Cell Reports MedicinePub Date : 2025-05-20Epub Date: 2025-04-15DOI: 10.1016/j.xcrm.2025.102084
Xudong Han, Yichi Zhang, Jillian N Petrosky, Sarah Bald, Richard M Sherva, Adam Labadorf, Jonathan D Cherry, Jaeyoon Chung, Kurt Farrell, Bobak Abdolmohammadi, Shruti Durape, Brett M Martin, Joseph N Palmisano, John J Farrell, Victor E Alvarez, Bertrand R Huber, Brigid Dwyer, Daniel H Daneshvar, Kristen Dams-O'Connor, Gyungah R Jun, Kathryn L Lunetta, Lee E Goldstein, Douglas I Katz, Robert C Cantu, Martha E Shenton, Jeffrey L Cummings, Eric M Reiman, Robert A Stern, Michael L Alosco, Yorghos Tripodis, Lindsay A Farrer, Thor D Stein, John F Crary, Ann C McKee, Jesse Mez
{"title":"A structural haplotype in the 17q21.31 MAPT region is associated with increased risk for chronic traumatic encephalopathy endophenotypes.","authors":"Xudong Han, Yichi Zhang, Jillian N Petrosky, Sarah Bald, Richard M Sherva, Adam Labadorf, Jonathan D Cherry, Jaeyoon Chung, Kurt Farrell, Bobak Abdolmohammadi, Shruti Durape, Brett M Martin, Joseph N Palmisano, John J Farrell, Victor E Alvarez, Bertrand R Huber, Brigid Dwyer, Daniel H Daneshvar, Kristen Dams-O'Connor, Gyungah R Jun, Kathryn L Lunetta, Lee E Goldstein, Douglas I Katz, Robert C Cantu, Martha E Shenton, Jeffrey L Cummings, Eric M Reiman, Robert A Stern, Michael L Alosco, Yorghos Tripodis, Lindsay A Farrer, Thor D Stein, John F Crary, Ann C McKee, Jesse Mez","doi":"10.1016/j.xcrm.2025.102084","DOIUrl":"10.1016/j.xcrm.2025.102084","url":null,"abstract":"<p><p>Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. Genetic variation in the 17q21.31 region, containing microtubule-associated protein tau (MAPT), has been implicated in tauopathies but has not been investigated in CTE. The region includes a megabase-long inversion (H1/H2) and copy-number variations, including α, β, and γ segments, which can be characterized as nine segregating structural haplotypes. We leveraged array SNP data and a reference panel across the 17q21.31 region to impute structural haplotypes and test their association with CTE endophenotypes in 447 European ancestry brain donors with RHI exposure. The H1β1γ1 haplotype was significantly associated with dementia and semi-quantitative tau burden in multiple cortical and medial temporal regions commonly affected in CTE. H1β1γ1 differential expression analyses in dorsolateral frontal cortex implicated cis-acting genes and inflammatory pathways. Taken together, the H1β1γ1 haplotype may help explain CTE heterogeneity among those with similar RHI exposure.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102084"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954084","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}
Cell Reports MedicinePub Date : 2025-05-20Epub Date: 2025-04-17DOI: 10.1016/j.xcrm.2025.102085
William De Nardo, Olivia Lee, Yazmin Johari, Jacqueline Bayliss, Marcus Pensa, Paula M Miotto, Stacey N Keenan, Andrew Ryan, Amber Rucinski, Tessa M Svinos, Geraldine J Ooi, Wendy A Brown, William Kemp, Stuart K Roberts, Benjamin L Parker, Magdalene K Montgomery, Mark Larance, Paul R Burton, Matthew J Watt
{"title":"Integrated liver-secreted and plasma proteomics identify a predictive model that stratifies MASH.","authors":"William De Nardo, Olivia Lee, Yazmin Johari, Jacqueline Bayliss, Marcus Pensa, Paula M Miotto, Stacey N Keenan, Andrew Ryan, Amber Rucinski, Tessa M Svinos, Geraldine J Ooi, Wendy A Brown, William Kemp, Stuart K Roberts, Benjamin L Parker, Magdalene K Montgomery, Mark Larance, Paul R Burton, Matthew J Watt","doi":"10.1016/j.xcrm.2025.102085","DOIUrl":"10.1016/j.xcrm.2025.102085","url":null,"abstract":"<p><p>Obesity is a major risk factor for metabolic-associated steatotic liver disease (MASLD), which can progress to metabolic-associated steatohepatitis (MASH). There are no validated non-invasive tests to stratify persons with obesity with a greater risk for MASH. Herein, we assess plasma and liver from 266 obese individuals spanning the MASLD spectrum. Ninety-six human livers were precision-cut, and mass spectrometry-based proteomics identifies 3,333 proteins in the liver-secretion medium, of which 107 are differentially secreted in MASH compared with no pathology. The plasma proteome is markedly remodeled in MASH but is not different between patients with steatosis and no pathology. The APASHA model, comprising plasma apolipoprotein F (APOF), proprotein convertase subtilisin/kexin type 9 (PCSK9), afamin (AFM), S100 calcium-binding protein A6 (S100A6), HbA1c, and zinc-alpha-2-glycoprotein (AZGP1), stratifies MASH (area under receiver operating characteristic [AUROC] = 0.88). Our investigations detail the evolution of liver-secreted and plasma proteins with MASLD progression, providing a rich resource defining human liver-secreted proteins and creating a predictive model to stratify patients with obesity at risk of MASH.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102085"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983120","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}
Cell Reports MedicinePub Date : 2025-05-20Epub Date: 2025-05-07DOI: 10.1016/j.xcrm.2025.102126
Serena Silvano, Tiziana Napolitano, Magali Plaisant, Anette Sousa-De-Veiga, Hugo Fofo, Chaïma Ayachi, Benoit Allegrini, Samah Rekima, Estelle Pichery, Jérôme Becam, Valentin Lepage, Caroline Treins, Laura Etasse, Loan Tran, Julien Thévenet, Gianni Pasquetti, Julie Kerr-Conte, François Pattou, Paolo Botti, Arduino Arduini, Jacques Mizrahi, Benjamin Charles, Patrick Collombat
{"title":"RSPO1, a potent inducer of pancreatic β cell neogenesis.","authors":"Serena Silvano, Tiziana Napolitano, Magali Plaisant, Anette Sousa-De-Veiga, Hugo Fofo, Chaïma Ayachi, Benoit Allegrini, Samah Rekima, Estelle Pichery, Jérôme Becam, Valentin Lepage, Caroline Treins, Laura Etasse, Loan Tran, Julien Thévenet, Gianni Pasquetti, Julie Kerr-Conte, François Pattou, Paolo Botti, Arduino Arduini, Jacques Mizrahi, Benjamin Charles, Patrick Collombat","doi":"10.1016/j.xcrm.2025.102126","DOIUrl":"10.1016/j.xcrm.2025.102126","url":null,"abstract":"<p><p>Inducing the neogenesis of pancreatic insulin-producing β cells holds great promise for diabetes research. However, non-toxic compounds with such activities remain to be discovered. Herein, we report the identification of RSPO1, a key agonist of the Wnt/β-catenin pathway, as an inducer of β cell replication. Specifically, we provide evidence that RSPO1 promotes a significant increase in β cell neogenesis in vitro, ex vivo, and in vivo. Importantly, RSPO1 administration is sufficient to activate Wnt/β-catenin signaling in β cells and counter chemically induced or autoimmune-mediated diabetes. Similarly, an optimized analog of RSPO1, allowing for weekly administration, also prevents diabetes in vivo. Lastly, the treatment of transplanted human islets with RSPO1 induces a significant 2.78-fold increase in human β cell numbers in only 60 days, these cells being functional. Such activities of RSPO1 to promote β cell neogenesis could therefore represent an unprecedented hope in the continued search for diabetes alternative therapies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102126"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983990","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":"Integrative proteomic profiling of tumor and plasma extracellular vesicles identifies a diagnostic biomarker panel for colorectal cancer.","authors":"Jun Wang, Chen-Zheng Gu, Peng-Xiang Wang, Jing-Rong Xian, Hao Wang, An-Quan Shang, Yu-Chen Zhong, Wen-Jing Zheng, Jian-Wen Cheng, Wen-Jing Yang, Jian Zhou, Jia Fan, Wei Guo, Xin-Rong Yang, Hao-Jie Lu","doi":"10.1016/j.xcrm.2025.102090","DOIUrl":"10.1016/j.xcrm.2025.102090","url":null,"abstract":"<p><p>The lack of reliable non-invasive biomarkers for early colorectal cancer (CRC) diagnosis underscores the need for improved diagnostic tools. Extracellular vesicles (EVs) have emerged as promising candidates for liquid-biopsy-based cancer monitoring. Here, we propose a comprehensive workflow that integrates staged mass spectrometry (MS)-based discovery and verification with ELISA-based validation to identify EV protein biomarkers for CRC. Our approach, applied to 1,272 individuals, yields a machine learning model, ColonTrack, incorporating EV proteins HNRNPK, CTTN, and PSMC6. ColonTrack effectively distinguishes CRC from non-CRC cases and identifies early-stage CRC with high accuracy (combined area under the curve [AUC] >0.97, sensitivity ∼0.94, specificity ∼0.93). Our analysis of EV protein profiles from tissue and plasma demonstrates ColonTrack's potential as a robust non-invasive biomarker panel for CRC diagnosis and early detection.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102090"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986224","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":"Co-targeting BMI1 and MYC to eliminate cancer stem cells in squamous cell carcinoma.","authors":"Zhen Qin, Shuo Liu, Yunfei Zheng, Yujia Wang, Yiwen Chen, Xin Peng, Lingfei Jia","doi":"10.1016/j.xcrm.2025.102077","DOIUrl":"10.1016/j.xcrm.2025.102077","url":null,"abstract":"<p><p>Bmi1<sup>+</sup> tumor cells act as cancer stem cells (CSCs) driving relapse and therapy resistance in head and neck squamous cell carcinoma (HNSCC). Although BMI1 inhibitors reduce CSCs, combined cisplatin treatment targeting non-stem tumor cells is more effective in eliminating CSCs. Non-stem tumor cells may revert to CSCs post-treatment. However, in vivo evidence and underlying mechanisms remain unclear. Here, we demonstrate that BMI1 inhibitors induce temporary tumor regression followed by relapse. Lineage tracing reveals that keratin 16-marked non-stem tumor cells revert to Bmi1<sup>+</sup> CSCs, which drive compensatory tumor growth after BMI1 targeting therapy. Mechanistically, BMI1 inhibitors activate DNA damage/nuclear factor κB (NF-κB) signaling and inflammatory cytokine secretion, subsequently stimulating myelocytomatosis viral oncogene homolog (MYC) expression in non-stem tumor cells to promote the reversion process. Genetic and pharmacological inhibition of MYC synergizes with BMI1 targeting, achieving sustained CSC eradication and relapse prevention. These findings provide insights into CSCs' plasticity and suggest dual BMI1/MYC blockade as an effective HNSCC treatment strategy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102077"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974493","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":"Targeting STING antagonism in HSV-1: A peptide-based strategy to restore antiviral immunity and suppress viral pathogenesis.","authors":"Jiangwei Song, Mengzhou Xue, Chunfu Zheng","doi":"10.1016/j.xcrm.2025.102088","DOIUrl":"10.1016/j.xcrm.2025.102088","url":null,"abstract":"<p><p>Herpes simplex virus 1 (HSV-1) poses significant threats to human health. Wang et al.<sup>1</sup> show that the HSV-1 protein directly antagonizes stimulator of interferon genes (STING). A designed peptide derived from STING can restore virus-subverted immunity and inhibit HSV-1 replication and pathogenesis in mice.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 5","pages":"102088"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119012","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}
Cell Reports MedicinePub Date : 2025-05-20Epub Date: 2025-05-01DOI: 10.1016/j.xcrm.2025.102096
Xiu-Feng Liu, Bin Song, Chang-Bin Sun, Qian Zhu, Jian-Hui Yue, Yu-Jing Liang, Jia He, Xi-Liang Zeng, Ye-Chi Qin, Qiu-Yan Chen, Hai-Qiang Mai, Xi Zhang, Jiang Li
{"title":"Tumor-infiltrated double-negative regulatory T cells predict outcome of T cell-based immunotherapy in nasopharyngeal carcinoma.","authors":"Xiu-Feng Liu, Bin Song, Chang-Bin Sun, Qian Zhu, Jian-Hui Yue, Yu-Jing Liang, Jia He, Xi-Liang Zeng, Ye-Chi Qin, Qiu-Yan Chen, Hai-Qiang Mai, Xi Zhang, Jiang Li","doi":"10.1016/j.xcrm.2025.102096","DOIUrl":"10.1016/j.xcrm.2025.102096","url":null,"abstract":"<p><p>Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has demonstrated clinical success in solid tumors. We analyze 47 TIL infusion products and 62 pretreatment tumor microenvironments (TMEs) from a randomized phase 2 clinical study of concurrent chemoradiotherapy plus TIL-ACT (NCT02421640). Using single-cell and bulk RNA sequencing along with flow cytometry, we identify 14 CD3<sup>+</sup> T cell clusters within 26 TIL infusion products: 11 CD3<sup>+</sup>CD8<sup>+</sup> TILs, 2 CD3<sup>+</sup>CD4<sup>+</sup> TILs, and 1 CD3<sup>+</sup>CD8<sup>-</sup>CD4<sup>-</sup> double-negative (DN) TIL. (DN) TILs, significantly associated with poor TIL-ACT outcomes, exhibit an activated regulatory T cell-like phenotype and include two CD56<sup>+</sup> and four CD56<sup>-</sup> subsets. Among them, CD56<sup>-</sup>KZF2<sup>+</sup> (DN) TILs are predominantly suppressive. (DN) TILs inhibit CD8<sup>+</sup> TIL expansion via Fas-FasL, transforming growth factor β (TGF-β), and interleukin (IL)-10 signaling. Distinct CD8<sup>+</sup> T subsets differentially impact on TIL-ACT outcomes, while 9 baseline TME gene signatures and 14 intracellular T cell genes hold prognostic value. Our findings identify predictive TIL subsets and biomarkers for TIL-ACT outcomes.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102096"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963085","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}
Cell Reports MedicinePub Date : 2025-05-20Epub Date: 2025-05-06DOI: 10.1016/j.xcrm.2025.102121
Yan Xu, James Chih-Hsin Yang, Yanqiu Zhao, Ludovic Doucet, Jianying Zhou, Yongsheng Wang, David Planchard, Yun Fan, Bo Jin, Zhigang Han, Laurent Greillier, Julien Mazieres, Meili Sun, Ying Hu, Xia Song, Cuimin Ding, Lin Wu, Kejing Tang, Li Liang, Yu Yao, Ying Cheng, Yong He, Bruna Pellini Ferreira, François Ghiringhelli, Enriqueta Felip, Joaquim Bosch-Barrera, Anwen Liu, Yan Yu, Xiaorong Dong, Junzhen Gao, D Ross Camidge, Weiqi Nian, Chengzhi Zhou, Runxiang Yang, Thomas John, Bo Gao, Lyudmila Bazhenova, Misako Nagasaka, Jianghong Wang, Xiubao Ren, Fei Xu, Wen Li, Dahai Zhao, Huijie Wang, Si Sun, Jian'an Huang, Xuehua Zhu, Li Zheng, Pasi A Jänne, Mengzhao Wang
{"title":"Genetic biomarker study of sunvozertinib for clinical prognosis and prediction in NSCLC with EGFR exon 20 insertion mutation.","authors":"Yan Xu, James Chih-Hsin Yang, Yanqiu Zhao, Ludovic Doucet, Jianying Zhou, Yongsheng Wang, David Planchard, Yun Fan, Bo Jin, Zhigang Han, Laurent Greillier, Julien Mazieres, Meili Sun, Ying Hu, Xia Song, Cuimin Ding, Lin Wu, Kejing Tang, Li Liang, Yu Yao, Ying Cheng, Yong He, Bruna Pellini Ferreira, François Ghiringhelli, Enriqueta Felip, Joaquim Bosch-Barrera, Anwen Liu, Yan Yu, Xiaorong Dong, Junzhen Gao, D Ross Camidge, Weiqi Nian, Chengzhi Zhou, Runxiang Yang, Thomas John, Bo Gao, Lyudmila Bazhenova, Misako Nagasaka, Jianghong Wang, Xiubao Ren, Fei Xu, Wen Li, Dahai Zhao, Huijie Wang, Si Sun, Jian'an Huang, Xuehua Zhu, Li Zheng, Pasi A Jänne, Mengzhao Wang","doi":"10.1016/j.xcrm.2025.102121","DOIUrl":"10.1016/j.xcrm.2025.102121","url":null,"abstract":"<p><p>This is a report of biomarker analysis for sunvozertinib, a leading epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting EGFR exon 20 insertion mutation (exon20ins) non-small cell lung cancer (NSCLC). There is a positive correlation between positive EGFR exon20ins in plasma circulating tumor DNA (ctDNA) and advanced disease. Shorter progression-free survival and lower objective response rate (45.8% vs. 68.0%) were observed in patients with positive EGFR exon20ins compared to those with negative status. Droplet digital PCR analysis showed that the EGFR exon20ins allele in ctDNA decreased over time in 85.7% of patients, with the earliest clearance occurred after 1 week of sunvozertinib treatment. Acquired EGFR C797S is identified as a potential on-target resistance mutation to sunvozertinib. Finally, efforts are undertaken to investigate therapeutic approaches that aim to overcome the putative acquired resistance to sunvozertinib.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102121"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966350","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}
Cell Reports MedicinePub Date : 2025-05-20Epub Date: 2025-05-08DOI: 10.1016/j.xcrm.2025.102127
James R Tribble, Vickie H Y Wong, Kelsey V Stuart, Glyn Chidlow, Alan Nicol, Anne Rombaut, Alessandro Rabiolo, Anh Hoang, Pei Ying Lee, Carola Rutigliani, Tim J Enz, Alessio Canovai, Emma Lardner, Gustav Stålhammar, Christine T O Nguyen, David F Garway-Heath, Robert J Casson, Anthony P Khawaja, Bang V Bui, Pete A Williams
{"title":"Dysfunctional one-carbon metabolism identifies vitamins B<sub>6</sub>, B<sub>9</sub>, B<sub>12</sub>, and choline as neuroprotective in glaucoma.","authors":"James R Tribble, Vickie H Y Wong, Kelsey V Stuart, Glyn Chidlow, Alan Nicol, Anne Rombaut, Alessandro Rabiolo, Anh Hoang, Pei Ying Lee, Carola Rutigliani, Tim J Enz, Alessio Canovai, Emma Lardner, Gustav Stålhammar, Christine T O Nguyen, David F Garway-Heath, Robert J Casson, Anthony P Khawaja, Bang V Bui, Pete A Williams","doi":"10.1016/j.xcrm.2025.102127","DOIUrl":"10.1016/j.xcrm.2025.102127","url":null,"abstract":"<p><p>Glaucoma, characterized by the loss of retinal ganglion cells (RGCs), is a leading cause of blindness for which there are no neuroprotective therapies. To explore observations of elevated homocysteine in glaucoma, we elevate vitreous homocysteine, which increases RGC death by 6% following ocular hypertension. Genetic association with higher homocysteine does not affect glaucoma-associated outcomes from the UK Biobank and serum homocysteine levels have no effect on glaucomatous visual field progression. This supports a hypothesis in which elevated homocysteine is a pathogenic, rather than causative, feature of glaucoma. Further exploration of homocysteine metabolism in glaucoma animal models demonstrates early and sustained dysregulation of genes involved in one-carbon metabolism and the interaction of essential cofactors and precursors (B<sub>6</sub>, B<sub>9</sub>, B<sub>12</sub>, and choline) in whole retina and optic nerve head and RGCs. Supplementing these provides neuroprotection in an acute model and prevents neurodegeneration and protects visual function in a chronic model of glaucoma.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102127"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974516","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}
Cell Reports MedicinePub Date : 2025-05-20Epub Date: 2025-05-08DOI: 10.1016/j.xcrm.2025.102120
David J Park, Min Thura, Vi K Chiu, Brian Vicuna, Koon Hwee Ang, Blanca Sanchez, Pei Ling Chia, Kam Yew Kuan, Jie Li, Ke Zhang, Wei Hui Zheng, Matthew Chau Hsien Ng, Qi Zeng
{"title":"The PRL3-zumab paradigm: A multicenter, single-dose-level phase 2 basket clinical trial design of an unconventional cancer immunotherapy.","authors":"David J Park, Min Thura, Vi K Chiu, Brian Vicuna, Koon Hwee Ang, Blanca Sanchez, Pei Ling Chia, Kam Yew Kuan, Jie Li, Ke Zhang, Wei Hui Zheng, Matthew Chau Hsien Ng, Qi Zeng","doi":"10.1016/j.xcrm.2025.102120","DOIUrl":"10.1016/j.xcrm.2025.102120","url":null,"abstract":"<p><p>This Food and Drug Administration (FDA)-approved phase 2 basket trial has three highlights: (1) PRL3, an intracellular oncotarget that is highly (∼80.6%) expressed in multiple cancers; (2) PRL3-zumab, the first-in-class humanized antibody (immunoglobulin G1 [IgG1]) with high affinity to PRL3 (K<sub>d</sub> = 7.57 pM); and (3) proof of concept: targeting intracellular oncoprotein with antibody-based therapy. A full analysis set (FAS, 51 patients received ≥1 dose) is used for pharmacokinetic and safety studies. Out of FAS, 20 patients are eligible to constitute the efficacy evaluable set (EES). To circumvent the heterogeneities from different individuals/cancers, we propose single evaluable patient single cohort (SEPSC) and apply comparison using double stringent/rigorous controls with (1) historical progression-free survival (PFS) and (2) prior lines' PFS within the same patients. PRL3-zumab shows longer PFS than prior line(s) of anti-PD-(L)1 therapies. PRL3-zumab demonstrates excellent safety and clear clinical benefits in late-stage IV solid cancer patients. This trial is registered at ClinicalTrials.gov as NCT04452955.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102120"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982194","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}
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