Cell Reports Medicine最新文献_第8页

A functional cardiac patch promotes cardiac repair by modulating the CCR2^- cardiac-resident macrophage niche and their cell crosstalk.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-02-18 Epub Date: 2025-01-28 DOI: 10.1016/j.xcrm.2025.101932

Chengbin Ding, Guofeng Tang, Yan Sun, Xiaodong Fu, Ye Tian, Jiamian Zhan, Songtao Zhang, Xianglong Xing, Jianing Liu, Xiaozhong Qiu, Leyu Wang

{"title":"A functional cardiac patch promotes cardiac repair by modulating the CCR2- cardiac-resident macrophage niche and their cell crosstalk.","authors":"Chengbin Ding, Guofeng Tang, Yan Sun, Xiaodong Fu, Ye Tian, Jiamian Zhan, Songtao Zhang, Xianglong Xing, Jianing Liu, Xiaozhong Qiu, Leyu Wang","doi":"10.1016/j.xcrm.2025.101932","DOIUrl":"10.1016/j.xcrm.2025.101932","url":null,"abstract":"C-C chemokine receptor type 2 (CCR2-) cardiac-resident macrophages (CCR2- cRMs) are known to promote cardiac repair after myocardial infarction (MI). However, the substantial depletion and slow recovery of CCR2- cRMs pose significant barriers in cardiac recovery. Here, we construct a functional conductive cardiac patch (CCP) that can provide exogenously elastic conductive microenvironment and induce endogenously reparative microenvironment mediated by CCR2- cRMs for MI repair. This CCP exhibits suitable mechanical properties, conductivity, and high water retention, reminiscent of natural myocardium, which can actively engage in modulating CCR2- cRM renewal and their cell crosstalk. The functional CCP can promote the expression of Connexin43 between CCR2- cRMs and cardiomyocytes (CMs) and regulate paracrine signaling to activate epicardial cell epithelial-to-mesenchymal transition (EMT) toward endothelial cells using rat and Wt1CreERT2 transgenic lineage tracing mice. Overall, this study provides a promising strategy to construct a synergistic reparative microenvironment for MI repair.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101932"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064196","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

An integrative multiparametric approach stratifies putative distinct phenotypes of blast phase chronic myelomonocytic leukemia.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-02-18 Epub Date: 2025-01-31 DOI: 10.1016/j.xcrm.2025.101933

Kristian Gurashi, Yu-Hung Wang, Fabio M R Amaral, Katherine Spence, Rachel Cant, Chi-Yuan Yao, Chien-Chin Lin, Christopher Wirth, David C Wedge, Guillermo Montalban-Bravo, Simona Colla, Hwei-Fang Tien, Tim C P Somervaille, Kiran Batta, Daniel H Wiseman

{"title":"An integrative multiparametric approach stratifies putative distinct phenotypes of blast phase chronic myelomonocytic leukemia.","authors":"Kristian Gurashi, Yu-Hung Wang, Fabio M R Amaral, Katherine Spence, Rachel Cant, Chi-Yuan Yao, Chien-Chin Lin, Christopher Wirth, David C Wedge, Guillermo Montalban-Bravo, Simona Colla, Hwei-Fang Tien, Tim C P Somervaille, Kiran Batta, Daniel H Wiseman","doi":"10.1016/j.xcrm.2025.101933","DOIUrl":"10.1016/j.xcrm.2025.101933","url":null,"abstract":"Approximately 30% of patients with chronic myelomonocytic leukemia (CMML) undergo transformation to a chemo-refractory blastic phase (BP-CMML). Seeking novel therapeutic approaches, we profiled blast transcriptomes from 42 BP-CMMLs, observing extensive transcriptional heterogeneity and poor alignment to current acute myeloid leukemia (AML) classifications. BP-CMMLs display distinctive transcriptomic profiles, including enrichment for quiescence and variability in drug response signatures. Integrating clinical, immunophenotype, and transcriptome parameters, Random Forest unsupervised clustering distinguishes immature and mature subtypes characterized by differential expression of transcriptional modules, oncogenes, apoptotic regulators, and patterns of surface marker expression. Subtypes differ in predicted response to AML drugs, validated ex vivo in primary samples. Iteratively refined stratification resolves a classification structure comprising five subtypes along a maturation spectrum, predictive of response to novel agents including consistent patterns for receptor tyrosine kinase (RTK), cyclin-dependent kinase (CDK), mechanistic target of rapamycin (MTOR), and mitogen-activated protein kinase (MAPK) inhibitors. Finally, we generate a prototype decision tree to stratify BP-CMML with high specificity and sensitivity, requiring validation but with potential clinical applicability to guide personalized drug selection for improved outcomes.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101933"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073936","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 genome-wide association study identified PRKCB as a causal gene and therapeutic target for Mycobacterium avium complex disease.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-02-18 Epub Date: 2025-01-22 DOI: 10.1016/j.xcrm.2024.101923

Ruijuan Zheng, Zhiqiang Li, Weijun Fang, Hai Lou, Feng Liu, Qin Sun, Xiang Shi, Hua Liu, Qing Chen, Xiaona Shen, Lan Yao, Liru Guan, Jianxia Chen, Yingzhou Xie, Yifan Yang, Hua Yang, Ling Wang, Lianhua Qin, Xiaochen Huang, Jie Wang, Zhonghua Liu, Haipeng Liu, Baoxue Ge, Jinfu Xu, Wei Sha

{"title":"A genome-wide association study identified PRKCB as a causal gene and therapeutic target for Mycobacterium avium complex disease.","authors":"Ruijuan Zheng, Zhiqiang Li, Weijun Fang, Hai Lou, Feng Liu, Qin Sun, Xiang Shi, Hua Liu, Qing Chen, Xiaona Shen, Lan Yao, Liru Guan, Jianxia Chen, Yingzhou Xie, Yifan Yang, Hua Yang, Ling Wang, Lianhua Qin, Xiaochen Huang, Jie Wang, Zhonghua Liu, Haipeng Liu, Baoxue Ge, Jinfu Xu, Wei Sha","doi":"10.1016/j.xcrm.2024.101923","DOIUrl":"10.1016/j.xcrm.2024.101923","url":null,"abstract":"Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is a chronic progressive lung disease that is increasing in incidence. Host genetic factors are associated with NTM-PD susceptibility. However, the heritability of NTM-PD is not well understood. Here, we perform a two-stage genome-wide association study (GWAS) and discover a susceptibility locus at 16p21 associated with NTM-PD, especially with pulmonary Mycobacterium avium complex (MAC) disease. As the lead variant, rs194800 C allele augments protein kinase C beta (PRKCB) gene expression and associates with severer NTM-PD. The functional studies show that PRKCB exacerbates M. avium infection and promotes intracellular survival of M. avium in macrophages by inhibiting phagosomal acidification. Mechanistically, PRKCB interacts with subunit G of the vacuolar-H+-ATPase (V-ATPase) and vacuolar protein sorting-associated protein 16 homolog (VPS16), blocking the fusion between lysosomes and mycobacterial phagosomes. PRKCB inhibitor has therapeutic potential against M. avium infection. These findings provide insights into the genetic etiology of NTM-PD and highlight PRKCB as an attractive target for host-directed therapy of MAC disease.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101923"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028057","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

Disrupting AGR2/IGF1 paracrine and reciprocal signaling for pancreatic cancer therapy.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-02-18 Epub Date: 2025-02-05 DOI: 10.1016/j.xcrm.2024.101927

Hongzhen Li, Zhiheng Zhang, Zhao Shi, Siqi Zhou, Shuang Nie, Yuanyuan Yu, Lingling Zhang, Yifeng Sun, Chao Fang, Jingxiong Hu, Yiqi Niu, Kathleen Schuck, Lei Wang, Kuirong Jiang, Zipeng Lu, Christoph Kahlert, Susanne Roth, Martin Loos, Ingrid Herr, Yoshiaki Sunami, Jörg Kleeff, Helmut Friess, Maximilian Reichert, Zahra Dantes, Xiaoping Zou, Christoph W Michalski, Shanshan Shen, Bo Kong

{"title":"Disrupting AGR2/IGF1 paracrine and reciprocal signaling for pancreatic cancer therapy.","authors":"Hongzhen Li, Zhiheng Zhang, Zhao Shi, Siqi Zhou, Shuang Nie, Yuanyuan Yu, Lingling Zhang, Yifeng Sun, Chao Fang, Jingxiong Hu, Yiqi Niu, Kathleen Schuck, Lei Wang, Kuirong Jiang, Zipeng Lu, Christoph Kahlert, Susanne Roth, Martin Loos, Ingrid Herr, Yoshiaki Sunami, Jörg Kleeff, Helmut Friess, Maximilian Reichert, Zahra Dantes, Xiaoping Zou, Christoph W Michalski, Shanshan Shen, Bo Kong","doi":"10.1016/j.xcrm.2024.101927","DOIUrl":"10.1016/j.xcrm.2024.101927","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive and characterized by pronounced desmoplasia. PDAC cells communicate with cancer-associated fibroblasts (CAFs) in a paracrine/reciprocal manner, substantially promoting tumor growth and desmoplastic responses. This study highlights the critical role of anterior gradient 2 (AGR2), an endoplasmic reticulum protein disulfide isomerase, secreted by PDAC cells to activate CAFs via the Wnt signaling pathway. Activated CAFs, in turn, secrete insulin-like growth factor 1 (IGF1), which enhances AGR2 expression and secretion in PDAC cells through the IGF1 receptor (IGF1R)/c-JUN axis. Within PDAC cells, AGR2 acts as a thioredoxin, aiding the folding and cell surface presentation of IGF1R, essential for PDAC's response to CAF-derived IGF1. This reciprocal AGR2/IGF1 signaling loop intensifies desmoplasia, immunosuppression, and tumorigenesis, creating a harmful feedback loop. Targeting both pathways disrupts this interaction, reduces desmoplasia, and restores anti-tumor immunity in preclinical models, offering a promising therapeutic strategy against PDAC.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101927"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363602","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

Homologous recombination repair status in metastatic prostate cancer by next-generation sequencing and functional immunofluorescence.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-02-18 Epub Date: 2025-02-05 DOI: 10.1016/j.xcrm.2025.101937

Sara Arce-Gallego, Pablo Cresta Morgado, Luisa Delgado-Serrano, Sara Simonetti, Macarena Gonzalez, Paula Romero-Lozano, David Marmolejo, Rafael Morales-Barrera, Gisela Mir Arnau, Maria Eugenia Semidey, Daniel Aguilar, Sarai Cordoba-Terreros, Richard Mast, Matias de Albert, Jacques Planas, Mercè Cuadras, Xavier Maldonado, Cristina Suarez, Irene Casanova-Salas, Mariona Figols, Sara Cros, Alba Mas, Lara Nonell, Rodrigo Dienstmann, Paolo Nuciforo, Ana Vivancos, Alba Llop-Guevara, Joan Carles, Violeta Serra, Joaquin Mateo

{"title":"Homologous recombination repair status in metastatic prostate cancer by next-generation sequencing and functional immunofluorescence.","authors":"Sara Arce-Gallego, Pablo Cresta Morgado, Luisa Delgado-Serrano, Sara Simonetti, Macarena Gonzalez, Paula Romero-Lozano, David Marmolejo, Rafael Morales-Barrera, Gisela Mir Arnau, Maria Eugenia Semidey, Daniel Aguilar, Sarai Cordoba-Terreros, Richard Mast, Matias de Albert, Jacques Planas, Mercè Cuadras, Xavier Maldonado, Cristina Suarez, Irene Casanova-Salas, Mariona Figols, Sara Cros, Alba Mas, Lara Nonell, Rodrigo Dienstmann, Paolo Nuciforo, Ana Vivancos, Alba Llop-Guevara, Joan Carles, Violeta Serra, Joaquin Mateo","doi":"10.1016/j.xcrm.2025.101937","DOIUrl":"10.1016/j.xcrm.2025.101937","url":null,"abstract":"Metastatic prostate cancer (mPC) is enriched for homologous recombination repair (HRR) gene alterations, which have prognostic and predictive value. Routine clinical implementation of next-generation sequencing (NGS) is still limited. We investigated the association between genomic and functional loss of HRR, using NGS and RAD51 immunofluorescence (RAD51-IF) in 219 primary or metastatic biopsies from 187 patients with stage IV prostate cancer. NGS showed frequent genomic alterations in TP53 (40%), AR (15%), PTEN (14%), FOXA1 (12%), MYC (10%), BRCA2 (9%), ATM (8%), and BRCA1 (2%). We pursued RAD51-IF in 206 samples; of those, 139/206 (67%) were evaluable. 21% of samples had RAD51-low score compatible with HRR deficiency (HRD). RAD51-IF showed high sensitivity (71%) and specificity (86%) for BRCA1/2 alterations. Patients with RAD51-low scores experienced longer progression-free survival (PFS) on poly(ADP-ribose) polymerase inhibitors (PARPi) or platinum chemotherapy. RAD51-IF is feasible in routine clinical samples from patients with mPC and is associated with clinically relevant HRR gene alterations.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101937"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363770","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

An update on non-pharmacological interventions for pain relief.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-02-18 DOI: 10.1016/j.xcrm.2025.101940

Yang Wang, Rachel Aaron, Nadine Attal, Luana Colloca

{"title":"An update on non-pharmacological interventions for pain relief.","authors":"Yang Wang, Rachel Aaron, Nadine Attal, Luana Colloca","doi":"10.1016/j.xcrm.2025.101940","DOIUrl":"10.1016/j.xcrm.2025.101940","url":null,"abstract":"Chronic pain affects a substantial portion of the population, yet current treatments often fail to provide adequate relief. Non-pharmacological interventions, which target behaviors and brain processes underlying the experience of pain, hold promises in offering relief for people with chronic pain. This review consolidates the current knowledge concerning the efficacy of non-pharmacological interventions for chronic pain. We focus on psychological interventions (e.g., cognitive behavioral therapy-based interventions and emotion-based therapies) that use mental techniques and physical practices (e.g., exercise, massage, acupuncture, and yoga) that use body techniques to reduce pain. The efficacy of neuromodulation is also discussed. Given that placebo and expectation effects may enhance benefits for non-pharmacological interventions, we also discuss placebo interventions and expectation management practices. Finally, we describe digital therapeutics as an emerging approach for managing chronic pain. We argue that non-pharmacological interventions are critical adjunctive or stand-alone interventions for chronic pain conditions.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 2","pages":"101940"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457048","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

KRAS^G12D-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-02-18 DOI: 10.1016/j.xcrm.2025.101966

Xiangyan Jiang, Tao Wang, Bin Zhao, Haonan Sun, Yuman Dong, Yong Ma, Zhigang Li, Yuxia Wu, Keshen Wang, Xiaoying Guan, Bo Long, Long Qin, Wengui Shi, Lei Shi, Qichen He, Wenbo Liu, Mingdou Li, Lixia Xiao, Chengliang Zhou, Hui Sun, Jing Yang, Junhong Guan, Huinian Zhou, Zeyuan Yu, Zuoyi Jiao

{"title":"KRASG12D-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC.","authors":"Xiangyan Jiang, Tao Wang, Bin Zhao, Haonan Sun, Yuman Dong, Yong Ma, Zhigang Li, Yuxia Wu, Keshen Wang, Xiaoying Guan, Bo Long, Long Qin, Wengui Shi, Lei Shi, Qichen He, Wenbo Liu, Mingdou Li, Lixia Xiao, Chengliang Zhou, Hui Sun, Jing Yang, Junhong Guan, Huinian Zhou, Zeyuan Yu, Zuoyi Jiao","doi":"10.1016/j.xcrm.2025.101966","DOIUrl":"10.1016/j.xcrm.2025.101966","url":null,"abstract":"The KRASG12D inhibitor MRTX1133 shows the potential to revolutionize the treatment paradigm for pancreatic ductal adenocarcinoma (PDAC), yet presents challenges. Our findings indicate that KRASG12D remodels a pentose phosphate pathway (PPP)-dominant central carbon metabolism pattern, facilitating malignant progression and resistance to MRTX1133 in PDAC. Mechanistically, KRASG12D drives excessive degradation of p53 and glucose-6-phosphate dehydrogenase (G6PD)-mediated PPP reprogramming through retinoblastoma (Rb)/E2F1/p53 axis-regulated feedback loops that amplify ubiquitin-conjugating enzyme E2T (UBE2T) transcription. Genetic ablation or pharmacological inhibition of UBE2T significantly suppresses PDAC progression and potentiates MRTX1133 efficacy. Leveraging structure advantages of the UBE2T inhibitor pentagalloylglucose (PGG), we develop a self-assembling nano co-delivery system with F-127, PGG, and MRTX1133. This system enhances the efficacy of PGG and MRTX1133, achieving durable remissions (85% overall response rate) and long-term survival (100% progression-free survival) in patient-derived xenografts and spontaneous PDAC mice. This study reveals the role of KRASG12D-preferred PPP reprogramming in MRTX1133 resistance and proposes a potentially therapeutic strategy for KRASG12D-mutated PDAC.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 2","pages":"101966"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457067","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

Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity. 靶向甲羟戊酸途径增强NUAK1抑制诱导的免疫原性细胞死亡和抗肿瘤免疫。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-02-18 Epub Date: 2025-01-16 DOI: 10.1016/j.xcrm.2024.101913

Liming Gui, Kaiwen Chen, Jingjing Yan, Ping Chen, Wei-Qiang Gao, Bin Ma

{"title":"Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity.","authors":"Liming Gui, Kaiwen Chen, Jingjing Yan, Ping Chen, Wei-Qiang Gao, Bin Ma","doi":"10.1016/j.xcrm.2024.101913","DOIUrl":"10.1016/j.xcrm.2024.101913","url":null,"abstract":"The induction of immunogenic cell death (ICD) impedes tumor progression via both tumor cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, ICD-targeted therapy remains to be explored and optimized. Through kinome-wide CRISPR-Cas9 screen, NUAK family SNF1-like kinase 1 (NUAK1) is identified as a potential target. The ICD-provoking effect of NUAK1 inhibition depends on the production of reactive oxygen species (ROS), consequent to the downregulation of nuclear factor erythroid 2-related factor 2 (NRF2)-mediated antioxidant gene expression. Moreover, the mevalonate pathway/cholesterol biosynthesis, activated by spliced form of X-box binding protein 1 (XBP1s) downstream of ICD-induced endoplasmic reticulum (ER) stress, functions as a negative feedback mechanism. Targeting the mevalonate pathway with CRISPR knockout or the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor simvastatin amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol dampens ROS and ICD, and therefore also dampens tumor suppression. The combination of NUAK1 inhibitor and statin enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate-cholesterol pathway in conjunction with ICD-targeted immunotherapy.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101913"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000992","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

Bioengineering of a human iPSC-derived vascularized endocrine pancreas for type 1 diabetes.

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-02-18 Epub Date: 2025-02-07 DOI: 10.1016/j.xcrm.2025.101938

Francesco Campo, Alessia Neroni, Cataldo Pignatelli, Silvia Pellegrini, Ilaria Marzinotto, Libera Valla, Fabio Manenti, Martina Policardi, Vito Lampasona, Lorenzo Piemonti, Antonio Citro

{"title":"Bioengineering of a human iPSC-derived vascularized endocrine pancreas for type 1 diabetes.","authors":"Francesco Campo, Alessia Neroni, Cataldo Pignatelli, Silvia Pellegrini, Ilaria Marzinotto, Libera Valla, Fabio Manenti, Martina Policardi, Vito Lampasona, Lorenzo Piemonti, Antonio Citro","doi":"10.1016/j.xcrm.2025.101938","DOIUrl":"10.1016/j.xcrm.2025.101938","url":null,"abstract":"Intrahepatic islet transplantation in patients with type 1 diabetes is limited by donor availability and lack of engraftment. Alternative β cell sources and transplantation sites are needed. We demonstrate the feasibility to repurpose a decellularized lung as an endocrine pancreas for β cell replacement. We bioengineer an induced pluripotent stem cell (iPSC)-based version, fabricating a human iPSC-based vascularized endocrine pancreas (iVEP) using iPSC-derived β cells (iPSC-derived islets [SC-islets]) and endothelial cells (iECs). SC-islets and iECs are aggregated into vascularized iβ spheroids (ViβeSs), and over 7 days of culture, spheroids integrate into the bioengineered vasculature, generating a functional, perfusable human endocrine organ. In vitro, the vascularized extracellular matrix (ECM) sustained SC-islet engraftment and survival with a significantly preserved β cell mass and a physiologic insulin release. In vivo, iVEP restores normoglycemia in diabetic NSG mice. We report a human iVEP providing a controlled in vitro insulin-secreting phenotype and in vivo function.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101938"},"PeriodicalIF":11.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373736","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

How close are we to a cAMP- and cGMP-theory-based pharmacological therapy for fragile X syndrome?

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2025-02-18 DOI: 10.1016/j.xcrm.2025.101972

Barbara Bardoni, Carole Gwizdek, Thomas Maurin

引用次数: 0