, Jean-Bernard Denault, Eric Marsault, Jerome
Impaired skeletal muscle stem cell (MuSC) function has long been suspected to contribute to the pathogenesis of muscular dystrophy (MD). Here, we showed that defects in the endothelial cell (EC) compartment of the vascular stem cell niche in mouse models of Duchenne MD, laminin α2–related MD, and collagen VI–related myopathy were associated with inefficient mobilization of MuSCs after tissue damage
-
Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Jianxing Yin, Xin Ge, Fangshu Ding, Liuguijie He, Keying Song, Zhumei Shi, Zehe Ge, Junxia Zhang, Jing Ji, Xiefeng Wang, Ningwei Zhao, Chuanjun Shu, Fan Lin, Qianghu Wang, Qigang Zhou, Yuandong Cao, Wentao Liu, Dan Ye, Jeremy N. Rich, Xiuxing Wang, Yongping You, Xu Qian
Glioblastoma, the most lethal primary brain tumor, harbors glioma stem cells (GSCs) that not only initiate and maintain malignant phenotypes but also enhance therapeutic resistance. Although frequently mutated in glioblastomas, the function and regulation of PTEN in PTEN-intact GSCs are unknown. Here, we found that PTEN directly interacted with MMS19 and competitively disrupted MMS19-based cytosolic
-
The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Martin Skov, Titia Q. Ruijs, Thomas S. Grønnebæk, Marianne Skals, Anders Riisager, Jeppe Blichfeldt Winther, Kamilla Løhde Tordrup Dybdahl, Anders Findsen, Jeanette J. Morgen, Nete Huus, Martin Broch-Lips, Ole B. Nielsen, Catherine M.K.E. de Cuba, Jules A.A.C. Heuberger, Marieke L. de Kam, Martijn Tannemaat, Jan J. G. M. Verschuuren, Lars J. S. Knutsen, Nicholas M. Kelly, Klaus G. Jensen, William D
Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl − ) ion channel that plays
-
Apelin stimulation of the vascular skeletal muscle stem cell niche enhances endogenous repair in dystrophic mice Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Emmeran Le Moal, Yuguo Liu, Jasmin Collerette-Tremblay, Simon Dumontier, Paul Fabre, Thomas Molina, Junio Dort, Zakaria Orfi, Nicolas Denault, Joël Boutin, Joris Michaud, Hugo Giguère, Alexandre Desroches, Kien Trân, Benjamin Ellezam, François Vézina, Sonia Bedard, Catherine Raynaud, Frederic Balg, Philippe Sarret, Pierre-Luc Boudreault, Michelle S. Scott, Jean-Bernard Denault, Eric Marsault, Jerome
Impaired skeletal muscle stem cell (MuSC) function has long been suspected to contribute to the pathogenesis of muscular dystrophy (MD). Here, we showed that defects in the endothelial cell (EC) compartment of the vascular stem cell niche in mouse models of Duchenne MD, laminin α2–related MD, and collagen VI–related myopathy were associated with inefficient mobilization of MuSCs after tissue damage
-
A tough bioadhesive hydrogel supports sutureless sealing of the dural membrane in porcine and ex vivo human tissue Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Kyle C. Wu, Benjamin R. Freedman, Phoebe S. Kwon, Matthew Torre, Daniel O. Kent, Wenya Linda Bi, David J. Mooney
Complete sequestration of central nervous system tissue and cerebrospinal fluid by the dural membrane is fundamental to maintaining homeostasis and proper organ function, making reconstruction of this layer an essential step during neurosurgery. Primary closure of the dura by suture repair is the current standard, despite facing technical, microenvironmental, and anatomic challenges. Here, we apply
-
An anti–TNF–glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-20 Michael J. McPherson, Adrian D. Hobson, Axel Hernandez, Christopher C. Marvin, Wendy Waegell, Christian Goess, Jason Z. Oh, Dan Shi, Martin E. Hayes, Lu Wang, Lu Wang, Diana Schmidt, Zhi Wang, Victoria Pitney, Kimberley McCarthy, Ying Jia, Ce Wang, Bit Na Kang, Shaughn Bryant, Suzanne Mathieu, Melanie Ruzek, Julie Parmentier, Ronilda R. D’Cunha, Yinuo Pang, Lucy Phillips, Nathan J. Brown, Jianwen Xu
Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti–tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore
-
An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Michael Westberg, Yichi Su, Xinzhi Zou, Pinghan Huang, Arjun Rustagi, Jaishree Garhyan, Puja Bhavesh Patel, Daniel Fernandez, Yan Wu, Chenzhou Hao, Chieh-Wen Lo, Marwah Karim, Lin Ning, Aimee Beck, Panatda Saenkham-Huntsinger, Vivian Tat, Aleksandra Drelich, Bi-Hung Peng, Shirit Einav, Chien-Te K. Tseng, Catherine Blish, Michael Z. Lin
Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants
-
Genome-wide repeat landscapes in cancer and cell-free DNA Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Akshaya V. Annapragada, Noushin Niknafs, James R. White, Daniel C. Bruhm, Christopher Cherry, Jamie E. Medina, Vilmos Adleff, Carolyn Hruban, Dimitrios Mathios, Zachariah H. Foda, Jillian Phallen, Robert B. Scharpf, Victor E. Velculescu
Genetic changes in repetitive sequences are a hallmark of cancer and other diseases, but characterizing these has been challenging using standard sequencing approaches. We developed a de novo kmer finding approach, called ARTEMIS (Analysis of RepeaT EleMents in dISease), to identify repeat elements from whole-genome sequencing. Using this method, we analyzed 1.2 billion kmers in 2837 tissue and plasma
-
Hepatic danger signaling triggers TREM2+ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Linkang Zhou, Xiaoxue Qiu, Ziyi Meng, Tongyu Liu, Zhimin Chen, Peng Zhang, Henry Kuang, Tong Pan, You Lu, Ling Qi, David P. Olson, X. Z. Shawn Xu, Y. Eugene Chen, Siming Li, Jiandie D. Lin
Metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2+ macrophages in various disease conditions, and substantial induction of
-
Harnessing regulatory T cells to establish immune tolerance Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Patrick Ho, Ellen Cahir-McFarland, Jason D. Fontenot, Tracey Lodie, Adel Nada, Qizhi Tang, Laurence A. Turka, Jeffrey A. Bluestone
Engineered regulatory T (Treg) cells have emerged as precision therapeutics aimed at inducing immune tolerance while reducing the risks associated with generalized immunosuppression. This Viewpoint highlights the opportunities and challenges for engineered Treg cell therapies in treating autoimmune and other inflammatory diseases.
-
Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Jelena Scekic-Zahirovic, Cristina Benetton, Aurore Brunet, XiaoQian Ye, Evgeny Logunov, Vincent Douchamps, Salim Megat, Virginie Andry, Vanessa Wing Yin Kan, Geoffrey Stuart-Lopez, Johan Gilet, Simon J. Guillot, Sylvie Dirrig-Grosch, Charlotte Gorin, Margaux Trombini, Stéphane Dieterle, Jérôme Sinniger, Mathieu Fischer, Frédérique René, Zeynep Gunes, Pascal Kessler, Luc Dupuis, Pierre-François Pradat
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability
-
Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Jelena Scekic-Zahirovic, Cristina Benetton, Aurore Brunet, XiaoQian Ye, Evgeny Logunov, Vincent Douchamps, Salim Megat, Virginie Andry, Vanessa Wing Yin Kan, Geoffrey Stuart-Lopez, Johan Gilet, Simon J. Guillot, Sylvie Dirrig-Grosch, Charlotte Gorin, Margaux Trombini, Stéphane Dieterle, Jérôme Sinniger, Mathieu Fischer, Frédérique René, Zeynep Gunes, Pascal Kessler, Luc Dupuis, Pierre-François Pradat
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability
-
Hepatic danger signaling triggers TREM2 + macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Linkang Zhou, Xiaoxue Qiu, Ziyi Meng, Tongyu Liu, Zhimin Chen, Peng Zhang, Henry Kuang, Tong Pan, You Lu, Ling Qi, David P. Olson, X. Z. Shawn Xu, Y. Eugene Chen, Siming Li, Jiandie D. Lin
Metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2 + macrophages in various disease conditions, and substantial induction of
-
Genome-wide repeat landscapes in cancer and cell-free DNA Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Akshaya V. Annapragada, Noushin Niknafs, James R. White, Daniel C. Bruhm, Christopher Cherry, Jamie E. Medina, Vilmos Adleff, Carolyn Hruban, Dimitrios Mathios, Zachariah H. Foda, Jillian Phallen, Robert B. Scharpf, Victor E. Velculescu
Genetic changes in repetitive sequences are a hallmark of cancer and other diseases, but characterizing these has been challenging using standard sequencing approaches. We developed a de novo kmer finding approach, called ARTEMIS (Analysis of RepeaT EleMents in dISease), to identify repeat elements from whole-genome sequencing. Using this method, we analyzed 1.2 billion kmers in 2837 tissue and plasma
-
Harnessing regulatory T cells to establish immune tolerance Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Patrick Ho, Ellen Cahir-McFarland, Jason D. Fontenot, Tracey Lodie, Adel Nada, Qizhi Tang, Laurence A. Turka, Jeffrey A. Bluestone
Engineered regulatory T (T reg ) cells have emerged as precision therapeutics aimed at inducing immune tolerance while reducing the risks associated with generalized immunosuppression. This Viewpoint highlights the opportunities and challenges for engineered T reg cell therapies in treating autoimmune and other inflammatory diseases.
-
An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-13 Michael Westberg, Yichi Su, Xinzhi Zou, Pinghan Huang, Arjun Rustagi, Jaishree Garhyan, Puja Bhavesh Patel, Daniel Fernandez, Yan Wu, Chenzhou Hao, Chieh-Wen Lo, Marwah Karim, Lin Ning, Aimee Beck, Panatda Saenkham-Huntsinger, Vivian Tat, Aleksandra Drelich, Bi-Hung Peng, Shirit Einav, Chien-Te K. Tseng, Catherine Blish, Michael Z. Lin
Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro ) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants
-
Immunocytokines with target cell–restricted IL-15 activity for treatment of B cell malignancies Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-06 Latifa Zekri, Ilona Hagelstein, Melanie Märklin, Boris Klimovich, Mary Christie, Cornelia Lindner, Sofie Kämereit, Nisha Prakash, Stefanie Müller, Sophie Stotz, Andreas Maurer, Carsten Greve, Bastian Schmied, Daniel Atar, Hans-Georg Rammensee, Gundram Jung, Helmut R. Salih
Despite the advances in cancer treatment achieved, for example, by the CD20 antibody rituximab, an urgent medical need remains to optimize the capacity of such antibodies to induce antibody-dependent cellular cytotoxicity (ADCC) that determines therapeutic efficacy. The cytokine IL-15 stimulates proliferation, activation, and cytolytic capacity of NK cells, but broad clinical use is prevented by short
-
B cell depletion with anti-CD20 promotes neuroprotection in a BAFF-dependent manner in mice and humans Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-06 Angela A. Wang, Felix Luessi, Tradite Neziraj, Elisabeth Pössnecker, Michelle Zuo, Sinah Engel, Nicholas Hanuscheck, Alexandra Florescu, Eryn Bugbee, Xianjie I. Ma, Fatima Rana, Dennis Lee, Lesley A. Ward, Jens Kuhle, Johannes Himbert, Muriel Schraad, Erwin van Puijenbroek, Christian Klein, Eduard Urich, Valeria Ramaglia, Anne-Katrin Pröbstel, Frauke Zipp, Jennifer L. Gommerman
Anti-CD20 therapy to deplete B cells is highly efficacious in preventing new white matter lesions in patients with relapsing-remitting multiple sclerosis (RRMS), but its protective capacity against gray matter injury and axonal damage is unclear. In a passive experimental autoimmune encephalomyelitis (EAE) model whereby T H 17 cells promote brain leptomeningeal immune cell aggregates, we found that
-
Gamma entrainment using audiovisual stimuli alleviates chemobrain pathology and cognitive impairment induced by chemotherapy in mice Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-06 TaeHyun Kim, Benjamin T. James, Martin C. Kahn, Cristina Blanco-Duque, Fatema Abdurrob, Md Rezaul Islam, Nicolas S. Lavoie, Manolis Kellis, Li-Huei Tsai
Patients with cancer undergoing chemotherapy frequently experience a neurological condition known as chemotherapy-related cognitive impairment, or “chemobrain,” which can persist for the remainder of their lives. Despite the growing prevalence of chemobrain, both its underlying mechanisms and treatment strategies remain poorly understood. Recent findings suggest that chemobrain shares several characteristics
-
Inactivation of adenosine receptor 2A suppresses endothelial-to-mesenchymal transition and inhibits subretinal fibrosis in mice Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-06 Qiuhua Yang, Yongfeng Cai, Qian Ma, Albert Xiong, Peishan Xu, Zhidan Zhang, Jiean Xu, Yaqi Zhou, Zhiping Liu, Dingwei Zhao, John Asara, Wei Li, Huidong Shi, Ruth B. Caldwell, Akrit Sodhi, Yuqing Huo
Anti–vascular endothelial growth factor therapy has had a substantial impact on the treatment of choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (nAMD), the leading cause of vision loss in older adults. Despite treatment, many patients with nAMD still develop severe and irreversible visual impairment because of the development of subretinal fibrosis
-
Immunocytokines with target cell–restricted IL-15 activity for treatment of B cell malignancies Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-06 Latifa Zekri, Ilona Hagelstein, Melanie Märklin, Boris Klimovich, Mary Christie, Cornelia Lindner, Sofie Kämereit, Nisha Prakash, Stefanie Müller, Sophie Stotz, Andreas Maurer, Carsten Greve, Bastian Schmied, Daniel Atar, Hans-Georg Rammensee, Gundram Jung, Helmut R. Salih
Despite the advances in cancer treatment achieved, for example, by the CD20 antibody rituximab, an urgent medical need remains to optimize the capacity of such antibodies to induce antibody-dependent cellular cytotoxicity (ADCC) that determines therapeutic efficacy. The cytokine IL-15 stimulates proliferation, activation, and cytolytic capacity of NK cells, but broad clinical use is prevented by short
-
Sex differences in kidney metabolism may reflect sex-dependent outcomes in human diabetic kidney disease Sci. Transl. Med. (IF 17.1) Pub Date : 2024-03-06 Sergi Clotet-Freixas, Olga Zaslaver, Max Kotlyar, Chiara Pastrello, Andrew T. Quaile, Caitriona M. McEvoy, Aninda D. Saha, Sofia Farkona, Alex Boshart, Katarina Zorcic, Slaghaniya Neupane, Kieran Manion, Maya Allen, Michael Chan, Xuqi Chen, Arthur P. Arnold, Peggy Sekula, Inga Steinbrenner, Anna Köttgen, Allison B. Dart, Brandy Wicklow, Jon M. McGavock, Tom D. Blydt-Hansen, Clara Barrios, Marta Riera
Diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD) and progresses faster in males than in females. We identify sex-based differences in kidney metabolism and in the blood metabolome of male and female individuals with diabetes. Primary human proximal tubular epithelial cells (PTECs) from healthy males displayed increased mitochondrial respiration, oxidative stress, apoptosis
-
Endothelial cells drive organ fibrosis in mice by inducing expression of the transcription factor SOX9 Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-28 Felix A. Trogisch, Aya Abouissa, Merve Keles, Anne Birke, Manuela Fuhrmann, Gesine M. Dittrich, Nina Weinzierl, Elvira Wink, Julio Cordero, Adel Elsherbiny, Abel Martin-Garrido, Steve Grein, Shruthi Hemanna, Ellen Hofmann, Luka Nicin, Sofia-Iris Bibli, Rannar Airik, Andreas Kispert, Ralf Kist, Sun Quanchao, Sina W. Kürschner, Manuel Winkler, Norbert Gretz, Carolin Mogler, Thomas Korff, Philipp-Sebastian
Fibrosis is a hallmark of chronic disease. Although fibroblasts are involved, it is unclear to what extent endothelial cells also might contribute. We detected increased expression of the transcription factor Sox9 in endothelial cells in several different mouse fibrosis models. These models included systolic heart failure induced by pressure overload, diastolic heart failure induced by high-fat diet
-
Endothelial cells drive organ fibrosis in mice by inducing expression of the transcription factor SOX9 Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-28 Felix A. Trogisch, Aya Abouissa, Merve Keles, Anne Birke, Manuela Fuhrmann, Gesine M. Dittrich, Nina Weinzierl, Elvira Wink, Julio Cordero, Adel Elsherbiny, Abel Martin-Garrido, Steve Grein, Shruthi Hemanna, Ellen Hofmann, Luka Nicin, Sofia-Iris Bibli, Rannar Airik, Andreas Kispert, Ralf Kist, Sun Quanchao, Sina W. Kürschner, Manuel Winkler, Norbert Gretz, Carolin Mogler, Thomas Korff, Philipp-Sebastian
Fibrosis is a hallmark of chronic disease. Although fibroblasts are involved, it is unclear to what extent endothelial cells also might contribute. We detected increased expression of the transcription factor Sox9 in endothelial cells in several different mouse fibrosis models. These models included systolic heart failure induced by pressure overload, diastolic heart failure induced by high-fat diet
-
A functional identification platform reveals frequent, spontaneous neoantigen-specific T cell responses in patients with cancer Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-28 Aaron M. Miller, Zeynep Koşaloğlu-Yalçın, Luise Westernberg, Leslie Montero, Milad Bahmanof, Angela Frentzen, Manasa Lanka, Ashmitaa Logandha Ramamoorthy Premlal, Gregory Seumois, Jason Greenbaum, Spencer E. Brightman, Karla Soria Zavala, Rukman R. Thota, Martin S. Naradikian, Samir S. Makani, Scott M. Lippman, Alessandro Sette, Ezra E. W. Cohen, Bjoern Peters, Stephen P. Schoenberger
The clinical impact of tumor-specific neoantigens as both immunotherapeutic targets and biomarkers has been impeded by the lack of efficient methods for their identification and validation from routine samples. We have developed a platform that combines bioinformatic analysis of tumor exomes and transcriptional data with functional testing of autologous peripheral blood mononuclear cells (PBMCs) to
-
Inflammation and epithelial repair predict mortality, hospital readmission, and growth recovery in complicated severe acute malnutrition Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-28 Jonathan P. Sturgeon, Joice Tome, Cherlynn Dumbura, Florence D. Majo, Deophine Ngosa, Kuda Mutasa, Kanekwa Zyambo, Ellen Besa, Kanta Chandwe, Chanda Kapoma, Benjamin Mwapenya, Kusum J. Nathoo, Claire D. Bourke, Robert Ntozini, Bernard Chasekwa, Melanie Smuk, Mutsa Bwakura-Dangarembizi, Beatrice Amadi, Paul Kelly, Andrew J. Prendergast
Severe acute malnutrition (SAM) is the most high-risk form of undernutrition, particularly when children require hospitalization for complications. Complicated SAM is a multisystem disease with high inpatient and postdischarge mortality, especially in children with comorbidities such as HIV; however, the underlying pathogenesis of complicated SAM is poorly understood. Targeted multiplex biomarker analysis
-
Acetyl-CoA carboxylase 1 controls a lipid droplet–peroxisome axis and is a vulnerability of endocrine-resistant ER + breast cancer Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-28 Marina Bacci, Nicla Lorito, Alfredo Smiriglia, Angela Subbiani, Francesca Bonechi, Giuseppina Comito, Ludivine Morriset, Rania El Botty, Matteo Benelli, Joanna I. López-Velazco, Maria M. Caffarel, Ander Urruticoechea, George Sflomos, Luca Malorni, Michela Corsini, Luigi Ippolito, Elisa Giannoni, Icro Meattini, Vittoria Matafora, Kristina Havas, Angela Bachi, Paola Chiarugi, Elisabetta Marangoni, Andrea
Targeting aromatase deprives ER + breast cancers of estrogens and is an effective therapeutic approach for these tumors. However, drug resistance is an unmet clinical need. Lipidomic analysis of long-term estrogen-deprived (LTED) ER + breast cancer cells, a model of aromatase inhibitor resistance, revealed enhanced intracellular lipid storage. Functional metabolic analysis showed that lipid droplets
-
APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-28 Shihe Jiang, Xindi Li, Yan Li, Zhilin Chang, Meng Yuan, Ying Zhang, Huimin Zhu, Yuwen Xiu, Hengri Cong, Linlin Yin, Zhen-Wei Yu, Junwan Fan, Wenyan He, Kaibin Shi, De-Cai Tian, Jing Zhang, Alexei Verkhratsky, Wei-Na Jin, Fu-Dong Shi
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with
-
An anti-mycobacterial conjugated oligoelectrolyte effective against Mycobacterium abscessus Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-21 Kaixi Zhang, Jakkarin Limwongyut, Alex S. Moreland, Samuel Chan Jun Wei, Tania Jim Jia Min, Yan Sun, Sung Jae Shin, Su-Young Kim, Byung Woo Jhun, Kevin Pethe, Guillermo C. Bazan
Infections caused by nontuberculous mycobacteria have increased more than 50% in the past two decades and more than doubled in the elderly population. Mycobacterium abscessus (Mab), one of the most prevalent of these rapidly growing species, is intrinsically resistant to numerous antibiotics. Current standard-of-care treatments are not satisfactory, with high failure rate and notable adverse effects
-
Synthetic development of a broadly neutralizing antibody against snake venom long-chain α-neurotoxins Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-21 Irene S. Khalek, R. R. Senji Laxme, Yen Thi Kim Nguyen, Suyog Khochare, Rohit N. Patel, Jordan Woehl, Jessica M. Smith, Karen Saye-Francisco, Yoojin Kim, Laetitia Misson Mindrebo, Quoc Tran, Mateusz Kędzior, Evy Boré, Oliver Limbo, Megan Verma, Robyn L. Stanfield, Stefanie K. Menzies, Stuart Ainsworth, Robert A. Harrison, Dennis R. Burton, Devin Sok, Ian A. Wilson, Nicholas R. Casewell, Kartik Sunagar
Snakebite envenoming is a major global public health concern for which improved therapies are urgently needed. The antigenic diversity present in snake venom toxins from various species presents a considerable challenge to the development of a universal antivenom. Here, we used a synthetic human antibody library to find and develop an antibody that neutralizes long-chain three-finger α-neurotoxins
-
Lipid nanoparticles and siRNA targeting plasminogen provide lasting inhibition of fibrinolysis in mouse and dog models of hemophilia A Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-21 Amy W. Strilchuk, Woosuk S. Hur, Paul Batty, Yaqiu Sang, Sara R. Abrahams, Alyssa S.M. Yong, Jerry Leung, Lakmali M. Silva, Jocelyn A. Schroeder, Kate Nesbitt, Bas de Laat, Niki M. Moutsopoulos, Thomas H. Bugge, Qizhen Shi, Pieter R. Cullis, Elizabeth P. Merricks, Alisa S. Wolberg, Matthew J. Flick, David Lillicrap, Timothy C. Nichols, Christian J. Kastrup
Antifibrinolytic drugs are used extensively for on-demand treatment of severe acute bleeding. Controlling fibrinolysis may also be an effective strategy to prevent or lessen chronic recurring bleeding in bleeding disorders such as hemophilia A (HA), but current antifibrinolytics have unfavorable pharmacokinetic profiles. Here, we developed a long-lasting antifibrinolytic using small interfering RNA
-
Chondrocyte membrane–coated nanoparticles promote drug retention and halt cartilage damage in rat and canine osteoarthritis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-21 Ronghui Deng, Ruifang Zhao, Zining Zhang, Yang Chen, Meng Yang, Yixuan Lin, Jing Ye, Nan Li, Hao Qin, Xin Yan, Jian Shi, Fuzhen Yuan, Shitang Song, Zijie Xu, Yifan Song, Jiangnan Fu, Bingbing Xu, Guangjun Nie, Jia-Kuo Yu
Osteoarthritis (OA) is a chronic joint disease characterized by progressive degeneration of articular cartilage. A challenge in the development of disease-modifying drugs is effective delivery to chondrocytes. The unique structure of the joint promotes rapid clearance of drugs through synovial fluid, and the dense and avascular cartilage extracellular matrix (ECM) limits drug penetration. Here, we
-
Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-21 Marie Czech, Sophia Schneider, Nina Peltokangas, Nadia El Khawanky, Sakhila Ghimire, Geoffroy Andrieux, Jan Hülsdünker, Máté Krausz, Michele Proietti, Lukas M. Braun, Tamina Rückert, Marlene Langenbach, Dominik Schmidt, Ina Martin, Valentin Wenger, Enrique de Vega, Eileen Haring, Mohsen Pourjam, Dietmar Pfeifer, Annette Schmitt-Graeff, Bodo Grimbacher, Konrad Aumann, Brigitte Kircher, Herbert Tilg
Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), for which therapeutic options are limited. Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA sequencing, we identified a lipocalin-2 (LCN2)–expressing neutrophil population in mice with intestinal aGVHD
-
Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-14 Jiajia Chen, Daniel J. Laverty, Surabhi Talele, Ashwin Bale, Brett L. Carlson, Kendra A. Porath, Katrina K. Bakken, Danielle M. Burgenske, Paul A. Decker, Rachael A. Vaubel, Jeanette E. Eckel-Passow, Rohit Bhargava, Zhenkun Lou, Petra Hamerlik, Brendan Harley, William F. Elmquist, Zachary D. Nagel, Shiv K. Gupta, Jann N. Sarkaria
ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390
-
Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-14 Laura Díez-Alonso, Aïda Falgas, Javier Arroyo-Ródenas, Paola A. Romencín, Alba Martínez, Marina Gómez-Rosel, Belén Blanco, Anaïs Jiménez-Reinoso, Andrea Mayado, Alba Pérez-Pons, Óscar Aguilar-Sopeña, Ángel Ramírez-Fernández, Alejandro Segura-Tudela, Lorena Perez-Amill, Antonio Tapia-Galisteo, Carmen Domínguez-Alonso, Laura Rubio-Pérez, Maria Jara, Francesc Solé, Oana Hangiu, Laura Almagro, Ángela Albitre
Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)–directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising
-
Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-14 Lan Bai, Weiyi Qu, Xu Cheng, Hailong Yang, Yong-Ping Huang, Zhenya Wang, Cuijuan Han, Rui-Feng Tian, Fengjiao Hu, Ling Yang, Song Tian, Han Tian, Zhiwei Cai, Juan Wan, Jingwei Jiang, Jiajun Fu, Junjie Zhou, Yufeng Hu, Tengfei Ma, Xin Zhang, Yan-Xiao Ji, Jingjing Cai, Zhi-Gang She, Yibin Wang, Peng Zhang, Lingli Huang, Hongliang Li, Xiao-Jing Zhang
Nonalcoholic fatty liver (NAFL) remains relatively benign, but high-risk to end-stage liver diseases become highly prevalent when it progresses into nonalcoholic steatohepatitis (NASH). Our current understanding of the development of NAFL to NASH remains insufficient. In this study, we revealed MAP kinase (MAPK) activation as the most notable molecular signature associated with NASH progression across
-
Autologous transplantation of P63 + lung progenitor cells for chronic obstructive pulmonary disease therapy Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-14 Yujia Wang, Zili Meng, Ming Liu, Yueqing Zhou, Difei Chen, Yu Zhao, Ting Zhang, Nanshan Zhong, Xiaotian Dai, Shiyue Li, Wei Zuo
Adult lung resident stem/progenitor cells, including P63 + progenitor cells, have demonstrated the capacity for regeneration of lung epithelium in preclinical models. Here, we report a clinical trial of intrapulmonary P63 + progenitor cell transplantation in 28 participants with stage II to IV chronic obstructive pulmonary disease (COPD). Autologous P63 + progenitor cells were isolated from the airway
-
Dynamic load modulation predicts right heart tolerance of left ventricular cardiovascular assist in a porcine model of cardiogenic shock Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-14 Kimberly K. Lamberti, Steven P. Keller, Elazer R. Edelman
Ventricular assist devices (VADs) offer mechanical support for patients with cardiogenic shock by unloading the impaired ventricle and increasing cardiac outflow and subsequent tissue perfusion. Their ability to adjust ventricular assistance allows for rapid and safe dynamic changes in cardiac load, which can be used with direct measures of chamber pressures to quantify cardiac pathophysiologic state
-
DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser 56 to diminish pancreatic β cell function upon overnutrition Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-07 Yuting Lu, Junyu Xu, Yufeng Li, Ruoran Wang, Chengqiu Dai, Bingqian Zhang, Xinwen Zhang, Lei Xu, Yunhua Tao, Ming Han, Ren Guo, Qingqian Wu, Linshi Wu, Zhuoxian Meng, Minjia Tan, Jingya Li
Impeded autophagy can impair pancreatic β cell function by causing apoptosis, of which DAP-related apoptosis-inducing kinase-2 (DRAK2) is a critical regulator. Here, we identified a marked up-regulation of DRAK2 in pancreatic tissue across humans, macaques, and mice with type 2 diabetes (T2D). Further studies in mice showed that conditional knockout (cKO) of DRAK2 in pancreatic β cells protected β
-
Exonic knockout and knockin gene editing in hematopoietic stem and progenitor cells rescues RAG1 immunodeficiency Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-07 Maria Carmina Castiello, Chiara Brandas, Samuele Ferrari, Simona Porcellini, Nicolò Sacchetti, Daniele Canarutto, Elena Draghici, Ivan Merelli, Matteo Barcella, Gabriele Pelosi, Valentina Vavassori, Angelica Varesi, Aurelien Jacob, Serena Scala, Luca Basso Ricci, Marianna Paulis, Dario Strina, Martina Di Verniere, Lucia Sergi Sergi, Marta Serafini, Steven M. Holland, Jenna R. E. Bergerson, Suk See
Recombination activating genes ( RAGs ) are tightly regulated during lymphoid differentiation, and their mutations cause a spectrum of severe immunological disorders. Hematopoietic stem and progenitor cell (HSPC) transplantation is the treatment of choice but is limited by donor availability and toxicity. To overcome these issues, we developed gene editing strategies targeting a corrective sequence
-
IgE in allergy: It takes two Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-07 Anouk von Borstel, Robyn E. O’Hehir, Menno C. van Zelm
A type 2 memory B cell subset is poised to differentiate into IgE-producing plasma cells in individuals with allergies (Ota et al . and Koenig et al .).
-
CD23 + IgG1 + memory B cells are poised to switch to pathogenic IgE production in food allergy Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-07 Miyo Ota, Kenneth B. Hoehn, Weslley Fernandes-Braga, Takayuki Ota, Carlos J. Aranda, Sara Friedman, Mariana G. C. Miranda-Waldetario, Jamie Redes, Maria Suprun, Galina Grishina, Hugh A. Sampson, Alefiyah Malbari, Steven H. Kleinstein, Scott H. Sicherer, Maria A. Curotto de Lafaille
Food allergy is caused by allergen-specific immunoglobulin E (IgE) antibodies, but little is known about the B cell memory of persistent IgE responses. Here, we describe, in human pediatric peanut allergy, a population of CD23 + IgG1 + memory B cells arising in type 2 immune responses that contain high-affinity peanut-specific clones and generate IgE-producing cells upon activation. The frequency of
-
Integrating spatial and single-cell transcriptomics to characterize the molecular and cellular architecture of the ischemic mouse brain Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-07 Bing Han, Shunheng Zhou, Yuan Zhang, Sina Chen, Wen Xi, Chenchen Liu, Xu Zhou, Mengqin Yuan, Xiaoyu Yu, Lu Li, Yu Wang, Hui Ren, Jian Xie, Bin Li, Minzi Ju, You Zhou, Ziqi Liu, Zhongli Xiong, Ling Shen, Yuan Zhang, Ying Bai, Jun Chen, Wei Jiang, Honghong Yao
Neuroinflammation is acknowledged as a pivotal pathological event after cerebral ischemia. However, there is limited knowledge of the molecular and spatial characteristics of nonneuronal cells, as well as of the interactions between cell types in the ischemic brain. Here, we used spatial transcriptomics to study the ischemic hemisphere in mice after stroke and sequenced the transcriptomes of 19,777
-
Type 2–polarized memory B cells hold allergen-specific IgE memory Sci. Transl. Med. (IF 17.1) Pub Date : 2024-02-07 Joshua F. E. Koenig, Niels Peter H. Knudsen, Allyssa Phelps, Kelly Bruton, Ilka Hoof, Gitte Lund, Danielle Della Libera, Anders Lund, Lars Harder Christensen, David R. Glass, Tina D. Walker, Allison Fang, Susan Waserman, Manel Jordana, Peter S. Andersen
Allergen-specific immunoglobulin E (IgE) antibodies mediate pathology in diseases such as allergic rhinitis and food allergy. Memory B cells (MBCs) contribute to circulating IgE by regenerating IgE-producing plasma cells upon allergen encounter. Here, we report a population of type 2–polarized MBCs defined as CD23 hi , IL-4Rα hi , and CD32 low at both the transcriptional and surface protein levels
-
TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-31 Gan Zhao, Lulu Xue, Aaron I. Weiner, Ningqiang Gong, Stephanie Adams-Tzivelekidis, Joanna Wong, Maria E. Gentile, Ana N. Nottingham, Maria C. Basil, Susan M. Lin, Terren K. Niethamer, Joshua M. Diamond, Christian A. Bermudez, Edward Cantu, Xuexiang Han, Yaqi Cao, Mohamad-Gabriel Alameh, Drew Weissman, Edward E. Morrisey, Michael J. Mitchell, Andrew E. Vaughan
Disruption of pulmonary vascular homeostasis is a central feature of viral pneumonia, wherein endothelial cell (EC) death and subsequent angiogenic responses are critical determinants of the outcome of severe lung injury. A more granular understanding of the fundamental mechanisms driving reconstitution of lung endothelium is necessary to facilitate therapeutic vascular repair. Here, we demonstrated
-
Rescuing lung development through embryonic inhibition of histone acetylation Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-31 Giangela Stokes, Zhuowei Li, Nicole Talaba, William Genthe, Maria B. Brix, Betty Pham, Mark D. Wienhold, Gracia Sandok, Rebecca Hernan, Julia Wynn, Haiyang Tang, Diana M. Tabima, Allison Rodgers, Timothy A. Hacker, Naomi C. Chesler, Pan Zhang, Rabi Murad, Jason X. -J. Yuan, Yufeng Shen, Wendy K. Chung, David J. McCulley
A major barrier to the impact of genomic diagnosis in patients with congenital malformations is the lack of understanding regarding how sequence variants contribute to disease pathogenesis and whether this information could be used to generate patient-specific therapies. Congenital diaphragmatic hernia (CDH) is among the most common and severe of all structural malformations; however, its underlying
-
Improved immunostaining of nanostructures and cells in human brain specimens through expansion-mediated protein decrowding Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-31 Pablo A. Valdes, Chih-Chieh (Jay) Yu, Jenna Aronson, Debarati Ghosh, Yongxin Zhao, Bobae An, Joshua D. Bernstock, Deepak Bhere, Michelle M. Felicella, Mariano S. Viapiano, Khalid Shah, E. Antonio Chiocca, Edward S. Boyden
Proteins are densely packed in cells and tissues, where they form complex nanostructures. Expansion microscopy (ExM) variants have been used to separate proteins from each other in preserved biospecimens, improving antibody access to epitopes. Here, we present an ExM variant, decrowding expansion pathology (dExPath), that can expand proteins away from each other in human brain pathology specimens,
-
Myeloid and lymphoid expression of C9orf72 regulates IL-17A signaling in mice Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-31 Francesco Limone, Alexander Couto, Jin-Yuan Wang, Yingying Zhang, Blake McCourt, Cerianne Huang, Adina Minkin, Marghi Jani, Sarah McNeer, James Keaney, Gaëlle Gillet, Rodrigo Lopez Gonzalez, Wendy A. Goodman, Irena Kadiu, Kevin Eggan, Aaron Burberry
A mutation in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Patients with ALS or FTD often develop autoimmunity and inflammation that precedes or coincides with the onset of neurological symptoms, but the underlying mechanisms are poorly understood. Here, we knocked out murine C9orf72 in seven hematopoietic progenitor compartments by conditional
-
Integrating the gut microbiome and pharmacology Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-31 Andrew A. Verdegaal, Andrew L. Goodman
The gut microbiome harbors trillions of organisms that contribute to human health and disease. These bacteria can also affect the properties of medical drugs used to treat these diseases, and drugs, in turn, can reshape the microbiome. Research addressing interdependent microbiome-host-drug interactions thus has broad impact. In this Review, we discuss these interactions from the perspective of drug
-
Bone morphogenetic protein 9 is a candidate prognostic biomarker and host-directed therapy target for sepsis Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-31 Haobo Bai, Qian Lu, Chunxiang Wu, Fang Xu, Jiayu Liu, Ke Wang, Hao Ding, Yibing Yin, Yi Liu, Xiaofei Lai, Ju Cao
Defining next-generation immune therapeutics for the treatment of sepsis will involve biomarker-based therapeutic decision-making. Bone morphogenetic protein 9 (BMP9) is a cytokine in the transforming growth factor–β superfamily. Here, circulating BMP9 concentrations were quantified in two independent cohorts of patients with sepsis. Decreased concentrations of serum BMP9 were observed in the patients
-
Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-26 Sahba Seddighi, Yue A. Qi, Anna-Leigh Brown, Oscar G. Wilkins, Colleen Bereda, Cedric Belair, Yong-Jie Zhang, Mercedes Prudencio, Matthew J. Keuss, Aditya Khandeshi, Sarah Pickles, Sarah E. Kargbo-Hill, James Hawrot, Daniel M. Ramos, Hebao Yuan, Jessica Roberts, Erika Kelmer Sacramento, Syed I. Shah, Mike A. Nalls, Jennifer M. Colón-Mercado, Joel F. Reyes, Veronica H. Ryan, Matthew P. Nelson, Casey
Functional loss of TDP-43, an RNA-binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that
-
Single-cell atlas of human infrapatellar fat pad and synovium implicates APOE signaling in osteoarthritis pathology Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-24 Su’an Tang, Lutian Yao, Jianzhao Ruan, Jingliang Kang, Yumei Cao, Xiaoyu Nie, Weiren Lan, Zhaohua Zhu, Weiyu Han, Yongguang Liu, Jing Tian, Patrick Seale, Ling Qin, Changhai Ding
The infrapatellar fat pad (IPFP) and synovium play essential roles in maintaining knee joint homeostasis and in the progression of osteoarthritis (OA). The cellular and transcriptional mechanisms regulating the function of these specialized tissues under healthy and diseased conditions are largely unknown. Here, single-cell and single-nuclei RNA sequencing of human IPFP and synovial tissues were performed
-
The CSF-1R inhibitor pexidartinib affects FLT3-dependent DC differentiation and may antagonize durvalumab effect in patients with advanced cancers Sci. Transl. Med. (IF 17.1) Pub Date : 2024-01-24 Aurélien Voissière, Carlos Gomez-Roca, Sylvie Chabaud, Céline Rodriguez, Axelle Nkodia, Justine Berthet, Laure Montane, Anne-Sophie Bidaux, Isabelle Treilleux, Lauriane Eberst, Catherine Terret, Iphigénie Korakis, Gwenaelle Garin, David Pérol, Jean-Pierre Delord, Christophe Caux, Bertrand Dubois, Christine Ménétrier-Caux, Nathalie Bendriss-Vermare, Philippe A. Cassier
Tumor-associated macrophages (TAMs) are a critical determinant of resistance to PD-1/PD-L1 blockade. This phase 1 study (MEDIPLEX, NCT02777710) investigated the safety and efficacy of pexidartinib, a CSF-1R–directed tyrosine kinase inhibitor (TKI), and durvalumab (anti–PD-L1) in patients with advanced colorectal and pancreatic carcinoma with the aim to enhance responses to PD-L1 blockade by eliminating