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Beclin 1 prevents ISG15-mediated cytokine storms to secure fetal hematopoiesis and survival J. Clin. Invest. (IF 13.3) Pub Date : 2024 Wen Wei, Xueqin Gao, Jiawei Qian, Lei Li, Chen Zhao, Li Xu, Yanfei Zhu, Zhenzhen Liu, Nengrong Liu, Xueqing Wang, Zhicong Jin, Bowen Liu, Lan Xu, Jin Dong, Suping Zhang, Jiarong Wang, Yumu Zhang, Yao Yu, Zhanjun Yan, Yanjun Yang, Jie Lu, Yixuan Fang, Na Yuan, Jianrong Wang
Proper control of inflammatory responses is essential for embryonic development, but the underlying mechanism is poorly understood. Here, we show that under physiological conditions, inactivation of ISG15, an inflammation amplifier, is associated with the interaction of Beclin 1 (Becn1), via its evolutionarily conserved domain, with STAT3 in the major fetal hematopoietic organ of mice. Conditional
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Metalloproteinase inhibitors regulate biliary progenitor cells through sDLK1 in organoid models of liver injury J. Clin. Invest. (IF 13.3) Pub Date : 2024 Virginie Defamie, Kazeera Aliar, Soumili Sarkar, Foram Vyas, Ronak Shetty, Swami Reddy Narala, Hui Fang, Sanjay Saw, Pirashaanthy Tharmapalan, Otto Sanchez, Jennifer J. Knox, Paul D. Waterhouse, Rama Khokha
Understanding cell fate regulation in the liver is necessary to advance cell therapies for hepatic disease. Liver progenitor cells (LPCs) contribute to tissue regeneration after severe hepatic injury, yet signals instructing progenitor cell dynamics and fate are largely unknown. Tissue inhibitor of metalloproteinases 1 (TIMP1) and TIMP3 control the sheddases ADAM10 and ADAM17, key for NOTCH activation
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Fusobacterium nucleatum promotes colorectal cancer through neogenesis of tumor stem cells J. Clin. Invest. (IF 13.3) Pub Date : 2024 Qinying Wang, Tingting Hu, Qinyuan Zhang, Yichi Zhang, Xiaoxu Dong, Yutao Jin, Jinming Li, Yangyang Guo, Fanying Guo, Ziying Chen, Peijie Zhong, Yongzhi Yang, Yanlei Ma
Intestinal stem cells are crucial for maintaining intestinal homeostasis, yet their transformation into tumor stem cells in the context of microbial infection remains poorly understood. Fusobacterium nucleatum is frequently associated with the onset and progression of colorectal cancer (CRC). In this study, we uncovered that F. nucleatum colonized the depths of gut crypts in both patients with CRC
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A deafness-blindness syndrome results from ATF6-based disruption of the unfolded protein response J. Clin. Invest. (IF 13.3) Pub Date : 2025 Yuvraj Joshi, Jeffrey N. Savas
Sensorineural hearing loss (SNHL) is the most prevalent form of permanent hearing impairment, arising from factors such as aging, exposure to loud noise, disease, ototoxic medications, and genetic mutations. Despite extensive research, effective treatments or cures for SNHL remain elusive. In this issue of the JCI, Lee et al. reveal a link between mutations in ATF6 and SNHL in patients with achromatopsia
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Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome J. Clin. Invest. (IF 13.3) Pub Date : 2024 Eun-Jin Lee, Kyle Kim, Monica Sophia Diaz-Aguilar, Hyejung Min, Eduardo Chavez, Korina J. Steinbergs, Lance A. Safarta, Guirong Zhang, Allen F. Ryan, Jonathan H. Lin
Activating transcription factor 6 (ATF6) is a key regulator of the unfolded protein response (UPR) and is important for ER function and protein homeostasis in metazoan cells. Patients carrying loss-of-function ATF6 disease alleles develop the cone dysfunction disorder achromatopsia. The effect of loss of ATF6 function on other cell types, organs, and diseases in people remains unclear. Here, we report
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NEDD4L mediates intestinal epithelial cell ferroptosis to restrict inflammatory bowel diseases and colorectal tumorigenesis J. Clin. Invest. (IF 13.3) Pub Date : 2024 Jingjing Liang, Ning Wang, Yihan Yao, Yingmei Wang, Xiang An, Haofei Wang, Huan Liu, Yu Jiang, Hui Li, Xiaoqing Cheng, Jiaqi Xu, Xiaojing Liang, Jun Lou, Zengfeng Xin, Ting Zhang, Xiaojian Wang, Wenlong Lin
Various factors play key roles in maintaining intestine homeostasis. Disruption of the balance may lead to inflammatory bowel diseases and even colorectal cancer (CRC). Loss or gain of function of many key proteins can result in dysregulated intestinal homeostasis. Our research demonstrated that neural precursor cells expressed developmentally downregulated 4–like protein (NEDD4L, or NEDD4-2), a type
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Gene-replacement therapy in neurodevelopmental disorders: progress and challenges J. Clin. Invest. (IF 13.3) Pub Date : 2025 Holger Lerche, Ulrike B.S. Hedrich, Thomas V. Wuttke
Heterozygous loss-of-function variants in the SLC6A1 gene, encoding GAT1, which is the main GABA transporter in the brain, lead to a broad spectrum of neuropsychiatric and neurodevelopmental disorders including epilepsy, developmental delay, intellectual disability, and autism. Gene-replacement strategies involving adeno-associated viruses (AAV) require the delivery of genes to specific types of neurons
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The gut microbiome and cancer response to immune checkpoint inhibitors J. Clin. Invest. (IF 13.3) Pub Date : 2025 Francesca S. Gazzaniga, Dennis L. Kasper
Immune checkpoint inhibitors (ICIs) are widely used for cancer immunotherapy, yet only a fraction of patients respond. Remarkably, gut bacteria impact the efficacy of ICIs in fighting tumors outside of the gut. Certain strains of commensal gut bacteria promote antitumor responses to ICIs in a variety of preclinical mouse tumor models. Patients with cancer who respond to ICIs have a different microbiome
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Structural characterization of human monoclonal antibodies targeting uncommon antigenic sites on spike glycoprotein of SARS-CoV J. Clin. Invest. (IF 13.3) Pub Date : 2024 Naveenchandra Suryadevara, Nurgun Kose, Sandhya Bangaru, Elad Binshtein, Jennifer Munt, David R. Martinez, Alexandra Schäfer, Luke Myers, Trevor D. Scobey, Robert H. Carnahan, Andrew B. Ward, Ralph S. Baric, James E. Crowe Jr
The function of the spike protein N terminal domain (NTD) in coronavirus (CoV) infections is poorly understood. However, some rare antibodies that target the SARS-CoV-2 NTD potently neutralize the virus. This finding suggests the NTD may contribute, in part, to protective immunity. Pansarbecovirus antibodies are desirable for broad protection, but the NTD region of SARS-CoV and SARS-CoV-2 exhibit a
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HMGA1 is a crucial mediator of colon tumorigenesis driven by the loss of APC J. Clin. Invest. (IF 13.3) Pub Date : 2025 Yuxiang Wang, Mikayla Ybarra, Zhenghe Wang
Colorectal cancer is the second leading cause of cancer death in the United States. The adenomatous polyposis coli (APC) pathway plays a critical role in colorectal tumorigenesis, but the mechanism is not fully understood. In this issue of the JCI, Luo and colleagues used genetically engineered mouse models to show that high mobility group A (HMGA1) is a critical mediator in the development of colon
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A deep intronic mutation causes RAD50 deficiency through an unusual mechanism of distant exon activation J. Clin. Invest. (IF 13.3) Pub Date : 2024 Kristine Bousset, Stefano Donega, Najim Ameziane, Tabea Fleischhammer, Dhanya Ramachandran, Miriam Poley-Gil, Detlev Schindler, Ingrid M. van de Laar, Franco Pagani, Thilo Dörk
To the editor: Human RAD50 deficiency is a very rare genomic instability syndrome associated with microcephaly and stunted growth (1). Here, we describe RAD50 deficiency in two siblings harboring a far-intronic RAD50 5 bp deletion (Δ5) in trans with a classic frameshift variant. The Δ5 mutation did not affect canonical splice sites but activated a poison 87 bp exon 30 nucleotides downstream. In the
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Vascular smooth muscle cell PRDM16 regulates circadian variation in blood pressure J. Clin. Invest. (IF 13.3) Pub Date : 2024 Zhenguo Wang, Wenjuan Mu, Juan Zhong, Ruiyan Xu, Yaozhong Liu, Guizhen Zhao, Yanhong Guo, Jifeng Zhang, Ida Surakka, Y. Eugene Chen, Lin Chang
Disruptions of blood pressure (BP) circadian variation are closely associated with an increased risk of cardiovascular disease. Thus, gaining insights into the molecular mechanisms of BP circadian variation is essential for comprehending BP regulation. Human genetic analyses suggest that PR domain–containing protein 16 (PRDM16), a transcription factor highly expressed in vascular smooth muscle cells
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HMGA1 acts as an epigenetic gatekeeper of ASCL2 and Wnt signaling during colon tumorigenesis J. Clin. Invest. (IF 13.3) Pub Date : 2025 Li Z. Luo, Jung-Hyun Kim, Iliana Herrera, Shaoguang Wu, Xinqun Wu, Seong-Sik Park, Juyoung Cho, Leslie Cope, Lingling Xian, Bailey E. West, Julian Calderon-Espinosa, Joseph Kim, Zanshé Thompson, Isha Maloo, Tatianna Larman, Karen L. Reddy, Ying Feng, Eric R. Fearon, Cynthia L. Sears, Linda Resar
Mutated tumor cells undergo changes in chromatin accessibility and gene expression, resulting in aberrant proliferation and differentiation, although how this occurs is unclear. HMGA1 chromatin regulators are abundant in stem cells and oncogenic in diverse tissues; however, their role in colon tumorigenesis is only beginning to emerge. Here, we uncover a previously unknown epigenetic program whereby
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Blood pressure regulation through circadian variation: PRDM16 as a target in vascular smooth muscle cells J. Clin. Invest. (IF 13.3) Pub Date : 2025 M. Adriana Cuibus, Omar Abdel-Wahab
The precise mechanisms of blood pressure (BP) regulation are not fully elucidated, and understanding BP regulation is crucial for managing hypertension and improving outcomes for cardiovascular disease. In this issue of the JCI, Wang et al. identified the transcription factor PR domain–containing protein 16 (PRDM16) as a regulator of both vascular smooth muscle cell contraction and the circadian response
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Lactobacillus rhamnosus GG induces STING-dependent IL-10 in intestinal monocytes and alleviates inflammatory colitis in mice J. Clin. Invest. (IF 13.3) Pub Date : 2025 Wei Si, Xin Zhao, Ruitong Li, Yaopeng Li, Cui Ma, Xiaohan Zhao, Jason Bugno, Yuchang Qin, Junmin Zhang, Hongwei Liu, Liangliang Wang
Preclinical and clinical observations indicate that the probiotic Lactobacillus rhamnosus GG (LGG) can modulate colonic inflammation. However, the underlying mechanisms have not been explored in depth. Here, we demonstrate that oral administration of live LGG alleviated inflammatory colitis by increasing IL-10 expression in intestinal Ly6C+ monocytes. Mechanistically, LGG induced IL-10 production via
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Ferumoxytol nanozymes effectively target chronic biofilm infections in apical periodontitis J. Clin. Invest. (IF 13.3) Pub Date : 2024 Alaa Babeer, Yuan Liu, Zhi Ren, Zhenting Xiang, Min Jun Oh, Nil Kanatha Pandey, Aurea Simon-Soro, Ranran Huang, Bekir Karabucak, David P. Cormode, Chider Chen, Hyun Koo
Bacterial biofilms are pervasive and recalcitrant to current antimicrobials, causing numerous infections. Iron oxide nanozymes, including an FDA-approved formulation, ferumoxytol (FMX), show potential against biofilm infections via catalytic activation of hydrogen peroxide (H2O2). However, clinical evidence regarding the efficacy and therapeutic mechanisms of FMX is lacking. Here, we investigate whether
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Cathelicidin antimicrobial peptide expression in neutrophils and neurons antagonistically modulates neuroinflammation J. Clin. Invest. (IF 13.3) Pub Date : 2024 Subash Chand Verma, Emmanuelle Enée, Kanchanadevi Manasse, Feriel Rebhi, Axelle Penc, David Romeo-Guitart, Cuc Bui Thi, Matthias Titeux, Franck Oury, Simon Fillatreau, Roland Liblau, Julien Diana
Multiple sclerosis (MS) is an autoimmune disease that affects the CNS, the pathophysiology of which remains unclear and for which there is no definitive cure. Antimicrobial peptides (AMPs) are immunomodulatory molecules expressed in various tissues, including the CNS. Here, we investigated whether the cathelicidin-related AMP (CRAMP) modulated the development of experimental autoimmune encephalomyelitis
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AAV9/SLC6A1 gene therapy rescues abnormal EEG patterns and cognitive behavioral deficiencies in Slc6a1–/– mice J. Clin. Invest. (IF 13.3) Pub Date : 2024 Weirui Guo, Matthew Rioux, Frances Shaffo, Yuhui Hu, Ze Yu, Chao Xing, Steven J. Gray
The solute carrier family 6 member 1 (SLC6A1) gene encodes the γ-aminobutyric acid (GABA) transporter GAT-1, the deficiency of which is associated with infantile encephalopathy with intellectual disability. We designed 2 AAV9 vectors, with either the JeT or MeP promoter, and conducted preclinical gene therapy studies using heterozygous and homozygous Slc6a1-KO mice at different developmental ages and
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Translational regulation of SND1 governs endothelial homeostasis during stress J. Clin. Invest. (IF 13.3) Pub Date : 2025 Zhenbo Han, Gege Yan, Jordan Jousma, Sarath Babu Nukala, Mehdi Amiri, Stephen Kiniry, Negar Tabatabaei, Youjeong Kwon, Sen Zhang, Jalees Rehman, Sandra Pinho, Sang-Bing Ong, Pavel V. Baranov, Soroush Tahmasebi, Sang-Ging Ong
Translational control shapes the proteome and is particularly important in regulating gene expression under stress. A key source of endothelial stress is treatment with tyrosine kinase inhibitors (TKIs), which lowers cancer mortality but increases cardiovascular mortality. Using a human induced pluripotent stem cell–derived endothelial cell (hiPSC-EC) model of sunitinib-induced vascular dysfunction
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ZDHHC18 promotes renal fibrosis development by regulating HRAS palmitoylation. J. Clin. Invest. (IF 13.3) Pub Date : 2025-02-04 Di Lu,Gulibositan Aji,Guanyu Li,Yue Li,Wenlin Fang,Shuai Zhang,Ruiqi Yu,Sheng Jiang,Xia Gao,Yuhang Jiang,Qi Wang
Fibrosis is the final common pathway leading to end stage chronic kidney disease (CKD). However, the function of protein palmitoylation in renal fibrosis and underlying mechanisms remain unclear. In this study, we observed that the expression of the palmitoyltransferase ZDHHC18 was significantly elevated in unilateral ureteral obstruction (UUO) and folic acid (FA)-induced renal fibrosis mouse models
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RNase L represses hair follicle regeneration through altered innate immune signaling. J. Clin. Invest. (IF 13.3) Pub Date : 2025-02-04 Charles S Kirby,Nasif Islam,Eric Wier,Martin P Alphonse,Evan Sweren,Gaofeng Wang,Haiyun Liu,Dongwon Kim,Ang Li,Sam S Lee,Andrew M Overmiller,Yingchao Xue,Sashank Reddy,Nathan K Archer,Lloyd S Miller,Jianshi Yu,Weiliang Huang,Jace W Jones,Sooah Kim,Maureen A Kane,Robert H Silverman,Luis A Garza
Mammalian injury responses are predominantly characterized by fibrosis and scarring rather than functional regeneration. This limited regenerative capacity in mammals could reflect a loss of pro-regeneration programs or active suppression by genes functioning akin to tumor suppressors. To uncover programs governing regeneration in mammals, we screened transcripts in human subjects following laser rejuvenation
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5-HT orchestrates Histone Serotonylation and Citrullination to Drive Neutrophil Extracellular Traps and Liver Metastasis. J. Clin. Invest. (IF 13.3) Pub Date : 2025-02-04 Kaiyuan Liu,Yingchao Zhang,Genyu Du,Xinyu Chen,Lingling Xiao,Luyao Jiang,Na Jing,Penghui Xu,Chaoxian Zhao,Yiyun Liu,Huifang Zhao,Yujiao Sun,Jinming Wang,Chaping Cheng,Deng Wang,Jiahua Pan,Wei Xue,Pengcheng Zhang,Zhi-Gang Zhang,Wei-Qiang Gao,Shu-Heng Jiang,Kai Zhang,Helen He Zhu
Serotonin (5-HT) is a neurotransmitter that has been linked to tumorigenesis. Whether and how 5-HT modulates cells in the microenvironment to regulate tumor metastasis remains to be largely unknown. Here, we demonstrate that 5-HT is secreted by neuroendocrine prostate cancer (NEPC) cells to communicate with neutrophils and to induce neutrophil extracellular traps (NETs) in the liver, which in turn
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Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau. J. Clin. Invest. (IF 13.3) Pub Date : 2025-02-04 Geoffrey Canet,Felipe Da Gama Monteiro,Emma Rocaboy,Sofia Diego-Diaz,Boutheyna Khelaifia,Kelly Godbout,Aymane Lachhab,Jessica Kim,Daphne I Valencia,Audrey Yin,Hau-Tieng Wu,Jordan C Howell,Emily Blank,Francis Laliberté,Nadia Fortin,Emmanuelle Boscher,Parissa Fereydouni-Forouzandeh,Stéphanie Champagne,Isabelle Guisle,Sébastien S Hébert,Vincent Pernet,Haiyan Liu,William Lu,Ludovic Debure,David M Rapoport
Sleep disturbance is bidirectionally associated with increased risks of Alzheimer's disease and other tauopathies. While the sleep-wake cycle regulates interstitial and cerebrospinal fluid (CSF) tau levels, the underlying mechanisms remain unknown. Understanding these mechanisms is crucial given evidence indicates that tau pathology spreads through neuron-to-neuron transfer, involving the secretion
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Estrogen receptor alpha ablation reverses muscle fibrosis and inguinal hernias. J. Clin. Invest. (IF 13.3) Pub Date : 2025-02-04 Tanvi Potluri,Tianming You,Ping Yin,John S Coon V,Jonah J Stulberg,Yang Dai,David J Escobar,Richard L Lieber,Hong Zhao,Serdar E Bulun
Fibrosis of the lower abdominal muscle (LAM) contributes to muscle weakening and inguinal hernia formation, an ailment affecting a noteworthy fifty percent of men by age 75, necessitating surgical correction as the singular therapy. Despite its prevalence, the mechanisms driving LAM fibrosis and hernia development remain poorly understood. Utilizing a humanized mouse model that replicates elevated
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Transcription of hepatitis B surface antigen shifts from cccDNA to integrated HBV DNA during treatment. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-30 Maraake Taddese,Tanner Grudda,Giulia Belluccini,Mark Anderson,Gavin Cloherty,Hyon S Hwang,Monika Mani,Che-Min Lo,Naomi Esrig,Mark S Sulkowski,Richard K Sterling,Yang Zhang,Ruy M Ribeiro,David L Thomas,Chloe L Thio,Ashwin Balagopal
The cornerstone of functional cure for chronic hepatitis B (CHB) is hepatitis B surface antigen (HBsAg) loss from blood. HBsAg is encoded by covalently closed circular DNA (cccDNA) and HBV DNA integrated into the host genome (iDNA). Nucleos(t)ide analogues (NUCs), the mainstay of CHB treatment, rarely lead to HBsAg loss, which we hypothesized was due to continued iDNA transcription despite decreased
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HoxBlinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98-rearranged leukemia. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-30 Karina Hamamoto,Ganqian Zhu,Qian Lai,Julia Lesperance,Huacheng Luo,Ying Li,Nupur Nigam,Arati Sharma,Feng-Chun Yang,David Claxton,Yi Qiu,Peter D Aplan,Mingjiang Xu,Suming Huang
Although nucleoporin 98 (NUP98) fusion oncogenes often drive aggressive pediatric leukemia by altering chromatin structure and expression of HOX genes, underlying mechanisms remain elusive. Here, we report that a Hoxb-associated lncRNA HoxBlinc was aberrantly activated in NUP98-PHF23 fusion-driven leukemias. HoxBlinc chromatin occupancies led to elevated MLL1 recruitment and aberrant homeotic topologically
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Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-30 Rahul Kumar,Kevin Nolan,Biruk Kassa,Neha Chanana,Tsering Palmo,Kavita Sharma,Kanika Singh,Claudia Mickael,Dara Fonseca Balladares,Julia Nilsson,Amit Prabhakar,Aastha Mishra,Michael H Lee,Linda Sanders,Sushil Kumar,Ari B Molofsky,Kurt R Stenmark,Dean Sheppard,Rubin M Tuder,Mohit D Gupta,Tashi Thinlas,Qadar Pasha,Brian B Graham
Hypoxia is a major cause of pulmonary hypertension (PH) worldwide, and it is likely that interstitial pulmonary macrophages contribute to this vascular pathology. We observed in hypoxia-exposed mice an increase in resident interstitial macrophages, which expanded through proliferation and expressed the monocyte recruitment ligand CCL2. We also observed an increase in CCR2+ macrophages through recruitment
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Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-30 Kang Sun,Xiaozhen Zhang,Jiatao Shi,Jinyan Huang,Sicheng Wang,Xiang Li,Haixiang Lin,Danyang Zhao,Mao Ye,Sirui Zhang,Li Qiu,Minqi Yang,Chuyang Liao,Lihong He,Mengyi Lao,Jinyuan Song,Na Lu,Yongtao Ji,Hanshen Yang,Lingyue Liu,Xinyuan Liu,Yan Chen,Shicheng Yao,Qianhe Xu,Jieru Lin,Yan Mao,Jingxin Zhou,Xiao Zhi,Ke Sun,Xiongbin Lu,Xueli Bai,Tingbo Liang
Metabolic reprogramming shapes tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. "Immune cold" PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of pro-tumor macrophages, and reduced
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Small molecule modulators of B56-PP2A restore 4E-BP function to suppress eIF4E-dependent translation in cancer cells. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-27 Michelle A Lum,Kayla A Jonas,Shreya Parmar,Adrian R Black,Caitlin M O'Connor,Stephanie Dobersch,Naomi Yamamoto,Tess M Robertson,Aidan Schutter,Miranda Giambi,Rita A Avelar,Analisa DiFeo,Nicholas T Woods,Sita Kugel,Goutham Narla,Jennifer D Black
Dysregulated eIF4E-dependent translation is a central driver of tumorigenesis and therapy resistance. eIF4E binding proteins (4E-BP1/2/3) are major negative regulators of eIF4E-dependent translation that are inactivated in tumors through inhibitory phosphorylation or downregulation. Previous studies have linked PP2A phosphatase(s) to activation of 4E-BP1. Here, we leveraged biased small molecule activators
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Neonatal but not Juvenile Gene Therapy Reduces Seizures and Prolongs Lifespan in SCN1B-Dravet Syndrome Mice. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-23 Chunling Chen,Yukun Yuan,Heather A O'Malley,Robert Duba-Kiss,Yan Chen,Karl Habig,Yosuke Niibori,Samantha L Hodges,David R Hampson,Lori L Isom
Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) that begins in the first year of life. While most cases of DS are caused by variants in SCN1A, variants in SCN1B, encoding voltage-gated sodium channel β1 subunits, are also linked to DS or to the more severe early infantile DEE. Both disorders fall under the OMIM term DEE52. Scn1b null mice model DEE52, with spontaneous generalized
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Human Oncostatin M deficiency underlies an inherited severe bone marrow failure syndrome. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-23 Alexandrine Garrigue,Laëtitia Kermasson,Sandrine Susini,Ingrid Fert,Christopher B Mahony,Hanem Sadek,Sonia Luce,Myriam Chouteau,Marina Cavazzana,Emmanuelle Six,Marie-Caroline Le Bousse-Kerdilès,Adrienne Anginot,Jean-Baptiste Souraud,Valérie Cormier-Daire,Marjolaine Willems,Anne Sirvent,Jennifer Russello,Isabelle Callebaut,Isabelle André,Julien Y Bertrand,Chantal Lagresle-Peyrou,Patrick Revy
Oncostatin M (OSM) is a cytokine with the unique ability to interact with both the OSM receptor (OSMR) and the leukemia inhibitory factor receptor (LIFR). On the other hand, OSMR interacts with IL31RA to form the interleukin-31 receptor. This intricate network of cytokines and receptors makes it difficult to understand the specific function of OSM. While monoallelic loss-of-function (LoF) mutations
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A whole-body imaging technique for tumor-specific diagnostics and screening of B7-H3-targeted therapies. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-23 Lei Xia,Yan Wu,Yanan Ren,Zhen Wang,Nina Zhou,Wenyuan Zhou,Lixin Zhou,Ling Jia,Chengxue He,Xiangxi Meng,Hua Zhu,Zhi Yang
BACKGROUND B7-H3 or CD276 is notably overexpressed in various malignant tumor cells in humans, with extremely high expression rates. The development of a radiotracer that targets B7-H3 may provide a universal tumor-specific imaging agent and allow the noninvasive assessment of the whole-body distribution of B7-H3-expressing lesions. METHODS We enhanced and optimized the structure of an affibody (ABY)
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Targeting allograft inflammatory factor-1 reprograms kidney macrophages to enhance repair. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-21 Irma Husain,Holly Shah,Collin Z Jordan,Naveen R Natesh,Olivia K Fay,Yanting Chen,Jamie R Privratsky,Hiroki Kitai,Tomokazu Souma,Shyni Varghese,David N Howell,Edward B Thorp,Xunrong Luo
The role of macrophages remains incompletely understood in kidney injury and repair. Their plasticity offers an opportunity to polarize them towards mediating injury resolution in both native and transplanted kidneys undergoing ischemia and/or rejection. Here, we show that infiltrating kidney macrophages augmented their AIF-1 expression after injury. Aif1 genetic deletion led to macrophage polarization
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Sex dimorphism in the mouse bone marrow niche regulates hematopoietic engraftment via sex-specific Kdm5c/Cxcl12 signaling. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-21 Xiaojing Cui,Liming Hou,Bowen Yan,Jinpeng Liu,Cuiping Zhang,Pinpin Sui,Sheng Tong,Larry Luchsinger,Avital Mendelson,Daohong Zhou,Feng-Chun Yang,Hui Zhong,Ying Liang
The bone marrow (BM) niche is critical in regulating hematopoiesis, and sexual dimorphism and its underlying mechanism in BM niche and its impact on hematopoiesis are not well understood. We show that male mice exhibited a higher abundance of leptin-receptor-expressing mesenchymal stromal cells (LepR-MSCs) compared to female mice. Sex-mismatched co-culture and BM transplantation showed that the male
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Mycobacterium tuberculosis resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-21 Monica Dallmann-Sauer,Vinicius M Fava,Stephanus T Malherbe,Candice E MacDonald,Marianna Orlova,Elouise E Kroon,Aurélie Cobat,Stéphanie Boisson-Dupuis,Eileen G Hoal,Laurent Abel,Marlo Möller,Jean-Laurent Casanova,Gerhard Walzl,Nelita Du Plessis,Erwin Schurr
Natural resistance to Mycobacterium tuberculosis (Mtb) infection in some people with HIV (PWH) is unexplained. We performed single cell RNA-sequencing of bronchoalveolar lavage cells, unstimulated or ex vivo stimulated with Mtb, for 7 PWH who were TST & IGRA positive (called LTBI) and 6 who were persistently TST & IGRA negative (called resisters). Alveolar macrophages (AM) from resisters displayed
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Low tristetraprolin expression activates phenotypic plasticity and primes transition to lethal prostate cancer in mice J. Clin. Invest. (IF 13.3) Pub Date : 2024 Katherine L. Morel, Beatriz Germán, Anis A. Hamid, Jagpreet S. Nanda, Simon Linder, Andries M. Bergman, Henk van der Poel, Ingrid Hofland, Elise M. Bekers, Shana Y. Trostel, Deborah L. Burkhart, Scott Wilkinson, Anson T. Ku, Minhyung Kim, Jina Kim, Duanduan Ma, Jasmine T. Plummer, Sungyong You, Xiaofeng A. Su, Wilbert Zwart, Adam G. Sowalsky, Christopher J. Sweeney, Leigh Ellis
Phenotypic plasticity is a hallmark of cancer and is increasingly realized as a mechanism of resistance to androgen receptor–targeted (AR-targeted) therapy. Now that many prostate cancer (PCa) patients are treated upfront with AR-targeted agents, it is critical to identify actionable mechanisms that drive phenotypic plasticity, to prevent the emergence of resistance. We showed that loss of tristetraprolin
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Assessing advances in three decades of clinical antiretroviral therapy on the HIV-1 reservoir J. Clin. Invest. (IF 13.3) Pub Date : 2024 Irene González-Navarro, Víctor Urrea, Cristina Gálvez, Maria del Carmen Garcia-Guerrero, Sara Morón-López, Maria C. Puertas, Eulàlia Grau, Beatriz Mothe, Lucía Bailón, Cristina Miranda, Felipe García, Lorna Leal, Linos Vandekerckhove, Vincent C. Marconi, Rafick P. Sekaly, Bonaventura Clotet, Javier Martinez-Picado, Maria Salgado, the NIH Reversing Immune Dysfunction for HIV-1 Eradication (RID-HIV)
BACKGROUND. Antiretroviral therapy (ART) has improved the clinical management of HIV-1 infection. However, little is known about how the latest ART recommendations affect the heterogeneity of the HIV-1 reservoir size.
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An inducible RIPK3-driven necroptotic system enhances cancer cell–based immunotherapy and ensures safety J. Clin. Invest. (IF 13.3) Pub Date : 2024 Kok-Siong Chen, Sarah Manoury-Battais, Nobuhiko Kanaya, Ioulia Vogiatzi, Paulo Borges, Sterre J. Kruize, Yi-Ching Chen, Laura Y. Lin, Filippo Rossignoli, Natalia Claire Mendonca, Khalid Shah
Recent progress in cancer cell–based therapies has led to effective targeting and robust immune responses against cancer. However, the inherent safety risks of using live cancer cells necessitate the creation of an optimized safety switch without hindering the efficacy of immunotherapy. The existing safety switches typically induce tolerogenic cell death, potentially leading to an immunosuppressive
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Endogenous antigens shape the transcriptome and TCR repertoire in an autoimmune arthritis model J. Clin. Invest. (IF 13.3) Pub Date : 2024 Elizabeth E. McCarthy, Steven Yu, Noah Perlmutter, Yuka Nakao, Ryota Naito, Charles Lin, Vivienne Riekher, Joe DeRisi, Chun Jimmie Ye, Arthur Weiss, Judith F. Ashouri
The development of pathogenic autoreactive CD4+ T cells, particularly in the context of impaired signaling, remains poorly understood. Unraveling how defective signaling pathways contribute to their activation and persistence is crucial for identifying new therapeutic targets. We performed bulk and single-cell RNA-Seq (scRNA-Seq) and single-cell T cell receptor sequencing (scTCR-Seq) to profile a highly
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YAP1 induces bladder cancer progression and promotes immune evasion through IL-6/STAT3 pathway and CXCL deregulation J. Clin. Invest. (IF 13.3) Pub Date : 2024 Pritam Sadhukhan, Mingxiao Feng, Emily Illingworth, Ido Sloma, Akira Ooki, Andres Matoso, David Sidransky, Burles A. Johnson III, Luigi Marchionni, Fenna C.M. Sillé, Woonyoung Choi, David McConkey, Mohammad Hoque
The Hippo signaling pathway plays a key role in tumorigenesis in different cancer types. We investigated the role of the Hippo effector YAP1 in the tumor immune microenvironment (TIME) of urothelial carcinoma of the bladder (UCB) and evaluated the efficacy of immunotherapy in the context of YAP1 signaling. We performed numerous in vitro and in vivo experiments to determine the role of YAP1 using genetic
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MAP3K1 mutations confer tumor immune heterogeneity in hormone receptor–positive HER2-negative breast cancer J. Clin. Invest. (IF 13.3) Pub Date : 2024 Yu-Wen Cai, Cui-Cui Liu, Yan-Wu Zhang, Yi-Ming Liu, Lie Chen, Xin Xiong, Zhi-Ming Shao, Ke-Da Yu
Treatment for hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) breast cancer, the most common type of breast cancer, has faced challenges such as endocrine therapy resistance and distant relapse. Immunotherapy has shown progress in treating triple-negative breast cancer, but immunological research on HR+/HER2– breast cancer is still in its early stages. Here,
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Single-nuclei transcriptomics reveals TBX5-dependent targets in a patient with Holt-Oram syndrome J. Clin. Invest. (IF 13.3) Pub Date : 2024 Jeffrey D. Steimle, Yi Zhao, Fansen Meng, Mikaela E. Taylor, Diwakar Turaga, Iki Adachi, Xiao Li, James F. Martin
To the Editor: Holt-Oram syndrome (HOS), characterized by heart and forelimb defects, is caused by mutations in the T-box transcription factor TBX5 (1). While much has been done to elucidate the transcriptional mechanisms of TBX5 in model systems (2–5), transcriptomics of tissue from patients with HOS is lacking. Here, we report a rare opportunity to interrogate the cardiac transcriptome of HOS using
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MicroRNAs: where brilliance, perseverance, and ambition converged J. Clin. Invest. (IF 13.3) Pub Date : 2024 Rares Drula, George A. Calin
Victor Ambros at the University of Massachusetts Medical School and Gary Ruvkun at Harvard University were awarded the 2024 Nobel Prize in Medicine and Physiology for the discovery of microRNAs. This “groundbreaking discovery revealed a completely new principle of gene regulation that turned out to be essential for multicellular organisms, including humans” (1). This is a well-deserved and highly anticipated
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Ferroptosis of select skin epithelial cells initiates and maintains chronic systemic immune-mediated psoriatic disease J. Clin. Invest. (IF 13.3) Pub Date : 2024 Kavita Vats, Hua Tian, Kunal Singh, Yulia Y. Tyurina, Louis J. Sparvero, Vladimir A. Tyurin, Oleg Kruglov, Alexander Chang, Jiefei Wang, Felicia Green, Svetlana N. Samovich, Jiying Zhang, Ansuman Chattopadhyay, Natalie Murray, Vrusha K. Shah, Alicia R. Mathers, Uma R. Chandran, Joseph M. Pilewski, John A. Kellum, Sally E. Wenzel, Hülya Bayır, Valerian E. Kagan, Yuri L. Bunimovich
Dysregulations of epithelial-immune interactions frequently culminate in chronic inflammatory diseases of the skin, lungs, kidneys, and gastrointestinal tract. Yet, the intraepithelial processes that initiate and perpetuate inflammation in these organs are poorly understood. Here, by utilizing redox lipidomics we identified ferroptosis-associated peroxidation of polyunsaturated phosphatidylethanolamines
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Targeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models J. Clin. Invest. (IF 13.3) Pub Date : 2024 Dezhi Li, Ke Geng, Yuan Hao, Jiajia Gu, Saurav Kumar, Annabel T. Olson, Christina C. Kuismi, Hye Mi Kim, Yuanwang Pan, Fiona Sherman, Asia M. Williams, Yiting Li, Fei Li, Ting Chen, Cassandra Thakurdin, Michela Ranieri, Mary Meynardie, Daniel S. Levin, Janaye Stephens, Alison Chafitz, Joy Chen, Mia S. Donald-Paladino, Jaylen M. Powell, Ze-Yan Zhang, Wei Chen, Magdalena Ploszaj, Han Han, Shengqing Stan
Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with the G12C mutation and advanced our understanding of the function of this mutation. However, little is known about the targeted disruption
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Neisseria gonorrhoeae induces local secretion of IL-10 at the human cervix to promote colonization J. Clin. Invest. (IF 13.3) Pub Date : 2024 Yiwei Dai, Vonetta L. Edwards, Qian Yu, Hervé Tettelin, Daniel C. Stein, Wenxia Song
Gonorrhea, caused by the human-restricted pathogen Neisseria gonorrhoeae, is a commonly reported sexually transmitted infection. Since most infections in women are asymptomatic, the true number of infections is likely much higher than reported. How gonococci (GC) colonize women’s cervixes without triggering symptoms remains elusive. Using a human cervical tissue explant model, we found that GC inoculation
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G-CSF resistance of ELANE-mutant neutropenia depends on SERF1-containing truncated–neutrophil elastase aggregates J. Clin. Invest. (IF 13.3) Pub Date : 2024 Ramesh C. Nayak, Sana Emberesh, Lisa R. Trump, Ashley M. Wellendorf, Abhishek K. Singh, Brice Korkmaz, Marshall S. Horwitz, Kasiani C. Myers, Theodosia A. Kalfa, Carolyn M. Lutzko, Jose A. Cancelas
Severe congenital neutropenia (SCN) is frequently associated with dominant point mutations in ELANE, the gene encoding neutrophil elastase (NE). Chronic administration of granulocyte colony–stimulating factor (G-CSF) is a first-line treatment of ELANE-mutant (ELANEmut) SCN. However, some ELANEmut patients, including patients with ELANE start codon mutations, do not respond to G-CSF. Here, through directed
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Rapid response of lichen planus to baricitinib associated with suppression of cytotoxic CXCL13+CD8+ T cells J. Clin. Invest. (IF 13.3) Pub Date : 2024 Angelina S. Hwang, Jacob A. Kechter, Tran H. Do, Alysia N. Hughes, Nan Zhang, Xing Li, Rachael Bogle, Caitlin M. Brumfiel, Meera H. Patel, Blake Boudreaux, Puneet Bhullar, Shams Nassir, Miranda L. Yousif, Alyssa L. Stockard, Zachary Leibovit-Reiben, Ewoma Ogbaudu, David J. DiCaudo, Jennifer Fox, Mehrnaz Gharaee-Kermani, Xianying Xing, Samantha Zunich, Emily Branch, J. Michelle Kahlenberg, Allison C
BACKGROUND. Cutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of IFN-γ, a cytokine implicated in the pathogenesis of LP.
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Progranulin-dependent repair function of regulatory T cells drives bone-fracture healing J. Clin. Invest. (IF 13.3) Pub Date : 2024 Ruiying Chen, Xiaomeng Zhang, Bin Li, Maurizio S. Tonetti, Yijie Yang, Yuan Li, Beilei Liu, Shujiao Qian, Yingxin Gu, Qingwen Wang, Kairui Mao, Hao Cheng, Hongchang Lai, Junyu Shi
Local immunoinflammatory events instruct skeletal stem cells (SSCs) to repair/regenerate bone after injury, but mechanisms are incompletely understood. We hypothesized that specialized Tregs are necessary for bone repair and interact directly with SSCs through organ-specific messages. Both in human patients with bone fracture and a mouse model of bone injury, we identified a bone injury–responding
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Passive transfer of patient-derived anti-nephrin autoantibodies causes a podocytopathy with minimal change lesions. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-16 Felicitas E Hengel,Silke Dehde,Oliver Kretz,Jonas Engesser,Tom Zimmermann,Tobias B Huber,Nicola M Tomas
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TRAIL agonists rescue mice from radiation-induced lung, skin or esophageal injury. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-14 Jillian Strandberg,Anna Louie,Seulki Lee,Marina Hahn,Praveen Srinivasan,Andrew George,Arielle De La Cruz,Leiqing Zhang,Liz Hernandez Borrero,Kelsey E Huntington,Payton De La Cruz,Attila A Seyhan,Paul P Koffer,David E Wazer,Thomas A DiPetrillo,Stephanie L Graff,Christopher G Azzoli,Sharon I Rounds,Andres J Klein-Szanto,Fabio Tavora,Evgeny Yakirevich,Abbas E Abbas,Lanlan Zhou,Wafik S El-Deiry
Radiotherapy can be limited by pneumonitis which is impacted by innate immunity, including pathways regulated by TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound (TIC10/ONC201) could reduce pneumonitis, alveolar-wall thickness
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Sequential intranasal booster triggers class switching from intramuscularly primed IgG to mucosal IgA against SARS-CoV-2. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-14 Yifan Lin,Xuejiao Liao,Xuezhi Cao,Zhaoyong Zhang,Xiuye Wang,Xiaomeng He,Huiping Liao,Bin Ju,Furong Qi,Hairong Xu,Zhenhua Ren,Yanqun Wang,Zhenxiang Hu,Jiaming Yang,Yang-Xin Fu,Jincun Zhao,Zheng Zhang,Hua Peng
The persistent emergence of COVID-19 variants and recurrent waves of infection worldwide underscores the urgent need for vaccines that effectively reduce viral transmission and prevent infections. Current intramuscular (IM) COVID-19 vaccines inadequately protect the upper respiratory mucosa. In response, we have developed a nonadjuvanted, interferon-armed SARS-CoV-2 fusion protein vaccine with IM priming
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Impaired hydrogen sulfide biosynthesis underlies eccentric contraction-induced force loss in dystrophin-deficient skeletal muscle. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-14 W Michael Southern,Erynn E Johnson,Elizabeth K Fasbender,Katherine S Fallon,Courtney L Cavazos,Dawn A Lowe,George G Rodney,James M Ervasti
Eccentric contraction- (ECC) induced force loss is a hallmark of murine dystrophin-deficient (mdx) skeletal muscle that is used to assess efficacy of potential therapies for Duchenne muscular dystrophy. While virtually all key proteins involved in muscle contraction have been implicated in ECC force loss, a unifying mechanism that orchestrates force loss across such diverse molecular targets has not
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PDGFRα inhibition reduces myofibroblast expansion in the fibrotic rim and enhances recovery after ischemic stroke. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-14 Jil Protzmann,Manuel Zeitelhofer,Christina Stefanitsch,Daniel Torrente,Milena Z Adzemovic,Kirils Matjunins,Stella Ji Randel,Sebastian A Lewandowski,Lars Muhl,Ulf Eriksson,Ingrid Nilsson,Enming J Su,Daniel A Lawrence,Linda Fredriksson
Ischemic stroke is a major cause of adult disability. Early treatment with thrombolytics and/or thrombectomy can significantly improve outcomes; however, following these acute interventions, treatment is limited to rehabilitation therapies. Thus, the identification of therapeutic strategies that can help restore brain function in the post-acute phase remains a major challenge. Here we report that genetic
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An Activin Receptor-Like Kinase 1-governed monocytic lineage shapes an immunosuppressive landscape in breast cancer metastases. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-14 Mehrnaz Safaee Talkhoncheh,Jonas Sjölund,Paulina Bolivar,Ewa Kurzejamska,Eugenia Cordero,Teia Vallès Pagès,Sara Larsson,Sophie Lehn,Gustav Frimannsson,Viktor Ingesson,Sebastian Braun,Jessica Pantaleo,Clara Oudenaarden,Martin Lauss,R Scott Pearsall,Göran B Jönsson,Charlotte Rolny,Matteo Bocci,Kristian Pietras
The biology centered around the TGF-beta type I receptor Activin Receptor-Like Kinase (ALK)1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages
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LIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-14 Alice E Shin,Kensuke Sugiura,Secunda W Kariuki,David A Cohen,Samuel P Flashner,Andres J Klein-Szanto,Noriyuki Nishiwaki,Dechokyab De,Neil Vasan,Joel T Gabre,Christopher J Lengner,Peter A Sims,Anil K Rustgi
Colorectal cancer (CRC) remains a leading cause of cancer death due to metastatic spread. LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, resulting in enhanced PI3K/AKT pathway activation and liver metastasis in mice. We developed genetically modified mouse models with constitutively
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Loss of Cpt1a results in elevated glucose-fueled mitochondrial oxidative phosphorylation and defective hematopoietic stem cells. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-09 Jue Li,Jie Bai,Vincent T Pham,Michihiro Hashimoto,Maiko Sezaki,Qili Shi,Qiushi Jin,Chenhui He,Amy Armstrong,Tian Li,Mingzhe Pan,Shujun Liu,Yu Luan,Hui Zeng,Paul R Andreassen,Gang Huang
Hematopoietic stem cells (HSCs) rely on self-renewal to sustain stem cell potential and undergo differentiation to generate mature blood cells. Mitochondrial fatty acid β-oxidation (FAO) is essential for HSC maintenance. However, the role of Carnitine palmitoyl transferase 1a (CPT1A), a key enzyme in FAO, remains unclear in HSCs. Using a Cpt1a hematopoietic specific conditional knock-out (Cpt1aΔ/Δ)
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Tumor initiating cells escape tumor immunity via CCL8 from tumor-associated macrophages in mice. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-07 Shuang Chen,Chen-Song Huang,Kang Li,Maosheng Cheng,Caihua Zhang,Jianqi Xiong,Guoli Tian,Ruoxing Zhou,Rongsong Ling,Xiaochen Wang,Gan Xiong,Zhihui Zhang,Jieyi Ma,Yan Zhu,Bin Zhou,Liang Peng,Zhenwei Peng,Heping Li,Demeng Chen
Tumor-initiating cells (TICs) play a key role in cancer progression and immune escape. However, how TICs evade immune elimination remains poorly characterized. Combining single-cell RNA sequencing (scRNA-seq), dual-recombinase-based lineage tracing, and other approaches, we identified a WNT-activated subpopulation of malignant cells that act as TICs in vivo. We found intensive reciprocal interactions
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Serum cAMP levels are increased in patients with asthma. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-07 Steven S An,Gaoyuan Cao,Kwangmi Ahn,Jordan Lee,Dae Young Jung,Loren Denlinger,John Fahy,Elliot Israel,Wendy Moore,Brenda Phillips,David Mauger,Sally Wenzel,Reynold A Panettieri
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CXCL12 ameliorates neutrophilia and disease severity in SARS-CoV-2 infection. J. Clin. Invest. (IF 13.3) Pub Date : 2025-01-07 Jian Zheng,Hima Dhakal,Enya Qing,Rejeena Shrestha,Anne E Geller,Samantha M Morrissey,Divyasha Saxena,Xiaoling Hu,Hong Li,Haiyan Li,Kevin Wilhelmsen,Linder H Wendt,Klaus Klumpp,Patrick S Hume,William J Janssen,Rachel Brody,Kenneth E Palmer,Silvia M Uriarte,Patrick P Ten Eyck,David K Meyerholz,Michael L Merchant,Kenneth McLeish,Tom Gallagher,Jiapeng Huang,Jun Yan,Stanley Perlman
Neutrophils, particularly low-density neutrophils (LDNs), are believed to contribute to acute COVID-19 severity. Here, we showed that neutrophilia can be detected acutely and even months after SARS-CoV-2 infection in patients and mice, while neutrophil depletion reduced disease severity in mice. A key factor in neutrophilia and severe disease in infected mice was traced to the chemokine CXCL12 secreted