Atrial natriuretic peptide promotes uterine decidualization and a TRAIL-dependent mechanism in spiral artery remodeling
Atrial natriuretic peptide (ANP) is an important hormone in cardiovascular biology. It is activated by the protease corin. In pregnancy, ANP and corin promote uterine spiral artery remodeling, but the underlying mechanism remains unknown. Here we report an ANP function in uterine decidualization and TNF-related apoptosis-inducing ligand–dependent (TRAIL-dependent) death in spiral arterial smooth muscle cells (SMCs) and endothelial cells (ECs). In ANP- or corin-deficient mice, uterine decidualization markers and TRAIL expression were decreased, whereas in cultured human endometrial stromal cells (HESCs), ANP increased...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Wei Zhang, Shuo Li, Jinglei Lou, Hui Li, Meng Liu, Ningzheng Dong, Qingyu Wu Source Type: research

A multicenter randomized open-label clinical trial for convalescent plasma in patients hospitalized with COVID-19 pneumonia
CONCLUSION CP showed a significant benefit in preventing progression to noninvasive ventilation or high-flow oxygen, invasive mechanical ventilation or ECMO, or death at 28 days. The effect on the predefined primary endpoint at 14 days and the effect on overall survival were not statistically significant.TRIAL REGISTRATION Clinicaltrials.gov, NCT04345523.FUNDING Government of Spain, Instituto de Salud Carlos III. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Cristina Avendaño-Solá, Antonio Ramos-Martínez, Elena Muñez-Rubio, Belen Ruiz-Antorán, Rosa Malo de Molina, Ferran Torres, Ana Fernández-Cruz, Jorge Calderón-Parra, Concepcion Payares-Herrera, Alberto Díaz de Santiago, Irene Romera-Martínez, Ildu Source Type: research

Skeleton-secreted PDGF-BB mediates arterial stiffening
Evidence links osteoporosis and cardiovascular disease but the cellular and molecular mechanisms are unclear. Here we identify skeleton-secreted platelet-derived growth factor–BB (PDGF-BB) as a key mediator of arterial stiffening in response to aging and metabolic stress. Aged mice and those fed high-fat diet (HFD), relative to young mice and those fed normal chow food diet, respectively, had higher serum PDGF-BB and developed bone loss and arterial stiffening. Bone/bone marrow preosteoclasts in aged mice and HFD mice secrete an excessive amount of PDGF-BB, contributing to the elevated PDGF-BB in blood circulation. C...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Lakshmi Santhanam, Guanqiao Liu, Sandeep Jandu, Weiping Su, Bulouere P. Wodu, William Savage, Alan Poe, Xiaonan Liu, Lacy M. Alexander, Xu Cao, Mei Wan Source Type: research

The role of PDGF-BB in the bone-vascular relationship during aging
Cardiovascular disease (CVD) and osteoporosis often occur together, suggesting an association between CVD and bone loss. Similarly, the correlation of bone loss, atherosclerosis, and aortic calcification, especially in patients with chronic kidney disease, exemplifies a bone-vessel connection. In this issue of the JCI, Santhanam et al. investigated the role of the angiogenesis factor platelet-derived growth factor–BB (PDGF-BB) in vascular stiffening. Serum levels of bone-derived PDGF-BB differed between young and aged mice, and in mice fed a high-fat diet (HFD) compared with those fed normal chow. Experiments with ge...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Mone Zaidi, Daria Lizneva, Tony Yuen Source Type: research

Breast cancer–derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment
Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (ARG1) promotes a protumor phenotype by inhibiting T cell function and depleting extracellular l-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor-derived GM-CSF as the primary regulator of myeloid cell ARG1 expression and local immune suppression through a gene-KO screen of breast tumor cell–produced factors. The induction of myeloid c...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Xinming Su, Yalin Xu, Gregory C. Fox, Jingyu Xiang, Kristin A. Kwakwa, Jennifer L. Davis, Jad I. Belle, Wen-Chih Lee, Wing H. Wong, Francesca Fontana, Leonel F. Hernandez-Aya, Takayuki Kobayashi, Helen M. Tomasson, Junyi Su, Suzanne J. Bakewell, Sheila A. Source Type: research

Results of the CAPSID randomized trial for high-dose convalescent plasma in patients with severe COVID-19
BACKGROUND COVID-19 convalescent plasma (CCP) has been considered a treatment option for COVID-19. This trial assessed the efficacy of a neutralizing antibody containing high-dose CCP in hospitalized adults with COVID-19 requiring respiratory support or intensive care treatment.METHODS Patients (n = 105) were randomized 1:1 to either receive standard treatment and 3 units of CCP or standard treatment alone. Control group patients with progress on day 14 could cross over to the CCP group. The primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria for severe COVID-19 on day 21.Resul...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Sixten Körper, Manfred Weiss, Daniel Zickler, Thomas Wiesmann, Kai Zacharowski, Victor M. Corman, Beate Grüner, Lucas Ernst, Peter Spieth, Philipp M. Lepper, Martin Bentz, Sebastian Zinn, Gregor Paul, Johannes Kalbhenn, Matthias M. Dollinger, Peter Rose Source Type: research

Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C
CONCLUSIONS Activated neutrophils expressing IL-1β can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDING Patient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Yanfang P. Zhu, Isaac Shamie, Jamie C. Lee, Cameron J. Nowell, Weiqi Peng, Shiela Angulo, Linh N.N. Le, Yushan Liu, Huilai Miao, Hainan Xiong, Cathleen J. Pena, Elizabeth Moreno, Eric Griffis, Stephanie G. Labou, Alessandra Franco, Lori Broderick, Hal M. Source Type: research

mTOR-dependent translation amplifies microglia priming in aging mice
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Lily Keane, Ignazio Antignano, Sean-Patrick Riechers, Raphael Zollinger, Anaelle A. Dumas, Nina Offermann, Maria E. Bernis, Jenny Russ, Frederike Graelmann, Patrick Neil McCormick, Julia Esser, Dario Tejera, Ai Nagano, Jun Wang, Claude Chelala, Yvonne Bie Source Type: research

A tribute to Paul S. Frenette (1965–2021)
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Johanna P. Daily, Arthur I. Skoultchi, Gordon F. Tomaselli Source Type: research

Imaging brain cortisol regulation in PTSD with a target for 11β-hydroxysteroid dehydrogenase type 1
CONCLUSION Higher brain cortisol–producing 11β-HSD1 in the PTSD group may represent a resilience-promoting neuroadaptation resulting in lower PTSD symptoms. Along with preliminary associations between 11β-HSD1 and TSPO, corroborating previous evidence of immune suppression in PTSD, these findings collectively challenge previous hypotheses of the deleterious effects of both excessive brain glucocorticoid and brain immune signaling in PTSD.FUNDING Brain and Behavior Research Foundation Independent Investigator Grant, National Institute of Mental Health grants F30MH116607 and R01MH110674, the Veterans Affairs ...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Shivani Bhatt, Ansel T. Hillmer, Aleksandra Rusowicz, Nabeel Nabulsi, David Matuskey, Gustavo A. Angarita, Soheila Najafzadeh, Michael Kapinos, Steven M. Southwick, John H. Krystal, Richard E. Carson, Yiyun Huang, Kelly P. Cosgrove Source Type: research

Resting innate-like B cells leverage sustained Notch2/mTORC1 signaling to achieve rapid and mitosis-independent plasma cell differentiation
Little is known about how cells regulate and integrate distinct biosynthetic pathways governing differentiation and cell division. For B lineage cells it is widely accepted that activated cells must complete several rounds of mitosis before yielding antibody-secreting plasma cells. However, we report that marginal zone (MZ) B cells, innate-like naive B cells known to generate plasma cells rapidly in response to blood-borne bacteria, generate functional plasma cells despite cell-cycle arrest. Further, short-term Notch2 blockade in vivo reversed division-independent differentiation potential and decreased transcript abundanc...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Brian T. Gaudette, Carly J. Roman, Trini A. Ochoa, Daniela Gómez Atria, Derek D. Jones, Christian W. Siebel, Ivan Maillard, David Allman Source Type: research

Convalescent plasma associates with reduced mortality and improved clinical trajectory in patients hospitalized with COVID-19
BACKGROUND Evidence supporting convalescent plasma (CP), one of the first investigational treatments for coronavirus disease 2019 (COVID-19), has been inconclusive, leading to conflicting recommendations. The primary objective was to perform a comparative effectiveness study of CP for all-cause, in-hospital mortality in patients with COVID-19.METHODS The multicenter, electronic health records–based, retrospective study included 44,770 patients hospitalized with COVID-19 in one of 176 HCA Healthcare–affiliated community hospitals. Coarsened exact matching (1:k) was employed, resulting in a sample of 3774 CP and ...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Shanna A. Arnold Egloff, Angela Junglen, Joseph S.A. Restivo, Marjorie Wongskhaluang, Casey Martin, Pratik Doshi, Daniel Schlauch, Gregg Fromell, Lindsay E. Sears, Mick Correll, Howard A. Burris III, Charles F. LeMaistre Source Type: research

Combined presentation and immunogenicity analysis reveals a recurrent RAS.Q61K neoantigen in melanoma
Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated pep...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Aviyah Peri, Erez Greenstein, Michal Alon, Joy A. Pai, Tamir Dingjan, Shlomit Reich-Zeliger, Eilon Barnea, Chaya Barbolin, Ronen Levy, Claudia Arnedo-Pac, Shelly Kalaora, Bareket Dassa, Ester Feldmesser, Ping Shang, Polina Greenberg, Yishai Levin, Gil Ben Source Type: research

Aducanumab for Alzheimer disease: the amyloid hypothesis moves from bench to bedside
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Erik S. Musiek, Teresa Gomez-Isla, David M. Holtzman Source Type: research

Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder–related deficits
CDKL5 deficiency disorder (CDD) is an early onset, neurodevelopmental syndrome associated with pathogenic variants in the X-linked gene encoding cyclin-dependent kinase-like 5 (CDKL5). CDKL5 has been implicated in neuronal synapse maturation, yet its postdevelopmental necessity and the reversibility of CDD-associated impairments remain unknown. We temporally manipulated endogenous Cdkl5 expression in male mice and found that postdevelopmental loss of CDKL5 disrupts numerous behavioral domains, hippocampal circuit communication, and dendritic spine morphology, demonstrating an indispensable role for CDKL5 in the adult brain...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Barbara Terzic, M. Felicia Davatolhagh, Yugong Ho, Sheng Tang, Yu-Ting Liu, Zijie Xia, Yue Cui, Marc V. Fuccillo, Zhaolan Zhou Source Type: research

ADGRG1 enriches for functional human hematopoietic stem cells following ex vivo expansion–induced mitochondrial oxidative stress
The heterogeneity of human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) under stress conditions such as ex vivo expansion is poorly understood. Here, we report that the frequencies of SCID-repopulating cells were greatly decreased in cord blood (CB) CD34+ HSCs and HPCs upon ex vivo culturing. Transcriptomic analysis and metabolic profiling demonstrated that mitochondrial oxidative stress of human CB HSCs and HPCs notably increased, along with loss of stemness. Limiting dilution analysis revealed that functional human HSCs were enriched in cell populations with low levels of mitochondrial ROS (m...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Yandan Chen, Shuyi Fang, Qingwei Ding, Rongzhen Jiang, Jiefeng He, Qin Wang, Yuting Jin, Xinxin Huang, Sheng Liu, Maegan L. Capitano, Thao Trinh, Yincheng Teng, Qingyou Meng, Jun Wan, Hal E. Broxmeyer, Bin Guo Source Type: research

Lymphatics in the broken heart
Cardiac lymphatics have emerged as a therapeutic target in cardiovascular diseases to limit myocardial edema and inflammation, notably after myocardial infarction (MI). While most experimental therapeutic approaches have focused on vascular endothelial growth factor C (VEGF-C) delivery, it remains uncertain to what degree the beneficial cardiac effects are related to lymphatic expansion in the heart. In this issue of the JCI, Keller, Lim, et al. reexamined the acute functional impact of endogenous cardiac lymphangiogenesis in the infarct zone after MI in mice. Their data, obtained by elegant comparisons of several compleme...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Ebba Bråkenhielm, Yuguo Chen, Yihai Cao Source Type: research

The key role of NLRP3 and STING in APOL1-associated podocytopathy
Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of APOL1-induced kidney dysfunction remain poorly understood. Here, we report that expression of G2 APOL1 in the podocytes of Nphs1rtTA/TRE-G2APOL1 (G2APOL1) mice leads to early activation of the cytosolic nucleotide sensor, stimulator of interferon genes (STING), and the NLR family pyrin domain–containing 3 (NLRP3) inflammasome. STING and NLRP3 expression was increased in podocytes from patients with high-risk APOL1 genotypes, and expression of APOL1 correl...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Junnan Wu, Archana Raman, Nathan J. Coffey, Xin Sheng, Joseph Wahba, Matthew J. Seasock, Ziyuan Ma, Pazit Beckerman, Dorottya Laczkó, Matthew B. Palmer, Jeffrey B. Kopp, Jay J. Kuo, Steven S. Pullen, Carine M. Boustany-Kari, Andreas Linkermann, Katalin S Source Type: research

Fibroblast pathology in inflammatory diseases
Fibroblasts are important cells for the support of homeostatic tissue function. In inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, fibroblasts take on different roles (a) as inflammatory cells themselves and (b) in recruiting leukocytes, driving angiogenesis, and enabling chronic inflammation in tissues. Recent advances in single-cell profiling techniques have transformed the ability to examine fibroblast states and populations in inflamed tissues, providing evidence of previously underappreciated heterogeneity and disease-associated fibroblast populations. These studies challenge the pre...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Kevin Wei, Hung N. Nguyen, Michael B. Brenner Source Type: research

Targeting enhancer reprogramming to mitigate MEK inhibitor resistance in preclinical models of advanced ovarian cancer
Ovarian cancer is characterized by aberrant activation of the mitogen-activated protein kinase (MAPK), highlighting the importance of targeting the MAPK pathway as an attractive therapeutic strategy. However, the clinical efficacy of MEK inhibitors is limited by intrinsic or acquired drug resistance. Here, we established patient-derived ovarian cancer models resistant to MEK inhibitors and demonstrated that resistance to the clinically approved MEK inhibitor trametinib was associated with enhancer reprogramming. We also showed that enhancer decommissioning induced the downregulation of negative regulators of the MAPK pathw...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Shini Liu, Qiong Zou, Jie-Ping Chen, Xiaosai Yao, Peiyong Guan, Weiting Liang, Peng Deng, Xiaowei Lai, Jiaxin Yin, Jinghong Chen, Rui Chen, Zhaoliang Yu, Rong Xiao, Yichen Sun, Jing Han Hong, Hui Liu, Huaiwu Lu, Jianfeng Chen, Jin-Xin Bei, Joanna Koh, Jas Source Type: research

Sparcl1 promotes nonalcoholic steatohepatitis progression in mice through upregulation of CCL2
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of chronic liver disease ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms of NASH progression remain incompletely understood. White adipose tissue (WAT) has emerged as an important endocrine organ and contributes not only to the initial stage of NAFLD, but also to its severity. In the current study, through transcriptomic analysis we identified increased expression of Sparcl1, a secreted glycoprotein, in the WAT from NASH mice. Plasma Sparcl1 levels were similarly elevated and positively correlated w...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Bin Liu, Liping Xiang, Jing Ji, Wei Liu, Ying Chen, Mingfeng Xia, Yuejun Liu, Wenyue Liu, Peiwu Zhu, Yi Jin, Yu Han, Jieli Lu, Xiaoying Li, Minghua Zheng, Yan Lu Source Type: research

Rethinking endometriosis and pelvic pain
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Kristin Patzkowsky Source Type: research

A randomized controlled trial of the GLP-1 receptor agonist dulaglutide in primary polydipsia
CONCLUSIONS GLP-1 receptor agonists reduce fluid intake and thirst perception in patients with primary polydipsia and could therefore be a treatment option for these patients.Trial registration Clinicaltrials.gov NCT02770885.Funding Swiss National Science Foundation (grant 32473B_162608); University Hospital and University of Basel; Young Talents in Clinical Research grant from the Swiss Academy of Medical Sciences and the Gottfried & Julia Bangerter-Rhyner Foundation; Top-up Grant from the PhD Programme in Health Sciences, University of Basel. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Bettina Winzeler, Clara O. Sailer, David Coynel, Davide Zanchi, Deborah R. Vogt, Sandrine A. Urwyler, Julie Refardt, Mirjam Christ-Crain Source Type: research

Genetic blockade of lymphangiogenesis does not impair cardiac function after myocardial infarction
In recent decades, treatments for myocardial infarction (MI), such as stem and progenitor cell therapy, have attracted considerable scientific and clinical attention but failed to improve patient outcomes. These efforts indicate that more rigorous mechanistic and functional testing of potential MI therapies is required. Recent studies have suggested that augmenting post-MI lymphatic growth via VEGF-C administration improves cardiac function. However, the mechanisms underlying this proposed therapeutic approach remain vague and untested. To more rigorously test the role of lymphatic vessel growth after MI, we examined the p...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: T.C. Stevenson Keller IV, Lillian Lim, Swapnil V. Shewale, Kendra McDaid, Íngrid Martí-Pàmies, Alan T. Tang, Carl Wittig, Andrea A. Guerrero, Stephanie Sterling, N. Adrian Leu, Marielle Scherrer-Crosbie, Phyllis A. Gimotty, Mark L. Kahn Source Type: research

Targeting adipose tissue to tackle NASH: SPARCL1 as an emerging player
Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease, affecting 1.5%–6.5% of the world population. Currently, there are no FDA-approved drugs to treat this disease. Accumulating evidence suggests that metabolically hazardous visceral fat contributes to NASH progression by releasing fatty acids and proinflammatory mediators. Therefore, targeting adipose tissue to reduce adipose inflammation may provide an effective strategy to treat NASH. Another strategy is to target specific inflammatory mediators that are produced by adipose tissue and contribute to NASH progression. In this issue of the ...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Robim M. Rodrigues, Yukun Guan, Bin Gao Source Type: research

The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children
Multisystem inflammatory syndrome in children (MIS-C) manifests as a severe and uncontrolled inflammatory response with multiorgan involvement, occurring weeks after SARS-CoV-2 infection. Here, we utilized proteomics, RNA sequencing, autoantibody arrays, and B cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission. Inflammation markers, humoral immune responses, neutrophil activation, and complement and coagulation pathways were highly enriched in MIS-C patient serum, with a more hyperinflammatory profile ...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Rebecca A. Porritt, Aleksandra Binek, Lisa Paschold, Magali Noval Rivas, Angela McArdle, Lael M. Yonker, Galit Alter, Harsha K. Chandnani, Merrick Lopez, Alessio Fasano, Jennifer E. Van Eyk, Mascha Binder, Moshe Arditi Source Type: research

Attenuated activation of pulmonary immune cells in mRNA-1273–vaccinated hamsters after SARS-CoV-2 infection
The mRNA-1273 vaccine is effective against SARS-CoV-2 and was granted emergency use authorization by the FDA. Clinical studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibits severe SARS-CoV-2 disease similar to that in hospitalized patients, making them pertinent for vaccine evaluation. We demonstrate that prime or prime-boost administration of mRNA-1273 in hamsters elicited robust neutralizing antibodies, ameliorated weight loss, suppressed SARS-CoV-2 replication in the airwa...
Source: Journal of Clinical Investigation - October 16, 2021 Category: Biomedical Science Authors: Michelle Meyer, Yuan Wang, Darin Edwards, Gregory R. Smith, Aliza B. Rubenstein, Palaniappan Ramanathan, Chad E. Mire, Colette Pietzsch, Xi Chen, Yongchao Ge, Wan Sze Cheng, Carole Henry, Angela Woods, LingZhi Ma, Guillaume B.E. Stewart-Jones, Kevin W. Bo Source Type: research

ZFP91 disturbs metabolic fitness and antitumor activity of tumor-infiltrating T cells
Proper metabolic activities facilitate T cell expansion and antitumor function; however, the mechanisms underlying disruption of the T cell metabolic program and function in the tumor microenvironment (TME) remain elusive. Here, we show a zinc finger protein 91–governed (ZFP91-governed) mechanism that disrupts the metabolic pathway and antitumor activity of tumor-infiltrating T cells. Single-cell RNA-Seq revealed that impairments in T cell proliferation and activation correlated with ZFP91 in tissue samples from patients with colorectal cancer. T cell–specific deletion of Zfp91 in mice led to enhanced T cell pr...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Feixiang Wang, Yuerong Zhang, Xiaoyan Yu, Xiao-Lu Teng, Rui Ding, Zhilin Hu, Aiting Wang, Zhengting Wang, Youqiong Ye, Qiang Zou Source Type: research

Disrupted PI3K subunit p110α signaling protects against pulmonary hypertension and reverses established disease in rodents
Enhanced signaling via RTKs in pulmonary hypertension (PH) impedes current treatment options because it perpetuates proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Here, we demonstrated hyperphosphorylation of multiple RTKs in diseased human vessels and increased activation of their common downstream effector phosphatidylinositol 3′-kinase (PI3K), which thus emerged as an attractive therapeutic target. Systematic characterization of class IA catalytic PI3K isoforms identified p110α as the key regulator of pathogenic signaling pathways and PASMC responses (proliferation...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Eva M. Berghausen, Wiebke Janssen, Marius Vantler, Leoni L. Gnatzy-Feik, Max Krause, Arnica Behringer, Christine Joseph, Mario Zierden, Henrik ten Freyhaus, Anna Klinke, Stephan Baldus, Miguel A. Alcazar, Rajkumar Savai, Soni Savai Pullamsetti, Dickson W. Source Type: research

Broadly neutralizing antibody–derived CAR T cells reduce viral reservoir in individuals infected with HIV-1
CONCLUSION No safety concerns were identified with adoptive transfer of bNAb-derived CAR T cells. They reduced viral reservoir. All the rebounds were due to preexisting or emergence of viral escape mutations.TRIAL REGISTRATION ClinicalTrials.gov (NCT03240328).FUNDING Ministry of Science and Technology of China, National Natural Science Foundation of China, and Department of Science and Technology of Guangdong Province. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Bingfeng Liu, Wanying Zhang, Baijin Xia, Shuliang Jing, Yingying Du, Fan Zou, Rong Li, Lijuan Lu, Shaozhen Chen, Yonghong Li, Qifei Hu, Yingtong Lin, Yiwen Zhang, Zhangping He, Xu Zhang, Xiejie Chen, Tao Peng, Xiaoping Tang, Weiping Cai, Ting Pan, Linghua Source Type: research

Propranolol inhibits cavernous vascular malformations by β1 adrenergic receptor antagonism in animal models
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Wenqing Li, Robert Shenkar, Mathew R. Detter, Thomas Moore, Christian Benavides, Rhonda Lightle, Romuald Girard, Nicholas Hobson, Ying Cao, Yan Li, Erin Griffin, Carol Gallione, Joseph M. Zabramski, Mark H. Ginsberg, Douglas A. Marchuk, Issam A. Awad Source Type: research

HIV-specific CAR T cells return to the clinic
Over the past decade, chimeric antigen receptor (CAR) T cells have emerged as the prototype gene therapy for B cell leukemias. These so-called living drugs are derived from a patient’s own cells, reprogrammed to recognize and destroy cancer cells, and then reintroduced into the body. The huge success of this therapy for cancer is rooted in pioneering clinical and preclinical studies, established more than three decades ago, focused on persistent HIV-1 infection. In this issue of the JCI, Bingfeng Liu et al. revisit HIV-specific CAR T cells in an important clinical study that supports broader application of this groun...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Christopher W. Peterson Source Type: research

Circadian disruption and human health
Circadian disruption is pervasive and can occur at multiple organizational levels, contributing to poor health outcomes at individual and population levels. Evidence points to a bidirectional relationship, in that circadian disruption increases disease severity and many diseases can disrupt circadian rhythms. Importantly, circadian disruption can increase the risk for the expression and development of neurologic, psychiatric, cardiometabolic, and immune disorders. Thus, harnessing the rich findings from preclinical and translational research in circadian biology to enhance health via circadian-based approaches represents a...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Anna B. Fishbein, Kristen L. Knutson, Phyllis C. Zee Source Type: research

Circular RNA cia-MAF drives self-renewal and metastasis of liver tumor-initiating cells via transcription factor MAFF
This study reveals an additional layer for liver TIC regulation as well as circRNA function, and provides an additional target for eliminating liver TICs, especially for liver tumors without MAFA/MAFG gene CNAs. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Zhenzhen Chen, Tiankun Lu, Lan Huang, Zhiwei Wang, Zhongyi Yan, Yubo Guan, Wenjing Hu, Zusen Fan, Pingping Zhu Source Type: research

NKTR-255 is a polymer-conjugated IL-15 with unique mechanisms of action on T and natural killer cells
NKTR-255 is a PEG conjugate of recombinant human IL-15 (rhIL-15) being examined as a potential cancer immunotherapeutic. Since IL-15 responses can be mediated by trans or cis presentation via IL-15Rα or soluble IL-15/IL-15Rα complexes, we investigated the role of IL-15Rα in driving NKTR-255 responses using defined naive and memory OVA-specific CD8+ T cells (OT-I) and NK cells in mice. NKTR-255 induced a 2.5- and 2.0-fold expansion of CD8+ T and NK cells, respectively, in WT mice. In adoptive transfer studies, proliferation of naive and memory WT OT-I T cells in response to NKTR-255 was not impaired in IL-...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Tanya O. Robinson, Shweta M. Hegde, Allison Chang, Achintyan Gangadharan, Sarai Rivas, Loui Madakamutil, Jonathan Zalevsky, Takahiro Miyazaki, Kimberly S. Schluns Source Type: research

Efficient maternal to neonatal transfer of antibodies against SARS-CoV-2 and BNT162b2 mRNA COVID-19 vaccine
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Ofer Beharier, Romina Plitman Mayo, Tal Raz, Kira Nahum Sacks, Letizia Schreiber, Yael Suissa-Cohen, Rony Chen, Rachel Gomez-Tolub, Eran Hadar, Rinat Gabbay-Benziv, Yuval Jaffe Moshkovich, Tal Biron-Shental, Gil Shechter-Maor, Sivan Farladansky-Gershnabel Source Type: research

In-hospital use of ACE inhibitors/angiotensin receptor blockers associates with COVID-19 outcomes in African American patients
CONCLUSION In-hospital use of ARB was associated with a significant reduction in in-hospital mortality among COVID-19–positive African American patients.FUNDING None. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Shilong Li, Rangaprasad Sarangarajan, Tomi Jun, Yu-Han Kao, Zichen Wang, Ke Hao, Emilio Schadt, Michael A. Kiebish, Elder Granger, Niven R. Narain, Rong Chen, Eric E. Schadt, Li Li Source Type: research

Differential roles of FOXO transcription factors on insulin action in brown and white adipose tissue
Insulin and IGF-1 are essential for adipocyte differentiation and function. Mice lacking insulin and IGF-1 receptors in fat (FIGIR-KO, fat-specific IGF-1 receptor and insulin receptor–KO) exhibit complete loss of white and brown adipose tissue (WAT and BAT), glucose intolerance, insulin resistance, hepatosteatosis, and cold intolerance. To determine the role of FOXO transcription factors in the altered adipose phenotype, we generated FIGIR-KO mice with fat-specific KO of fat-expressed Foxos [Foxo1, Foxo3, Foxo4] (F-Quint–KO). Unlike FIGIR-KO mice, F-Quint–KO mice had normal BAT, glucose tolerance, insulin...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Erica P. Homan, Bruna B. Brandão, Samir Softic, Abdelfattah El Ouaamari, Brian T. O’Neill, Rohit N. Kulkarni, Jason K. Kim, C. Ronald Kahn Source Type: research

Intravenous bamlanivimab use associates with reduced hospitalization in high-risk patients with mild to moderate COVID-19
CONCLUSIONS Among high-risk patients with mild to moderate COVID-19, treatment with bamlanivimab was associated with a statistically significant lower rate of hospitalization, ICU admission, and mortality compared with usual care.FUNDING Mayo Clinic. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Ravindra Ganesh, Colin F. Pawlowski, John C. O’Horo, Lori L. Arndt, Richard F. Arndt, Sarah J. Bell, Dennis M. Bierle, Molly Destro Borgen, Sara N. Hanson, Alexander Heyliger, Jennifer J. Larsen, Patrick J. Lenehan, Robert Orenstein, Arjun Puranik, Leig Source Type: research

Randomized controlled trial of fractionated laser resurfacing on aged skin as prophylaxis against actinic neoplasia
CONCLUSION The elimination of senescent fibroblasts via FLR reduced the procarcinogenic UVB response of aged skin. Thus, wounding therapies are a potentially effective prophylaxis for managing high-risk populations.TRIAL REGISTRATION ClinicalTrials.gov (NCT03906253).FUNDING National Institutes of Health, Veterans Administration. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Dan F. Spandau, Roy Chen, Jeffrey J. Wargo, Craig A. Rohan, David Southern, Angela Zhang, Mathew Loesch, Jonathan Weyerbacher, Sunil S. Tholpady, Davina A. Lewis, Matthew Kuhar, Kenneth Y. Tsai, Amber J. Castellanos, Michael G. Kemp, Michael Markey, Eliza Source Type: research

Basal epithelial stem cells cross an alarmin checkpoint for postviral lung disease
Epithelial cells are charged with protection at barrier sites, but whether this normally beneficial response might sometimes become dysfunctional still needs definition. Here, we recognized a pattern of imbalance marked by basal epithelial cell growth and differentiation that replaced normal airspaces in a mouse model of progressive postviral lung disease due to the Sendai virus. Single-cell and lineage-tracing technologies identified a distinct subset of basal epithelial stem cells (basal ESCs) that extended into gas-exchange tissue to form long-term bronchiolar-alveolar remodeling regions. Moreover, this cell subset was ...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Kangyun Wu, Kenji Kamimoto, Yong Zhang, Kuangying Yang, Shamus P. Keeler, Benjamin J. Gerovac, Eugene V. Agapov, Stephen P. Austin, Jennifer Yantis, Kelly A. Gissy, Derek E. Byers, Jennifer Alexander-Brett, Christy M. Hoffmann, Matthew Wallace, Michael E. Source Type: research

Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality
There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than ...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Justin M. Snider, Jeehyun Karen You, Xia Wang, Ashley J. Snider, Brian Hallmark, Manja M. Zec, Michael C. Seeds, Susan Sergeant, Laurel Johnstone, Qiuming Wang, Ryan Sprissler, Tara F. Carr, Karen Lutrick, Sairam Parthasarathy, Christian Bime, Hao Helen Z Source Type: research

Inducible cardiomyocyte injury within the atrioventricular conduction system uncovers latent regenerative capacity in mice
The cardiac conduction system (CCS) ensures regular contractile function, and injury to any of its components can cause cardiac dysrhythmia. Although all cardiomyocytes (CMs) originate from common progenitors, the CCS is composed of biologically distinct cell types with unique functional and developmental characteristics. In contrast to ventricular cardiomyocytes, which continue to proliferate after birth, most CCS cells terminally exit the cell cycle during fetal development. Although the CCS should thus provide a poor substrate for postnatal injury repair, its regenerative capacity remains untested. Here, we describe a g...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Lin Wang, Minoti Bhakta, Antonio Fernandez-Perez, Nikhil V. Munshi Source Type: research

Nuclear IL-33 as a growth and survival agent within basal cells
IL-33 is a well-studied cytokine that resides normally within nuclei but can be released by cell damage or stress to then signal via a single receptor widely expressed on immune cells to promote host resistance and type 2 allergic immunity. In this issue of the JCI, Wu et al. used a well-established model of mouse Sendai viral infection to show that IL-33 was induced in distal lung airway epithelium, specifically in cell-cycling basal cells. IL-33 induced cell-cycling basal cells to expand and migrate into the alveolar compartment, presumably to restore barrier function. However, restoring barrier function with airway-deri...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Harold A. Chapman Source Type: research

Cellular regeneration as a potential strategy to treat cardiac conduction disorders
Loss of atrioventricular conduction system (AVCS) cells due to either inherited or acquired deficits leads to conduction diseases, which can deteriorate into fatal cardiac arrhythmias and sudden death. In this issue of the JCI, Wang et al. constructed a mouse model of atrioventricular block (AVB) by inducing AVCS cell–specific injury using the Cx30.2 enhancer to drive expression of diphtheria toxin fragment A. AVCS cell ablation in adult mice led to irreversible AVB. jkjkIn contrast, AVCS cell injury in neonatal mice was followed by spontaneous recovery in a subset of mice, revealing a limited postnatal time window d...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Satadru K. Lahiri, Mohit M. Hulsurkar, Xander H.T. Wehrens Source Type: research

Insights into the anticancer mechanisms of interleukin-15 from engineered cytokine therapies
Innovative approaches in the field of cytokine engineering are revolutionizing the cancer therapeutic landscape. The IL-15 cytokine is particularly enticing as a cancer immunotherapy due to its natural propensity for stimulating the proliferation and activation of NK and CD8+ T cells. In a recent IL-15 engineering approach, the cytokine was conjugated to polyethylene glycol, and the resulting molecule (NKTR-255) exhibited potent antitumor activities. In this issue of the JCI, Robinson et al. mechanistically explored NKTR-255 and compared its immune profile to that of the unconjugated IL-15 cytokine. The authors found that ...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Zachary J. Bernstein, Jamie B. Spangler Source Type: research

Defining circadian disruption in neurodegenerative disorders
Neurodegenerative diseases encompass a large group of conditions that are clinically and pathologically diverse yet are linked by a shared pathology of misfolded proteins. The accumulation of insoluble aggregates is accompanied by a progressive loss of vulnerable neurons. For some patients, the symptoms are motor focused (ataxias), while others experience cognitive and psychiatric symptoms (dementias). Among the shared symptoms of neurodegenerative diseases is a disruption of the sleep/wake cycle that occurs early in the trajectory of the disease and may be a risk factor for disease development. In many cases, the disrupti...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Christopher S. Colwell Source Type: research

Functional Th1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity
We previously demonstrated that tumor-infiltrating lymphocytes (TIL) in human breast cancer sometimes form organized tertiary lymphoid structures (TLS) characterized by CXCL13-producing T follicular helper (Tfh) cells. The present study found that CD4+ Tfh TIL, CD8+ TIL, and TIL-B, colocalizing in TLS, all express the CXCL13 receptor CXCR5. An ex vivo functional assay determined that only activated, functional Th1-oriented Tfh TIL (PD-1hiICOSint phenotype) provide help for immunoglobulin and IFN-γ production. A functional Tfh TIL presence signals an active TLS, characterized by humoral (immunoglobulins, Ki-67+ TIL-B ...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Grégory Noël, Mireille Langouo Fontsa, Soizic Garaud, Pushpamali De Silva, Alexandre de Wind, Gert G. Van den Eynden, Roberto Salgado, Anaïs Boisson, Hanne Locy, Noémie Thomas, Cinzia Solinas, Edoardo Migliori, Céline Naveaux, Hugues Duvillier, Sophi Source Type: research

Stromal cell–derived DEL-1 inhibits Tfh cell activation and inflammatory arthritis
The secreted protein developmental endothelial locus 1 (DEL-1) regulates inflammatory cell recruitment and protects against inflammatory pathologies in animal models. Here, we investigated DEL-1 in inflammatory arthritis using collagen-induced arthritis (CIA) and collagen Ab–induced arthritis (CAIA) models. In both models, mice with endothelium-specific overexpression of DEL-1 were protected from arthritis relative to WT controls, whereas arthritis was exacerbated in DEL-1–deficient mice. Compared with WT controls, mice with collagen VI promoter–driven overexpression of DEL-1 in mesenchymal cells were pro...
Source: Journal of Clinical Investigation - October 1, 2021 Category: Biomedical Science Authors: Hui Wang, Xiaofei Li, Tetsuhiro Kajikawa, Jieun Shin, Jong-Hyung Lim, Ioannis Kourtzelis, Kosuke Nagai, Jonathan M. Korostoff, Sylvia Grossklaus, Ronald Naumann, Triantafyllos Chavakis, George Hajishengallis Source Type: research

The mRNA vaccine revolution is the dividend from decades of basic science research
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - September 24, 2021 Category: Biomedical Science Authors: Arturo Casadevall Source Type: research