Philipp Globig, Payam Morakabati, Veronika Höfer, Diana M Willmes, Magda Babina, Margitta Worm
{"title":"Acetylsalicylic acid aggravates anaphylaxis in a PGE2-dependent manner.","authors":"Philipp Globig, Payam Morakabati, Veronika Höfer, Diana M Willmes, Magda Babina, Margitta Worm","doi":"10.1172/JCI175397","DOIUrl":"10.1172/JCI175397","url":null,"abstract":"<p><p>Acetylsalicylic acid (ASA) can exert proanaphylactic effects, but the extent of this phenomenon and its underlying mechanisms are undefined. Yet, low homeostatic prostaglandin E2 (PGE2) levels have been associated with anaphylaxis. In this study, we investigated whether the proanaphylactic effect of ASA is PGE2 dependent. We assessed the effect of ASA in experimental anaphylaxis models, analyzed a large dataset of patients with anaphylaxis, and performed titrated allergen challenges in ASA-treated allergic individuals. Registry data indicated an increased risk for severe anaphylaxis in patients with ASA comedication. ASA pretreatment aggravated allergen-dependent anaphylaxis in mice, whereas histamine-induced anaphylaxis remained unaffected. Exacerbation was due to reduced PGE2, as its stabilization or the use of prostanoid E receptor (EP) agonists reversed the proanaphylactic effects of ASA. EP2-, EP3-, and EP4 receptor-deficient mice revealed that each receptor individually contributed to ASA susceptibility. In patients with allergy, prior ASA intake increased skin responsiveness to allergen but not to histamine. Conversely, the responses of basophils to ex vivo FcεRI aggregation remained unaltered, indicating that ASA operated by enhancing the stimulability of mast cells in a PGE2-dependent manner. Collectively, our data reveal a central role of the PGE2 network in ASA-aggravated anaphylaxis. EP receptors could be potential targets to prevent or alter the outcome of anaphylaxis.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11870728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542065","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}
Minyoung Kevin Kim, Gina A Suh, Grace D Cullen, Saumel Perez Rodriguez, Tejas Dharmaraj, Tony Hong Wei Chang, Zhiwei Li, Qingquan Chen, Sabrina I Green, Rob Lavigne, Jean-Paul Pirnay, Paul L Bollyky, Jessica C Sacher
{"title":"Bacteriophage therapy for multidrug-resistant infections: current technologies and therapeutic approaches.","authors":"Minyoung Kevin Kim, Gina A Suh, Grace D Cullen, Saumel Perez Rodriguez, Tejas Dharmaraj, Tony Hong Wei Chang, Zhiwei Li, Qingquan Chen, Sabrina I Green, Rob Lavigne, Jean-Paul Pirnay, Paul L Bollyky, Jessica C Sacher","doi":"10.1172/JCI187996","DOIUrl":"10.1172/JCI187996","url":null,"abstract":"<p><p>Bacteriophage (phage) therapy has emerged as a promising solution to combat the growing crisis of multidrug-resistant (MDR) infections. There are several international centers actively engaged in implementation of phage therapy, and recent case series have reported encouraging success rates in patients receiving personalized, compassionate phage therapy for difficult-to-treat infections. Nonetheless, substantial hurdles remain in the way of more widespread adoption and more consistent success. This Review offers a comprehensive overview of current phage therapy technologies and therapeutic approaches. We first delineate the common steps in phage therapy development, from phage bank establishment to clinical administration, and examine the spectrum of therapeutic approaches, from personalized to fixed phage cocktails. Using the framework of a conventional drug development pipeline, we then identify critical knowledge gaps in areas such as cocktail design, formulation, pharmacology, and clinical trial design. We conclude that, while phage therapy holds promise, a structured drug development pipeline and sustained government support are crucial for widespread adoption of phage therapy for MDR infections.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 5","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11870740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542170","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}
Gang Xi, Elizabeth A Mclnnis, Olivier Lardinois, Peiqi Hu, John S Poulton, Meghan E Free, Dhruti P Chen, Evan M Zeitler, Eveline Y Wu, Nicole M Orzechowski, Vimal K Derebail, J Charles Jennette, Ronald J Falk
{"title":"Sequential carbonyl derivatives and hydrazone adduct formation on myeloperoxidase contribute to development of ANCA-vasculitis.","authors":"Gang Xi, Elizabeth A Mclnnis, Olivier Lardinois, Peiqi Hu, John S Poulton, Meghan E Free, Dhruti P Chen, Evan M Zeitler, Eveline Y Wu, Nicole M Orzechowski, Vimal K Derebail, J Charles Jennette, Ronald J Falk","doi":"10.1172/JCI178813","DOIUrl":"10.1172/JCI178813","url":null,"abstract":"<p><p>Drug-induced autoimmune diseases are increasingly recognized although mechanistic insight into disease causation is lacking. Hydralazine exposure has been linked to autoimmune diseases, including anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. Our hypothesis posits that hydralazine covalently binds to myeloperoxidase (MPO), triggering the autoimmune response in ANCA vasculitis. We in vitro observed formation of carbonyl derivatives on amine groups in the presence of acrolein. This facilitated the subsequent binding of hydralazine to heme-containing proteins, including MPO, via a Michael addition. Our studies demonstrated that carbonyl derivatives and hydrazone adducts induce conformational changes in the MPO heavy chain, potentially changing its immunogenicity. We identified hydrazone adducts on circulating MPO in patients with hydralazine-associated ANCA vasculitis. These patients exhibited elevated anti-MPO IgM levels, while anti-MPO IgG levels were comparable between hydralazine-associated and non-hydralazine-associated vasculitis patients. IgM isolated from hydralazine-associated MPO ANCA patients demonstrated a heightened affinity to hydralazine-modified MPO and activated neutrophil-like HL-60 cells. Hydralazine-modified MPO was pathogenic, as demonstrated by splenocyte transfer in a mouse model of ANCA vasculitis. Our findings unveil a mechanism of drug-induced autoimmunity wherein stepwise chemical modifications of MPO lead to conformational changes and hydrazone adduct formation producing a neoantigen to which pathogenic autoantibodies are generated.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527819","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}
Chengjie Gao, Yitian Dai, Paul A Spezza, Paul Boasiako, Alice Tang, Giselle Rasquinha, Hui Zhong, Bojing Shao, Yunfeng Liu, Patricia A Shi, Cheryl A Lobo, Xiuli An, Anqi Guo, William B Mitchell, Deepa Manwani, Karina Yazdanbakhsh, Avital Mendelson
{"title":"Megakaryocytes transfer mitochondria to bone marrow mesenchymal stromal cells to lower platelet activation.","authors":"Chengjie Gao, Yitian Dai, Paul A Spezza, Paul Boasiako, Alice Tang, Giselle Rasquinha, Hui Zhong, Bojing Shao, Yunfeng Liu, Patricia A Shi, Cheryl A Lobo, Xiuli An, Anqi Guo, William B Mitchell, Deepa Manwani, Karina Yazdanbakhsh, Avital Mendelson","doi":"10.1172/JCI189801","DOIUrl":"https://doi.org/10.1172/JCI189801","url":null,"abstract":"<p><p>Newly produced platelets acquire a low activation state but whether the megakaryocyte plays a role in this outcome has not been fully uncovered. Mesenchymal stem cells (MSCs) were previously shown to promote platelet production and lower platelet activation. We found healthy megakaryocytes transfer mitochondria to MSCs mediated by Connexin 43 (Cx43) gap junctions on MSCs, which leads to platelets at a low energetic state with increased LYN activation, characteristic of resting platelets. On the contrary, MSCs have a limited ability to transfer mitochondria to megakaryocytes. Sickle cell disease (SCD) is characterized by hemolytic anemia and results in heightened platelet activation, contributing to numerous disease complications. Platelets in SCD mice and human patient samples had a heightened energetic state with increased glycolysis. MSC exposure to heme in SCD led to decreased Cx43 expression and a reduced ability to uptake mitochondria from megakaryocytes. This prevented LYN activation in platelets and contributed to increased platelet activation at steady state. Altogether, our findings demonstrate an effect of hemolysis in the microenvironment leading to increased platelet activation in SCD. These findings have the potential to inspire new therapeutic targets to relieve thrombosis-related complications of SCD and other hemolytic conditions.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523440","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}
Saireudee Chaturantabut, Sydney Oliver, Dennie T Frederick, Jiwan J Kim, Foxy P Robinson, Alessandro Sinopoli, Tian-Yu Song, Yao He, Yuan-Chen Chang, Diego J Rodriguez, Liang Chang, Devishi Kesar, Meilani Ching, Ruvimbo Dzvurumi, Adel Atari, Yuen-Yi Tseng, Nabeel Bardeesy, William R Sellers
{"title":"Identification of potent biparatopic antibodies targeting FGFR2 fusion driven cholangiocarcinoma.","authors":"Saireudee Chaturantabut, Sydney Oliver, Dennie T Frederick, Jiwan J Kim, Foxy P Robinson, Alessandro Sinopoli, Tian-Yu Song, Yao He, Yuan-Chen Chang, Diego J Rodriguez, Liang Chang, Devishi Kesar, Meilani Ching, Ruvimbo Dzvurumi, Adel Atari, Yuen-Yi Tseng, Nabeel Bardeesy, William R Sellers","doi":"10.1172/JCI182417","DOIUrl":"10.1172/JCI182417","url":null,"abstract":"<p><p>Translocations involving FGFR2 gene fusions are common in cholangiocarcinoma and predict response to FGFR kinase inhibitors. However, response rates and durability are limited due to the emergence of resistance, typically involving FGFR2 kinase domain mutations, and to sub-optimal dosing, relating to drug adverse effects. Here, we develop biparatopic antibodies targeting the FGFR2 extracellular domain (ECD), as candidate therapeutics. Biparatopic antibodies can overcome drawbacks of bivalent monospecific antibodies, which often show poor inhibitory or even agonist activity against oncogenic receptors. We show that oncogenic transformation by FGFR2 fusions requires an intact ECD. Moreover, by systematically generating biparatopic antibodies targeting distinct epitope pairs in FGFR2 ECD, we identified antibodies that effectively block signaling and malignant growth driven by FGFR2-fusions. Importantly, these antibodies demonstrate efficacy in vivo, synergy with FGFR inhibitors, and activity against FGFR2 fusions harboring kinase domain mutations. Thus, biparatopic antibodies may serve as an innovative treatment option for patients with FGFR2-altered cholangiocarcinoma.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523438","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}
Annegret Holm, Matthew S Graus, Jill Wylie-Sears, Jerry Wei Heng Tan, Maya Alvarez-Harmon, Luke Borgelt, Sana Nasim, Long Chung, Ashish Jain, Mingwei Sun, Liang Sun, Pascal Brouillard, Ramrada Lekwuttikarn, Yanfei Qi, Joyce Teng, Miikka Vikkula, Harry Kozakewich, John B Mulliken, Mathias Francois, Joyce Bischoff
{"title":"An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma.","authors":"Annegret Holm, Matthew S Graus, Jill Wylie-Sears, Jerry Wei Heng Tan, Maya Alvarez-Harmon, Luke Borgelt, Sana Nasim, Long Chung, Ashish Jain, Mingwei Sun, Liang Sun, Pascal Brouillard, Ramrada Lekwuttikarn, Yanfei Qi, Joyce Teng, Miikka Vikkula, Harry Kozakewich, John B Mulliken, Mathias Francois, Joyce Bischoff","doi":"10.1172/JCI179782","DOIUrl":"10.1172/JCI179782","url":null,"abstract":"<p><p>Infantile hemangioma (IH) is the most common tumor in children and a paradigm for pathological vasculogenesis, angiogenesis, and regression. Propranolol, the mainstay of treatment, inhibits IH vessel formation via a β-adrenergic receptor-independent off-target effect of its R(+) enantiomer on endothelial SOX18 - a member of the SOX (SRY-related HMG-box) family of transcription factors. Transcriptomic profiling of patient-derived hemangioma stem cells uncovered the mevalonate pathway (MVP) as a target of R(+) propranolol. Loss and gain of function of SOX18 confirmed it is both necessary and sufficient for R(+) propranolol suppression of the MVP, including regulation of sterol regulatory element-binding protein 2 (SREBP2) and the rate-limiting enzyme HMG-CoA reductase (HMGCR). A biological relevance of the endothelial SOX18-MVP axis in IH patient tissue was demonstrated by nuclear colocalization of SOX18 and SREBP2. Functional validation in a preclinical IH xenograft model revealed that statins - competitive inhibitors of HMGCR - efficiently suppress IH vessel formation. We propose an endothelial SOX18-MVP axis as a central regulator of IH pathogenesis and suggest statin repurposing to treat IH. The pleiotropic effects of R(+) propranolol and statins along the SOX18-MVP axis to disable an endothelial cell-specific program may have therapeutic implications for other vascular disease entities involving pathological vasculogenesis and angiogenesis.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143501465","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}
Ruixiang Zhang, Yongzhan Nie, Xiaobing Chen, Tao Jiang, Jinhai Wang, Yuhui Peng, Guangpeng Zhou, Yong Li, Lina Zhao, Beibei Chen, Yunfeng Ni, Yan Cheng, Yiwei Xu, Zhenyu Zhu, Xianchun Gao, Zhen Wu, Tianbao Li, Jie Zhao, Cantong Liu, Gang Zhao, Jiakuan Chen, Jing Zhao, Gang Ji, Xiaoliang Han, Jie He, Yin Li
{"title":"A multicenter prospective clinical trial reveals cell free DNA methylation markers for early esophageal cancer.","authors":"Ruixiang Zhang, Yongzhan Nie, Xiaobing Chen, Tao Jiang, Jinhai Wang, Yuhui Peng, Guangpeng Zhou, Yong Li, Lina Zhao, Beibei Chen, Yunfeng Ni, Yan Cheng, Yiwei Xu, Zhenyu Zhu, Xianchun Gao, Zhen Wu, Tianbao Li, Jie Zhao, Cantong Liu, Gang Zhao, Jiakuan Chen, Jing Zhao, Gang Ji, Xiaoliang Han, Jie He, Yin Li","doi":"10.1172/JCI186816","DOIUrl":"https://doi.org/10.1172/JCI186816","url":null,"abstract":"<p><strong>Background: </strong>Current methods for detecting esophageal cancer (EC) are generally invasive or exhibit limited sensitivity and specificity, especially for the identification of early-stage tumors.</p><p><strong>Methods: </strong>We identified potential methylated DNA markers (MDM) from multiple genomic regions in a discovery cohort and a diagnostic model was developed and verified in a model-verification cohort of 297 participants. The accuracy of the MDM panel was validated in a multicenter, prospective cohort (n = 1429). The clinical performance of identified MDMs were compared with current tumor-associated protein markers.</p><p><strong>Results: </strong>From 31 significant differentially methylated EC-associated regions identified in the marker discovery, we trained and validated a 3-MDM diagnostic model that could discriminate among EC patients and Non-EC volunteers in a multicenter clinical prospective cohort with a sensitivity of 85.5% and a specificity of 95.3%. This panel showed higher sensitivity in diagnosing early-stage tumors, with sensitivities of 56% for Stage 0 and 77% for Stage I, comparing with the performance of current biochemical markers. In population with high risk for EC, the sensitivity and specificity are 85.68% and 93.61% respectively.</p><p><strong>Conclusion: </strong>The assessment of tumor-associated methylation status in blood samples can facilitate non-invasive, and reliable diagnosis of early-stage EC, which warrants further development to expand screening and reduce mortality rates.</p><p><strong>Trial registration number: </strong>ChiCTR2400083525.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143501463","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":"An inherited predisposition allele promotes gastric cancer via enhancing deubiquitination-mediated activation of epithelial-to-mesenchymal transition signaling.","authors":"Bolin Tao, Zhenning Wang, Xuanyi Wang, Aixia Song, Jiaxian Liu, Jianan Wang, Qin Zhang, Zhaolin Chen, Zixian Wang, Wenjie Xu, Menghong Sun, Yanong Wang, Ping Zhang, Tao Xu, Gong-Hong Wei, Fei Xavier Chen, Mengyun Wang","doi":"10.1172/JCI179617","DOIUrl":"https://doi.org/10.1172/JCI179617","url":null,"abstract":"<p><p>Genome-wide human genetic studies have identified inherited cis-regulatory loci variants that predispose to cancers. However, the mechanisms by which these germline variants influence cancer progression, particularly through gene expression and proteostasis control, remain unclear. By analyzing genomic data from a gastric cancer (GC) case-control study (2,117 individuals), focusing on the ubiquitin-specific protease (USP) family, we identify the single nucleotide polymorphism (SNP) rs72856331 (G>A) in the promoter region of the proto-oncogene USP47 as a putative susceptibility allele for GC (OR = 0.78, P = 0.015). Mechanistically, the risk allele G is associated with enhanced USP47 expression, mediated by altered recruitment of the transcription factor GLI3 and changes in the epigenetic status at promoter. CRISPR/Cas9-mediated single-nucleotide conversion into risk allele G results in increased GLI3 binding and subsequent USP47 upregulation. The depletion of GLI3 results in a reduction of cancer-related phenotypes, similar to those observed following USP47 knockdown. Furthermore, we identify Snai1 as a deubiquitination target of USP47, explaining USP47-dependent activation of epithelial-mesenchymal transition pathway and tumor progression. Our findings identify an important genetic predisposition that implicates the perturbation of transcription and proteostasis programs in GC, offering insights into prevention and therapeutic strategies for genetically stratified patients.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492229","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":"Asparagine drives immune evasion in bladder cancer via RIG-I stability and type I IFN signaling.","authors":"Wenjie Wei, Hongzhao Li, Shuo Tian, Chi Zhang, Junxiao Liu, Wen Tao, Tianwei Cai, Yuhao Dong, Chuang Wang, Dingyi Lu, Yakun Ai, Wanlin Zhang, Hanfeng Wang, Kan Liu, Yang Fan, Yu Gao, Qingbo Huang, Xin Ma, Baojun Wang, Xu Zhang, Yan Huang","doi":"10.1172/JCI186648","DOIUrl":"https://doi.org/10.1172/JCI186648","url":null,"abstract":"<p><p>Tumor cells often employ many ways to restrain type I interferon signaling to evade immune surveillance. However, whether cellular amino acid metabolism regulate this process remains unclear and its effects on antitumor immunity are relatively unexplored. Here, we find that asparagine inhibits IFN-I signaling and promotes immune escape in bladder cancer. Depletion of asparagine synthetase (ASNS) strongly limits in vivo tumor growth in a CD8+ T cell-dependent manner and boosts immunotherapy efficacy. Moreover, clinically approved ASNase synergizes with anti-PD-1 therapy in suppressing tumor growth. Mechanistically, asparagine can directly bind to RIG-I and facilitate CBL-mediated RIG-I degradation, thereby suppressing IFN signaling and antitumor immune responses. Clinically, tumors with higher ASNS expression show decreased responsiveness to ICIs therapy. Together, our findings uncover asparagine as a natural metabolite to modulate RIG-I-mediated IFN-I signaling, providing the basis for developing the combinatorial use of ASNase and anti-PD-1 for bladder cancer.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449182","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}
Minkyung Kang, Jihye Choi, Jeongho Han, Toshiyuki Araki, Soo-Whee Kim, Hyun-Hee Ryu, Min-Gyun Kim, Seoyeon Kim, Hanbyul Jang, Sun Yong Kim, Kyoung-Doo Hwang, Soobin Kim, Myeongjong Yoo, Jaegeon Lee, Kitae Kim, Pojeong Park, Ja Eun Choi, Dae Hee Han, Yujin Kim, Jeongyeon Kim, Sunghoe Chang, Bong-Kiun Kaang, Jung Min Ko, Keun-Ah Cheon, Joon-Yong An, Sang Jeong Kim, Hyungju Park, Benjamin G Neel, Chul Hoon Kim, Yong-Seok Lee
{"title":"Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models.","authors":"Minkyung Kang, Jihye Choi, Jeongho Han, Toshiyuki Araki, Soo-Whee Kim, Hyun-Hee Ryu, Min-Gyun Kim, Seoyeon Kim, Hanbyul Jang, Sun Yong Kim, Kyoung-Doo Hwang, Soobin Kim, Myeongjong Yoo, Jaegeon Lee, Kitae Kim, Pojeong Park, Ja Eun Choi, Dae Hee Han, Yujin Kim, Jeongyeon Kim, Sunghoe Chang, Bong-Kiun Kaang, Jung Min Ko, Keun-Ah Cheon, Joon-Yong An, Sang Jeong Kim, Hyungju Park, Benjamin G Neel, Chul Hoon Kim, Yong-Seok Lee","doi":"10.1172/JCI176631","DOIUrl":"https://doi.org/10.1172/JCI176631","url":null,"abstract":"<p><p>RAS/MAPK pathway mutations often induce RASopathies with overlapping features, such as craniofacial dysmorphology, cardiovascular defects, dermatologic abnormalities, and intellectual disabilities. Although BRAF gene mutations are associated with cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome, it remains unclear how these mutations impair cognition. Here, we investigated the underlying neural mechanisms using several mouse models harboring a gain-of-function BRAF mutation (K499E) discovered in RASopathy patients. We found expressing BRAF K499E (KE) in neural stem cells under the control of a Nestin-Cre promoter (Nestin;BRAFKE/+) induced hippocampal memory deficits, but expressing it in excitatory or inhibitory neurons did not. BRAF KE expression in neural stem cells led to aberrant reactive astrogliosis, increased astrocytic Ca2+ fluctuations, and reduced hippocampal long-term depression (LTD) in mice. Consistently, 3D human cortical spheroids expressing BRAF KE also showed reactive astrogliosis. Astrocyte-specific AAV-BRAF KE delivery induced memory deficits, reactive astrogliosis, and increased astrocytic Ca2+ fluctuations. Notably, reducing ERK activity in astrocytes rescued the memory deficits and altered astrocytic Ca2+ activity of Nestin;BRAFKE/+ mice. Furthermore, reducing astrocyte Ca2+ activity rescued the spatial memory impairments of BRAF KE-expressing mice. Our results demonstrate that ERK hyperactivity contributes to astrocyte dysfunction associated with Ca2+ dysregulation, leading to the memory deficits of BRAF-associated RASopathies.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449180","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
