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JCI - PROTOTYPE PATHOGEN APPROACH FOR PANDEMIC7 The COVID-19 pandemic of acute respiratory disease caused by SARS–CoV-2 coronavirus (CoV) is an unparalleled event that harkens back to days before viruses could be seen or understood. JCI - NASAL CILIATED CELLS ARE PRIMARY TARGETS FOR SARS 2 Department of Otorhinolaryngology-Head and Neck Surgery, Uijeongbu Eulji Medical Center, Uijeongbu, Korea, Republic of. 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea, Republic of. JCI - SARS–COV-2 INFECTION OF THE PLACENTA BACKGROUND The effects of the novel coronavirus disease 2019 (COVID-19) in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic COVID-19 complicated by severe preeclampsia and placental abruption.METHODS We analyzed the placenta for the presence of severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) through molecular JCI - A TRIBUTE TO BETH LEVINE (1960–2020) Beth C. Levine, MD, professor of internal medicine and microbiology at UT Southwestern and investigator at the Howard Hughes Medical Institute, passed away on June 15, 2020, of metastatic breast cancer ().She is survived by her husband, Dr. Milton Packer, a cardiologist and expert in heart failure, and her children, Rachel and Benjamin. JCI - CLIMATE CHANGE BRINGS THE SPECTER OF NEW INFECTIOUS20 View PDF. Climate change will bring major changes to the epidemiology of infectious diseases through changes in microbial and vector geographic range. Human defenses against microbial diseases rely on advanced immunity that includes innate and adaptive arms and endothermy, which creates a thermal restriction zone for many microbes. Given that JCI - TARGETING THE MYOSTATIN SIGNALING PATHWAY TO TREAT Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. JCI - CONTROVERSIES SURROUNDING FEMALE ATHLETES WITH The above-mentioned advantages explain why testosterone is the most common illicit performance-enhancing drug used by female athletes. However, the advantages of endogenously occurring androgens are unclear and remain debatable in the literature. JCI - LEAP2 CHANGES WITH BODY MASS AND FOOD INTAKE IN LEAP2 is synthesized as a 77–amino acid prohormone in humans (76 amino acids in mice) ( 42) that subsequently is processed to its mature form consisting of 40 amino acids with 2 disulfide bridges spanning 4 highly conserved cysteine residues ( 41, 44 ). The mature LEAP2 sequence is identical in mice and humans. JCI - TLR3 AGONIST AND CD40-TARGETING VACCINATION INDUCES 1 Lineberger Comprehensive Cancer Center, and. 2 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.. 3 Service of Immunology and Allergy and. 4 Swiss Vaccine Research Institute, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.. 5 Research Center for Clinical & Translational JCI - IMMUNOASSAY OF ENDOGENOUS PLASMA INSULIN IN MAN Published in Volume 39, Issue 7 on July 1, 1960 J Clin Invest. 1960;39(7):1157–1175. https://doi.org/10.1172/JCI104130. © 1960 The American Society for Clinical JCI - PROTOTYPE PATHOGEN APPROACH FOR PANDEMIC7 The COVID-19 pandemic of acute respiratory disease caused by SARS–CoV-2 coronavirus (CoV) is an unparalleled event that harkens back to days before viruses could be seen or understood. JCI - NASAL CILIATED CELLS ARE PRIMARY TARGETS FOR SARS 2 Department of Otorhinolaryngology-Head and Neck Surgery, Uijeongbu Eulji Medical Center, Uijeongbu, Korea, Republic of. 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea, Republic of. JCI - SARS–COV-2 INFECTION OF THE PLACENTA BACKGROUND The effects of the novel coronavirus disease 2019 (COVID-19) in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic COVID-19 complicated by severe preeclampsia and placental abruption.METHODS We analyzed the placenta for the presence of severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) through molecular JCI - A TRIBUTE TO BETH LEVINE (1960–2020) Beth C. Levine, MD, professor of internal medicine and microbiology at UT Southwestern and investigator at the Howard Hughes Medical Institute, passed away on June 15, 2020, of metastatic breast cancer ().She is survived by her husband, Dr. Milton Packer, a cardiologist and expert in heart failure, and her children, Rachel and Benjamin. JCI - CLIMATE CHANGE BRINGS THE SPECTER OF NEW INFECTIOUS20 View PDF. Climate change will bring major changes to the epidemiology of infectious diseases through changes in microbial and vector geographic range. Human defenses against microbial diseases rely on advanced immunity that includes innate and adaptive arms and endothermy, which creates a thermal restriction zone for many microbes. Given that JCI - TARGETING THE MYOSTATIN SIGNALING PATHWAY TO TREAT Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. JCI - CONTROVERSIES SURROUNDING FEMALE ATHLETES WITH The above-mentioned advantages explain why testosterone is the most common illicit performance-enhancing drug used by female athletes. However, the advantages of endogenously occurring androgens are unclear and remain debatable in the literature. JCI - LEAP2 CHANGES WITH BODY MASS AND FOOD INTAKE IN LEAP2 is synthesized as a 77–amino acid prohormone in humans (76 amino acids in mice) ( 42) that subsequently is processed to its mature form consisting of 40 amino acids with 2 disulfide bridges spanning 4 highly conserved cysteine residues ( 41, 44 ). The mature LEAP2 sequence is identical in mice and humans. JCI - TLR3 AGONIST AND CD40-TARGETING VACCINATION INDUCES 1 Lineberger Comprehensive Cancer Center, and. 2 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.. 3 Service of Immunology and Allergy and. 4 Swiss Vaccine Research Institute, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.. 5 Research Center for Clinical & Translational JCI - IMMUNOASSAY OF ENDOGENOUS PLASMA INSULIN IN MAN Published in Volume 39, Issue 7 on July 1, 1960 J Clin Invest. 1960;39(7):1157–1175. https://doi.org/10.1172/JCI104130. © 1960 The American Society for Clinical JCI - PROTOTYPE PATHOGEN APPROACH FOR PANDEMIC The COVID-19 pandemic of acute respiratory disease caused by SARS–CoV-2 coronavirus (CoV) is an unparalleled event that harkens back to days before viruses could be seen or understood. JCI - SARS–COV-2 INFECTION OF THE PLACENTA For the tissues, 80–160 mg was used for extractions, and for the swabs in viral transport media and other liquid samples, 0.25–0.4 mL was used. ND, not detected. ( B) The SARS–CoV-2 genome sequenced from the infected placenta was combined with 289 other genomes available from GISAID from around the world. JCI - SARS–COV-2 INFECTION OF THE PLACENTA BACKGROUND The effects of the novel coronavirus disease 2019 (COVID-19) in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic COVID-19 complicated by severe preeclampsia and placental abruption.METHODS We analyzed the placenta for the presence of severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) through molecular JCI - TURNING LEAD INTO GOLD: REPROGRAMMING RETINAL CELLS 1 Departments of Neuroscience,. 2 Neurology, and. 3 Ophthalmology,. 4 Institute for Cell Engineering, and. 5 Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.. 6 Center for Brain Science and. 7 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.. Address correspondence to: Seth JCI - CHRONIC LYMPHOCYTIC LEUKEMIA B CELLS CONTAIN 1 Department of Clinical and Experimental Medicine, Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy. 2 Venetian Institute for Molecular Medicine (VIMM), Centro di Eccellenza per la Ricerca Biomedica, and 3 Department of Biological Chemistry, University of Padua, Padua, Italy.. Address correspondence to: Livio Trentin, Università di Padova, Dipartimento di JCI - IMPAIRED HUMORAL AND CELLULAR IMMUNITY AFTER SARS 1 Department for General and Visceral Surgery, Charité–Universitätsmedizin Berlin, Berlin, Germany. 2 Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Berlin, Germany. 3 Department of Dialysis, MVZ Diaverum Neubrandenburg, Neubrandenburg, Germany. 4 General and Visceral Department for General and Visceral Surgery, Charité–Universitätsmedizin Berlin JCI - SEX-DEPENDENT COMPENSATORY MECHANISMS PRESERVE BLOOD 1 Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Phialdelphia, United States of America. 2 Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America. 3 Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Phialdelphia, United JCI - MONOCYTE METABOLIC TRANSCRIPTIONAL PROGRAMS 1 Department of Medicine, University of Washington, Seattle, United States of America. 2 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States of America. 3 Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, United States of America. 4 School of Public Health, University of Witwatersrand JCI - HISTONE DEFICIENCY AND ACCELERATED REPLICATION With increasing age, individuals are more vulnerable to viral infections such as with influenza or the SARS-CoV-2 virus. One age-associated defect in human T cells is the reduced expression of miR-181a. miR-181ab1 deficiency in peripheral murine T cells causes delayed viral clearance after infection, resembling human immune

aging.

JCI - SEX-DEPENDENT COMPENSATORY MECHANISMS PRESERVE BLOOD Inhibitors of mPges-1 are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis and fails to accelerate thrombogenesis, while suppressing PGE2, but increasing biosynthesis of PGI2. JCI - NASAL CILIATED CELLS ARE PRIMARY TARGETS FOR SARS 2 Department of Otorhinolaryngology-Head and Neck Surgery, Uijeongbu Eulji Medical Center, Uijeongbu, Korea, Republic of. 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea, Republic of. JCI - CLIMATE CHANGE BRINGS THE SPECTER OF NEW INFECTIOUS20 View PDF. Climate change will bring major changes to the epidemiology of infectious diseases through changes in microbial and vector geographic range. Human defenses against microbial diseases rely on advanced immunity that includes innate and adaptive arms and endothermy, which creates a thermal restriction zone for many microbes. Given that JCI - TARGETING THE MYOSTATIN SIGNALING PATHWAY TO TREAT Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. JCI - TURNING LEAD INTO GOLD: REPROGRAMMING RETINAL CELLS 1 Departments of Neuroscience,. 2 Neurology, and. 3 Ophthalmology,. 4 Institute for Cell Engineering, and. 5 Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.. 6 Center for Brain Science and. 7 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.. Address correspondence to: Seth JCI - FOLLICULAR DENDRITIC CELL DYSFUNCTION CONTRIBUTES TO 1 Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institutes for Medical Research, Manhasset, United States of America. 2 Center for Biomedical Science, The Feinstein Institutes for Medical Research, Manhasset, United States of America. 3 Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, United States of America JCI - A TRIBUTE TO BETH LEVINE (1960–2020) Beth C. Levine, MD, professor of internal medicine and microbiology at UT Southwestern and investigator at the Howard Hughes Medical Institute, passed away on June 15, 2020, of metastatic breast cancer ( Figure 1 ). She is survived by her husband, Dr. Milton Packer, a cardiologist and expert in heart failure, and her children, Rachel and

Benjamin.

JCI - INHIBITING THE MNK1/2-EIF4E AXIS IMPAIRS MELANOMA Melanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Such tumor cell plasticity contributes to immunotherapy resistance; however, the mechanisms are not completely understood and thus are therapeutically unexploited. JCI - INCREASED ADIPOSE TISSUE EXPRESSION OF TUMOR Obesity is frequently associated with insulin resistance and abnormal glucose homeostasis. Recent studies in animal models have indicated that TNF-alpha plays an important role in mediating the insulin resistance of obesity through its overexpression in fat tissue. JCI - CANNABINOIDS PROMOTE EMBRYONIC AND ADULT HIPPOCAMPUS 1 Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. 2 Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China. 3 Department of Biomedical Sciences, Dental School, Program in Neuroscience, University of Maryland, Baltimore, Maryland, USA.

JCI INSIGHT

Publication fees (in US$) assessed to authors help support publication of JCI Insight. Authors will be assessed $3650 for publication of articles, and the invoice will be provided along with the publication proofs. See JCI Insight’s Open Access information page for further

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JCI - NASAL CILIATED CELLS ARE PRIMARY TARGETS FOR SARS 2 Department of Otorhinolaryngology-Head and Neck Surgery, Uijeongbu Eulji Medical Center, Uijeongbu, Korea, Republic of. 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea, Republic of. JCI - CLIMATE CHANGE BRINGS THE SPECTER OF NEW INFECTIOUS20 View PDF. Climate change will bring major changes to the epidemiology of infectious diseases through changes in microbial and vector geographic range. Human defenses against microbial diseases rely on advanced immunity that includes innate and adaptive arms and endothermy, which creates a thermal restriction zone for many microbes. Given that JCI - TARGETING THE MYOSTATIN SIGNALING PATHWAY TO TREAT Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. JCI - TURNING LEAD INTO GOLD: REPROGRAMMING RETINAL CELLS 1 Departments of Neuroscience,. 2 Neurology, and. 3 Ophthalmology,. 4 Institute for Cell Engineering, and. 5 Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.. 6 Center for Brain Science and. 7 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.. Address correspondence to: Seth JCI - FOLLICULAR DENDRITIC CELL DYSFUNCTION CONTRIBUTES TO 1 Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institutes for Medical Research, Manhasset, United States of America. 2 Center for Biomedical Science, The Feinstein Institutes for Medical Research, Manhasset, United States of America. 3 Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, United States of America JCI - A TRIBUTE TO BETH LEVINE (1960–2020) Beth C. Levine, MD, professor of internal medicine and microbiology at UT Southwestern and investigator at the Howard Hughes Medical Institute, passed away on June 15, 2020, of metastatic breast cancer ( Figure 1 ). She is survived by her husband, Dr. Milton Packer, a cardiologist and expert in heart failure, and her children, Rachel and

Benjamin.

JCI INSIGHT

details.

JCI - WELCOME

The Journal of Clinical Investigation; Current issue; Past issues; Specialties; Reviews; Review series; Videos; Conversations with Giants

in Medicine

JCI - PROTOTYPE PATHOGEN APPROACH FOR PANDEMIC The COVID-19 pandemic of acute respiratory disease caused by SARS–CoV-2 coronavirus (CoV) is an unparalleled event that harkens back to days before viruses could be seen or understood. JCI - A TRIBUTE TO BETH LEVINE (1960–2020) Beth C. Levine, MD, professor of internal medicine and microbiology at UT Southwestern and investigator at the Howard Hughes Medical Institute, passed away on June 15, 2020, of metastatic breast cancer ( Figure 1 ). She is survived by her husband, Dr. Milton Packer, a cardiologist and expert in heart failure, and her children, Rachel and

Benjamin.

JCI - TURNING LEAD INTO GOLD: REPROGRAMMING RETINAL CELLS 1 Departments of Neuroscience,. 2 Neurology, and. 3 Ophthalmology,. 4 Institute for Cell Engineering, and. 5 Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.. 6 Center for Brain Science and. 7 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.. Address correspondence to: Seth JCI - CHRONIC LYMPHOCYTIC LEUKEMIA B CELLS CONTAIN 1 Department of Clinical and Experimental Medicine, Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy. 2 Venetian Institute for Molecular Medicine (VIMM), Centro di Eccellenza per la Ricerca Biomedica, and 3 Department of Biological Chemistry, University of Padua, Padua, Italy.. Address correspondence to: Livio Trentin, Università di Padova, Dipartimento di JCI - MONOCYTE METABOLIC TRANSCRIPTIONAL PROGRAMS 1 Department of Medicine, University of Washington, Seattle, United States of America. 2 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States of America. 3 Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, United States of America. 4 School of Public Health, University of Witwatersrand JCI - IMPAIRED HUMORAL AND CELLULAR IMMUNITY AFTER SARS 1 Department for General and Visceral Surgery, Charité–Universitätsmedizin Berlin, Berlin, Germany. 2 Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Berlin, Germany. 3 Department of Dialysis, MVZ Diaverum Neubrandenburg, Neubrandenburg, Germany. 4 General and Visceral Department for General and Visceral Surgery, Charité–Universitätsmedizin Berlin JCI - SEX-DEPENDENT COMPENSATORY MECHANISMS PRESERVE BLOOD 1 Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Phialdelphia, United States of America. 2 Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America. 3 Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Phialdelphia, United JCI - HISTONE DEFICIENCY AND ACCELERATED REPLICATION With increasing age, individuals are more vulnerable to viral infections such as with influenza or the SARS-CoV-2 virus. One age-associated defect in human T cells is the reduced expression of miR-181a. miR-181ab1 deficiency in peripheral murine T cells causes delayed viral clearance after infection, resembling human immune

aging.

JCI INSIGHT

In this issue of JCI Insight, Artibani et al. characterized the molecular characteristics of minimal residual disease in patients with ovarian cancer to better understand the drivers of survival and cancer recurrence. Their findings identified metabolic rewiring and fat dependency, as well as a portion of cells that had undergone epithelial-mesenchymal transition. JCI - NASAL CILIATED CELLS ARE PRIMARY TARGETS FOR SARS 2 Department of Otorhinolaryngology-Head and Neck Surgery, Uijeongbu Eulji Medical Center, Uijeongbu, Korea, Republic of. 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea, Republic of. JCI - CLIMATE CHANGE BRINGS THE SPECTER OF NEW INFECTIOUS20 View PDF. Climate change will bring major changes to the epidemiology of infectious diseases through changes in microbial and vector geographic range. Human defenses against microbial diseases rely on advanced immunity that includes innate and adaptive arms and endothermy, which creates a thermal restriction zone for many microbes. Given that JCI - TARGETING THE MYOSTATIN SIGNALING PATHWAY TO TREAT Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. JCI - TURNING LEAD INTO GOLD: REPROGRAMMING RETINAL CELLS 1 Departments of Neuroscience,. 2 Neurology, and. 3 Ophthalmology,. 4 Institute for Cell Engineering, and. 5 Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.. 6 Center for Brain Science and. 7 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.. Address correspondence to: Seth JCI - FOLLICULAR DENDRITIC CELL DYSFUNCTION CONTRIBUTES TO 1 Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institutes for Medical Research, Manhasset, United States of America. 2 Center for Biomedical Science, The Feinstein Institutes for Medical Research, Manhasset, United States of America. 3 Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, United States of America JCI - A TRIBUTE TO BETH LEVINE (1960–2020) Beth C. Levine, MD, professor of internal medicine and microbiology at UT Southwestern and investigator at the Howard Hughes Medical Institute, passed away on June 15, 2020, of metastatic breast cancer ( Figure 1 ). She is survived by her husband, Dr. Milton Packer, a cardiologist and expert in heart failure, and her children, Rachel and

Benjamin.

JCI INSIGHT

details.

Benjamin.

JCI INSIGHT

details.

JCI - WELCOME

The Journal of Clinical Investigation; Current issue; Past issues; Specialties; Reviews; Review series; Videos; Conversations with Giants

in Medicine

Benjamin.

aging.

JCI INSIGHT

In this issue of JCI Insight, Artibani et al. characterized the molecular characteristics of minimal residual disease in patients with ovarian cancer to better understand the drivers of survival and cancer recurrence. Their findings identified metabolic rewiring and fat dependency, as well as a portion of cells that had undergone epithelial-mesenchymal transition. JCI - NASAL CILIATED CELLS ARE PRIMARY TARGETS FOR SARS 2 Department of Otorhinolaryngology-Head and Neck Surgery, Uijeongbu Eulji Medical Center, Uijeongbu, Korea, Republic of. 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea, Republic of. JCI - CLIMATE CHANGE BRINGS THE SPECTER OF NEW INFECTIOUS19 View PDF. Climate change will bring major changes to the epidemiology of infectious diseases through changes in microbial and vector geographic range. Human defenses against microbial diseases rely on advanced immunity that includes innate and adaptive arms and endothermy, which creates a thermal restriction zone for many microbes. Given that JCI - TARGETING THE MYOSTATIN SIGNALING PATHWAY TO TREAT Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. JCI - TURNING LEAD INTO GOLD: REPROGRAMMING RETINAL CELLS 1 Departments of Neuroscience,. 2 Neurology, and. 3 Ophthalmology,. 4 Institute for Cell Engineering, and. 5 Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.. 6 Center for Brain Science and. 7 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.. Address correspondence to: Seth JCI - FOLLICULAR DENDRITIC CELL DYSFUNCTION CONTRIBUTES TO 1 Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institutes for Medical Research, Manhasset, United States of America. 2 Center for Biomedical Science, The Feinstein Institutes for Medical Research, Manhasset, United States of America. 3 Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, United States of America JCI - A TRIBUTE TO BETH LEVINE (1960–2020) Beth C. Levine, MD, professor of internal medicine and microbiology at UT Southwestern and investigator at the Howard Hughes Medical Institute, passed away on June 15, 2020, of metastatic breast cancer ( Figure 1 ). She is survived by her husband, Dr. Milton Packer, a cardiologist and expert in heart failure, and her children, Rachel and

Benjamin.

JCI INSIGHT

details.

JCI - NASAL CILIATED CELLS ARE PRIMARY TARGETS FOR SARS 2 Department of Otorhinolaryngology-Head and Neck Surgery, Uijeongbu Eulji Medical Center, Uijeongbu, Korea, Republic of. 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea, Republic of. JCI - CLIMATE CHANGE BRINGS THE SPECTER OF NEW INFECTIOUS19 View PDF. Climate change will bring major changes to the epidemiology of infectious diseases through changes in microbial and vector geographic range. Human defenses against microbial diseases rely on advanced immunity that includes innate and adaptive arms and endothermy, which creates a thermal restriction zone for many microbes. Given that JCI - TARGETING THE MYOSTATIN SIGNALING PATHWAY TO TREAT Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. JCI - TURNING LEAD INTO GOLD: REPROGRAMMING RETINAL CELLS 1 Departments of Neuroscience,. 2 Neurology, and. 3 Ophthalmology,. 4 Institute for Cell Engineering, and. 5 Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.. 6 Center for Brain Science and. 7 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.. Address correspondence to: Seth JCI - FOLLICULAR DENDRITIC CELL DYSFUNCTION CONTRIBUTES TO 1 Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institutes for Medical Research, Manhasset, United States of America. 2 Center for Biomedical Science, The Feinstein Institutes for Medical Research, Manhasset, United States of America. 3 Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, United States of America JCI - A TRIBUTE TO BETH LEVINE (1960–2020) Beth C. Levine, MD, professor of internal medicine and microbiology at UT Southwestern and investigator at the Howard Hughes Medical Institute, passed away on June 15, 2020, of metastatic breast cancer ( Figure 1 ). She is survived by her husband, Dr. Milton Packer, a cardiologist and expert in heart failure, and her children, Rachel and

Benjamin.

JCI INSIGHT

details.

JCI - WELCOME

The Journal of Clinical Investigation; Current issue; Past issues; Specialties; Reviews; Review series; Videos; Conversations with Giants

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JCI - WELCOME

Vyacheslav Y. Melnikov, Sarah Faubel, Britta Siegmund, M. Scott Lucia, Danica Ljubanovic, Charles L. Edelstein JCI - MONOCYTE METABOLIC TRANSCRIPTIONAL PROGRAMS 1 Department of Medicine, University of Washington, Seattle, United States of America. 2 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States of America. 3 Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, United States of America. 4 School of Public Health, University of Witwatersrand JCI - SEX-DEPENDENT COMPENSATORY MECHANISMS PRESERVE BLOOD 1 Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Phialdelphia, United States of America. 2 Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America. 3 Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Phialdelphia, United JCI - IMPAIRED HUMORAL AND CELLULAR IMMUNITY AFTER SARS 1 Department for General and Visceral Surgery, Charité–Universitätsmedizin Berlin, Berlin, Germany. 2 Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Berlin, Germany. 3 Department of Dialysis, MVZ Diaverum Neubrandenburg, Neubrandenburg, Germany. 4 General and Visceral Department for General and Visceral Surgery, Charité–Universitätsmedizin Berlin

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Korea, Republic of

JCI - A TRIBUTE TO BETH LEVINE (1960–2020) Beth C. Levine, MD, professor of internal medicine and microbiology at UT Southwestern and investigator at the Howard Hughes Medical Institute, passed away on June 15, 2020, of metastatic breast cancer ( Figure 1 ). She is survived by her husband, Dr. Milton Packer, a cardiologist and expert in heart failure, and her children, Rachel and

Benjamin.

JCI - TARGETING THE MYOSTATIN SIGNALING PATHWAY TO TREAT Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. JCI - CLIMATE CHANGE BRINGS THE SPECTER OF NEW INFECTIOUS19 View PDF. Climate change will bring major changes to the epidemiology of infectious diseases through changes in microbial and vector geographic range. Human defenses against microbial diseases rely on advanced immunity that includes innate and adaptive arms and endothermy, which creates a thermal restriction zone for many microbes. Given that JCI - GLOBAL WARMING THREATENS HUMAN THERMOREGULATION AND As the Earth’s climate warms, hotter days and nights and heat waves are becoming more frequent and intense (1, 2, 5).Global warming is pushing the climate temperature curve toward the extreme range ().Since the 1960s, the number of heat waves, defined as 2 or more consecutive days where temperatures exceeded historical summer (July and August) temperatures, has tripled in JCI - CONTROVERSIES SURROUNDING FEMALE ATHLETES WITH The above-mentioned advantages explain why testosterone is the most common illicit performance-enhancing drug used by female athletes. However, the advantages of endogenously occurring androgens are unclear and remain debatable in the literature. JCI - TLR3 AGONIST AND CD40-TARGETING VACCINATION INDUCES 1 Lineberger Comprehensive Cancer Center, and. 2 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.. 3 Service of Immunology and Allergy and. 4 Swiss Vaccine Research Institute, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.. 5 Research Center for Clinical & Translational

JCI - WELCOME

Hypoxia is a common finding in all stages of liver cancer development. Hypoxia drives the stabilization of hypoxia-inducible factors (HIFs), which act as central regulators to dampen the innate immunity of liver cancer. HIF signaling in innate immune cells and liver cancer cells together favors the recruitment and maintenance of pro-tumorigenic JCI - IMMUNOASSAY OF ENDOGENOUS PLASMA INSULIN IN MAN Published in Volume 39, Issue 7 on July 1, 1960 J Clin Invest. 1960;39(7):1157–1175. https://doi.org/10.1172/JCI104130. © 1960 The American Society for Clinical JCI - SARS–COV-2 INFECTION OF THE PLACENTA129 For the tissues, 80–160 mg was used for extractions, and for the swabs in viral transport media and other liquid samples, 0.25–0.4 mL was used. ND, not detected. ( B) The SARS–CoV-2 genome sequenced from the infected placenta was combined with 289 other genomes available from GISAID from around the world. JCI - NASAL CILIATED CELLS ARE PRIMARY TARGETS FOR SARS 1 Center for Vascular Research, Institute for Basic Science (IBS), Daejeon, Korea, Republic of. 2 Department of Otorhinolaryngology-Head and Neck Surgery, Uijeongbu Eulji Medical Center, Uijeongbu, Korea, Republic of. 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon,

Korea, Republic of

Benjamin.

JCI - WELCOME

Hypoxia is a common finding in all stages of liver cancer development. Hypoxia drives the stabilization of hypoxia-inducible factors (HIFs), which act as central regulators to dampen the innate immunity of liver cancer. HIF signaling in innate immune cells and liver cancer cells together favors the recruitment and maintenance of pro-tumorigenic JCI - IMMUNOASSAY OF ENDOGENOUS PLASMA INSULIN IN MAN Published in Volume 39, Issue 7 on July 1, 1960 J Clin Invest. 1960;39(7):1157–1175. https://doi.org/10.1172/JCI104130. © 1960 The American Society for Clinical JCI - PROTOTYPE PATHOGEN APPROACH FOR PANDEMIC The COVID-19 pandemic of acute respiratory disease caused by SARS–CoV-2 coronavirus (CoV) is an unparalleled event that harkens back to days before viruses could be seen or understood. JCI - SARS–COV-2 INFECTION OF THE PLACENTA For the tissues, 80–160 mg was used for extractions, and for the swabs in viral transport media and other liquid samples, 0.25–0.4 mL was used. ND, not detected. ( B) The SARS–CoV-2 genome sequenced from the infected placenta was combined with 289 other genomes available from GISAID from around the world.

JCI - WELCOME

Vyacheslav Y. Melnikov, Sarah Faubel, Britta Siegmund, M. Scott Lucia, Danica Ljubanovic, Charles L. Edelstein JCI - THE ISRAELI STUDY OF PFIZER BNT162B2 VACCINE IN Pregnant patients with COVID-19 are more likely to require intensive care and die compared with non-infected pregnant women. While the consequences of COVID-19 disease in pregnancy prompted many health care organizations to support vaccination in pregnancy, vaccine effects for mother and infant remained unclear. JCI - IMPAIRED HUMORAL AND CELLULAR IMMUNITY AFTER SARS Novel mRNA-based vaccines have been proven powerful tools to combat the global pandemic caused by SARS-CoV2 with BNT162b2 (trade name: Comirnaty) efficiently protecting individuals from COVID-19 across a

broad age range.

JCI - THE ISRAELI STUDY OF PFIZER BNT162B2 VACCINE IN 1 Integrated Research Center for Fetal Medicine, Department of Gynecology and, Johns Hopkins University School of Medicine, Baltimore, United States of America. 2 Laboratory of Molecular and Genomic Endocrinology, Sidra Medicine, Doha, Qatar. 3 Division of Reproductive Sciences, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, United States of JCI - HISTONE DEFICIENCY AND ACCELERATED REPLICATION With increasing age, individuals are more vulnerable to viral infections such as with influenza or the SARS-CoV-2 virus. One age-associated defect in human T cells is the reduced expression of miR-181a. miR-181ab1 deficiency in peripheral murine T cells causes delayed viral clearance after infection, resembling human immune

aging.

JCI - STRUCTURE-BASED PHYLOGENY IDENTIFIES AVORALSTAT AS A Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals and

vaccination.

JCI - SIGLEC-3 (CD33) SERVES AS AN IMMUNE CHECKPOINT Chronic hepatitis B (CHB) infection is rarely eradicated by current antiviral nucleos(t)ide analogues. We found that α2,6-biantennary sialoglycans of HBV surface antigen (HBsAg) bound human SIGLEC-3 (CD33) by IP and ELISA, and the binding affinity between SIGLEC-3 and α2,6-biantennary sialoglycans was determined by biolayer interferometry (equilibrium dissociation constant : 1.95 × 10 JCI - SEX-DEPENDENT COMPENSATORY MECHANISMS PRESERVE BLOOD Inhibitors of mPges-1 are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis and fails to accelerate thrombogenesis, while suppressing PGE2, but increasing biosynthesis of PGI2. JCI - SARS–COV-2 INFECTION OF THE PLACENTA129 For the tissues, 80–160 mg was used for extractions, and for the swabs in viral transport media and other liquid samples, 0.25–0.4 mL was used. ND, not detected. ( B) The SARS–CoV-2 genome sequenced from the infected placenta was combined with 289 other genomes available from GISAID from around the world. JCI - NASAL CILIATED CELLS ARE PRIMARY TARGETS FOR SARS 1 Center for Vascular Research, Institute for Basic Science (IBS), Daejeon, Korea, Republic of. 2 Department of Otorhinolaryngology-Head and Neck Surgery, Uijeongbu Eulji Medical Center, Uijeongbu, Korea, Republic of. 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon,

Korea, Republic of

Benjamin.

JCI - WELCOME

Korea, Republic of

Benjamin.

JCI - WELCOME

Hypoxia is a common finding in all stages of liver cancer development. Hypoxia drives the stabilization of hypoxia-inducible factors (HIFs), which act as central regulators to dampen the innate immunity of liver cancer. HIF signaling in innate immune cells and liver cancer cells together favors the recruitment and maintenance of pro-tumorigenic JCI - IMMUNOASSAY OF ENDOGENOUS PLASMA INSULIN IN MAN Published in Volume 39, Issue 7 on July 1, 1960 J Clin Invest. 1960;39(7):1157–1175. https://doi.org/10.1172/JCI104130. © 1960 The American Society for Clinical JCI - PROTOTYPE PATHOGEN APPROACH FOR PANDEMIC The COVID-19 pandemic of acute respiratory disease caused by SARS–CoV-2 coronavirus (CoV) is an unparalleled event that harkens back to days before viruses could be seen or understood. JCI - SARS–COV-2 INFECTION OF THE PLACENTA For the tissues, 80–160 mg was used for extractions, and for the swabs in viral transport media and other liquid samples, 0.25–0.4 mL was used. ND, not detected. ( B) The SARS–CoV-2 genome sequenced from the infected placenta was combined with 289 other genomes available from GISAID from around the world.

JCI - WELCOME

broad age range.

JCI - HISTONE DEFICIENCY AND ACCELERATED REPLICATION With increasing age, individuals are more vulnerable to viral infections such as with influenza or the SARS-CoV-2 virus. One age-associated defect in human T cells is the reduced expression of miR-181a. miR-181ab1 deficiency in peripheral murine T cells causes delayed viral clearance after infection, resembling human immune

aging.

JCI - HISTONE DEFICIENCY AND ACCELERATED REPLICATION (A – C) Naive CD4 + T cells from young and old individuals were activated for 5 days. Cycling cells were sorted based on DNA content. (A) Quantitative RT-PCR of indicated transcripts associated with ATR signaling.Results, normalized to ACTB, are presented for old relative to cycling young cells (n = 6, mean ± SEM). (B) Immunoblot for p-RPA32 (S8), p-CHK1 (S345), γH2aX (S139), and p21 and JCI - STRUCTURE-BASED PHYLOGENY IDENTIFIES AVORALSTAT AS A Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals and

vaccination.

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ISSUE PUBLISHED JUNE 1, 2021 PREVIOUS ISSUE * Volume 131, Issue 11

GO TO SECTION:

* Viewpoints

* Reviews

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* Corrigendum

ON THE COVER: CANCER-ASSOCIATED FIBROBLASTS IN LIVER METASTASIS In this issue, Bhattacharjee et al. investigated the origin and functions of cancer-associated fibroblasts (CAF) in liver metastasis. They found that hepatic stellate cell-derived CAF promoted the growth of desmoplastic tumors, mediated by direct CAF-tumor interactions. Myofibroblastic CAF-secreted hyaluronan and inflammatory CAF-secreted HGF promoted tumor growth, which was opposed by myofibroblastic CAF-expressed type-I collagen, physically restraining tumors. The cover image shows a mouse liver section 14 days after intrasplenic injection of pancreatic tumor cells. Tumor cells are marked by CK19 (cyan), surrounded by subpopulations of Col1a1-GFP+ CAF (green), primarily derived from LratCre+ HSC (red), and nuclei are stained with DAPI (blue). S _Indicates subscriber content_

Viewpoints

THE QUAGMIRE OF RACE, GENETIC ANCESTRY, AND HEALTH DISPARITIES Giorgio Sirugo, … , Sarah A. Tishkoff, Scott M. Williams Giorgio Sirugo, … , Sarah A. Tishkoff, Scott M. Williams Published

June 1, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e150255.

https://doi.org/10.1172/JCI150255.

View: Text | PDF

THE QUAGMIRE OF RACE, GENETIC ANCESTRY, AND HEALTH DISPARITIES

* Text

* PDF

ABSTRACT

AUTHORS

Giorgio Sirugo, Sarah A. Tishkoff, Scott M. Williams

×

------------------------- IS COMPLEMENT THE CULPRIT BEHIND COVID-19 VACCINE-RELATED ADVERSE

REACTIONS?

Dimitrios C. Mastellos, … , Panagiotis Skendros, John D. Lambris Dimitrios C. Mastellos, … , Panagiotis Skendros, John D. Lambris Published May 4, 2021 Citation Information: _J Clin Invest._ 2021;131(11)

:e151092.

https://doi.org/10.1172/JCI151092.

View: Text | PDF

IS COMPLEMENT THE CULPRIT BEHIND COVID-19 VACCINE-RELATED ADVERSE

REACTIONS?

* Text

* PDF

ABSTRACT

AUTHORS

Dimitrios C. Mastellos, Panagiotis Skendros, John D. Lambris

×

Reviews

TUMOR INNERVATION: PERIPHERAL NERVES TAKE CONTROL OF THE TUMOR

MICROENVIRONMENT

S

Stefan M. Gysler, Ronny Drapkin Stefan M. Gysler, Ronny Drapkin Published June 1, 2021 Citation Information: _J Clin Invest._ 2021;131(11)

:e147276.

https://doi.org/10.1172/JCI147276.

View: Text | PDF

TUMOR INNERVATION: PERIPHERAL NERVES TAKE CONTROL OF THE TUMOR

MICROENVIRONMENT

* Text

* PDF

ABSTRACT

In recent decades, cancer research has expanded exponentially beyond the study of abnormally dividing cells to include complex and extensive heterotypic interactions between cancer and noncancer cells that constitute the tumor microenvironment (TME). Modulation of stromal, immune, and endothelial cells by cancer cells promotes proliferation, survival, and metabolic changes that support tumor growth and metastasis. Recent evidence demonstrates that tumors can recruit peripheral nerves to the TME, leading to enhanced tumor growth in a range of cancer models through distinct mechanisms. This process, termed tumor innervation, is associated with an aggressive tumor phenotype and correlates with poor prognosis in clinical studies. Therefore, the peripheral nervous system may play an underrecognized role in cancer development, harboring targetable pathways that warrant investigation. To date, nerves have been implicated in driving proliferation, invasion, metastasis, and immune evasion through locally delivered neurotransmitters. However, emerging evidence suggests that cell-cell communication via exosomes induces tumor innervation, and thus exosomes may also mediate neural regulation of the TME. In this Review, seminal studies establishing tumor innervation are discussed, and known and putative signaling mechanisms between peripheral nerves and components of the TME are explored as a means to identify potential opportunities for therapeutic

intervention.

AUTHORS

Stefan M. Gysler, Ronny Drapkin

×

------------------------- BCG TURNS 100: ITS NONTRADITIONAL USES AGAINST VIRUSES, CANCER, AND IMMUNOLOGIC DISEASES

S

Alok K. Singh, … , Mihai G. Netea, William R. Bishai Alok K. Singh, … , Mihai G. Netea, William R. Bishai Published June

1, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e148291.

https://doi.org/10.1172/JCI148291.

View: Text | PDF

BCG TURNS 100: ITS NONTRADITIONAL USES AGAINST VIRUSES, CANCER, AND IMMUNOLOGIC DISEASES

* Text

* PDF

ABSTRACT

First administered to a human subject as a tuberculosis (TB) vaccine on July 18, 1921, Bacillus Calmette-Guérin (BCG) has a long history of use for the prevention of TB and later the immunotherapy of bladder cancer. For TB prevention, BCG is given to infants born globally across over 180 countries and has been in use since the late 1920s. With about 352 million BCG doses procured annually and tens of billions of doses having been administered over the past century, it is estimated to be the most widely used vaccine in human history. While its roles for TB prevention and bladder cancer immunotherapy are widely appreciated, over the past century, BCG has been also studied for nontraditional purposes, which include (a) prevention of viral infections and nontuberculous mycobacterial infections, (b) cancer immunotherapy aside from bladder cancer, and (c) immunologic diseases, including multiple sclerosis, type 1 diabetes, and atopic diseases. The basis for these heterologous effects lies in the ability of BCG to alter immunologic set points via heterologous T cell immunity, as well as epigenetic and metabolomic changes in innate immune cells, a process called “trained immunity.” In this Review, we provide an overview of what is known regarding the trained immunity mechanism of heterologous protection, and we describe the current knowledge base for these nontraditional uses of BCG.

AUTHORS

Alok K. Singh, Mihai G. Netea, William R. Bishai

×

------------------------- IRONING OUT MECHANISMS OF IRON HOMEOSTASIS AND DISORDERS OF IRON

DEFICIENCY

S

Navid Koleini, … , Justin Geier, Hossein Ardehali Navid Koleini, … , Justin Geier, Hossein Ardehali Published June 1,

2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e148671.

https://doi.org/10.1172/JCI148671.

View: Text | PDF

IRONING OUT MECHANISMS OF IRON HOMEOSTASIS AND DISORDERS OF IRON

DEFICIENCY

* Text

* PDF

ABSTRACT

Iron plays an important role in mammalian physiological processes. It is a critical component for the function of many proteins, including enzymes that require heme and iron-sulfur clusters. However, excess iron is also detrimental because of its ability to catalyze the formation of reactive oxygen species. As a result, cellular and systemic iron levels are tightly regulated to prevent oxidative damage. Iron deficiency can lead to a number of pathological conditions, the most prominent being anemia. Iron deficiency should be corrected to improve adult patients’ symptoms and to facilitate normal growth during fetal development and childhood. However, inappropriate use of intravenous iron in chronic conditions, such as cancer and heart failure, in the absence of clear iron deficiency can lead to unwanted side effects. Thus, this form of therapy should be reserved for certain patients who cannot tolerate oral iron and need rapid iron replenishment. Here, we will review cellular and systemic iron homeostasis and will discuss complications of iron deficiency.

AUTHORS

Navid Koleini, Jason S. Shapiro, Justin Geier, Hossein Ardehali

×

------------------------- HOW ELITE CONTROLLERS AND POSTTREATMENT CONTROLLERS INFORM OUR SEARCH

FOR AN HIV-1 CURE

S

Jonathan Z. Li, Joel N. Blankson Jonathan Z. Li, Joel N. Blankson Published June 1, 2021 Citation Information: _J Clin Invest._ 2021;131(11)

:e149414.

https://doi.org/10.1172/JCI149414.

View: Text | PDF

HOW ELITE CONTROLLERS AND POSTTREATMENT CONTROLLERS INFORM OUR SEARCH

FOR AN HIV-1 CURE

* Text

* PDF

ABSTRACT

A small percentage of people living with HIV-1 can control viral replication without antiretroviral therapy (ART). These patients are called elite controllers (ECs) if they are able to maintain viral suppression without initiating ART and posttreatment controllers (PTCs) if they control HIV replication after ART has been discontinued. Both types of controllers may serve as a model of a functional cure for HIV-1 but the mechanisms responsible for viral control have not been fully elucidated. In this review, we highlight key lessons that have been learned so far in the study of ECs and PTCs and their implications for HIV cure research.

AUTHORS

Jonathan Z. Li, Joel N. Blankson

×

Commentaries

ADENO-ASSOCIATED VIRUS GENE THERAPY TO THE RESCUE FOR CHARCOT-MARIE-TOOTH DISEASE TYPE 4J

S

John Svaren

John Svaren Published June 1, 2021 Citation Information: _J Clin Invest._ 2021;131(11)

:e149492.

https://doi.org/10.1172/JCI149492.

View: Text | PDF

ADENO-ASSOCIATED VIRUS GENE THERAPY TO THE RESCUE FOR CHARCOT-MARIE-TOOTH DISEASE TYPE 4J

* Text

* PDF

ABSTRACT

The genetic peripheral neuropathy known as Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by recessive mutations in the FIG4 gene. The transformational success of adeno-associated virus (AAV) gene therapy for spinal muscular atrophy has generated substantial interest in using this approach to create similar treatments for CMT. In this issue of the JCI, Presa et al. provide a preclinical demonstration of efficacy using AAV-directed gene therapy for CMT4J. The study showed a dramatic improvement in both survival and neuropathy symptoms in a severe mouse model of CMT4J after administration of AAV gene therapy at several time points. The authors’ approach advances the technique for delivering treatments to individuals with CMT, for which FDA-approved therapies have not yet come to the clinic.

AUTHORS

John Svaren

×

------------------------- FRATAXIN AND ENDOTHELIAL CELL SENESCENCE IN PULMONARY HYPERTENSION

S

Allan Lawrie, Sheila E. Francis Allan Lawrie, Sheila E. Francis Published June 1, 2021 Citation Information: _J Clin Invest._ 2021;131(11)

:e149721.

https://doi.org/10.1172/JCI149721.

View: Text | PDF

FRATAXIN AND ENDOTHELIAL CELL SENESCENCE IN PULMONARY HYPERTENSION

* Text

* PDF

ABSTRACT

Pulmonary hypertension (PH), increased blood pressure within the lungs, is classified into five diagnostic groups based on etiology, with treatment assigned on this basis. Currently, only Group 1 pulmonary arterial hypertension (PAH) and Group 4 chronic thromboembolic PH (CTEPH) have pharmacological treatments available. The role of the endothelial cell in pulmonary hypertension has long been debated, and in this issue of the JCI, Culley et al. present evidence for the reduction in frataxin expression across multiple groups of PH. Reduced frataxin expression led to endothelial cell senescence and associated with the development of PH. Removal of the senescent cells using the senolytic drug Navitoclax in multiple models of PH effectively treated PH, suggesting a new class of treatments that may work beyond Group 1 and Group 4 PH in patients with evidence of pulmonary vascular endothelial senescence.

AUTHORS

Allan Lawrie, Sheila E. Francis

×

------------------------- CALCINEURIN INHIBITORS TARGET LCK ACTIVATION IN GRAFT-VERSUS-HOST

DISEASE

S

Nicole M. Carter, Joel L. Pomerantz Nicole M. Carter, Joel L. Pomerantz Published June 1, 2021 Citation Information: _J Clin Invest._ 2021;131(11)

:e149934.

https://doi.org/10.1172/JCI149934.

View: Text | PDF

CALCINEURIN INHIBITORS TARGET LCK ACTIVATION IN GRAFT-VERSUS-HOST

DISEASE

* Text

* PDF

ABSTRACT

Calcineurin inhibitors (CNIs) such as cyclosporin A and FK506 are widely administered immunosuppressive drugs. Calcineurin relieves inhibitory phosphorylation from nuclear factor of activated T cells (NFAT) transcription factors downstream of T cell receptor engagement, resulting in their nuclear translocation and the production of cytokines, including IL-2, IFN-γ, and TNF-α. It was previously believed that CNIs downregulate immunity by reducing NFAT activation. However, work from Otsuka et al. in this issue of the JCI revealed a second mechanism by which CNIs suppress T cell function. The authors previously reported that calcineurin removes an inhibitory phosphate from the tyrosine kinase Lck at Ser59 (Lck-S59) and that this dephosphorylation positively regulates T cell activation. In the present work, the authors showed that inhibition of Lck-S59 dephosphorylation was essential for the CNI-mediated suppression of acute graft-versus-host disease (aGVHD). These findings have important implications for future approaches to the management of aGVHD, organ transplant rejection, and autoimmune disease.

AUTHORS

Nicole M. Carter, Joel L. Pomerantz

×

------------------------- PARKINSON DISEASE RISKS: CORRECTLY IDENTIFYING ENVIRONMENTAL FACTORS FOR A CHRONIC DISEASE

S

Karl Kieburtz, E. Ray Dorsey Karl Kieburtz, E. Ray Dorsey Published June 1, 2021 Citation Information: _J Clin Invest._ 2021;131(11)

:e150252.

https://doi.org/10.1172/JCI150252.

View: Text | PDF

PARKINSON DISEASE RISKS: CORRECTLY IDENTIFYING ENVIRONMENTAL FACTORS FOR A CHRONIC DISEASE

* Text

* PDF

ABSTRACT

Parkinson disease (PD) is now the world’s fastest growing brain disease; however, the factors underlying this rise are unclear. The past 25 years has witnessed a vast expansion in our understanding of the genetics of PD, but few individuals with PD carry one of the major known genetic risk factors. Environmental factors, including individual (e.g., medications) and ambient (e.g., pollutants), may contribute to this rise. In this issue of the JCI, Sasane et al. examined the risk of PD associated with medications commonly used to treat benign prostatic hypertrophy. In contrast with previous studies, certain α1 receptor antagonists failed to lower PD risk. Rather, the commonly used comparator drug, tamsulosin, increased PD risk. This finding highlights the importance of selecting comparator groups to correctly identify risk factors. Future studies to address the rise of PD with emphasis on both individual as well as the understudied ambient environmental factors are warranted.

AUTHORS

Karl Kieburtz, E. Ray Dorsey

×

Research Articles

PRO-CACHECTIC FACTORS LINK EXPERIMENTAL AND HUMAN CHRONIC KIDNEY DISEASE TO SKELETAL MUSCLE WASTING PROGRAMS Francesca Solagna, … , Ketan Patel, Tobias B. Huber Francesca Solagna, … , Ketan Patel, Tobias B. Huber Published June

1, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e135821.

https://doi.org/10.1172/JCI135821.

View: Text | PDF

PRO-CACHECTIC FACTORS LINK EXPERIMENTAL AND HUMAN CHRONIC KIDNEY DISEASE TO SKELETAL MUSCLE WASTING PROGRAMS

* Text

* PDF

ABSTRACT

Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and muscle function remains poorly understood. Here, we took a complementary interorgan approach to investigate skeletal muscle wasting in CKD. We identified increased production and elevated blood levels of soluble pro-cachectic factors, including activin A, directly linking experimental and human CKD to skeletal muscle wasting programs. Single-cell sequencing data identified the expression of activin A in specific kidney cell populations of fibroblasts and cells of the juxtaglomerular apparatus. We propose that persistent and increased kidney production of pro-cachectic factors, combined with a lack of kidney clearance, facilitates a vicious kidney/muscle signaling cycle, leading to exacerbated blood accumulation and, thereby, skeletal muscle wasting. Systemic pharmacological blockade of activin A using soluble activin receptor type IIB ligand trap as well as muscle-specific adeno-associated virus–mediated downregulation of its receptor ACVR2A/B prevented muscle wasting in different mouse models of experimental CKD, suggesting that activin A is a key factor in CKD-induced cachexia. In summary, we uncovered a crosstalk between kidney and muscle and propose modulation of activin signaling as a potential therapeutic strategy for skeletal muscle wasting in CKD.

AUTHORS

Francesca Solagna, Caterina Tezze, Maja T. Lindenmeyer, Shun Lu, Guochao Wu, Shuya Liu, Yu Zhao, Robert Mitchell, Charlotte Meyer, Saleh Omairi, Temel Kilic, Andrea Paolini, Olli Ritvos, Arja Pasternack, Antonios Matsakas, Dominik Kylies, Julian Schulze zur Wiesch, Jan-Eric Turner, Nicola Wanner, Viji Nair, Felix Eichinger, Rajasree Menon, Ina V. Martin, Barbara M. Klinkhammer, Elion Hoxha, Clemens D. Cohen, Pierre-Louis Tharaux, Peter Boor, Tammo Ostendorf, Matthias Kretzler, Marco Sandri, Oliver Kretz, Victor G. Puelles, Ketan Patel, Tobias B. Huber

×

------------------------- FRATAXIN DEFICIENCY PROMOTES ENDOTHELIAL SENESCENCE IN PULMONARY

HYPERTENSION

Miranda K. Culley, … , Thomas Bertero, Stephen Y. Chan Miranda K. Culley, … , Thomas Bertero, Stephen Y. Chan Published

April 27, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e136459.

https://doi.org/10.1172/JCI136459.

View: Text | PDF

FRATAXIN DEFICIENCY PROMOTES ENDOTHELIAL SENESCENCE IN PULMONARY

HYPERTENSION

* Text

* PDF

ABSTRACT

The dynamic regulation of endothelial pathophenotypes in pulmonary hypertension (PH) remains undefined. Cellular senescence is linked to PH with intracardiac shunts; however, its regulation across PH subtypes is unknown. Since endothelial deficiency of iron-sulfur (Fe-S) clusters is pathogenic in PH, we hypothesized that a Fe-S biogenesis protein, frataxin (FXN), controls endothelial senescence. An endothelial subpopulation in rodent and patient lungs across PH subtypes exhibited reduced FXN and elevated senescence. In vitro, hypoxic and inflammatory FXN deficiency abrogated activity of endothelial Fe-S–containing polymerases, promoting replication stress, DNA damage response, and senescence. This was also observed in stem cell–derived endothelial cells from Friedreich’s ataxia (FRDA), a genetic disease of FXN deficiency, ataxia, and cardiomyopathy, often with PH. In vivo, FXN deficiency–dependent senescence drove vessel inflammation, remodeling, and PH, whereas pharmacologic removal of senescent cells in Fxn-deficient rodents ameliorated PH. These data offer a model of endothelial biology in PH, where FXN deficiency generates a senescent endothelial subpopulation, promoting vascular inflammatory and proliferative signals in other cells to drive disease. These findings also establish an endothelial etiology for PH in FRDA and left heart disease and support therapeutic development of senolytic drugs, reversing effects of Fe-S deficiency

across PH subtypes.

AUTHORS

Miranda K. Culley, Jingsi Zhao, Yi Yin Tai, Ying Tang, Dror Perk, Vinny Negi, Qiujun Yu, Chen-Shan C. Woodcock, Adam Handen, Gil Speyer, Seungchan Kim, Yen-Chun Lai, Taijyu Satoh, Annie M.M. Watson, Yassmin Al Aaraj, John Sembrat, Mauricio Rojas, Dmitry Goncharov, Elena A. Goncharova, Omar F. Khan, Daniel G. Anderson, James E. Dahlman, Aditi U. Gurkar, Robert Lafyatis, Ahmed U. Fayyaz, Margaret M. Redfield, Mark T. Gladwin, Marlene Rabinovitch, Mingxia Gu, Thomas Bertero,

Stephen Y. Chan

×

------------------------- PPARΓ AGONISTS PROMOTE THE RESOLUTION OF MYELOFIBROSIS IN PRECLINICAL

MODELS

Juliette Lambert, … , Philippe Rousselot, Stéphane Prost Juliette Lambert, … , Philippe Rousselot, Stéphane Prost Published

April 29, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e136713.

https://doi.org/10.1172/JCI136713.

View: Text | PDF

PPARΓ AGONISTS PROMOTE THE RESOLUTION OF MYELOFIBROSIS IN PRECLINICAL

MODELS

* Text

* PDF

ABSTRACT

Myelofibrosis (MF) is a non–BCR-ABL myeloproliferative neoplasm associated with poor outcomes. Current treatment has little effect on the natural history of the disease. MF results from complex interactions between (a) the malignant clone, (b) an inflammatory context, and (c) remodeling of the bone marrow (BM) microenvironment. Each of these points is a potential target of PPARγ activation. Here, we demonstrated the therapeutic potential of PPARγ agonists in resolving MF in 3 mouse models. We showed that PPARγ agonists reduce myeloproliferation, modulate inflammation, and protect the BM stroma in vitro and ex vivo. Activation of PPARγ constitutes a relevant therapeutic target in MF, and our data support the possibility of using PPARγ agonists in clinical practice.

AUTHORS

Juliette Lambert, Joseph Saliba, Carolina Calderon, Karine Sii-Felice, Mohammad Salma, Valérie Edmond, Jean-Claude Alvarez, Marc Delord, Caroline Marty, Isabelle Plo, Jean-Jacques Kiladjian, Eric Soler, William Vainchenker, Jean-Luc Villeval, Philippe Rousselot, Stéphane

Prost

×

------------------------- AAV9-MEDIATED FIG4 DELIVERY PROLONGS LIFE SPAN IN CHARCOT-MARIE-TOOTH DISEASE TYPE 4J MOUSE MODEL Maximiliano Presa, … , Steven J. Gray, Cathleen Lutz Maximiliano Presa, … , Steven J. Gray, Cathleen Lutz Published

April 20, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e137159.

https://doi.org/10.1172/JCI137159.

View: Text | PDF

AAV9-MEDIATED FIG4 DELIVERY PROLONGS LIFE SPAN IN CHARCOT-MARIE-TOOTH DISEASE TYPE 4J MOUSE MODEL

* Text

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ABSTRACT

Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by recessive, loss-of-function mutations in FIG4, encoding a phosphoinositol(3,5)P2-phosphatase. CMT4J patients have both neuron loss and demyelination in the peripheral nervous system, with vacuolization indicative of endosome/lysosome trafficking defects. Although the disease is highly variable, the onset is often in childhood and FIG4 mutations can dramatically shorten life span. There is currently no treatment for CMT4J. Here, we present the results of preclinical studies testing a gene-therapy approach to restoring FIG4 expression. A mouse model of CMT4J, the Fig4–pale tremor (plt) allele, was dosed with a single-stranded adeno-associated virus serotype 9 (AAV9) to deliver a codon-optimized human FIG4 sequence. Untreated, Fig4plt/plt mice have a median survival of approximately 5 weeks. When treated with the AAV9-FIG4 vector at P1 or P4, mice survived at least 1 year, with largely normal gross motor performance and little sign of neuropathy by neurophysiological or histopathological evaluation. When mice were treated at P7 or P11, life span was still significantly prolonged and peripheral nerve function was improved, but rescue was less complete. No unanticipated adverse effects were observed. Therefore, AAV9-mediated delivery of FIG4 is a well-tolerated and efficacious strategy in a mouse model of

CMT4J.

AUTHORS

Maximiliano Presa, Rachel M. Bailey, Crystal Davis, Tara Murphy, Jenn Cook, Randy Walls, Hannah Wilpan, Laurent Bogdanik, Guy M. Lenk, Robert W. Burgess, Steven J. Gray, Cathleen Lutz

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------------------------- DESMOSOMAL COP9 REGULATES PROTEOME DEGRADATION IN ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA/CARDIOMYOPATHY Yan Liang, … , Kirk L. Peterson, Farah Sheikh Yan Liang, … , Kirk L. Peterson, Farah Sheikh Published April 15,

2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e137689.

https://doi.org/10.1172/JCI137689.

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DESMOSOMAL COP9 REGULATES PROTEOME DEGRADATION IN ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA/CARDIOMYOPATHY

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ABSTRACT

Dysregulated protein degradative pathways are increasingly recognized as mediators of human disease. This mechanism may have particular relevance to desmosomal proteins that play critical structural roles in both tissue architecture and cell-cell communication, as destabilization/breakdown of the desmosomal proteome is a hallmark of genetic-based desmosomal-targeted diseases, such as the cardiac disease arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, no information exists on whether there are resident proteins that regulate desmosomal proteome homeostasis. Here, we uncovered a cardiac constitutive photomorphogenesis 9 (COP9) desmosomal resident protein complex, composed of subunit 6 of the COP9 signalosome (CSN6), that enzymatically restricted neddylation and targeted desmosomal proteome degradation. CSN6 binding, localization, levels, and function were affected in hearts of classic mouse and human models of ARVD/C affected by desmosomal loss and mutations, respectively. Loss of desmosomal proteome degradation control due to junctional reduction/loss of CSN6 and human desmosomal mutations destabilizing junctional CSN6 were also sufficient to trigger ARVD/C in mice. We identified a desmosomal resident regulatory complex that restricted desmosomal proteome degradation and disease.

AUTHORS

Yan Liang, Robert C. Lyon, Jason Pellman, William H. Bradford, Stephan Lange, Julius Bogomolovas, Nancy D. Dalton, Yusu Gu, Marcus Bobar, Mong-Hong Lee, Tomoo Iwakuma, Vishal Nigam, Angeliki Asimaki, Melvin Scheinman, Kirk L. Peterson, Farah Sheikh

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------------------------- ENHANCED TRIACYLGLYCEROL CATABOLISM BY CARBOXYLESTERASE 1 PROMOTES AGGRESSIVE COLORECTAL CARCINOMA Daria Capece, … , Gabriele Cruciani, Guido Franzoso Daria Capece, … , Gabriele Cruciani, Guido Franzoso Published April

20, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e137845.

https://doi.org/10.1172/JCI137845.

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ENHANCED TRIACYLGLYCEROL CATABOLISM BY CARBOXYLESTERASE 1 PROMOTES AGGRESSIVE COLORECTAL CARCINOMA

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ABSTRACT

The ability to adapt to low-nutrient microenvironments is essential for tumor cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-κB transcription factor pathway associates with advanced disease stages and shorter survival in patients with CRC. NF-κB has been shown to drive tumor-promoting inflammation, cancer cell survival, and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC. However, whether NF-κB affects the metabolic adaptations that fuel aggressive disease in patients with CRC is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-κB–regulated lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC cell survival via cell-autonomous mechanisms that fuel fatty acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight patients with CRC. Accordingly, NF-κB drove CES1 expression in CRC consensus molecular subtype 4 (CMS4), which is associated with obesity, stemness, and inflammation. CES1 was also upregulated by gene amplifications of its transcriptional regulator HNF4A in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavorable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC.

AUTHORS

Daria Capece, Daniel D’Andrea, Federica Begalli, Laura Goracci, Laura Tornatore, James L. Alexander, Alessandra Di Veroli, Shi-Chi Leow, Thamil S. Vaiyapuri, James K. Ellis, Daniela Verzella, Jason Bennett, Luca Savino, Yue Ma, James S. McKenzie, Maria Luisa Doria, Sam E. Mason, Kern Rei Chng, Hector C. Keun, Gary Frost, Vinay Tergaonkar, Katarzyna Broniowska, Walter Stunkel, Zoltan Takats, James M. Kinross, Gabriele Cruciani, Guido Franzoso

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------------------------- LUNG-RESIDENT MEMORY B CELLS PROTECT AGAINST BACTERIAL PNEUMONIA Kimberly A. Barker, … , Lee J. Quinton, Joseph P. Mizgerd Kimberly A. Barker, … , Lee J. Quinton, Joseph P. Mizgerd Published

June 1, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e141810.

https://doi.org/10.1172/JCI141810.

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LUNG-RESIDENT MEMORY B CELLS PROTECT AGAINST BACTERIAL PNEUMONIA

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ABSTRACT

Lung-resident memory B cells (BRM cells) are elicited after influenza infections of mice, but connections to other pathogens and hosts — as well as their functional significance — have yet to be determined. We postulate that BRM cells are core components of lung immunity. To test this, we examined whether lung BRM cells are elicited by the respiratory pathogen pneumococcus, are present in humans, and are important in pneumonia defense. Lungs of mice that had recovered from pneumococcal infections did not contain organized tertiary lymphoid organs, but did have plasma cells and noncirculating memory B cells. The latter expressed distinctive surface markers (including CD69, PD-L2, CD80, and CD73) and were poised to secrete antibodies upon stimulation. Human lungs also contained B cells with a resident memory phenotype. In mice recovered from pneumococcal pneumonia, depletion of PD-L2+ B cells, including lung BRM cells, diminished bacterial clearance and the level of pneumococcus-reactive antibodies in the lung. These data define lung BRM cells as a common feature of pathogen-experienced lungs and provide direct evidence of a role for these cells in pulmonary antibacterial immunity.

AUTHORS

Kimberly A. Barker, Neelou S. Etesami, Anukul T. Shenoy, Emad I. Arafa, Carolina Lyon de Ana, Nicole M.S. Smith, Ian M.C. Martin, Wesley N. Goltry, Alexander M.S. Barron, Jeffrey L. Browning, Hasmeena Kathuria, Anna C. Belkina, Antoine Guillon, Xuemei Zhong, Nicholas A. Crossland, Matthew R. Jones, Lee J. Quinton, Joseph P. Mizgerd

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------------------------- SIGLEC-3 (CD33) SERVES AS AN IMMUNE CHECKPOINT RECEPTOR FOR HBV

INFECTION

Tsung-Yu Tsai, … , James C Paulson, Shie-Liang Hsieh Tsung-Yu Tsai, … , James C Paulson, Shie-Liang Hsieh Published June

1, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e141965.

https://doi.org/10.1172/JCI141965.

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SIGLEC-3 (CD33) SERVES AS AN IMMUNE CHECKPOINT RECEPTOR FOR HBV

INFECTION

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ABSTRACT

Chronic hepatitis B (CHB) infection is rarely eradicated by current antiviral nucleos(t)ide analogues. We found that α2,6-biantennary sialoglycans of HBV surface antigen (HBsAg) bound human SIGLEC-3 (CD33) by IP and ELISA, and the binding affinity between SIGLEC-3 and α2,6-biantennary sialoglycans was determined by biolayer interferometry (equilibrium dissociation constant : 1.95 × 10–10 ± 0.21 × 10–10 M). Moreover, HBV activated SIGLEC-3 on myeloid cells and induced immunosuppression by stimulating immunoreceptor tyrosine-based inhibitory motif phosphorylation and SHP-1/-2 recruitment via α2,6-biantennary sialoglycans on HBsAg. An antagonistic anti–SIGLEC-3 mAb reversed this effect and enhanced cytokine production in response to TLR-7 agonist GS-9620 in PBMCs from CHB patients. Moreover, anti–SIGLEC-3 mAb alone was able to upregulate the expression of molecules involved in antigen presentation, such as CD80, CD86, CD40, MHC-I, MHC-II, and PD-L1 in CD14+ cells. Furthermore, SIGLEC-3 SNP rs12459419 C, which expressed a higher amount of SIGLEC-3, was associated with increased risk of hepatocellular carcinoma (HCC) in CHB patients (HR: 1.256, 95% CI: 1.027–1.535, P = 0.0266). Thus, blockade of SIGLEC-3 is a promising strategy to reactivate host immunity to HBV and lower the incidence of HCC in the CHB patient population.

AUTHORS

Tsung-Yu Tsai, Ming-Ting Huang, Pei-Shan Sung, Cheng-Yuan Peng, Mi-Hua Tao, Hwai-I Yang, Wei-Chiao Chang, An-Suei Yang, Chung-Ming Yu, Ya-Ping Lin, Ching-Yu Bau, Chih-Jen Huang, Mei-Hung Pan, Chung-Yi Wu, Chwan-Deng Hsiao, Yi-Hung Yeh, Shiteng Duan, James C Paulson,

Shie-Liang Hsieh

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------------------------- GLUCOSE DEPRIVATION–INDUCED ABERRANT FUT1-MEDIATED FUCOSYLATION DRIVES CANCER STEMNESS IN HEPATOCELLULAR CARCINOMA Jane H.C. Loong, … , Jing-Ping Yun, Stephanie K.Y. Ma Jane H.C. Loong, … , Jing-Ping Yun, Stephanie K.Y. Ma Published

April 20, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e143377.

https://doi.org/10.1172/JCI143377.

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GLUCOSE DEPRIVATION–INDUCED ABERRANT FUT1-MEDIATED FUCOSYLATION DRIVES CANCER STEMNESS IN HEPATOCELLULAR CARCINOMA

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ABSTRACT

Rapidly growing tumors often experience hypoxia and nutrient (e.g., glucose) deficiency because of poor vascularization. Tumor cells respond to the cytotoxic effects of such stresses by inducing molecular adaptations that promote clonal selection of a more malignant tumor-initiating cell phenotype, especially in the innermost tumor regions. Here, we report a regulatory mechanism involving fucosylation by which glucose restriction promotes cancer stemness to drive drug resistance and tumor recurrence. Using hepatocellular carcinoma (HCC) as a model, we showed that restricted glucose availability enhanced the PERK/eIF2α/ATF4 signaling axis to drive fucosyltransferase 1 (FUT1) transcription via direct binding of ATF4 to the FUT1 promoter. FUT1 overexpression is a poor prognostic indicator for HCC. FUT1 inhibition could mitigate tumor initiation, self-renewal, and drug resistance. Mechanistically, we demonstrated that CD147, ICAM-1, EGFR, and EPHA2 are glycoprotein targets of FUT1, in which such fucosylation would consequently converge on deregulated AKT/mTOR/4EBP1 signaling to drive cancer stemness. Treatment with an α-(1,2)-fucosylation inhibitor sensitized HCC tumors to sorafenib, a first-line molecularly targeted drug used for advanced HCC patients, and reduced the tumor-initiating subset. FUT1 overexpression and/or CD147, ICAM-1, EGFR, and EPHA2 fucosylation may be good prognostic markers and therapeutic targets for cancer patients.

AUTHORS

Jane H.C. Loong, Tin-Lok Wong, Man Tong, Rakesh Sharma, Lei Zhou, Kai-Yu Ng, Hua-Jian Yu, Chi-Han Li, Kwan Man, Chung-Mau Lo, Xin-Yuan Guan, Terence K. Lee, Jing-Ping Yun, Stephanie K.Y. Ma

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------------------------- HISTONE DEFICIENCY AND ACCELERATED REPLICATION STRESS IN T CELL AGING Chulwoo Kim, … , Cornelia M. Weyand, Jörg J. Goronzy Chulwoo Kim, … , Cornelia M. Weyand, Jörg J. Goronzy Published

June 1, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e143632.

https://doi.org/10.1172/JCI143632.

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HISTONE DEFICIENCY AND ACCELERATED REPLICATION STRESS IN T CELL AGING

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ABSTRACT

With increasing age, individuals are more vulnerable to viral infections such as with influenza or the SARS-CoV-2 virus. One age-associated defect in human T cells is the reduced expression of miR-181a. miR-181ab1 deficiency in peripheral murine T cells causes delayed viral clearance after infection, resembling human immune aging. Here we show that naive T cells from older individuals as well as miR-181ab1–deficient murine T cells develop excessive replication stress after activation, due to reduced histone expression and delayed S-phase cell cycle progression. Reduced histone expression was caused by the miR-181a target SIRT1 that directly repressed transcription of histone genes by binding to their promoters and reducing histone acetylation. Inhibition of SIRT1 activity or SIRT1 silencing increased histone expression, restored cell cycle progression, diminished the replication-stress response, and reduced the production of inflammatory mediators in replicating T cells from old individuals. Correspondingly, treatment with SIRT1 inhibitors improved viral clearance in mice with miR-181a–deficient T cells after LCMV infection. In conclusion, SIRT1 inhibition may be beneficial to treat systemic viral infection in older individuals by targeting antigen-specific T cells that develop replication stress due to miR-181a deficiency.

AUTHORS

Chulwoo Kim, Jun Jin, Zhongde Ye, Rohit R. Jadhav, Claire E. Gustafson, Bin Hu, Wenqiang Cao, Lu Tian, Cornelia M. Weyand, Jörg J.

Goronzy

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------------------------- DELETION OF LATS1/2 IN ADULT KIDNEY EPITHELIA LEADS TO RENAL CELL

CARCINOMA

Phoebe Carter, … , Payal Kapur, Thomas J. Carroll Phoebe Carter, … , Payal Kapur, Thomas J. Carroll Published June 1,

2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e144108.

https://doi.org/10.1172/JCI144108.

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DELETION OF LATS1/2 IN ADULT KIDNEY EPITHELIA LEADS TO RENAL CELL

CARCINOMA

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ABSTRACT

AUTHORS

Phoebe Carter, Ulrike Schnell, Christopher Chaney, Betty Tong, Xinchao Pan, Jianhua Ye, Glenda Mernaugh, Jennifer L. Cotton, Vitaly Margulis, Junhao Mao, Roy Zent, Bret M. Evers, Payal Kapur, Thomas J. Carroll

×

------------------------- BLOCKING _BORRELIA_ _BURGDORFERI_ TRANSMISSION FROM INFECTED TICKS TO NONHUMAN PRIMATES WITH A HUMAN MONOCLONAL ANTIBODY Zachary A. Schiller, … , Mark S. Klempner, Yang Wang Zachary A. Schiller, … , Mark S. Klempner, Yang Wang Published

April 29, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e144843.

https://doi.org/10.1172/JCI144843.

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BLOCKING _BORRELIA_ _BURGDORFERI_ TRANSMISSION FROM INFECTED TICKS TO NONHUMAN PRIMATES WITH A HUMAN MONOCLONAL ANTIBODY

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ABSTRACT

Disrupting transmission of Borrelia burgdorferi sensu lato complex (B. burgdorferi) from infected ticks to humans is one strategy to prevent the significant morbidity from Lyme disease. We have previously shown that an anti-OspA human mAb, 2217, prevents transmission of B. burgdorferi from infected ticks in animal models. Maintenance of a protective plasma concentration of a human mAb for tick season presents a significant challenge for a preexposure prophylaxis strategy. Here, we describe the optimization of mAb 2217 by amino acid substitutions (2217LS: M428L and N434S) in the Fc domain. The LS mutation led to a 2-fold increase in half-life in cynomolgus monkeys. In a rhesus macaque model, 2217LS protected animals from tick transmission of spirochetes at a dose of 3 mg/kg. Crystallographic analysis of Fab in complex with OspA revealed that 2217 bound an epitope that was highly conserved among the B. burgdorferi, B. garinii, and B. afzelii species. Unlike most vaccines that may require boosters to achieve protection, our work supports the development of 2217LS as an effective preexposure prophylaxis in Lyme-endemic regions, with a single dose at the beginning of tick season offering immediate protection that remains for the duration of exposure risk.

AUTHORS

Zachary A. Schiller, Michael J. Rudolph, Jacqueline R. Toomey, Monir Ejemel, Alan LaRochelle, Simon A. Davis, Havard S. Lambert, Aurélie Kern, Amanda C. Tardo, Colby A. Souders, Eric Peterson, Rebecca D. Cannon, Chandrashekar Ganesa, Frank Fazio, Nicholas J. Mantis, Lisa A. Cavacini, John Sullivan-Bolyai, Linden T. Hu, Monica E. Embers, Mark S. Klempner, Yang Wang

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------------------------- PARKINSON DISEASE AMONG PATIENTS TREATED FOR BENIGN PROSTATIC HYPERPLASIA WITH Α1 ADRENERGIC RECEPTOR ANTAGONISTS Rahul Sasane, … , John J. Renger, David J. Stone Rahul Sasane, … , John J. Renger, David J. Stone Published April 6,

2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e145112.

https://doi.org/10.1172/JCI145112.

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Clinical Medicine

PARKINSON DISEASE AMONG PATIENTS TREATED FOR BENIGN PROSTATIC HYPERPLASIA WITH Α1 ADRENERGIC RECEPTOR ANTAGONISTS

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ABSTRACT

BACKGROUND Recently the α1 adrenergic receptor antagonist terazosin was shown to activate PGK1, a possible target for the mitochondrial deficits in Parkinson disease related to its function as the initial enzyme in ATP synthesis during glycolysis. An epidemiological study of terazosin users showed a lower incidence of Parkinson disease when compared with users of tamsulosin, an α1 adrenergic receptor antagonist of a different class that does not activate PGK1. However, prior research on tamsulosin has suggested that it may in fact potentiate neurodegeneration, raising the question of whether it is an appropriate control group.METHODS To address this question, we undertook an epidemiological study on Parkinson disease occurrence rate in 113,450 individuals from the United States with 5 or more years of follow-up. Patients were classified as tamsulosin users (n = 45,380), terazosin/alfuzosin/doxazosin users (n = 22,690), or controls matched for age, sex, and Charlson comorbidity index score (n = 45,380).RESULTS Incidence of Parkinson disease in tamsulosin users was 1.53%, which was significantly higher than that in both terazosin/alfuzosin/doxazosin users (1.10%, P < 0.0001) and matched controls (1.01%, P < 0.0001). Terazosin/alfuzosin/doxazosin users did not differ in Parkinson disease risk from matched controls (P = 0.29).CONCLUSION These results suggest that zosins may not confer a protective effect against Parkinson disease, but rather that tamsulosin may in some way potentiate Parkinson disease progression.FUNDING This work was supported by Cerevel Therapeutics.

AUTHORS

Rahul Sasane, Amy Bartels, Michelle Field, Maria I. Sierra, Sridhar Duvvuri, David L. Gray, Sokhom S. Pin, John J. Renger, David J. Stone

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------------------------- ELIMINATING HYPOXIC TUMOR CELLS IMPROVES RESPONSE TO PARP INHIBITORS IN HOMOLOGOUS RECOMBINATION–DEFICIENT CANCER MODELS Manal Mehibel, … , Erinn B. Rankin, Amato J. Giaccia Manal Mehibel, … , Erinn B. Rankin, Amato J. Giaccia Published June

1, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e146256.

https://doi.org/10.1172/JCI146256.

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ELIMINATING HYPOXIC TUMOR CELLS IMPROVES RESPONSE TO PARP INHIBITORS IN HOMOLOGOUS RECOMBINATION–DEFICIENT CANCER MODELS

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ABSTRACT

Hypoxia, a hallmark feature of the tumor microenvironment, causes resistance to conventional chemotherapy, but was recently reported to synergize with poly(ADP-ribose) polymerase inhibitors (PARPis) in homologous recombination–proficient (HR-proficient) cells through suppression of HR. While this synergistic killing occurs under severe hypoxia (<0.5% oxygen), our study shows that moderate hypoxia (2% oxygen) instead promotes PARPi resistance in both HR-proficient and -deficient cancer cells. Mechanistically, we identify reduced ROS-induced DNA damage as the cause for the observed resistance. To determine the contribution of hypoxia to PARPi resistance in tumors, we used the hypoxic cytotoxin tirapazamine to selectively kill hypoxic tumor cells. We found that the selective elimination of hypoxic tumor cells led to a substantial antitumor response when used with PARPi compared with that in tumors treated with PARPi alone, without enhancing normal tissue toxicity. Since human breast cancers with BRAC1/2 mutations have an increased hypoxia signature and hypoxia reduces the efficacy of PARPi, then eliminating hypoxic tumor cells should enhance the efficacy of PARPi therapy.

AUTHORS

Manal Mehibel, Yu Xu, Caiyun G. Li, Eui Jung Moon, Kaushik N. Thakkar, Anh N. Diep, Ryan K. Kim, Joshua D. Bloomstein, Yiren Xiao, Julien Bacal, Joshua C. Saldivar, Quynh-Thu Le, Karlene A. Cimprich, Erinn B. Rankin, Amato J. Giaccia

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------------------------- TUMOR RESTRICTION BY TYPE I COLLAGEN OPPOSES TUMOR-PROMOTING EFFECTS OF CANCER-ASSOCIATED FIBROBLASTS Sonakshi Bhattacharjee, … , Ingmar Mederacke, Robert F. Schwabe Sonakshi Bhattacharjee, … , Ingmar Mederacke, Robert F. Schwabe Published April 27, 2021 Citation Information: _J Clin Invest._ 2021;131(11)

:e146987.

https://doi.org/10.1172/JCI146987.

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TUMOR RESTRICTION BY TYPE I COLLAGEN OPPOSES TUMOR-PROMOTING EFFECTS OF CANCER-ASSOCIATED FIBROBLASTS

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ABSTRACT

Cancer-associated fibroblasts (CAF) may exert tumor-promoting and tumor-suppressive functions, but the mechanisms underlying these opposing effects remain elusive. Here, we sought to understand these potentially opposing functions by interrogating functional relationships among CAF subtypes, their mediators, desmoplasia, and tumor growth in a wide range of tumor types metastasizing to the liver, the most common organ site for metastasis. Depletion of hepatic stellate cells (HSC), which represented the main source of CAF in mice and patients in our study, or depletion of all CAF decreased tumor growth and mortality in desmoplastic colorectal and pancreatic metastasis but not in nondesmoplastic metastatic tumors. Single-cell RNA-Seq in conjunction with CellPhoneDB ligand-receptor analysis, as well as studies in immune cell–depleted and HSC-selective knockout mice, uncovered direct CAF-tumor interactions as a tumor-promoting mechanism, mediated by myofibroblastic CAF–secreted (myCAF-secreted) hyaluronan and inflammatory CAF–secreted (iCAF-secreted) HGF. These effects were opposed by myCAF-expressed type I collagen, which suppressed tumor growth by mechanically restraining tumor spread, overriding its own stiffness-induced mechanosignals. In summary, mechanical restriction by type I collagen opposes the overall tumor-promoting effects of CAF, thus providing a mechanistic explanation for their dual functions in cancer. Therapeutic targeting of tumor-promoting CAF mediators while preserving type I collagen may convert CAF from tumor promoting to tumor restricting.

AUTHORS

Sonakshi Bhattacharjee, Florian Hamberger, Aashreya Ravichandra, Maximilian Miller, Ajay Nair, Silvia Affo, Aveline Filliol, LiKang Chin, Thomas M. Savage, Deqi Yin, Naita Maren Wirsik, Adam Mehal, Nicholas Arpaia, Ekihiro Seki, Matthias Mack, Di Zhu, Peter A. Sims, Raghu Kalluri, Ben Z. Stanger, Kenneth P. Olive, Thomas Schmidt, Rebecca G. Wells, Ingmar Mederacke, Robert F. Schwabe

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------------------------- CORONAVIRUS-SPECIFIC ANTIBODY PRODUCTION IN MIDDLE-AGED MICE REQUIRES

PHOSPHOLIPASE A2G2D

Jian Zheng, … , Makoto Murakami, Stanley Perlman Jian Zheng, … , Makoto Murakami, Stanley Perlman Published June 1,

2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e147201.

https://doi.org/10.1172/JCI147201.

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CORONAVIRUS-SPECIFIC ANTIBODY PRODUCTION IN MIDDLE-AGED MICE REQUIRES

PHOSPHOLIPASE A2G2D

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ABSTRACT

Worse outcomes occur in aged compared with young populations after infections with respiratory viruses, including pathogenic coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2), and are associated with a suboptimal lung milieu (“inflammaging”). We previously showed that a single inducible phospholipase, PLA2G2D, is associated with a proresolving/antiinflammatory response in the lungs, and increases with age. Survival was increased in naive Pla2g2d–/– mice infected with SARS-CoV resulting from augmented respiratory dendritic cell (rDC) activation and enhanced priming of virus-specific T cells. Here, in contrast, we show that intranasal immunization provided no additional protection in middle-aged Pla2g2d–/– mice infected with any of the 3 pathogenic human coronaviruses because virtually no virus-specific antibodies or follicular helper CD4+ T (Tfh) cells were produced. Using MERS-CoV–infected mice, we found that these effects did not result from T or B cell intrinsic factors. Rather, they resulted from enhanced, and ultimately, pathogenic rDC activation, as manifested most prominently by enhanced IL-1β expression. Wild-type rDC transfer to Pla2g2d–/– mice in conjunction with partial IL-1β blockade reversed this defect and resulted in increased virus-specific antibody and Tfh responses. Together, these results indicate that PLA2G2D has an unexpected role in the lungs, serving as an important modulator of rDC activation, with protective and pathogenic effects in respiratory coronavirus infections and immunization, respectively.

AUTHORS

Jian Zheng, David Meyerholz, Lok-Yin Roy Wong, Michael Gelb, Makoto Murakami, Stanley Perlman

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------------------------- CALCINEURIN INHIBITORS SUPPRESS ACUTE GRAFT-VERSUS-HOST DISEASE VIA NFAT-INDEPENDENT INHIBITION OF T CELL RECEPTOR SIGNALING Shizuka Otsuka, … , Roberto Weigert, Jonathan D. Ashwell Shizuka Otsuka, … , Roberto Weigert, Jonathan D. Ashwell Published

April 6, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e147683.

https://doi.org/10.1172/JCI147683.

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CALCINEURIN INHIBITORS SUPPRESS ACUTE GRAFT-VERSUS-HOST DISEASE VIA NFAT-INDEPENDENT INHIBITION OF T CELL RECEPTOR SIGNALING

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ABSTRACT

Inhibitors of calcineurin phosphatase activity (CNIs) such as cyclosporin A (CsA) are widely used to treat tissue transplant rejection and acute graft-versus-host disease (aGVHD), for which inhibition of gene expression dependent on nuclear factor of activated T cells (NFAT) is the mechanistic paradigm. We recently reported that CNIs inhibit TCR-proximal signaling by preventing calcineurin-mediated dephosphorylation of LckS59, an inhibitory modification, raising the possibility of another mechanism by which CNIs suppress immune responses. Here we used T cells from mice that express LckS59A, which cannot accept a phosphate at residue 59, to initiate aGVHD. Although CsA inhibited NFAT-dependent gene upregulation in allo-aggressive T cells expressing either LckWT or LckS59A, it was ineffective in treating disease when the T cells expressed LckS59A. Two important NFAT-independent T cell functions were found to be CsA-resistant in LckS59A T cells: upregulation of the cytolytic protein perforin in tissue-infiltrating CD8+ T cells and antigen-specific T/DC adhesion and clustering in lymph nodes. These results demonstrate that effective treatment of aGVHD by CsA requires NFAT-independent inhibition of TCR signaling. Given that NFATs are widely expressed and off-target effects are a major limitation in CNI use, it is possible that targeting TCR-associated calcineurin directly may provide effective therapies with less toxicity.

AUTHORS

Shizuka Otsuka, Nicolas Melis, Matthias M. Gaida, Debjani Dutta, Roberto Weigert, Jonathan D. Ashwell

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------------------------- CCL17-PRODUCING CDC2S ARE ESSENTIAL IN END-STAGE LUPUS NEPHRITIS AND AVERTED BY A PARASITIC INFECTION Laura Amo, … , Juan Wu, Silvia Bolland Laura Amo, … , Juan Wu, Silvia Bolland Published June 1, 2021 Citation Information: _J Clin Invest._ 2021;131(11)

:e148000.

https://doi.org/10.1172/JCI148000.

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CCL17-PRODUCING CDC2S ARE ESSENTIAL IN END-STAGE LUPUS NEPHRITIS AND AVERTED BY A PARASITIC INFECTION

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ABSTRACT

Lupus nephritis is a severe organ manifestation in systemic lupus erythematosus leading to kidney failure in a subset of patients. In lupus-prone mice, controlled infection with Plasmodium parasites protects against the progression of autoimmune pathology including lethal glomerulonephritis. Here, we demonstrate that parasite-induced protection was not due to a systemic effect of infection on autoimmunity as previously assumed, but rather to specific alterations in immune cell infiltrates into kidneys and renal draining lymph nodes. Infection of lupus-prone mice with a Plasmodium parasite did not reduce the levels or specificities of autoreactive antibodies, vasculitis, immune complex–induced innate activation, or hypoxia. Instead, infection uniquely reduced kidney-infiltrating CCL17-producing bone marrow–derived type 2 inflammatory dendritic cells (iDC2s). Bone marrow reconstitution experiments revealed that infection with Plasmodium caused alterations in bone marrow cells that hindered the ability of DC2s to infiltrate the kidneys. The essential role for CCL17 in lupus nephritis was confirmed by in vivo depletion with a blocking antibody, which reduced kidney pathology and immune infiltrates, while bypassing the need for parasitic infection. Therefore, infiltration into the kidneys of iDC2s, with the potential to prime local adaptive responses, is an essential regulated event in the transition from manageable glomerulonephritis to lethal tubular

injury.

AUTHORS

Laura Amo, Hemanta K. Kole, Bethany Scott, Chen-Feng Qi, Juan Wu,

Silvia Bolland

×

Corrigendum

THE MULTIFACETED NATURE OF HIV LATENCY Caroline Dufour, … , Rémi Fromentin, Nicolas Chomont Caroline Dufour, … , Rémi Fromentin, Nicolas Chomont Published

June 1, 2021

Citation Information: _J Clin Invest._ 2021;131(11)

:e151380.

https://doi.org/10.1172/JCI151380.

View: Text | PDF

| Amended Article

THE MULTIFACETED NATURE OF HIV LATENCY

* Text

* PDF

ABSTRACT

AUTHORS

Caroline Dufour, Pierre Gantner, Rémi Fromentin, Nicolas Chomont

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------------------------- IN-PRESS PREVIEW - MORE DO MONOGENIC INBORN ERRORS OF IMMUNITY CAUSE SUSCEPTIBILITY TO SEVERE

COVID-19?

The SARS-CoV-2 virus, which causes COVID-19, has been associated globally with substantial morbidity and mortality. Numerous reports over the past year have described the clinical and immunological... Published June 1, 2021 Commentary In-Press Preview DO MONOGENIC INBORN ERRORS OF IMMUNITY CAUSE SUSCEPTIBILITY TO SEVERE

COVID-19?

* Text

* PDF

ABSTRACT

The SARS-CoV-2 virus, which causes COVID-19, has been associated globally with substantial morbidity and mortality. Numerous reports over the past year have described the clinical and immunological profiles of COVID-19 patients, and while some trends have emerged for risk stratification, they do not provide a complete picture. Therefore, efforts are ongoing to identify genetic susceptibility factors of severe disease. In this issue of the JCI, Povysil et al. performed a large, multi-country study, sequencing genomes from patients with mild and severe COVID-19, along with population controls. Contrary to previous reports, the authors observed no enrichment of predicted loss-of-function variants in genes in the type I interferon pathway, which might predispose to severe disease. These studies suggest that more evidence is needed to substantiate the hypothesis for a genetic immune predisposition to severe COVID-19, and highlights the importance of considering experimental design when implicating a monogenic basis for severe disease.

AUTHORS

Chris Cotsapas, Janna Saarela, Jocelyn R. Farmer, Vinod Scaria,

Roshini S. Abraham

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------------------------- TRIP13 MODULATES PROTEIN DEUBIQUITINATION AND ACCELERATES TUMOR DEVELOPMENT AND PROGRESSION OF B-CELL MALIGNANCIES Multiple myeloma (MM), a terminally differentiated B-cell malignancy, remains difficult to cure. Understanding the molecular mechanisms underlying the progression of MM may identify therapeutic... Published

June 1, 2021

Research In-Press Preview Hematology TRIP13 MODULATES PROTEIN DEUBIQUITINATION AND ACCELERATES TUMOR DEVELOPMENT AND PROGRESSION OF B-CELL MALIGNANCIES

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* PDF

ABSTRACT

Multiple myeloma (MM), a terminally differentiated B-cell malignancy, remains difficult to cure. Understanding the molecular mechanisms underlying the progression of MM may identify therapeutic targets and lead to a fundamental shift in treatment of the disease. Deubiquitination like ubiquitination is a highly regulated process, implicated in almost every cellular process. Multiple deubiquitinating enzymes (DUBs) have been identified but their regulation is poorly defined. Here, we determined that TRIP13 increases cellular deubiquitination. Overexpression of TRIP13 in mice and cultured cells resulted in excess cellular deubiquitination by enhancing the association of the DUB USP7 with its substrates. We show that TRIP13 is an oncogenic protein because it accelerates B-cell tumor development in transgenic mice. TRIP13-induced resistance to proteasome inhibition can be overcome by a USP7 inhibitor in vitro and in vivo. These findings point to a critical role for TRIP13 expression in B-cell lymphoma and MM by governing deubiquitination of critical oncogenic (NEK2) and tumor suppressor (PTEN, P53) proteins. High TRIP13 identifies a high-risk patient group amendable to adjuvant

anti-USP7 therapy.

AUTHORS

Can Li, Jiliang Xia, Reinaldo Franqui Machin, Fangping Chen, Yanjuan He, Timothy Cody Ashby, Feixiang Teng, Hongwei Xu, Dingxiao Liu, Dongzheng Gai, Sarah K. Johnson, Frits van Rhee, Siegfried Janz, John D. Shaughnessy Jr, Guido Tricot, Ivana Frech, Fenghuang Zhan

×

------------------------- ASTROCYTES PROPEL NEUROVASCULAR DYSFUNCTION DURING CEREBRAL CAVERNOUS MALFORMATION LESION FORMATION Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in one of three genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally... Published May 27, 2021 Research In-Press Preview Angiogenesis

Cell biology

ASTROCYTES PROPEL NEUROVASCULAR DYSFUNCTION DURING CEREBRAL CAVERNOUS MALFORMATION LESION FORMATION

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* PDF

ABSTRACT

Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in one of three genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we reported that proliferative astrocytes played a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2 and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilized HIF-1a in astrocytes, resulting in increased VEGF production and expression of a “hypoxic” program under normoxic conditions. We showed that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1a target gene and a known component of the hypoxic program, contributed to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevented the progression of CCM lesions. Thus, non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.

AUTHORS

Miguel Alejandro Lopez-Ramirez, Catherine Chinhchu Lai, Shady Ibrahim Soliman, Preston Hale, Angela Pham, Esau J. Estrada, Sara McCurdy, Romuald Girard, Riya Verma, Thomas Moore, Rhonda Lightle, Nicholas Hobson, Robert Shenkar, Orit Poulsen, Gabriel G. Haddad, Richard Daneman, Brendan Gongol, Hao Sun, Frederic Lagarrigue, Issam A. Awad,

Mark H. Ginsberg

×

------------------------- RARE LOSS-OF-FUNCTION VARIANTS IN TYPE I IFN IMMUNITY GENES ARE NOT ASSOCIATED WITH SEVERE COVID-19 A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We... Published May 27, 2021 Concise Communication In-Press Preview Genetics Infectious disease RARE LOSS-OF-FUNCTION VARIANTS IN TYPE I IFN IMMUNITY GENES ARE NOT ASSOCIATED WITH SEVERE COVID-19

* Text

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ABSTRACT

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched population controls across four independent COVID-19 biobanks. We then tested if rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only one rare pLOF mutation across these genes amongst 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We find no evidence of association of rare loss-of-function variants in the proposed 13 candidate genes with severe COVID-19 outcomes.

AUTHORS

Gundula Povysil, Guillaume Butler-Laporte, Ning Shang, Chen Wang, Atlas Khan, Manal Alaamery, Tomoko Nakanishi, Sirui Zhou, Vincenzo Forgetta, Robert J. M. Eveleigh, Mathieu Bourgey, Naveed Aziz, Steven J.M. Jones, Bartha Knoppers, Stephen W. Scherer, Lisa J. Strug, Pierre Lepage, Jiannis Ragoussis, Guillaume Bourque, Jahad Alghamdi, Nora Aljawini, Nour Albesher, Hani M. Al-Afghani, Bader Alghamdi, Mansour S. Almutair, Ebrahim Sabri Mahmoud, Leen Abu-Safieh, Hadeel El Bardisy, Fawz S. Al Harthi, Abdulraheem Alshareef, Bandar Ali Suliman, Saleh A. Alqahtani, Abdulaziz Almalik, May M. Alrashed, Salam Massadeh, Vincent Mooser, Mark Lathrop, Mohamed Fawzy, Yaseen M. Arabi, Hamdi Mbarek, Chadi Saad, Wadha Al-Muftah, Junghyun Jung, Serghei Mangul, Radja Badji, Asma Al Thani, Said I. Ismail, Ali G. Gharavi, Malak S. Abedalthagafi, J Brent Richards, David B. Goldstein,

Krzysztof Kiryluk

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------------------------- CHRONIC T CELL RECEPTOR STIMULATION UNMASKS NK RECEPTOR SIGNALING IN PERIPHERAL T CELL LYMPHOMAS VIA EPIGENTIC REPROGRAMMING Peripheral T-cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcome. T-cell receptor (TCR) is emerging as a key driver of T lymphocytes transformation.... Published

May 27, 2021

Research In-Press Preview Hematology

Immunology

CHRONIC T CELL RECEPTOR STIMULATION UNMASKS NK RECEPTOR SIGNALING IN PERIPHERAL T CELL LYMPHOMAS VIA EPIGENTIC REPROGRAMMING

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ABSTRACT

Peripheral T-cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcome. T-cell receptor (TCR) is emerging as a key driver of T lymphocytes transformation. However, the role of chronic TCR activation in lymphomagenesis and in survival of lymphoma cells is still poorly understood. Using an original mouse model, we report here that chronic TCR stimulation drives T-cell lymphomagenesis whereas TCR signaling does not contribute to PTCL survival. The combination of kinome, transcriptome and epigenome analyses of mouse PTCLs revealed a NK-like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and Syk. Activating NKR were functional in PTCLs and dependent of Syk activity. In vivo blockade of NKR signaling prolonged mouse survival, demonstrating the addiction of PTCLs to NKR and downstream Syk/mTOR activity for their survival. Studying a large collection of human primary samples, we identified several PTCLs recapitulating the phenotype described in this model by expressing NKR and Syk, suggesting similar mechanism of lymphomagenesis and establishing rationales for clinical trials targeting such molecules.

AUTHORS

Sylvain Carras, Dimitri Chartoire, Sylvain Mareschal, Maël Heiblig, Antoine Marçais, Rémy Robinot, Mirjam Urb, Roxane M. Pommier, Edith Julia, Amel Chebel, Aurélie Verney, Charlotte Bertheau, Emilie Bardel, Caroline Fezelot, Lucien Courtois, Camille Lours, Alyssa Bouska, Sunandini Sharma, Christine Lefebvre, Jean-Pierre Rouault, David Sibon, Anthony Ferrari, Javeed Iqbal, Laurence de Leval, Philippe Gaulard, Alexandra Traverse-Glehen, Pierre Sujobert, Mathieu Bléry, Gilles Salles, Thierry Walzer, Emmanuel Bachy, Laurent

Genestier

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JCI THIS MONTH

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REVIEW SERIES - MORE TUMOR MICROENVIRONMENT SERIES EDITED BY ANDREW J EWALD Cancer cells in a solid tumor are supported by vasculature, extracellular matrix, nerves, and an immunological milieu collectively known as the tumor microenvironment. Elements within the tumor... TUMOR MICROENVIRONMENT SERIES EDITED BY ANDREW J EWALD Cancer cells in a solid tumor are supported by vasculature, extracellular matrix, nerves, and an immunological milieu collectively known as the tumor microenvironment. Elements within the tumor microenvironment can act in a coordinated fashion to support tumor growth, immune evasion, and metastasis. In this series, reviews curated by Series Editor Andrew Ewald highlight the tumor microenvironment’s complex effects in cancer, describing its modulation of immune cells and the tumor stroma as well as its role in disseminating metastases. * View this review series * View all review series

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In recent decades, cancer research has expanded exponentially beyond the study of abnormally dividing cells to include complex and extensive heterotypic interactions between cancer and noncancer... AUTHOR'S TAKE - MORE IMMUNE CHECKPOINT RECEPTORS FOR HBV INFECTION In this episode, Shie-Liang Hsieh and Tsung-Yu Tsai explain that HBV interacts with SIGLEC-3 and causes impairment of host immunity... CONVERSATIONS WITH GIANTS IN MEDICINE - MORE CONVERSATIONS WITH GIANTS IN MEDICINE: ROBERT LEFKOWITZ Robert Lefkowitz, physician-scientist from Duke University and the 2012 Nobel laureate in chemistry for his studies of GPCRs has recently written a memoir called A Funny Thing Happened on the Way to

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