Journal of Clinical Investigation最新文献

{"title":"Clinical tolerance but no protective efficacy in a placebo-controlled trial of repeated controlled schistosome infection.","authors":"Jan Pieter R Koopman, Emma L Houlder, Jacqueline J Janse, Olivia Ac Lamers, Geert Vt Roozen, Jeroen C Sijtsma, Miriam Casacuberta-Partal, Stan T Hilt, M Y Eileen C van der Stoep, Inge M van Amerongen-Westra, Eric At Brienen, Linda J Wammes, Lisette van Lieshout, Govert J van Dam, Paul Lam Corstjens, Angela van Diepen, Maria Yazdanbakhsh, Cornelis H Hokke, Meta Roestenberg","doi":"10.1172/JCI185422","DOIUrl":"https://doi.org/10.1172/JCI185422","url":null,"abstract":"<p><strong>Background: </strong>Partial protective immunity to schistosomiasis develops over time, following repeated praziquantel treatment. Moreover, animals develop protective immunity after repeated immunisation with irradiated cercariae. Here, we evaluated development of natural immunity through consecutive exposure-treatment cycles with Schistosoma mansoni (Sm) in healthy, Schistosoma-naïve participants using single-sex controlled human Sm infection.</p><p><strong>Methods: </strong>Twenty-four participants were randomised double-blind (1:1) to either the reinfection group, which received three exposures (week 0,9,18) to 20 male cercariae or the infection control group, which received two mock exposures with water (week 0,9) prior to cercariae exposure (week 18). Participants were treated with praziquantel (or placebo) at week 8, 17 and 30. Attack rates after the final exposure (week 19-30) using serum circulating anodic antigen (CAA) positivity were compared between groups. Adverse events were collected for safety.</p><p><strong>Results: </strong>Twenty-three participants completed follow-up. No protective efficacy was seen, given 82% (9/11) attack rate after the final exposure in the reinfection group and 92% (11/12) in the infection control group (protective efficacy 11%; 95% CI -24% to 35%; p =0.5). Related adverse events were higher after the first infection (45%), compared to the second (27%) and third infection (28%). Severe acute schistosomiasis was observed after the first infections only (2/12 in reinfection group and 2/12 in infection control group).</p><p><strong>Conclusion: </strong>Repeated Schistosoma exposure and treatment cycles resulted in apparent clinical tolerance, with fewer symptoms reported with subsequent infections, but did not result in protection against reinfection.</p><p><strong>Trial registration: </strong></p><p><strong>Clinicaltrials: </strong>gov NCT05085470.</p><p><strong>Funding: </strong>ERC Starting grant (no. 101075876).</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A deep intronic mutation causes RAD50 deficiency through an unusual mechanism of distant exon activation.","authors":"Kristine Bousset, Stefano Donega, Najim Ameziane, Tabea Fleischhammer, Dhanya Ramachandran, Miriam Poley-Gil, Detlev Schindler, Ingrid M van de Laar, Franco Pagani, Thilo Dörk","doi":"10.1172/JCI178528","DOIUrl":"https://doi.org/10.1172/JCI178528","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Red Blood Cells Capture and Deliver Bacterial DNA to Drive Host Responses During Polymicrobial Sepsis.","authors":"L K Metthew Lam, Nathan J Klingensmith, Layal Sayegh, Emily Oatman, Joshua S Jose, Christopher V Cosgriff, Kaitlyn A Eckart, John McGinnis, Piyush Ranjan, Matthew Lanza, Nadir Yehya, Nuala J Meyer, Robert P Dickson, Nilam S Mangalmurti","doi":"10.1172/JCI182127","DOIUrl":"10.1172/JCI182127","url":null,"abstract":"<p><p>Red blood cells (RBCs), traditionally recognized for their role in transporting oxygen, play a pivotal role in the body's immune response by expressing TLR9 and scavenging excess host cell-free DNA. DNA capture by RBCs leads to accelerated RBC clearance and triggers inflammation. Whether RBCs can also acquire microbial DNA during infections is unknown. Murine RBCs acquire microbial DNA in vitro and bacterial-DNA-induced macrophage activation was augmented by WT but not Tlr9-deleted RBCs. In a mouse model of polymicrobial sepsis, RBC-bound bacterial DNA was elevated in WT but not in erythroid Tlr9-deleted mice. Plasma cytokine analysis in these mice revealed distinct sepsis clusters characterized by persistent hypothermia and hyperinflammation in the most severely affected subjects. RBC-Tlr9 deletion attenuated plasma and tissue IL-6 production in the most severe group. Parallel findings in human subjects confirmed that RBCs from septic patients harbored more bacterial DNA compared to healthy individuals. Further analysis through 16S sequencing of RBC-bound DNA illustrated distinct microbial communities, with RBC-bound DNA composition correlating with plasma IL-6 in patients with sepsis. Collectively, these findings unveil RBCs as overlooked reservoirs and couriers of microbial DNA, capable of influencing host inflammatory responses in sepsis.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estimation of prevalence of autoimmune diseases in the United States using electronic health record data.","authors":"Aaron H Abend, Ingrid He, Neil Bahroos, Stratos Christianakis, Ashley B Crew, Leanna M Wise, Gloria P Lipori, Xing He, Shawn N Murphy, Christopher D Herrick, Jagannadha Avasarala, Mark G Weiner, Jacob S Zelko, Erica Matute-Arcos, Mark Abajian, Philip Ro Payne, Albert M Lai, Heath A Davis, Asher A Hoberg, Chris E Ortman, Amit D Gode, Bradley W Taylor, Kristen I Osinski, Damian N Di Florio, Noel R Rose, Frederick W Miller, George C Tsokos, DeLisa Fairweather","doi":"10.1172/JCI178722","DOIUrl":"https://doi.org/10.1172/JCI178722","url":null,"abstract":"<p><strong>Background: </strong>Previous epidemiologic studies of autoimmune diseases in the United States (US) have included a limited number of diseases or used meta-analyses that rely on different data collection methods and analyses for each disease.</p><p><strong>Methods: </strong>To estimate the prevalence of autoimmune diseases in the US, we used electronic health record data from six large medical systems in the US. We developed a software program using common methodology to compute the estimated prevalence of autoimmune diseases alone and in aggregate that can be readily used by other investigators to replicate or modify the analysis over time.</p><p><strong>Results: </strong>Our findings indicate that over 15 million people, or 4.6% of the US population, have been diagnosed with at least one autoimmune disease from January 1, 2011, to June 1, 2022, and 34% of those are diagnosed with more than one autoimmune disease. As expected, females (63% of those with autoimmune disease) were almost twice as likely as males to be diagnosed with an autoimmune disease. We identified the top 20 autoimmune diseases based on prevalence and according to sex and age.</p><p><strong>Conclusion: </strong>Thus, we provide, for the first time, a large-scale prevalence estimate of autoimmune disease in the US by sex and age.</p><p><strong>Funding: </strong>Autoimmune Registry Inc., the National Heart Lung and Blood Institute, the National Center for Advancing Translational Sciences, the Intramural Research Program of the National Institute of Environmental Health Sciences.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fusobacterium nucleatum promotes colorectal cancer through neogenesis of tumor stem cells.","authors":"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","doi":"10.1172/JCI181595","DOIUrl":"https://doi.org/10.1172/JCI181595","url":null,"abstract":"<p><p>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 (F. 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 human CRC patients and mouse models. Through single-cell sequencing analysis, we demonstrated that F. nucleatum infection reprogrammed crypt cells and activated LY6A+ revival stem cells (RSCs), promoting their hyperproliferation and subsequent transformation into tumor stem cells, which accelerated intestinal carcinogenesis. Mechanistically, we identified LY6A as a GPI-anchored membrane receptor for F. nucleatum. Upon binding, F. nucleatum induced upregulation of RPS14 via the LY6A receptor, driving RSC hyperactivity and tumorigenic conversion. Functional studies showed that genetic ablation of Ly6a in intestinal epithelial cells or Rps14 in LY6A+ RSCs substantially reduced F. nucleatum colonization and tumorigenesis. Moreover, clinical CRC cohorts analysis revealed a strong correlation between F. nucleatum infection, RSC expansion, and elevated RPS14 expression in tumor tissues. These findings highlight an alternative F. nucleatum-LY6A-RPS14 signaling axis as a critical driver of CRC progression and propose potential therapeutic targets for effective CRC intervention.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNAs: where brilliance, perseverance, and ambition converged.","authors":"Rares Drula, George A Calin","doi":"10.1172/JCI189625","DOIUrl":"10.1172/JCI189625","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cathelicidin antimicrobial peptide expression in neutrophils and neurons antagonistically modulates neuroinflammation.","authors":"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","doi":"10.1172/JCI184502","DOIUrl":"https://doi.org/10.1172/JCI184502","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system (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 (EAE), a mouse model of MS. We showed that, at early stage, CNS-recruited neutrophils produced neutrophil extracellular traps (NETs) rich in CRAMP that was required for EAE initiation. NET-associated CRAMP stimulated IL-6 production by dendritic cells via the cGAS/STING pathway, thereby promoting encephalitogenic Th17 response. However, at a later disease stage, neurons also expressed CRAMP that reduced EAE severity. Camp knockdown in neurons led to disease exacerbation, while local injection of CRAMP1-39 at the peak of EAE promoted disease remission. In vitro, CRAMP1-39 regulated the activation of microglia and astrocytes through the formyl peptide receptor (FPR)2. Finally, administration of butyrate, a gut microbiota-derived metabolite, stimulated the expression of neural CRAMP via the free fatty acids receptors (FFAR)2/3, and prevented EAE. This study shows that CRAMP produced by different cell types have opposing effects on neuroinflammation, offering therapeutic opportunities for MS and other neuroinflammatory disorders.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C2230, a preferential use- and state-dependent CaV2.2 channel blocker, mitigates pain behaviors across multiple pain models.","authors":"Cheng Tang, Kimberly Gomez, Yan Chen, Heather N Allen, Sara Hestehave, Erick J Rodríguez-Palma, Santiago Loya-Lopez, Aida Calderon-Rivera, Paz Duran, Tyler S Nelson, Siva Rama Raju Kanumuri, Bijal Shah, Nihar R Panigrahi, Samantha Perez-Miller, Morgan K Schackmuth, Shivani Ruparel, Amol Patwardhan, Theodore J Price, Paramjit S Arora, Ravindra K Sharma, Abhisheak Sharma, Jie Yu, Olga A Korczeniewska, Rajesh Khanna","doi":"10.1172/JCI177429","DOIUrl":"https://doi.org/10.1172/JCI177429","url":null,"abstract":"<p><p>Antagonists (e.g., Ziconotide, Gabapentin) of the CaV2.2 (N-type) calcium channels are used clinically as analgesics for chronic pain. However, their use is limited by narrow therapeutic windows, difficult dosing routes (Ziconotide), misuse and overdoses (Gabapentin), as well as a litany of adverse effects. Expansion of novel pain therapeutics may emerge from mechanism-based interrogation of CaV2.2. Here we report the identification of C2230, an aryloxy-hydroxypropylamine, as a CaV2.2 blocker. C2230 trapped and stabilized inactivated CaV2.2 in a slow-recovering state and accelerated the open-state inactivation of the channel, conferring an advantageous use-dependent inhibition profile. C2230 inhibited CaV2.2 during high-frequency stimulation, while sparing other voltage-gated ion channels. C2230 inhibited CaV2.2 in dorsal root and trigeminal ganglia neurons from rats, marmosets, and humans in a G-protein-coupled receptor-independent manner. Further, C2230 reduced evoked excitatory postsynaptic currents and excitatory neurotransmitter release in the spinal cord, leading to relief of neuropathic, orofacial, and osteoarthritic pain-like behaviors via three different routes of administration. C2230 also decreased fiber photometry-based calcium responses in the parabrachial nucleus, mitigated aversive behavioral responses to mechanical stimuli after neuropathic injury, and preserved protective pain responses, all without affecting motor or cardiovascular function. Finally, site-directed mutation analysis demonstrated that C2230 binds differently than other known CaV2.2 blockers, making it a promising lead compound for analgesic development.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YAP1 induces bladder cancer progression and promotes immune evasion through IL-6/STAT3 pathway and CXCL deregulation.","authors":"Pritam Sadhukhan, Mingxiao Feng, Emily Illingworth, Ido Sloma, Akira Ooki, Andres Matoso, David Sidransky, Burles A Johnson, Luigi Marchionni, Fenna Cm Sillé, Woonyoung Choi, David McConkey, Mohammad Hoque","doi":"10.1172/JCI171164","DOIUrl":"10.1172/JCI171164","url":null,"abstract":"<p><p>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 and pharmacological attenuation of YAP1 activity. Briefly, RNA sequencing was carried out with mouse and human cell lines to identify novel YAP1-regulated downstream targets unbiasedly. We then experimentally confirmed that YAP1 regulates the TIME through the IL-6/STAT3 signaling pathway and varied C-X-C motif chemokine regulation. We analyzed several human sample sets to explore the TIME status in the context of YAP1 expression. Our data indicate that YAP1 attenuation decreases M2 macrophages and myeloid-derived suppressor cells in the TIME compared with YAP1-expressing cells. In summary, this study provides insights into YAP1 signaling as a driver for cancer stemness and an inducer of immunosuppressive TIME. Moreover, the therapeutic efficacy of YAP1 attenuation indicates that combined blockade of YAP1 and immune checkpoints may yield clinical value for treating patients with UCB.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascular smooth muscle cell PRDM16 regulates circadian variation in blood pressure.","authors":"Zhenguo Wang, Wenjuan Mu, Juan Zhong, Ruiyan Xu, Yaozhong Liu, Guizhen Zhao, Yanhong Guo, Jifeng Zhang, Ida Surakka, Y Eugene Chen, Lin Chang","doi":"10.1172/JCI183409","DOIUrl":"https://doi.org/10.1172/JCI183409","url":null,"abstract":"<p><p>Disruptions of blood pressure (BP) circadian variation are closely associated with an increased risk of cardiovascular disease (CVD). 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 (VSMC), is significantly associated with BP-related traits. However, the roles of PRDM16 in BP regulation are largely unknown. Here, we demonstrate that BP in VSMC-specific Prdm16 knockout (Prdm16SMKO) mice was significantly lower than that in control mice during the active period, resulting in aberrant BP circadian variation. Mesenteric artery rings from Prdm16SMKO mice showed reduced response to phenylephrine. Mechanistically, we identified adrenergic receptor alpha 1d (Adra1d) as a transcriptional target of PRDM16. Notably, PRDM16 exhibits a remarkable circadian expression pattern and regulates the expression of clock genes, particularly Npas2, which is crucial for BP circadian variation regulation. Consequently, PRDM16 deficiency in VSMC causes disrupted BP circadian variation through reduced response to adrenergic signaling and clock gene regulation. Our findings offer substantial insights into the intricate molecular pathways that govern circadian fluctuations in BP.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}