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Metabolic changes in aging humans: current evidence and therapeutic strategies J. Clin. Invest. (IF 19.456) Pub Date : 2022 Allyson K. Palmer, Michael D. Jensen
Aging and metabolism are inextricably linked, and many age-related changes in body composition, including increased central adiposity and sarcopenia, have underpinnings in fundamental aging processes. These age-related changes are further exacerbated by a sedentary lifestyle and can be in part prevented by maintenance of activity with aging. Here we explore the age-related changes seen in individual
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Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity J. Clin. Invest. (IF 19.456) Pub Date : 2022 Evan R. Abt, Khalid Rashid, Thuc M. Le, Suwen Li, Hailey R. Lee, Vincent Lok, Luyi Li, Amanda L. Creech, Amanda N. Labora, Hanna K. Mandl, Alex K. Lam, Arthur Cho, Valerie Rezek, Nanping Wu, Gabriel Abril-Rodriguez, Ethan W. Rosser, Steven D. Mittelman, Willy Hugo, Thomas Mehrling, Shanta Bantia, Antoni Ribas, Timothy R. Donahue, Gay M. Crooks, Ting-Ting Wu, Caius G. Radu
Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here, we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T
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Immunodeficiency and autoimmunity: companions not opposites J. Clin. Invest. (IF 19.456) Pub Date : 2022 David A. Fox
Autoimmunity has long been regarded as the polar opposite of immunodeficiency, but clinical and experimental evidence refute this notion. Indeed, numerous inborn or acquired immunodeficiency syndromes are characterized by the development of autoimmune complications in the setting of deficient immune defenses against microbial pathogens. Appreciation that much of the daily business of a healthy immune
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Supercharged chimeric antigen receptor T cells in solid tumors J. Clin. Invest. (IF 19.456) Pub Date : 2022 Ayush Pant, Christopher M. Jackson
Chimeric antigen receptor (CAR) T cells have demonstrated success in treating select hematological malignancies, but their activity in solid tumors has been comparably modest. Challenges specific to treating solid tumors include trafficking and distribution throughout the tumor site, overcoming the immunosuppressive tumor microenvironment (TME), and identifying antigenic targets that are widely expressed
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An optimized bicistronic chimeric antigen receptor against GPC2 or CD276 overcomes heterogeneous expression in neuroblastoma J. Clin. Invest. (IF 19.456) Pub Date : 2022 Meijie Tian, Adam T. Cheuk, Jun S. Wei, Abdalla Abdelmaksoud, Hsien-Chao Chou, David Milewski, Michael C. Kelly, Young K. Song, Christopher M. Dower, Nan Li, Haiying Qin, Yong Yean Kim, Jerry T. Wu, Xinyu Wen, Mehdi Benzaoui, Katherine E. Masih, Xiaolin Wu, Zhongmei Zhang, Sherif Badr, Naomi Taylor, Brad St. Croix, Mitchell Ho, Javed Khan
Chimeric antigen receptor (CAR) T cell therapies targeting single antigens have performed poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated antigens (TAAs), limited T cell persistence, and T cell exhaustion. Here, we aimed to identify optimal CARs against glypican 2 (GPC2) or CD276 (B7-H3), which were highly but heterogeneously expressed in neuroblastoma
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Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells J. Clin. Invest. (IF 19.456) Pub Date : 2022 Rob S. Sellar, Adam S. Sperling, Mikołaj Słabicki, Jessica A. Gasser, Marie E. McConkey, Katherine A. Donovan, Nada Mageed, Dylan N. Adams, Charles Zou, Peter G. Miller, Ravi K. Dutta, Steffen Boettcher, Amy E. Lin, Brittany Sandoval, Vanessa A. Quevedo Barrios, Veronica Kovalcik, Jonas Koeppel, Elizabeth K. Henderson, Emma C. Fink, Lu Yang, Anthony Chan, Sheela Pangeni Pokharel, Erik J. Bergstrom
Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4CRBN ubiquitin ligase are a new class of cancer therapy in active clinical development with evidence of activity against acute myeloid leukemia in early-phase trials. However, other than activation of the integrated stress response, the downstream effects of GSPT1 degradation
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Functional imaging of immune cell subpopulations in the tumor microenvironment: clinical implications J. Clin. Invest. (IF 19.456) Pub Date : 2022 Amy B. Heimberger
Noninvasive interrogation of CD8+ T cell effector function for monitoring early tumor responses to immunotherapy Haoyi Zhou, … , Zhi Yang, Zhaofei Liu Haoyi Zhou, … , Zhi Yang, Zhaofei Liu Research Article Oncology
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Breaking satellite silence: human satellite II RNA expression in ovarian cancer J. Clin. Invest. (IF 19.456) Pub Date : 2022 Shridar Ganesan
Multiple cancer types demonstrate abnormal expression of repetitive RNA sequences as a form of epigenetic instability. There is growing interest in understanding the role of repetitive RNAs in cancer pathogenesis and immunogenicity and in their potential role as diagnostic or therapeutic biomarkers. In this issue of the JCI, Porter and colleagues report on satellite RNA in a subset of ovarian cancers
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Satellite repeat RNA expression in epithelial ovarian cancer associates with a tumor-immunosuppressive phenotype J. Clin. Invest. (IF 19.456) Pub Date : 2022 Rebecca L. Porter, Siyu Sun, Micayla N. Flores, Emily Berzolla, Eunae You, Ildiko E. Phillips, Neelima KC, Niyati Desai, Eric C. Tai, Annamaria Szabolcs, Evan R. Lang, Amaya Pankaj, Michael J. Raabe, Vishal Thapar, Katherine H. Xu, Linda T. Nieman, Daniel C. Rabe, David L. Kolin, Elizabeth H. Stover, David Pepin, Shannon L. Stott, Vikram Deshpande, Joyce F. Liu, Alexander Solovyov, Ursula A. Matulonis
Aberrant expression of viral-like repeat elements is a common feature of epithelial cancers, and the substantial diversity of repeat species provides a distinct view of the cancer transcriptome. Repeatome profiling across ovarian, pancreatic, and colorectal cell lines identifies distinct clustering independent of tissue origin that is seen with coding gene analysis. Deeper analysis of ovarian cancer
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The NCF1 variant p.R90H aggravates autoimmunity by facilitating the activation of plasmacytoid dendritic cells J. Clin. Invest. (IF 19.456) Pub Date : 2022 Yao Meng, Jianyang Ma, Chao Yao, Zhizhong Ye, Huihua Ding, Can Liu, Jun Li, Guanhua Li, Yuke He, Jia Li, Zhihua Yin, Li Wu, Haibo Zhou, Nan Shen
Plasmacytoid dendritic cells (pDCs) are a professional type I IFN producer that play critical roles in the pathogenesis of autoimmune diseases. However, both genetic regulation of the function of pDCs and their relationships with autoimmunity are largely undetermined. Here, we investigated the causality of the neutrophil cytosolic factor 1 (NCF1) missense variant, which is one of the most significant
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Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease J. Clin. Invest. (IF 19.456) Pub Date : 2022 Jeffrey W. Pippin, Natalya Kaverina, Yuliang Wang, Diana G. Eng, Yuting Zeng, Uyen Tran, Carol J. Loretz, Anthony Chang, Shreeram Akilesh, Chetan Poudel, Hannah S. Perry, Christopher O’Connor, Joshua C. Vaughan, Markus Bitzer, Oliver Wessely, Stuart J. Shankland
With an aging population, kidney health becomes an important medical and socioeconomic factor. Kidney aging mechanisms are not well understood. We previously showed that podocytes isolated from aged mice exhibit increased expression of programmed cell death protein 1 (PD-1) surface receptor and its 2 ligands (PD-L1 and PD-L2). PDCD1 transcript increased with age in microdissected human glomeruli, which
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Noninvasive interrogation of CD8+ T cell effector function for monitoring early tumor responses to immunotherapy J. Clin. Invest. (IF 19.456) Pub Date : 2022 Haoyi Zhou, Yanpu Wang, Hongchuang Xu, Xiuling Shen, Ting Zhang, Xin Zhou, Yuwen Zeng, Kui Li, Li Zhang, Hua Zhu, Xing Yang, Nan Li, Zhi Yang, Zhaofei Liu
Accurately identifying patients who respond to immunotherapy remains clinically challenging. A noninvasive method that can longitudinally capture information about immune cell function and assist in the early assessment of tumor responses is highly desirable for precision immunotherapy. Here, we show that PET imaging using a granzyme B–targeted radiotracer named 68Ga-grazytracer, could noninvasively
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Maternal Fc-mediated non-neutralizing antibody responses correlate with protection against congenital human cytomegalovirus infection J. Clin. Invest. (IF 19.456) Pub Date : 2022 Eleanor C. Semmes, Itzayana G. Miller, Courtney E. Wimberly, Caroline T. Phan, Jennifer A. Jenks, Melissa J. Harnois, Stella J. Berendam, Helen Webster, Jillian H. Hurst, Joanne Kurtzberg, Genevieve G. Fouda, Kyle M. Walsh, Sallie R. Permar
Human cytomegalovirus (HCMV) is the most common congenital infection and a leading cause of stillbirth, neurodevelopmental impairment, and pediatric hearing loss worldwide. Development of a maternal vaccine or therapeutic to prevent congenital HCMV has been hindered by limited knowledge of the immune responses that protect against HCMV transmission in utero. To identify protective antibody responses
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Aged glomeruli: a link between PD-1 and podocytes J. Clin. Invest. (IF 19.456) Pub Date : 2022 Samuel Mon-Wei Yu, John Cijiang He
Understanding the loss of kidney function resulting from kidney aging has become an emerging research focus that will facilitate the future development of antisenolytic treatments. In this issue of the JCI, Pippin et al. first identified PD-1 upregulation in the aged mouse podocyte via unbiased RNA-seq analysis. Overexpression of PD-1 in immortalized mouse podocytes induced cell death and a senescence-associated
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TDO2+ myofibroblasts mediate immune suppression in malignant transformation of squamous cell carcinoma. J. Clin. Invest. (IF 19.456) Pub Date : 2022-08-16 Simeng Hu,Huanzi Lu,Wenqiang Xie,Dikan Wang,Zhongyan Shan,Xudong Xing,Xiang-Ming Wang,Juan Fang,Wei Dong,Wenxiao Dai,Junyi Guo,Yanshu Zhang,Shuqiong Wen,Xin-Yu Guo,Qianming Chen,Fan Bai,Zhi Wang
Characterization of the dynamic change of immunological landscape during malignant transformation from precancerous lesion to cancerous lesion in squamous cell carcinoma (SCC) is critical for the application of immunotherapy. Here we performed single-cell RNA sequencing (scRNA-seq) of 131,702 cells from 13 cancerous tissues of oral squamous cell carcinoma (OSCC), 3 precancerous oral leukoplakia and
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HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity. J. Clin. Invest. (IF 19.456) Pub Date : 2022-08-16 Andrew Nguyen,Louisa Ho,Richard Hogg,Lan Chen,Scott R Walsh,Yonghong Wan
Adoptive cell therapy (ACT) with tumor-specific memory T cells has shown increasing efficacy in regressing solid tumors. However, tumor antigen heterogeneity represents a longitudinal challenge for durable clinical responses due to the therapeutic selective pressure for immune escape variants. Here, we demonstrate that delivery of class I histone deacetylase inhibitor, MS-275, promotes sustained tumor
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Targeting FAPα-expressing hepatic stellate cells overcomes resistance to anti-angiogenics in colorectal cancer liver metastasis models. J. Clin. Invest. (IF 19.456) Pub Date : 2022-08-11 Ming Qi,Shuran Fan,Maohua Huang,Jinghua Pan,Yong Li,Qun Miao,Wenyu Lyu,Xiaobo Li,Lijuan Deng,Shenghui Qiu,Tongzheng Liu,Weiqing Deng,Xiaodong Chu,Chang Jiang,Wenzhuo He,Liangping Xia,Yunlong Yang,Jian Hong,Qi Qi,Wenqian Yin,Xiangning Liu,Changzheng Shi,Minfeng Chen,Wencai Ye,Dongmei Zhang
Vessel co-option has been demonstrated to mediate colorectal cancer liver metastasis (CRCLM) resistance to anti-angiogenic therapy. The current mechanisms underlying vessel co-option have mainly focused on the "hijacker" tumor cells, whereas the function of the "hijackee" sinusoidal blood vessels has not been explored. Here, we found that the occurrence of vessel co-option in bevacizumab-resistant
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In vivo visualization and molecular targeting of the cardiac conduction system. J. Clin. Invest. (IF 19.456) Pub Date : 2022-08-11 William R Goodyer,Benjamin M Beyersdorf,Lauren Duan,Nynke S van den Berg,Sruthi Mantri,Francisco X Galdos,Nazan Puluca,Jan W Buikema,Soah Lee,Darren Salmi,Elise R Robinson,Stephan Rogalla,Dillon P Cogan,Chaitan Khosla,Eben L Rosenthal,Sean M Wu
Accidental injury to the cardiac conduction system (CCS), a network of specialized cells embedded within the heart and indistinguishable from the surrounding heart muscle tissue, is a major complication in cardiac surgeries. Here, we addressed this unmet need by engineering targeted antibody-dye conjugates directed against CCS, allowing for the visualization of the CCS in vivo following a single intravenous
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Impaired renal reserve contributes to preeclampsia via the kynurenine and soluble fms-like tyrosine kinase 1 pathway. J. Clin. Invest. (IF 19.456) Pub Date : 2022-08-09 Vincent Dupont,Anders H Berg,Michifumi Yamashita,Chengqun Huang,Ambart E Covarrubias,Shafat Ali,Aleksandr Stotland,Jennifer E Van Eyk,Belinda Jim,Ravi Thadhani,S Ananth Karumanchi
To understand how kidney donation leads to excess preeclampsia risk, we studied pregnant outbred mice with prior uninephrectomy and compared them to sham-treated littermates carrying both kidneys. During pregnancy, uninephrectomized mice failed to achieve physiological increase of glomerular filtration rate, and during late gestation developed hypertension, albuminuria, glomerular endothelial damage
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Relieving Dyrk1a repression of MKL1 confers an adult-like phenotype to human infantile megakaryocytes. J. Clin. Invest. (IF 19.456) Pub Date : 2022-08-04 Kamaleldin E Elagib,Ashton Brock,Cara M Clementelli,Gohar Mosoyan,Lorrie L Delehanty,Ranjit K Sahu,Alexandra Pacheco-Benichou,Corinne Fruit,Thierry Besson,Stephan W Morris,Koji Eto,Chintan Jobaliya,Deborah L French,Paul Gadue,Sandeep Singh,Xinrui Shi,Fujun Qin,Robert Cornelison,Hui Li,Camelia Iancu-Rubin,Adam N Goldfarb
Infantile (fetal and neonatal) megakaryocytes have a distinct phenotype consisting of hyperproliferation, limited morphogenesis, and low platelet production capacity. These properties contribute to clinical problems that include thrombocytopenia in neonates, delayed platelet engraftment in recipients of cord blood stem cell transplants, and inefficient ex vivo platelet production from pluripotent stem
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Breast cancer cell-derived microRNA-155 suppresses tumor progression via enhancing immune cell recruitment and anti-tumor function. J. Clin. Invest. (IF 19.456) Pub Date : 2022-08-04 Junfeng Wang,Quanyi Wang,Yinan Guan,Yulu Sun,Xiaozhi Wang,Kaylie Lively,Yuzhen Wang,Ming Luo,Julian A Kim,E Angela Murphy,Yongzhong Yao,Guoshuai Cai,Daping Fan
Evidence suggests that increased microRNA-155 (miR-155) expression in immune cells enhances anti-tumor immune responses. However, given the reported association of miR-155 to tumorigenesis in various cancers, a debate is provoked on whether miR-155 is oncogenic or tumor suppressive. We aimed to interrogate the impact of tumor miR-155 expression, particularly cancer cell-derived miR-155, on anti-tumor
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Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells J. Clin. Invest. (IF 19.456) Pub Date : 2022 Peng Wang, Esra Karakose, Carmen Argmann, Huan Wang, Metodi Balev, Rachel I. Brody, Hembly G. Rivas, Xinyue Liu, Olivia Wood, Hongtao Liu, Lauryn Choleva, Dan Hasson, Emily Bernstein, Joao A. Paulo, Donald K. Scott, Luca Lambertini, James A. DeCaprio, Andrew F. Stewart
Resistance to regeneration of insulin-producing pancreatic β cells is a fundamental challenge for type 1 and type 2 diabetes. Recently, small molecule inhibitors of the kinase DYRK1A have proven effective in inducing adult human β cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and β cell transcriptomic databases seeking
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Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer J. Clin. Invest. (IF 19.456) Pub Date : 2022 He Huang, Cai-ping Nie, Xiu-feng Liu, Bin Song, Jian-hui Yue, Jing-xiao Xu, Jia He, Kui Li, Yan-ling Feng, Ting Wan, Min Zheng, Yan-Na Zhang, Wei-Jun Ye, Jun-Dong Li, Yan-Fang Li, Jun-yun Li, Xin-Ping Cao, Zhi-min Liu, Xiao-shi Zhang, Qing Liu, Xi Zhang, Ji-Hong Liu, Jiang Li
BACKGROUND. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has achieved remarkable clinical efficacy in metastatic cancers such as melanoma and cervical cancer (CC). Here, we explored the safety, feasibility, and preliminary tumor response and performed translational investigations of adjuvant immunotherapy using infusion of autogenous TILs (auto-TILs) following concurrent chemoradiotherapy
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Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression J. Clin. Invest. (IF 19.456) Pub Date : 2022 Emilia A. Korhonen, Aino Murtomäki, Sawan Kumar Jha, Andrey Anisimov, Anne Pink, Yan Zhang, Simon Stritt, Inam Liaqat, Lukas Stanczuk, Laura Alderfer, Zhiliang Sun, Emmi Kapiainen, Abhishek Singh, Ibrahim Sultan, Anni Lantta, Veli-Matti Leppänen, Lauri Eklund, Yulong He, Hellmut G. Augustin, Kari Vaahtomeri, Pipsa Saharinen, Taija Mäkinen, Kari Alitalo
Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor 3 (VEGFR3), which is encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development, and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, the mechanistic basis of Ang2 activity in
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Repeated exposure to heterologous hepatitis C viruses associates with enhanced neutralizing antibody breadth and potency J. Clin. Invest. (IF 19.456) Pub Date : 2022 Nicole Frumento, Alexis Figueroa, Tingchang Wang, Muhammad N. Zahid, Shuyi Wang, Guido Massaccesi, Georgia Stavrakis, James E. Crowe Jr, Andrew I. Flyak, Hongkai Ji, Stuart C. Ray, George M. Shaw, Andrea L. Cox, Justin R. Bailey
A prophylactic hepatitis C virus (HCV) vaccine that elicits neutralizing antibodies could be key to HCV eradication. However, the genetic and antigenic properties of HCV envelope (E1E2) proteins capable of inducing anti-HCV broadly neutralizing antibodies (bNAbs) in humans have not been defined. Here, we investigated the development of bNAbs in longitudinal plasma of HCV-infected persons with persistent
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Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia J. Clin. Invest. (IF 19.456) Pub Date : 2022 José A. Casado, Antonio Valeri, Rebeca Sanchez-Domínguez, Paula Vela, Andrea López, Susana Navarro, Omaira Alberquilla, Helmut Hanenberg, Roser Pujol, José-Carlos Segovia, Jordi Minguillón, Jordi Surrallés, Cristina Díaz de Heredia, Julián Sevilla, Paula Rio, Juan A. Bueren
Fanconi anemia (FA) is the most prevalent inherited bone marrow failure (BMF) syndrome. Nevertheless, the pathophysiological mechanisms of BMF in FA have not been fully elucidated. Since FA cells are defective in DNA repair, we hypothesized that FA hematopoietic stem and progenitor cells (HSPCs) might express DNA damage–associated stress molecules such as natural killer group 2 member D ligands (NKG2D-Ls)
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GIGYF1 disruption associates with autism and impaired IGF-1R signaling. J. Clin. Invest. (IF 19.456) Pub Date : 2022-08-02 Guodong Chen,Bin Yu,Senwei Tan,Jieqiong Tan,Xiangbin Jia,Qiumeng Zhang,Xiaolei Zhang,Qian Jiang,Yue Hua,Yaoling Han,Shengjie Luo,Kendra Hoekzema,Raphael A Bernier,Rachel K Earl,Evangeline C Kurtz-Nelson,Michaela J Idleburg,Suneeta Madan Khetarpal,Rebecca Clark,Jessica Sebastian,Alberto Fernandez-Jaen,Sara Alvarez,Staci D King,Luiza Lp Ramos,Mara Lucia Sf Santos,Donna M Martin,Dan Brooks,Joseph D Symonds
Autism spectrum disorder (ASD) represents a group of neurodevelopmental phenotypes with a strong genetic component. Excess of likely gene-disruptive (LGD) mutations of GIGYF1 was implicated in ASD. Here, we reported that GIGYF1 was the second most mutated gene among known ASD high-confidence risk genes. We investigated the inheritance of 46 GIGYF1 LGD variants, including the highly recurrent mutation
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SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-28 Museer A Lone,Mari J Aaltonen,Aliza Zidell,Helio F Pedro,Jonas A Morales Saute,Shalett Mathew,Payam Mohassel,Carsten G Bonnemann,Eric A Shoubridge,Thorsten Hornemann
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Mutations in the SPTLC1 subunit of serine-palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity. We show
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Small molecule eRF3a degraders rescue CFTR nonsense mutations by promoting premature termination codon readthrough. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-28 Rhianna E Lee,Catherine A Lewis,Lihua He,Emily C Bulik-Sullivan,Samuel C Gallant,Teresa M Mascenik,Hong Dang,Deborah M Cholon,Martina Gentzsch,Lisa C Morton,John T Minges,Jonathan W Theile,Neil A Castle,Michael R Knowles,Adam J Kimple,Scott H Randell
The vast majority of people with cystic fibrosis (CF) are now eligible for CF transmembrane regulator (CFTR) modulator therapy. Remaining individuals harbor premature termination codons (PTCs) or rare CFTR variants with limited treatment options. Although clinical modulator response can be reliably predicted using primary airway epithelial cells, primary cells carrying rare CFTR variants are scarce
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Bone marrow confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-28 Yang Mei,Kehan Ren,Yijie Liu,Annabel Ma,Zongjun Xia,Xu Han,Ermin Li,Hamza Tariq,Haiyan Bao,Xinshu Xie,Cheng Zou,Dingxiao Zhang,Zhaofeng Li,Lili Dong,Amit Verma,Xinyan Lu,Yasmin Abaza,Jessica K Altman,Madina Sukhanova,Jing Yang,Peng Ji
Myelodysplastic syndromes (MDS) are age-related myeloid neoplasms with increased risks of progression to acute myeloid leukemia (AML). The mechanisms of MDS to AML transformation are poorly understood, especially in relation to the aging microenvironment. We previously established a mDia1/miR-146a double knockout (DKO) mouse model phenocopying MDS. These mice develop age-related pancytopenia with over-secretion
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CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-26 Dongzheng Gai,Jin-Ran Chen,James P Stewart,Intawat Nookaew,Hasem Habelhah,Cody Ashby,Fumou Sun,Yan Cheng,Can Li,Hongwei Xu,Bailu Peng,Tarun K Garg,Carolina Schinke,Sharmilan Thanendrarajan,Maurizio Zangari,Fangping Chen,Bart Barlogie,Frits van Rhee,Guido Tricot,John D Shaughnessy,Fenghuang Zhan
Osteolytic bone disease is a hallmark of multiple myeloma (MM). A significant fraction (~20%) of MM patients do not develop osteolytic lesions (OL). The molecular basis for the absence of bone disease in MM is not understood. We combined PET-CT and gene expression profiling (GEP) of purified bone marrow (BM) CD138+ MM cells from 512 newly diagnosed MM patients to reveal that elevated expression of
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Isoniazid and rifapentine treatment effectively reduces persistent M. tuberculosis infection in macaque lungs. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-21 Riti Sharan,Shashank R Ganatra,Dhiraj K Singh,Journey Cole,Taylor W Foreman,Rajesh Thippeshappa,Charles A Peloquin,Vinay Shivanna,Olga Gonzalez,Cheryl L Day,Neel R Gandhi,Edward J Dick,Shannan Hall-Ursone,Smriti Mehra,Larry S Schlesinger,Jyothi Rengarajan,Deepak Kaushal
Once-weekly oral dose of isoniazid and rifapentine for 12 weeks (3HP) is recommended by CDC for treatment of latent tuberculosis infection (LTBI). The aim of this study is to assess 3HP-mediated clearance of Mtb bacteria in macaques with asymptomatic LTBI. Twelve Indian rhesus macaques were infected with low dose (~10 CFU) of Mtb CDC1551 via aerosol. Six animals were treated with 3HP and six were left
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Herpes simplex virus lymphadenitis is associated with tumor reduction in a chronic lymphocytic leukemia patient. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-21 Andres Chang,Anton M Sholukh,Andreas Wieland,David L Jaye,Mary Carrington,Meei-Li Huang,Hong Xie,Keith R Jerome,Pavitra Roychoudhury,Alexander L Greninger,Jean L Koff,Jonathon B Cohen,David M Koelle,Lawrence Corey,Christopher R Flowers,Rafi Ahmed
BACKGROUND Herpes simplex virus lymphadenitis (HSVL) is an unusual presentation of HSV reactivation in chronic lymphocytic leukemia (CLL) patients characterized by systemic symptoms and no herpetic lesions. The immune responses during HSVL have not been studied. METHODS Peripheral blood and lymph node samples of a patient with HSVL were obtained. HSV-2 viral load, antibody levels, B and T cell responses
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Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic therapeutic viruses. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-19 Juan Yan,Yuedan Chen,Amish J Patel,Sarah Warda,Cindy J Lee,Briana G Nixon,Elissa Wp Wong,Miguel A Miranda-Román,Ning Yang,Yi Wang,Mohini R Pachai,Jessica Sher,Emily Giff,Fanying Tang,Ekta Khurana,Samuel Singer,Yang Liu,Phillip M Galbo,Jesper Lv Maag,Richard P Koche,Deyou Zheng,Cristina Antonescu,Liang Deng,Ming Li,Yu Chen,Ping Chi
Immune checkpoint blockade (ICB) has demonstrated clinical success in "inflamed" tumors with substantial T-cell infiltrates, but tumors with an immune-desert tumor microenvironment (TME) fail to benefit. The tumor cell-intrinsic molecular mechanisms of the immune-desert phenotype remain poorly understood. Here, we demonstrated that inactivation of the Polycomb-repressive complex 2 (PRC2) core components
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Human midbrain dopaminergic neuronal differentiation markers predict cell therapy outcomes in a Parkinson’s disease model J. Clin. Invest. (IF 19.456) Pub Date : 2022 Peibo Xu, Hui He, Qinqin Gao, Yingying Zhou, Ziyan Wu, Xiao Zhang, Linyu Sun, Gang Hu, Qian Guan, Zhiwen You, Xinyue Zhang, Wenping Zheng, Man Xiong, Yuejun Chen
Human pluripotent stem cell–based (hPSC-based) replacement therapy holds great promise for the treatment of Parkinson’s disease (PD). However, the heterogeneity of hPSC-derived donor cells and the low yield of midbrain dopaminergic (mDA) neurons after transplantation hinder its broad clinical application. Here, we have characterized the single-cell molecular landscape during mDA neuron differentiation
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Stepwise GATA1 and SMC3 mutations alter megakaryocyte differentiation in a Down syndrome leukemia model J. Clin. Invest. (IF 19.456) Pub Date : 2022 Brahim Arkoun, Elie Robert, Fabien Boudia, Stefania Mazzi, Virginie Dufour, Aurélie Siret, Yasmine Mammasse, Zakia Aid, Matthieu Vieira, Imanci Aygun, Marine Aglave, Marie Cambot, Rachel Petermann, Sylvie Souquere, Philippe Rameau, Cyril Catelain, Romain Diot, Gérard Tachdjian, Olivier Hermine, Nathalie Droin, Najet Debili, Isabelle Plo, Sébastien Malinge, Eric Soler, Hana Raslova, Thomas Mercher,
Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modeled the megakaryocyte differentiation defect through stepwise gene editing of GATA1s, SMC3+/–, and MPLW515K, providing 20 different T21 or
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Schwann cell nodal membrane disruption triggers bystander axonal degeneration in a Guillain-Barré syndrome mouse model J. Clin. Invest. (IF 19.456) Pub Date : 2022 Rhona McGonigal, Clare I. Campbell, Jennifer A. Barrie, Denggao Yao, Madeleine E. Cunningham, Colin L. Crawford, Simon Rinaldi, Edward G. Rowan, Hugh J. Willison
In Guillain-Barré syndrome (GBS), both axonal and demyelinating variants can be mediated by complement-fixing anti–GM1 ganglioside autoantibodies that target peripheral nerve axonal and Schwann cell (SC) membranes, respectively. Critically, the extent of axonal degeneration in both variants dictates long-term outcome. The differing pathomechanisms underlying direct axonal injury and the secondary bystander
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Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer J. Clin. Invest. (IF 19.456) Pub Date : 2022 Siqi Chen, Ping Xie, Matthew Cowan, Hao Huang, Horacio Cardenas, Russell Keathley, Edward J. Tanner, Gini F. Fleming, John W. Moroney, Alok Pant, Azza M. Akasha, Ramana V. Davuluri, Masha Kocherginsky, Bin Zhang, Daniela Matei
Background. Immune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC). To augment their activity, we used priming with the hypomethylating agent guadecitabine in a phase II study.
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A Shigella species variant is causally linked to intractable functional constipation J. Clin. Invest. (IF 19.456) Pub Date : 2022 Xin Chen, Tian-Tian Qiu, Ye Wang, Li-Yang Xu, Jie Sun, Zhi-Hui Jiang, Wei Zhao, Tao Tao, Yu-Wei Zhou, Li-Sha Wei, Ye-Qiong Li, Yan-Yan Zheng, Guo-Hua Zhou, Hua-Qun Chen, Jian Zhang, Xiao-Bo Feng, Fang-Yu Wang, Ning Li, Xue-Na Zhang, Jun Jiang, Min-Sheng Zhu
Intractable functional constipation (IFC) is the most severe form of constipation, but its etiology has long been unknown. We hypothesized that IFC is caused by refractory infection by a pathogenic bacterium. Here, we isolated from patients with IFC a Shigella species — peristaltic contraction–inhibiting bacterium (PIB) — that significantly inhibited peristaltic contraction of the colon by production
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Myeloid FoxO1 depletion attenuates hepatic inflammation and prevents nonalcoholic steatohepatitis J. Clin. Invest. (IF 19.456) Pub Date : 2022 Sojin Lee, Taofeek O. Usman, Jun Yamauchi, Goma Chhetri, Xingchun Wang, Gina M. Coudriet, Cuiling Zhu, Jingyang Gao, Riley McConnell, Kyler Krantz, Dhivyaa Rajasundaram, Sucha Singh, Jon Piganelli, Alina Ostrowska, Alejandro Soto-Gutierrez, Satdarshan P. Monga, Aatur D. Singhi, Radhika Muzumdar, Allan Tsung, H. Henry Dong
Hepatic inflammation is culpable for the evolution of asymptomatic steatosis to nonalcoholic steatohepatitis (NASH). Hepatic inflammation results from abnormal macrophage activation. We found that FoxO1 links overnutrition to hepatic inflammation by regulating macrophage polarization and activation. FoxO1 was upregulated in hepatic macrophages, correlating with hepatic inflammation, steatosis, and
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Frequent detection but lack of infectivity of SARS-CoV-2 RNA in pre-symptomatic, infected blood donor plasma. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-14 Paula Saá,Rebecca V Fink,Sonia Bakkour,Jing Jin,Graham Simmons,Marcus O Muench,Hina Dawar,Clara Di Germanio,Alvin J Hui,David J Wright,David E Krysztof,Steven H Kleinman,Angela Cheung,Theresa Nester,Debra A Kessler,Rebecca L Townsend,Bryan R Spencer,Hany Kamel,Jacquelyn M Vannoy,Honey Dave,Michael P Busch,Susan L Stramer,Mars Stone,Rachael P Jackman,Philip J Norris
Respiratory viruses such as influenza do not typically cause viremia; however, SARS-CoV-2 has been detected in the blood of COVID-19 patients with mild and severe symptoms. Detection of SARS-CoV-2 in blood raises questions about its role in pathogenesis as well as transfusion safety concerns. Blood donor reports of symptoms or a diagnosis of COVID-19 after donation (post-donation information, PDI)
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Host-versus-commensal immune responses participate in the rejection of colonized solid organ transplants. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-14 Isabella D Pirozzolo,Martin Sepulveda,Luqiu Chen,Ying Wang,Yuk Man Lei,Zhipeng Li,Rena Li,Husain Sattar,Betty R Theriault,Yasmine Belkaid,Anita S Chong,Maria-Luisa Alegre
Solid organ transplantation is the preferred treatment for end-stage organ failure. Although transplant recipients takelife-long immunosuppressive drugs, a substantial percentage of them still reject their allografts. Strikingly, barrier organs colonized with microbiota have significantly shorter half-lives than non-barrier transplanted organs, even in immunosuppressed hosts. We previously demonstrated
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Human-β-defensin-3 attenuates atopic dermatitis-like inflammation through autophagy activation and the aryl hydrocarbon receptor signaling pathway. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-14 Ge Peng,Saya Tsukamoto,Risa Ikutama,Hai Le Thanh Nguyen,Yoshie Umehara,Juan V Trujillo-Paez,Hainan Yue,Miho Takahashi,Takasuke Ogawa,Ryoma Kishi,Mitsutoshi Tominaga,Kenji Takamori,Jiro Kitaura,Shun Kageyama,Masaaki Komatsu,Ko Okumura,Hideoki Ogawa,Shigaku Ikeda,François Niyonsaba
Human-β-defensin (hBD)-3 exhibits antimicrobial and immunomodulatory activities; however, its contribution to autophagy regulation remains unclear, and the role of autophagy in the regulation of the epidermal barrier in atopic dermatitis (AD) is poorly understood. Here, keratinocyte autophagy was restrained in the skin lesions of patients with AD and murine models of AD. Interestingly, hBD-3 alleviated
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Genome-wide DNA hypermethylation opposes healing in chronic wound patients by impairing epithelial-to-mesenchymal transition. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-12 Kanhaiya Singh,Yashika Rustagi,Ahmed S Abouhashem,Saba Tabasum,Priyanka Verma,Edward Hernandez,Durba Pal,Dolly K Khona,Sujit K Mohanty,Manishekhar Kumar,Rajneesh Srivastava,Poornachander R Guda,Sumit S Verma,Sanskruti Mahajan,Jackson A Killian,Logan A Walker,Subhadip Ghatak,Shomita S Mathew-Steiner,Kristen Wanczyk,Sheng Liu,Jun Wan,Pearlly Yan,Ralf Bundschuh,Savita Khanna,Gayle M Gordillo,Michael P
An extreme chronic wound tissue microenvironment causes epigenetic gene silencing. Unbiased whole-genome methylome was studied in the wound-edge (WE) tissue of chronic wound patients. A total of 4689 differentially methylated regions (DMRs) were identified in chronic WE compared to unwounded (UW) human skin. Hypermethylation was more frequently observed (3661 DMRs) in the chronic WE compared to hypomethylation
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Hematopoietic transcription factor GFI1 promotes anchorage independence by sustaining ERK activity in cancer cells. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-12 Hao Wang,Zhenzhen Lin,Zhe Nian,Wei Zhang,Wenxu Liu,Fei Yan,Zengtuan Xiao,Xia Wang,Zhenfa Zhang,Zhenyi Ma,Zhe Liu
The switch from anchorage-dependent to anchorage-independent growth is essential for epithelial metastasis. The underlying mechanism, however, is not fully understood. Here in this study, we identified growth factor independent-1 (GFI1), a transcription factor that drives transition from adherent endothelial cells to suspended hematopoietic cells during hematopoiesis, as a critical regulator of an
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Integrated hepatitis B virus DNA maintains surface antigen production during antivirals. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-07 Tanner Grudda,Hyon S Hwang,Maraake Taddese,Jeffrey Quinn,Mark S Sulkowski,Richard K Sterling,Ashwin Balagopal,Chloe L Thio
The focus of hepatitis B functional cure, defined as sustained loss of hepatitis B surface antigen (HBsAg) and HBV DNA from blood, is on eliminating or silencing the intranuclear template for HBV replication, covalently closed circular DNA (cccDNA). However, HBsAg also derives from HBV DNA integrated into the host genome (iDNA). Little is known about the contribution of iDNA to circulating HBsAg with
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Tetracycline-induced mitohormesis mediates disease tolerance against influenza. J. Clin. Invest. (IF 19.456) Pub Date : 2022-07-05 Adrienne Mottis,Terytty Y Li,Gaby El Alam,Alexis Rapin,Elena Katsyuba,David Liaskos,Davide D'Amico,Nicola L Harris,Mark C Grier,Laurent Mouchiroud,Mark L Nelson,Johan Auwerx
Mitohormesis defines the increase in fitness mediated by adaptive responses to mild mitochondrial stress. Tetracyclines inhibit not only bacterial but also mitochondrial translation, thus imposing a low level of mitochondrial stress to eukaryotic cells. We demonstrate in cell and germ-free mouse models, that tetracyclines induce a mild adaptive mitochondrial stress response (MSR), involving both the
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LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade J. Clin. Invest. (IF 19.456) Pub Date : 2022 Amber Hickman, Joost Koetsier, Trevin Kurtanich, Michael C. Nielsen, Glenn Winn, Yunfei Wang, Salah-Eddine Bentebibel, Leilei Shi, Simone Punt, Leila Williams, Cara Haymaker, Charles B. Chesson, Faisal Fa’ak, Ana L. Dominguez, Richard Jones, Isere Kuiatse, Amy R. Caivano, Sayadeth Khounlo, Navin D. Warier, Upendra Marathi, Robert V. Market, Ronald J. Biediger, John W. Craft Jr., Patrick Hwu, Michael
The inability of CD8+ effector T cells (Teffs) to reach tumor cells is an important aspect of tumor resistance to cancer immunotherapy. The recruitment of these cells to the tumor microenvironment (TME) is regulated by integrins, a family of adhesion molecules that are expressed on T cells. Here, we show that 7HP349, a small-molecule activator of lymphocyte function–associated antigen-1 (LFA-1) and
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The Achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence J. Clin. Invest. (IF 19.456) Pub Date : 2022 Shameel Shafqat, Evelyn Arana Chicas, Areez Shafqat, Shahrukh K. Hashmi
Recent improvements in cancer treatment have increased the lifespan of pediatric and adult cancer survivors. However, cancer treatments accelerate aging in survivors, which manifests clinically as the premature onset of chronic diseases, such as endocrinopathies, osteoporosis, cardiac dysfunction, subsequent cancers, and geriatric syndromes of frailty, among others. Therefore, cancer treatment–induced
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miR-181b targets semaphorin 3A to mediate TGF-β–induced endothelial-mesenchymal transition related to atrial fibrillation J. Clin. Invest. (IF 19.456) Pub Date : 2022 Ying-Ju Lai, Feng-Chun Tsai, Gwo-Jyh Chang, Shang-Hung Chang, Chung-Chi Huang, Wei-Jan Chen, Yung-Hsin Yeh
Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition (EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-β–treated human AEECs, cardiac-specific TGF-β–transgenic mice, and heart failure rabbits to identify the underlying mechanism of
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Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma J. Clin. Invest. (IF 19.456) Pub Date : 2022 Patrick C. Lee, Susan Klaeger, Phuong M. Le, Keegan Korthauer, Jingwei Cheng, Varsha Ananthapadmanabhan, Thomas C. Frost, Jonathan D. Stevens, Alan Y.L. Wong, J. Bryan Iorgulescu, Anna Y. Tarren, Vipheaviny A. Chea, Isabel P. Carulli, Camilla K. Lemvigh, Christina B. Pedersen, Ashley K. Gartin, Siranush Sarkizova, Kyle T. Wright, Letitia W. Li, Jason Nomburg, Shuqiang Li, Teddy Huang, Xiaoxi Liu, Lucas
Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I–low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of
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RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis J. Clin. Invest. (IF 19.456) Pub Date : 2022 Jonathan Shintaku, Wolfgang M. Pernice, Wafaa Eyaid, Jeevan B. GC, Zuben P. Brown, Marti Juanola-Falgarona, Javier Torres-Torronteras, Ewen W. Sommerville, Debby M.E.I. Hellebrekers, Emma L. Blakely, Alan Donaldson, Ingrid van de Laar, Cheng-Shiun Leu, Ramon Marti, Joachim Frank, Kurenai Tanji, David A. Koolen, Richard J. Rodenburg, Patrick F. Chinnery, H.J.M. Smeets, Gráinne S. Gorman, Penelope E
Mitochondrial DNA (mtDNA) depletion/deletions syndromes (MDDS) encompass a clinically and etiologically heterogenous group of mitochondrial disorders caused by impaired mtDNA maintenance. Among the most frequent causes of MDDS are defects in nucleoside/nucleotide metabolism, which is critical for synthesis and homeostasis of the deoxynucleoside triphosphate (dNTP) substrates of mtDNA replication. A
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Specific in situ inflammatory states associate with progression to renal failure in lupus nephritis J. Clin. Invest. (IF 19.456) Pub Date : 2022 Rebecca Abraham, Madeleine S. Durkee, Junting Ai, Margaret Veselits, Gabriel Casella, Yuta Asano, Anthony Chang, Kichul Ko, Charles Oshinsky, Emily Peninger, Maryellen L. Giger, Marcus R. Clark
BACKGROUND. In human lupus nephritis (LN), tubulointerstitial inflammation (TII) on biopsy predicts progression to end-stage renal disease (ESRD). However, only about half of patients with moderate-to-severe TII develop ESRD. We hypothesized that this heterogeneity in outcome reflects different underlying inflammatory states. Therefore, we interrogated renal biopsies from LN longitudinal and cross-sectional
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Lymphocytes in the neighborhood: good or bad for the kidney? J. Clin. Invest. (IF 19.456) Pub Date : 2022 Hao Li, Maria G. Tsokos, George C. Tsokos
Lupus nephritis (LN) is common in people with systemic lupus erythematosus (SLE) and advances, almost invariably, to end-stage renal disease (ESRD). In this issue of the JCI, Abraham, Durkee, et al. presented a large-scale immune cell landscape of kidney biopsies from patients with LN by combining multiplexed confocal microscopy imaging with customized computer vision and quantification. The presence
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TGF-β1–induced endothelial-mesenchymal transition: a potential contributor to fibrotic remodeling in atrial fibrillation? J. Clin. Invest. (IF 19.456) Pub Date : 2022 Arnela Saljic, Eleonora Grandi, Dobromir Dobrev
Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with an unmet therapeutic need. Fibrotic remodeling, in which collagen-producing atrial fibroblasts play a crucial role, substantially contributes to arrhythmia promotion and progression. In this issue of the JCI, Lai, Tsai, and co-authors reveal that TGF-β1 promoted endothelial-mesenchymal transition during AF and put forward
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Glycoengineered anti-CD39 promotes anticancer responses by depleting suppressive cells and inhibiting angiogenesis in tumor models J. Clin. Invest. (IF 19.456) Pub Date : 2022 Haohai Zhang, Lili Feng, Paola de Andrade Mello, Changchuin Mao, Richard Near, Eva Csizmadia, Leo Li-Ying Chan, Keiichi Enjyoji, Wenda Gao, Haitao Zhao, Simon C. Robson
Immunosuppressive cells accumulating in the tumor microenvironment constitute a formidable barrier that interferes with current immunotherapeutic approaches. A unifying feature of these tumor-associated immune and vascular endothelial cells appears to be the elevated expression of ectonucleotidase CD39, which in tandem with ecto-5′-nucleotidase CD73, catalyzes the conversion of extracellular ATP into
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Breast cancer chemotherapy induces vascular dysfunction and hypertension through a NOX4-dependent mechanism J. Clin. Invest. (IF 19.456) Pub Date : 2022 Piotr Szczepaniak, Mateusz Siedlinski, Diana Hodorowicz-Zaniewska, Ryszard Nosalski, Tomasz P. Mikolajczyk, Aneta M. Dobosz, Anna Dikalova, Sergey Dikalov, Joanna Streb, Katarzyna Gara, Pawel Basta, Jaroslaw Krolczyk, Joanna Sulicka-Grodzicka, Ewelina Jozefczuk, Anna Dziewulska, Blessy Saju, Iwona Laksa, Wei Chen, John Dormer, Maciej Tomaszewski, Pasquale Maffia, Marta Czesnikiewicz-Guzik, Filippo
Cardiovascular disease is the major cause of morbidity and mortality in breast cancer survivors. Chemotherapy contributes to this risk. We aimed to define the mechanisms of long-term vascular dysfunction caused by neoadjuvant chemotherapy (NACT) and identify novel therapeutic targets. We studied arteries from postmenopausal women who had undergone breast cancer treatment using docetaxel, doxorubicin
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Brush cells fine-tune neurogenic inflammation in the airways J. Clin. Invest. (IF 19.456) Pub Date : 2022 Qihua Ye, Lora G. Bankova
Airway epithelial cells, once considered a simple barrier layer, are now recognized as providing an active site for antigen sensing and immune response initiation. Most mucosal sites contain chemosensory epithelial cells, rare and specialized cells gaining recognition for their unique functions in sensing and directing the immune response symphony. In this issue of the JCI, Hollenhorst, Nandigama,
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Erythroid lineage Jak2V617F expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis J. Clin. Invest. (IF 19.456) Pub Date : 2022 Wenli Liu, Nataliya Östberg, Mustafa Yalcinkaya, Huijuan Dou, Kaori Endo-Umeda, Yang Tang, Xintong Hou, Tong Xiao, Trevor P. Fidler, Sandra Abramowicz, Yong-Guang Yang, Oliver Soehnlein, Alan R. Tall, Nan Wang
Elevated hematocrit is associated with cardiovascular risk; however, the causality and mechanisms are unclear. The JAK2V617F (Jak2VF) mutation increases cardiovascular risk in myeloproliferative disorders and in clonal hematopoiesis. Jak2VF mice with elevated WBCs, platelets, and RBCs display accelerated atherosclerosis and macrophage erythrophagocytosis. To investigate whether selective erythroid
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A nerve injury–specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression J. Clin. Invest. (IF 19.456) Pub Date : 2022 Shibin Du, Shaogen Wu, Xiaozhou Feng, Bing Wang, Shangzhou Xia, Lingli Liang, Li Zhang, Gokulapriya Govindarajalu, Alexander Bunk, Feni Kadakia, Qingxiang Mao, Xinying Guo, Hui Zhao, Tolga Berkman, Tong Liu, Hong Li, Jordan Stillman, Alex Bekker, Steve Davidson, Yuan-Xiang Tao
Maladaptive changes of nerve injury–associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury–specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury. This upregulation