Journal of Clinical Investigation最新文献_第10页

A conversation with Zhijian (James) Chen. 与陈志坚（James）的对话。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-01-02 DOI: 10.1172/JCI189543

Ushma S Neill

引用次数: 0

Mechanisms of postischemic cardiac death and protection following myocardial injury. 心肌损伤后心肌死亡的机制及保护。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-01-02 DOI: 10.1172/JCI184134

Yusuf Mastoor, Elizabeth Murphy, Barbara Roman

{"title":"Mechanisms of postischemic cardiac death and protection following myocardial injury.","authors":"Yusuf Mastoor, Elizabeth Murphy, Barbara Roman","doi":"10.1172/JCI184134","DOIUrl":"10.1172/JCI184134","url":null,"abstract":"Acute myocardial infarction (MI) is a leading cause of death worldwide. Although with current treatment, acute mortality from MI is low, the damage and remodeling associated with MI are responsible for subsequent heart failure. Reducing cell death associated with acute MI would decrease the mortality associated with heart failure. Despite considerable study, the precise mechanism by which ischemia and reperfusion (I/R) trigger cell death is still not fully understood. In this Review, we summarize the changes that occur during I/R injury, with emphasis on those that might initiate cell death, such as calcium overload and oxidative stress. We review cell-death pathways and pathway crosstalk and discuss cardioprotective approaches in order to provide insight into mechanisms that could be targeted with therapeutic interventions. Finally, we review cardioprotective clinical trials, with a focus on possible reasons why they were not successful. Cardioprotection has largely focused on inhibiting a single cell-death pathway or one death-trigger mechanism (calcium or ROS). In treatment of other diseases, such as cancer, the benefit of targeting multiple pathways with a \"drug cocktail\" approach has been demonstrated. Given the crosstalk between cell-death pathways, targeting multiple cardiac death mechanisms should be considered.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915009","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}

引用次数: 0

Preexisting vaccine-primed heterosubtypic T cell immunity protects the maternal-fetal unit from adverse influenza outcomes in mice. 预先存在的疫苗引发的异亚型T细胞免疫保护母胎单位免受小鼠不良流感结果的影响。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-01-02 DOI: 10.1172/JCI179230

Valeria Flores Malavet, Kunal Dhume, Ali Satchmei, Andrea C Arvelo, Aaron J Beaird, Siva N Annamalai, Lauren A Kimball, K Kai McKinstry, Tara M Strutt

{"title":"Preexisting vaccine-primed heterosubtypic T cell immunity protects the maternal-fetal unit from adverse influenza outcomes in mice.","authors":"Valeria Flores Malavet, Kunal Dhume, Ali Satchmei, Andrea C Arvelo, Aaron J Beaird, Siva N Annamalai, Lauren A Kimball, K Kai McKinstry, Tara M Strutt","doi":"10.1172/JCI179230","DOIUrl":"10.1172/JCI179230","url":null,"abstract":"The risk of severe outcomes of influenza increases during pregnancy. Whether vaccine-induced T cell memory-primed prepregnancy retains the ability to mediate protection during pregnancy, when systemic levels of several hormones with putative immunomodulatory functions are increased, is unknown. Here, using murine adoptive transfer systems and a translationally relevant model of cold-adapted live-attenuated influenza A virus vaccination, we show that preexisting virus-specific memory T cell responses are largely unaltered and highly protective against heterotypic viral challenges during pregnancy. Expression of the transcription factor T-bet, which is upregulated in antiviral T cells responding in pregnant mice, is critical in preventing hormone-associated gain of detrimental T helper type 2 (TH2) attributes reported in other settings. Beyond antiviral effects, preexisting vaccine-primed T cell immunity prevents metabolic dysfunction in gravid dams and adverse neonatal outcomes often associated with maternal influenza infection. These results demonstrate robust protection of the maternal-fetal unit from severe consequences of respiratory virus infection by preexisting T cell immunity.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915032","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}

引用次数: 0

TGF-β drives differentiation of intraepithelial mast cells in inflamed airway mucosa. TGF-β促进气道炎症黏膜上皮内肥大细胞的分化。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-01-02 DOI: 10.1172/JCI186337

Axel Roers

引用次数: 0

Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium. 进行性肺纤维化：基因易损支气管肺泡上皮的重编程。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-01-02 DOI: 10.1172/JCI183836

James P Bridges, Eszter K Vladar, Jonathan S Kurche, Andrei Krivoi, Ian T Stancil, Evgenia Dobrinskikh, Yan Hu, Sarah K Sasse, Joyce S Lee, Rachel Z Blumhagen, Ivana V Yang, Anthony N Gerber, Anna L Peljto, Christopher M Evans, Elizabeth F Redente, David Wh Riches, David A Schwartz

{"title":"Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium.","authors":"James P Bridges, Eszter K Vladar, Jonathan S Kurche, Andrei Krivoi, Ian T Stancil, Evgenia Dobrinskikh, Yan Hu, Sarah K Sasse, Joyce S Lee, Rachel Z Blumhagen, Ivana V Yang, Anthony N Gerber, Anna L Peljto, Christopher M Evans, Elizabeth F Redente, David Wh Riches, David A Schwartz","doi":"10.1172/JCI183836","DOIUrl":"10.1172/JCI183836","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: the first establishes a vulnerable bronchoalveolar epithelium, and the second triggers mechanisms that reprogram distal epithelia to initiate and perpetuate a profibrotic phenotype. While vulnerability of the bronchoalveolar epithelia is most often driven by common or rare genetic variants, subsequent injury of the bronchoalveolar epithelia results in persistent changes in cell biology that disrupt tissue homeostasis and activate fibroblasts. The dynamic biology of IPF can best be contextualized etiologically and temporally, including stages of vulnerability, early disease, and persistent and progressive lung fibrosis. These dimensions of IPF highlight critical mechanisms that adversely disrupt epithelial function, activate fibroblasts, and lead to lung remodeling. Together with better recognition of early disease, this conceptual approach should lead to the development of novel therapeutics directed at the etiologic and temporal drivers of lung fibrosis that will ultimately transform the care of patients with IPF from palliative to curative.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"135 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915046","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}

引用次数: 0

FOXO1 pathway activation by VISTA immune checkpoint restrains pulmonary ILC2 functions. VISTA免疫检查点激活fox01通路抑制肺ILC2功能。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-01-02 DOI: 10.1172/JCI184932

Mohammad Hossein Kazemi, Zahra Momeni-Varposhti, Xin Li, Benjamin P Hurrell, Yoshihiro Sakano, Stephen Shen, Pedram Shafiei-Jahani, Kei Sakano, Omid Akbari

{"title":"FOXO1 pathway activation by VISTA immune checkpoint restrains pulmonary ILC2 functions.","authors":"Mohammad Hossein Kazemi, Zahra Momeni-Varposhti, Xin Li, Benjamin P Hurrell, Yoshihiro Sakano, Stephen Shen, Pedram Shafiei-Jahani, Kei Sakano, Omid Akbari","doi":"10.1172/JCI184932","DOIUrl":"10.1172/JCI184932","url":null,"abstract":"Group 2 innate lymphoid cells (ILC2s) play a pivotal role in the development of airway hyperreactivity (AHR). However, the regulatory mechanisms governing ILC2 function remain inadequately explored. This study uncovers V-domain Ig suppressor of T cell activation (VISTA) as an inhibitory immune checkpoint crucial for modulating ILC2-driven lung inflammation. VISTA is upregulated in activated pulmonary ILC2s and plays a key role in regulating lung inflammation, as VISTA-deficient ILC2s demonstrate increased proliferation and function, resulting in elevated type 2 cytokine production and exacerbation of AHR. Mechanistically, VISTA stimulation activates Forkhead box O1 (FOXO1), leading to modulation of ILC2 proliferation and function. The suppressive effects of FOXO1 on ILC2 effector function were confirmed using FOXO1 inhibitors and activators. Moreover, VISTA-deficient ILC2s exhibit enhanced fatty acid oxidation and oxidative phosphorylation to meet their high energy demands. Therapeutically, VISTA agonist treatment reduces ILC2 function both ex vivo and in vivo, significantly alleviating ILC2-driven AHR. Our murine findings were validated in human ILC2s, whose function was reduced ex vivo by a VISTA agonist, and in a humanized mouse model of ILC2-driven AHR. Our studies unravel VISTA as an immune checkpoint for ILC2 regulation via the FOXO1 pathway, presenting potential therapeutic strategies for allergic asthma by modulating ILC2 responses.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921908","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}

引用次数: 0

Disrupted callosal connectivity underlies long-lasting sensory-motor deficits in an NMDAreceptor antibody encephalitis mouse model. 在nmda受体抗体脑炎小鼠模型中，胼胝体连通性的破坏是长期感觉运动缺陷的基础。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-31 DOI: 10.1172/JCI173493

Jing Zhou, Ariele L Greenfield, Rita P Loudermilk, Christopher M Bartley, Chun Chen, Xiumin Chen, Morgane Ah Leroux, Yujun Lu, Deanna Necula, Thomas T Ngo, Baouyen T Tran, Patrick S Honma, Kelli Lauderdale, Chao Zhao, Xiaoyuan Zhou, Hong Wang, Roger A Nicoll, Cong Wang, Jeanne T Paz, Jorge J Palop, Michael R Wilson, Samuel J Pleasure

{"title":"Disrupted callosal connectivity underlies long-lasting sensory-motor deficits in an NMDAreceptor antibody encephalitis mouse model.","authors":"Jing Zhou, Ariele L Greenfield, Rita P Loudermilk, Christopher M Bartley, Chun Chen, Xiumin Chen, Morgane Ah Leroux, Yujun Lu, Deanna Necula, Thomas T Ngo, Baouyen T Tran, Patrick S Honma, Kelli Lauderdale, Chao Zhao, Xiaoyuan Zhou, Hong Wang, Roger A Nicoll, Cong Wang, Jeanne T Paz, Jorge J Palop, Michael R Wilson, Samuel J Pleasure","doi":"10.1172/JCI173493","DOIUrl":"10.1172/JCI173493","url":null,"abstract":"NMDA receptor mediated autoimmune encephalitis (NMDAR-AE) frequently results in persistent sensory-motor deficits, especially in children, yet the underlying mechanisms remain unclear. This study investigated the long- term effects of exposure to a patient-derived GluN1-specific monoclonal antibody (mAb) during a critical developmental period (from postnatal day 3 to day 12) in mice. We observed long-lasting sensory-motor deficits characteristic of NMDAR-AE, along with permanent changes in callosal axons within the primary somatosensory cortex (S1) in adulthood, including increased terminal branch complexity. This complexity was associated with paroxysmal recruitment of neurons in S1 in response to callosal stimulation. Particularly during complex motor tasks, mAb3-treated mice exhibited significantly reduced inter-hemispheric functional connectivity between S1 regions, consistent with pronounced sensory-motor behavioral deficits. These findings suggest that transient exposure to anti-GluN1 mAb during a critical developmental window may lead to irreversible morphological and functional changes in callosal axons, which could significantly impair sensory-motor integration and contribute to long-lasting sensory-motor deficits. Our study establishes a new model of NMDAR-AE and identifies novel cellular and network-level mechanisms underlying persistent sensory-motor deficits in this context. These insights lay the foundation for future research into molecular mechanisms and the development of targeted therapeutic interventions.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909750","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}

引用次数: 0

Apex1 safeguards genomic stability to ensure a cytopathic T cell fate in autoimmune disease models. Apex1保护基因组稳定性，以确保自身免疫性疾病模型中的细胞病变T细胞命运。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-31 DOI: 10.1172/JCI183671

Xiang Xiao, Yong Du, Si Sun, Xiaojun Su, Junji Xing, Guangchuan Wang, Steven M Elzein, Dawei Zou, Laurie J Minze, Zhuyun Mao, Rafik M Ghobrial, Ashton A Connor, Wenhao Chen, Zhiqiang Zhang, Xian C Li

{"title":"Apex1 safeguards genomic stability to ensure a cytopathic T cell fate in autoimmune disease models.","authors":"Xiang Xiao, Yong Du, Si Sun, Xiaojun Su, Junji Xing, Guangchuan Wang, Steven M Elzein, Dawei Zou, Laurie J Minze, Zhuyun Mao, Rafik M Ghobrial, Ashton A Connor, Wenhao Chen, Zhiqiang Zhang, Xian C Li","doi":"10.1172/JCI183671","DOIUrl":"10.1172/JCI183671","url":null,"abstract":"T cells have a remarkable capacity to clonally expand, a process that is intricately linked to their effector activities. As vigorously proliferating T cell also incur substantial DNA lesions, how the dividing T cells safeguard their genomic integrity to allow the generation of T effector cells remains largely unknown. Here we report the identification of the apurinic/apyrimidinic endonuclease-1 (Apex1) as an indispensable molecule for the induction of cytopathic T effectors in mouse models. We demonstrate that conditional deletion of Apex1 in T cells resulted in a remarkable accumulation of baseless DNA sites in the genome of proliferating T cells, which further led to genomic instability and apoptotic cell death. Consequently, Apex1-deleted T cells failed to acquire any effector features after activation and failed to mediate autoimmune diseases and allergic tissue damages. Detailed mutational analyses pinpointed the importance of its endonuclease domain in the generation of T effector cells. We provide further evidence that inhibiting the base repair activities of Apex1 with chemical inhibitors similarly abrogated the induction of autoimmune diseases. Collectively, our study suggests that Apex1 serves as a gatekeeper for the generation of cytopathic T cells and that therapeutically targeting Apex1 may have important clinical implications in the treatment of autoimmune diseases.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909748","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}

引用次数: 0

A conserved human CD4+ T cell subset recognizing the mycobacterial adjuvant, trehalose monomycolate. 一个保守的人CD4+ T细胞亚群识别分枝杆菌佐剂，海藻糖单菌酸。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-24 DOI: 10.1172/JCI185443

Yuki Sakai, Minori Asa, Mika Hirose, Wakana Kusuhara, Nagatoshi Fujiwara, Hiroto Tamashima, Takahiro Ikazaki, Shiori Oka, Kota Kuraba, Kentaro Tanaka, Takashi Yoshiyama, Masamichi Nagae, Yoshihiko Hoshino, Daisuke Motooka, Ildiko Van Rhijn, Xiuyuan Lu, Eri Ishikawa, D Branch Moody, Takayuki Kato, Shinsuke Inuki, Go Hirai, Sho Yamasaki

{"title":"A conserved human CD4+ T cell subset recognizing the mycobacterial adjuvant, trehalose monomycolate.","authors":"Yuki Sakai, Minori Asa, Mika Hirose, Wakana Kusuhara, Nagatoshi Fujiwara, Hiroto Tamashima, Takahiro Ikazaki, Shiori Oka, Kota Kuraba, Kentaro Tanaka, Takashi Yoshiyama, Masamichi Nagae, Yoshihiko Hoshino, Daisuke Motooka, Ildiko Van Rhijn, Xiuyuan Lu, Eri Ishikawa, D Branch Moody, Takayuki Kato, Shinsuke Inuki, Go Hirai, Sho Yamasaki","doi":"10.1172/JCI185443","DOIUrl":"https://doi.org/10.1172/JCI185443","url":null,"abstract":"Mycobacterium tuberculosis causes human tuberculosis. As mycobacteria are protected by thick lipid cell wall, humans have developed immune responses against diverse mycobacterial lipids. Most of these immunostimulatory lipids are known as adjuvants acting through innate immune receptors, such as C-type lectin receptors. Although a few mycobacterial lipid antigens activate unconventional T cells, antigenicity of most adjuvantic lipids are unknown. Here, we identified that trehalose monomycolate (TMM), an abundant mycobacterial adjuvant, activates human T cells bearing a unique ɑβTCR. This recognition was restricted by CD1b, a monomorphic antigen-presenting molecule conserved in primates but not mice. Single-cell TCR-RNA sequencing using newly established CD1b-TMM tetramers revealed that TMM-specific T cells are present as CD4+ effector memory T cells in the periphery of uninfected donors, but express IFNγ, TNF and anti-mycobacterial effectors upon TMM stimulation. TMM-specific T cells are detected in cord blood and PBMCs of non-BCG-vaccinated donors, but are expanded in active tuberculosis patients. A cryo-electron microscopy study of CD1b-TMM-TCR complexes revealed unique antigen recognition by conserved features of TCRs, positively-charged CDR3ɑ and long CDR3β regions. These results indicate that humans have a commonly-shared and pre-formed CD4+ T cell subset recognizing a typical mycobacterial adjuvant as an antigen. Furthermore, the dual role of TMM justifies reconsideration of the mechanism of action of adjuvants.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885437","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}

引用次数: 0

CRISPR/Cas9 screens identify LIG1 as a sensitizer of PARP inhibitors in castration-resistant prostate cancer. CRISPR/Cas9筛选发现，在去势抵抗性前列腺癌中，LIG1是PARP抑制剂的增敏剂。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-12-24 DOI: 10.1172/JCI179393

Giulia Fracassi, Francesca Lorenzin, Francesco Orlando, Ubaldo Gioia, Giacomo D'Amato, Arnau S Casaramona, Thomas Cantore, Davide Prandi, Frédéric R Santer, Helmut Klocker, Fabrizio d'Adda di Fagagna, Joaquin Mateo, Francesca Demichelis

{"title":"CRISPR/Cas9 screens identify LIG1 as a sensitizer of PARP inhibitors in castration-resistant prostate cancer.","authors":"Giulia Fracassi, Francesca Lorenzin, Francesco Orlando, Ubaldo Gioia, Giacomo D'Amato, Arnau S Casaramona, Thomas Cantore, Davide Prandi, Frédéric R Santer, Helmut Klocker, Fabrizio d'Adda di Fagagna, Joaquin Mateo, Francesca Demichelis","doi":"10.1172/JCI179393","DOIUrl":"10.1172/JCI179393","url":null,"abstract":"PARP inhibitors (PARPi) have received regulatory approval for the treatment of several tumors, including prostate cancer (PCa), and demonstrate remarkable results in the treatment of castration-resistant prostate cancer (CRPC) patients characterized by defects in homologous recombination repair (HRR) genes. Preclinical studies showed that DNA repair genes (DRG) other than HRR genes may have therapeutic value in the context of PARPi. To this end, we performed multiple CRISPR/Cas9 screens in PCa cell lines using a custom sgRNA library targeting DRG combined with PARPi treatment. We identified DNA ligase 1 (LIG1), essential meiotic structure-specific endonuclease 1 (EME1), and Fanconi anemia core complex associated protein 24 (FAAP24) losses as PARPi sensitizers and assessed their frequencies from 3% to 6% among CRPC patients. We showed that concomitant inactivation of LIG1 and PARP induced replication stress and DNA double-strand breaks, ultimately leading to apoptosis. This synthetic lethality (SL) is conserved across multiple tumor types (e.g., lung, breast, and colorectal), and its applicability might be extended to LIG1-functional tumors through a pharmacological combinatorial approach. Importantly, the sensitivity of LIG1-deficient cells to PARPi was confirmed in vivo. Altogether, our results argue for the relevance of determining the status of LIG1 and potentially other non-HRR DRG for CRPC patient stratification and provide evidence to expand their therapeutic options.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885629","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}

引用次数: 0