Pub Date : 2026-01-07DOI: 10.1126/scitranslmed.adt5626
Stephanus T. Malherbe, Ray Y. Chen, Xiang Yu, Bronwyn Smith, Xin Liu, Jingcai Gao, Andreas H. Diacon, Rodney Dawson, Michele Tameris, Hong Zhu, Yahong Qu, Hongjian Jin, Shouguo Pan, Lori E. Dodd, Jing Wang, Lisa C. Goldfeder, Ying Cai, Kriti Arora, Joel Vincent, Kim Narunsky, Keboile Serole, Rene T. Goliath, Laylah Da Costa, Arshad Taliep, Saalikha Aziz, Remy Daroowala, Friedrich Thienemann, Sandra Mukasa, Richard Court, Bianca Sossen, Petri Ahlers, Simon C. Mendelsohn, Lisa White, Aurélie Gouel, Chuen-Yen Lau, Samy Hassan, Lili Liang, Hongfei Duan, Gita K. Moghaddam, Praveen Paripati, Saher Lahouar, Michael Harris, Kurt Wollenberg, Brendan Jeffrey, Mike Tartakovsky, Alex Rosenthal, Michael Duvenhage, Derek T. Armstrong, Taeksun Song, Jill Winter, Qian Gao, Laura E. Via, Robert J. Wilkinson, Gerhard Walzl, Clifton E. Barry III
Six months of drug treatment is standard of care for drug-sensitive pulmonary tuberculosis (TB). Understanding the factors determining the length of treatment required for durable cure would allow individualization of treatment durations. We conducted a prospective, randomized, controlled noninferiority trial (PredictTB) of 4 versus 6 months of chemotherapy in patients with pulmonary TB in South Africa and China. Seven hundred and four participants with newly diagnosed, drug-sensitive TB were enrolled and stratified on the basis of radiographic disease characteristics assessed by FDG PET/CT imaging. Participants with less extensive disease (n = 273) were randomly assigned at week 16 to complete therapy after 4 months or continue receiving treatment for 6 months. This study was stopped early after an interim analysis revealed that patients assigned to the 4-month treatment arm had a higher risk of relapse. Among participants who received 4 months of chemotherapy, 17 of 141 (12.1%) experienced TB-specific unfavorable outcomes compared with only 2 of 132 (1.5%) who completed 6 months of treatment. In the nonrandomized arm that included participants with more extensive disease, only 8 of 248 (3.2%) experienced unfavorable outcomes. Total lung cavity volume and lesion glycolysis at week 16 were associated with the risk of unfavorable outcomes. PET/CT imaging at TB recurrence showed that bacteriological relapses predominantly occurred in active cavities originally present at baseline. Subsequent post hoc automated segmentation of serial PET/CT scans combined with machine learning enabled the classification of participants according to their likelihood of relapse.
{"title":"Clinical testing of drug treatment shortening in patients with TB using PET/CT imaging of lung lesions","authors":"Stephanus T. Malherbe, Ray Y. Chen, Xiang Yu, Bronwyn Smith, Xin Liu, Jingcai Gao, Andreas H. Diacon, Rodney Dawson, Michele Tameris, Hong Zhu, Yahong Qu, Hongjian Jin, Shouguo Pan, Lori E. Dodd, Jing Wang, Lisa C. Goldfeder, Ying Cai, Kriti Arora, Joel Vincent, Kim Narunsky, Keboile Serole, Rene T. Goliath, Laylah Da Costa, Arshad Taliep, Saalikha Aziz, Remy Daroowala, Friedrich Thienemann, Sandra Mukasa, Richard Court, Bianca Sossen, Petri Ahlers, Simon C. Mendelsohn, Lisa White, Aurélie Gouel, Chuen-Yen Lau, Samy Hassan, Lili Liang, Hongfei Duan, Gita K. Moghaddam, Praveen Paripati, Saher Lahouar, Michael Harris, Kurt Wollenberg, Brendan Jeffrey, Mike Tartakovsky, Alex Rosenthal, Michael Duvenhage, Derek T. Armstrong, Taeksun Song, Jill Winter, Qian Gao, Laura E. Via, Robert J. Wilkinson, Gerhard Walzl, Clifton E. Barry III","doi":"10.1126/scitranslmed.adt5626","DOIUrl":"10.1126/scitranslmed.adt5626","url":null,"abstract":"<div >Six months of drug treatment is standard of care for drug-sensitive pulmonary tuberculosis (TB). Understanding the factors determining the length of treatment required for durable cure would allow individualization of treatment durations. We conducted a prospective, randomized, controlled noninferiority trial (PredictTB) of 4 versus 6 months of chemotherapy in patients with pulmonary TB in South Africa and China. Seven hundred and four participants with newly diagnosed, drug-sensitive TB were enrolled and stratified on the basis of radiographic disease characteristics assessed by FDG PET/CT imaging. Participants with less extensive disease (<i>n</i> = 273) were randomly assigned at week 16 to complete therapy after 4 months or continue receiving treatment for 6 months. This study was stopped early after an interim analysis revealed that patients assigned to the 4-month treatment arm had a higher risk of relapse. Among participants who received 4 months of chemotherapy, 17 of 141 (12.1%) experienced TB-specific unfavorable outcomes compared with only 2 of 132 (1.5%) who completed 6 months of treatment. In the nonrandomized arm that included participants with more extensive disease, only 8 of 248 (3.2%) experienced unfavorable outcomes. Total lung cavity volume and lesion glycolysis at week 16 were associated with the risk of unfavorable outcomes. PET/CT imaging at TB recurrence showed that bacteriological relapses predominantly occurred in active cavities originally present at baseline. Subsequent post hoc automated segmentation of serial PET/CT scans combined with machine learning enabled the classification of participants according to their likelihood of relapse.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 831","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908258","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}
Pub Date : 2026-01-07DOI: 10.1126/scitranslmed.adw9930
Yuri Ciervo, Pietro Rigoni, Linda Bucciarelli, Martina Lombi, Federico Pratesi, Nadia Bologna, Massimo Accardo, Chiara Recchi, Rita Milazzo, Valentina Poletti, Alessandra Biffi
Autologous hematopoietic stem/progenitor cell (HSC)–gene therapy (GT) represents a promising therapeutic option for progranulin (PGRN)–related neurodegenerative diseases due to mutations in the PGRN encoding gene (GRN), such as frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis 11 (CLN11). These conditions are characterized by a deficiency in PGRN, have no cure, and represent an unmet medical need. We report on the efficacy and feasibility of an HSC GT approach that used a lentiviral vector encoding the human GRN complementary DNA to transduce HSCs that then were transplanted into a Grn−/− mouse model, which mirrors both FTD and CLN11 phenotypes. Two promoters, one with medium-low strength (HLA-DRA gene–based promoter regulated by inflammation) and the other with medium-high strength [ubiquitous phosphoglycerate kinase (PGK) promoter], were compared for HSC transduction. Moreover, intravenous and intracerebroventricular HSC administration were compared. Under all tested conditions, a partial reconstitution of PGRN production by microglia-like cells (MLCs) derived from genetically corrected Grn−/− HSCs was observed, which uniformly led to a correction of lipid accumulation, reduced gliosis, and improved social recognition in Grn−/− mice. Therapeutic effects were similarly achieved with either of the promoters and administration routes and particularly also when the PGRN-expressing cells and their MLC progeny had engrafted exclusively in the central nervous system (CNS) after intracerebroventricular transplantation. These findings suggest that a durable yet modest restoration of PGRN expression in the CNS is sufficient to correct pathology.
{"title":"Restoration of progranulin by engineered hematopoietic stem cell–derived microglia corrects phenotypes of granulin knockout mice","authors":"Yuri Ciervo, Pietro Rigoni, Linda Bucciarelli, Martina Lombi, Federico Pratesi, Nadia Bologna, Massimo Accardo, Chiara Recchi, Rita Milazzo, Valentina Poletti, Alessandra Biffi","doi":"10.1126/scitranslmed.adw9930","DOIUrl":"10.1126/scitranslmed.adw9930","url":null,"abstract":"<div >Autologous hematopoietic stem/progenitor cell (HSC)–gene therapy (GT) represents a promising therapeutic option for progranulin (PGRN)–related neurodegenerative diseases due to mutations in the PGRN encoding gene (<i>GRN</i>), such as frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis 11 (CLN11). These conditions are characterized by a deficiency in PGRN, have no cure, and represent an unmet medical need. We report on the efficacy and feasibility of an HSC GT approach that used a lentiviral vector encoding the human <i>GRN</i> complementary DNA to transduce HSCs that then were transplanted into a <i>Grn</i><sup>−/−</sup> mouse model, which mirrors both FTD and CLN11 phenotypes. Two promoters, one with medium-low strength (<i>HLA-DRA</i> gene–based promoter regulated by inflammation) and the other with medium-high strength [ubiquitous phosphoglycerate kinase (PGK) promoter], were compared for HSC transduction. Moreover, intravenous and intracerebroventricular HSC administration were compared. Under all tested conditions, a partial reconstitution of PGRN production by microglia-like cells (MLCs) derived from genetically corrected <i>Grn</i><sup>−/−</sup> HSCs was observed, which uniformly led to a correction of lipid accumulation, reduced gliosis, and improved social recognition in <i>Grn</i><sup>−/−</sup> mice. Therapeutic effects were similarly achieved with either of the promoters and administration routes and particularly also when the PGRN-expressing cells and their MLC progeny had engrafted exclusively in the central nervous system (CNS) after intracerebroventricular transplantation. These findings suggest that a durable yet modest restoration of PGRN expression in the CNS is sufficient to correct pathology.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 831","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908259","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}
Pub Date : 2026-01-07DOI: 10.1126/scitranslmed.adt1228
Greta Moschini, Archana G. Mohanan, Izabella S. Niewczas, Diane E. Taylor, Patrick K. Jaeger, Guillermo Turiel, Amro A. Hussien, Stefania L. Wunderli, Olivia Baumberger, Maja Wolleb, Florence Marti, Barbara Niederoest, Maja Bollhalder, Raphaela Ardicoglu, Nathalie Tisch, Evi Masschelein, Shauni Loopmans, Sarah Morice, Santiago Ardiles, Lieke Mous, Bart Ghesquière, Matthew R. Aronoff, Monika Hilbe, Farah Selman, Karl Wieser, Sandro F. Fucentese, Fabian S. Passini, Ulrich Blache, Didier Surdez, Helma Wennemers, Dirk Elewaut, Jonathan Clark, Katrien De Bock, Jess G. Snedeker
Tendons are sparsely vascularized connective tissues that link muscles to bones, withstanding some of the highest mechanical stresses in the body. Mechanical overloading and tissue hypervascularity are implicated in tendinopathy, a common musculoskeletal disorder, yet their mechanistic roles remain unclear. Here, we identify hypoxia-inducible factor 1α (HIF1α) as not only a marker but also a driver of tendinopathy. Histological and multiomics evaluation of human tendinopathic samples revealed extensive extracellular matrix remodeling, including pathological collagen cross-linking coinciding with active hypoxic signaling. Hypothesizing a causal contribution of hypoxia signaling, we generated mice with tenocyte-targeted deletions of the von Hippel–Lindau (Vhl) gene, which controls hypoxia signaling by regulating HIFα degradation. Vhl inactivation was sufficient to induce pathological hallmarks of tendinopathy, such as collagen matrix disorganization, cross-linking, altered mechanics, and neurovascular ingrowth. This phenotype was HIF1α dependent given that codeleting HIF1α rescued tendon morphology and mechanics. Moreover, deleting vascular endothelial growth factor A (Vegfa) alongside VHL effectively suppressed neovascularization but failed to rescue extracellular matrix abnormalities or restore mechanical function, emphasizing a direct role of HIF1α in driving tendon disease independently of angiogenesis. Mechanistically, we found that HIF1α activation was strain dependent in primary cultured human tendon cells and induced by mechanical overload in murine tendon explants. Furthermore, genetically removing Hif1α from tenocytes prevented aberrant tendon remodeling in response to chronic overload. These findings position HIF1α signaling as a central driver of tendinopathy that acts through a maladaptive tissue response to chronic overload, providing mechanistic insights that could be leveraged for therapeutic approaches.
{"title":"HIF1α gates tendon response to overload and drives tendinopathy independently of vascular recruitment","authors":"Greta Moschini, Archana G. Mohanan, Izabella S. Niewczas, Diane E. Taylor, Patrick K. Jaeger, Guillermo Turiel, Amro A. Hussien, Stefania L. Wunderli, Olivia Baumberger, Maja Wolleb, Florence Marti, Barbara Niederoest, Maja Bollhalder, Raphaela Ardicoglu, Nathalie Tisch, Evi Masschelein, Shauni Loopmans, Sarah Morice, Santiago Ardiles, Lieke Mous, Bart Ghesquière, Matthew R. Aronoff, Monika Hilbe, Farah Selman, Karl Wieser, Sandro F. Fucentese, Fabian S. Passini, Ulrich Blache, Didier Surdez, Helma Wennemers, Dirk Elewaut, Jonathan Clark, Katrien De Bock, Jess G. Snedeker","doi":"10.1126/scitranslmed.adt1228","DOIUrl":"10.1126/scitranslmed.adt1228","url":null,"abstract":"<div >Tendons are sparsely vascularized connective tissues that link muscles to bones, withstanding some of the highest mechanical stresses in the body. Mechanical overloading and tissue hypervascularity are implicated in tendinopathy, a common musculoskeletal disorder, yet their mechanistic roles remain unclear. Here, we identify hypoxia-inducible factor 1α (HIF1α) as not only a marker but also a driver of tendinopathy. Histological and multiomics evaluation of human tendinopathic samples revealed extensive extracellular matrix remodeling, including pathological collagen cross-linking coinciding with active hypoxic signaling. Hypothesizing a causal contribution of hypoxia signaling, we generated mice with tenocyte-targeted deletions of the von Hippel–Lindau (<i>Vhl</i>) gene, which controls hypoxia signaling by regulating HIFα degradation. <i>Vhl</i> inactivation was sufficient to induce pathological hallmarks of tendinopathy, such as collagen matrix disorganization, cross-linking, altered mechanics, and neurovascular ingrowth. This phenotype was HIF1α dependent given that codeleting HIF1α rescued tendon morphology and mechanics. Moreover, deleting vascular endothelial growth factor A (<i>Vegfa</i>) alongside VHL effectively suppressed neovascularization but failed to rescue extracellular matrix abnormalities or restore mechanical function, emphasizing a direct role of HIF1α in driving tendon disease independently of angiogenesis. Mechanistically, we found that HIF1α activation was strain dependent in primary cultured human tendon cells and induced by mechanical overload in murine tendon explants. Furthermore, genetically removing <i>Hif1</i>α from tenocytes prevented aberrant tendon remodeling in response to chronic overload. These findings position HIF1α signaling as a central driver of tendinopathy that acts through a maladaptive tissue response to chronic overload, providing mechanistic insights that could be leveraged for therapeutic approaches.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 831","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908261","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}
Pub Date : 2026-01-07DOI: 10.1126/scitranslmed.adx2876
Felix Polten, Mircea-Andrei Sandu, Jan Faix, Jan Hegermann, Nils Kriedemann, Robert Zweigerdt, Thomas Thum, Johann Bauersachs, Hans W. Niessen, Andrew L. Koenig, Kory J. Lavine, Andreas Pich, Yong Wang, Marc R. Reboll, Mortimer Korf-Klingebiel, Kai C. Wollert
Tissue repair after myocardial infarction entails a vigorous angiogenic response that mitigates scarring and worsening of heart function. Angiogenesis in the infarct wound is guided by incompletely defined myeloid cell–endothelial cell interactions. Here, we identify the 75–amino acid microprotein BRICK1 (BRK1) as an indispensable driver of postinfarction angiogenesis in a mouse model of reperfused myocardial infarction. We show that BRK1 is preferentially expressed by myeloid cells and translocates to the extracellular space after myocardial infarction in mice and humans. As a subunit of the intracellular actin-regulatory WAVE complex, BRK1 was not previously known to function outside the cell. We find that BRK1 is not actively secreted but released during myeloid cell death. Cre-loxP–driven myeloid cell–selective genetic deletion of Brk1 or antibody-mediated neutralization of extracellular BRK1 impaired microvessel formation in the infarct border zone and resulted in severe postinfarction heart failure in mice. Conversely, treatment with recombinant BRK1 preserved heart function in infarcted mice. Mechanistically, BRK1 induced an angiogenic phenotype in human cardiac endothelial cells by signaling via the small GTPase Ras-related protein Rap-1 and mitogen-activated protein kinases 1 and 3 to promote retinoblastoma protein hyperphosphorylation and E2F transcription factor activation. BRK1 thus emerges as an angiogenic factor linking myeloid cell death to ischemic tissue repair, potentially enabling a protein-based therapy for myocardial infarction.
{"title":"Extracellular BRICK1 drives heart repair after myocardial infarction in mice","authors":"Felix Polten, Mircea-Andrei Sandu, Jan Faix, Jan Hegermann, Nils Kriedemann, Robert Zweigerdt, Thomas Thum, Johann Bauersachs, Hans W. Niessen, Andrew L. Koenig, Kory J. Lavine, Andreas Pich, Yong Wang, Marc R. Reboll, Mortimer Korf-Klingebiel, Kai C. Wollert","doi":"10.1126/scitranslmed.adx2876","DOIUrl":"10.1126/scitranslmed.adx2876","url":null,"abstract":"<div >Tissue repair after myocardial infarction entails a vigorous angiogenic response that mitigates scarring and worsening of heart function. Angiogenesis in the infarct wound is guided by incompletely defined myeloid cell–endothelial cell interactions. Here, we identify the 75–amino acid microprotein BRICK1 (BRK1) as an indispensable driver of postinfarction angiogenesis in a mouse model of reperfused myocardial infarction. We show that BRK1 is preferentially expressed by myeloid cells and translocates to the extracellular space after myocardial infarction in mice and humans. As a subunit of the intracellular actin-regulatory WAVE complex, BRK1 was not previously known to function outside the cell. We find that BRK1 is not actively secreted but released during myeloid cell death. Cre-<i>loxP</i>–driven myeloid cell–selective genetic deletion of <i>Brk1</i> or antibody-mediated neutralization of extracellular BRK1 impaired microvessel formation in the infarct border zone and resulted in severe postinfarction heart failure in mice. Conversely, treatment with recombinant BRK1 preserved heart function in infarcted mice. Mechanistically, BRK1 induced an angiogenic phenotype in human cardiac endothelial cells by signaling via the small GTPase Ras-related protein Rap-1 and mitogen-activated protein kinases 1 and 3 to promote retinoblastoma protein hyperphosphorylation and E2F transcription factor activation. BRK1 thus emerges as an angiogenic factor linking myeloid cell death to ischemic tissue repair, potentially enabling a protein-based therapy for myocardial infarction.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 831","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908263","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}
Pub Date : 2026-01-07DOI: 10.1126/scitranslmed.aed6475
Manish C. Choudhary, Jonathan Z. Li
HIV can take several mutational pathways to become resistant to lenacapavir, each with distinct resistance and fitness profiles (Pennetzdorfer et al., this issue).
{"title":"When HIV pays the price: Fitness costs behind lenacapavir resistance","authors":"Manish C. Choudhary, Jonathan Z. Li","doi":"10.1126/scitranslmed.aed6475","DOIUrl":"10.1126/scitranslmed.aed6475","url":null,"abstract":"<div >HIV can take several mutational pathways to become resistant to lenacapavir, each with distinct resistance and fitness profiles (Pennetzdorfer <i>et al.</i>, this issue).</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 831","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908257","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}
Brain stimulation therapies have been increasingly applied to treat patients with drug-resistant epilepsy or other neuropsychiatric disorders, but identifying effective stimulation targets appropriate for individual patients remains challenging. Using intracranial electrophysiological recordings, we found that fast ripple (FR) activity was tightly correlated with the severity of consciousness impairment during seizures in patients with drug-resistant, consciousness-staged epilepsy. Epileptic network analysis based on FR coincidence across brain regions revealed hubs of ictal FR activity, defined as highly connected nodes, specific to individual patients. A small, exploratory study on eight patients with drug-resistant epilepsy showed that stimulating these hubs reduced FRs, ameliorated consciousness impairments, and reduced seizures during a poststimulation time window of up to 11 days. Moreover, FR hub stimulation showed a lower risk of evoking seizures than stimulating seizure onset zones, a now approved treatment option. These results suggest a potentially safe and effective strategy to alleviate epileptic seizures by stimulating patient-specific FR network hubs.
{"title":"Targeting brain hubs of ictal fast ripple activity to reduce seizures in patients with drug-resistant epilepsy","authors":"Shanshan Liang, Lukang Wang, Kaifeng Shen, Zhiji Wang, Xin Zheng, Qingtian Duan, Xianjun Shi, Lei Zhang, Yang Dai, Yuanxi Zou, Jing Deng, Xinyue Zhang, Hongbo Jia, Shiyong Liu, Hui Yang, Ying Mao, Xiang Liao, Chunqing Zhang, Xiaowei Chen","doi":"10.1126/scitranslmed.adq4423","DOIUrl":"10.1126/scitranslmed.adq4423","url":null,"abstract":"<div >Brain stimulation therapies have been increasingly applied to treat patients with drug-resistant epilepsy or other neuropsychiatric disorders, but identifying effective stimulation targets appropriate for individual patients remains challenging. Using intracranial electrophysiological recordings, we found that fast ripple (FR) activity was tightly correlated with the severity of consciousness impairment during seizures in patients with drug-resistant, consciousness-staged epilepsy. Epileptic network analysis based on FR coincidence across brain regions revealed hubs of ictal FR activity, defined as highly connected nodes, specific to individual patients. A small, exploratory study on eight patients with drug-resistant epilepsy showed that stimulating these hubs reduced FRs, ameliorated consciousness impairments, and reduced seizures during a poststimulation time window of up to 11 days. Moreover, FR hub stimulation showed a lower risk of evoking seizures than stimulating seizure onset zones, a now approved treatment option. These results suggest a potentially safe and effective strategy to alleviate epileptic seizures by stimulating patient-specific FR network hubs.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 830","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813644","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}
Pub Date : 2025-12-24DOI: 10.1126/scitranslmed.ads0594
Yifan Zhang, Dongsheng Wen, Chiakang Ho, Yangdan Liu, Xin Wang, Zhiyuan Zhou, Ya Gao, Qingfeng Li
Skin repair after injury is a complex multistage process. Reepithelialization is a vital component of skin wound healing and involves intricate molecular regulations that are still not fully understood. Here, using a combination of human tissue and animal models, we identified histone deacetylase 5 (HDAC5) as a key mediator of reepithelialization through a mechanism involving nucleocytoplasmic shuttling to regulate deacetylation of a nonhistone protein. We conducted functional validation through a conditional gene knockout mouse model. In addition, parallel studies using ex vivo human skin confirmed that HDAC5 cytoplasmic localization is necessary for efficient wound closure. Liquid chromatography–mass spectrometry of mouse wounds revealed that cytoplasmic HDAC5 interacts with alpha-actinin-4 (ACTN4). Site-directed mutagenesis, immunofluorescence, and luciferase assays demonstrated that HDAC5 deacetylates ACTN4 at the K417 site, allowing nuclear translocation of ACTN4 and subsequent modulation of transcriptional activity of Y-box–binding protein 1 (YBX1). Single-cell transcriptome analysis of mouse wounds revealed cystatin A as a key factor downstream of the HDAC5/ACTN4/YBX1 axis that enhanced reepithelialization and wound healing. We further identified an HDAC5-selective activator, G194-0712, and showed that it improved wound healing in three mouse models of chronic wounds: diabetic wounds, ischemic wounds, and radiation injury. Together, these results highlight a previously unappreciated mechanism involved in skin repair and suggest that HDAC5 activation may hold promise for the treatment of nonhealing skin wounds.
{"title":"HDAC5 deacetylates cytosolic ACTN4 during skin reepithelialization and represents a therapeutic target for chronic wound healing","authors":"Yifan Zhang, Dongsheng Wen, Chiakang Ho, Yangdan Liu, Xin Wang, Zhiyuan Zhou, Ya Gao, Qingfeng Li","doi":"10.1126/scitranslmed.ads0594","DOIUrl":"10.1126/scitranslmed.ads0594","url":null,"abstract":"<div >Skin repair after injury is a complex multistage process. Reepithelialization is a vital component of skin wound healing and involves intricate molecular regulations that are still not fully understood. Here, using a combination of human tissue and animal models, we identified histone deacetylase 5 (HDAC5) as a key mediator of reepithelialization through a mechanism involving nucleocytoplasmic shuttling to regulate deacetylation of a nonhistone protein. We conducted functional validation through a conditional gene knockout mouse model. In addition, parallel studies using ex vivo human skin confirmed that HDAC5 cytoplasmic localization is necessary for efficient wound closure. Liquid chromatography–mass spectrometry of mouse wounds revealed that cytoplasmic HDAC5 interacts with alpha-actinin-4 (ACTN4). Site-directed mutagenesis, immunofluorescence, and luciferase assays demonstrated that HDAC5 deacetylates ACTN4 at the K417 site, allowing nuclear translocation of ACTN4 and subsequent modulation of transcriptional activity of Y-box–binding protein 1 (YBX1). Single-cell transcriptome analysis of mouse wounds revealed cystatin A as a key factor downstream of the HDAC5/ACTN4/YBX1 axis that enhanced reepithelialization and wound healing. We further identified an HDAC5-selective activator, G194-0712, and showed that it improved wound healing in three mouse models of chronic wounds: diabetic wounds, ischemic wounds, and radiation injury. Together, these results highlight a previously unappreciated mechanism involved in skin repair and suggest that HDAC5 activation may hold promise for the treatment of nonhealing skin wounds.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 830","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813643","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}
Pub Date : 2025-12-24DOI: 10.1126/scitranslmed.aea9007
Grace A. Osborne, Lin Zhang, Feiyang Ma, Mehrnaz Gharaee-Kermani, Jessica L. Turnier, Amanda N. Victory, Amy Hurst, Bin Xu, Elisabeth A. Pedersen, Rachael Bogle, Celine C. Berthier, Vladimir Ognenovski, Mio Nakamura, Lam C. Tsoi, Allison C. Billi, Johann E. Gudjonsson, Benjamin Klein, Pei-Suen Tsou, J. Michelle Kahlenberg
Dermatomyositis is a rare yet devastating autoimmune disease characterized by inflammatory and vasculopathic changes in skin and muscle. Dermatomyositis and systemic lupus erythematosus (lupus) skin lesions have overlapping clinical and histopathological features but show disparate responses to available therapeutics, with dermatomyositis skin disease often relapsing and being recalcitrant. To investigate dermatomyositis immunopathogenesis, nonlesional skin, lesional skin, and circulating immune cells from patients with dermatomyositis were analyzed using single-cell RNA sequencing. Samples were analyzed in parallel with lesional and nonlesional lupus skin, healthy control skin, and peripheral blood from all three patient groups. We demonstrate a pervasive type I interferon signature in dermatomyositis stroma that persisted in culture and was distinguished from lupus by up-regulation of vascular endothelial growth factor and interleukin-18 signaling in dermatomyositis keratinocytes. Furthermore, endothelial cells in lesional dermatomyositis exhibited decreased proliferation, which was not observed in lupus skin. Using cell communication networks, we identified a population of dermatomyositis-specific monocytes interacting with nonproliferating endothelial cells. Coculture of monocytes from patients with dermatomyositis with endothelial cells resulted in increased endothelial cell apoptosis, which was inhibited by Janus kinase 1 (JAK1) blockade. JAK1 inhibition also resulted in reversal of dermatomyositis stromal and inflammatory signatures. Together, our data provide a comprehensive cross-disease characterization of lesional and nonlesional skin in dermatomyositis and implicate monocyte-mediated endothelial cell dysfunction in dermatomyositis vasculopathy. Moreover, these results suggest that JAK inhibition may offer a suitable therapeutic intervention for refractory skin disease.
{"title":"Dermatomyositis is characterized by JAK1-mediated monocyte-driven vasculopathy and inflammation","authors":"Grace A. Osborne, Lin Zhang, Feiyang Ma, Mehrnaz Gharaee-Kermani, Jessica L. Turnier, Amanda N. Victory, Amy Hurst, Bin Xu, Elisabeth A. Pedersen, Rachael Bogle, Celine C. Berthier, Vladimir Ognenovski, Mio Nakamura, Lam C. Tsoi, Allison C. Billi, Johann E. Gudjonsson, Benjamin Klein, Pei-Suen Tsou, J. Michelle Kahlenberg","doi":"10.1126/scitranslmed.aea9007","DOIUrl":"10.1126/scitranslmed.aea9007","url":null,"abstract":"<div >Dermatomyositis is a rare yet devastating autoimmune disease characterized by inflammatory and vasculopathic changes in skin and muscle. Dermatomyositis and systemic lupus erythematosus (lupus) skin lesions have overlapping clinical and histopathological features but show disparate responses to available therapeutics, with dermatomyositis skin disease often relapsing and being recalcitrant. To investigate dermatomyositis immunopathogenesis, nonlesional skin, lesional skin, and circulating immune cells from patients with dermatomyositis were analyzed using single-cell RNA sequencing. Samples were analyzed in parallel with lesional and nonlesional lupus skin, healthy control skin, and peripheral blood from all three patient groups. We demonstrate a pervasive type I interferon signature in dermatomyositis stroma that persisted in culture and was distinguished from lupus by up-regulation of vascular endothelial growth factor and interleukin-18 signaling in dermatomyositis keratinocytes. Furthermore, endothelial cells in lesional dermatomyositis exhibited decreased proliferation, which was not observed in lupus skin. Using cell communication networks, we identified a population of dermatomyositis-specific monocytes interacting with nonproliferating endothelial cells. Coculture of monocytes from patients with dermatomyositis with endothelial cells resulted in increased endothelial cell apoptosis, which was inhibited by Janus kinase 1 (JAK1) blockade. JAK1 inhibition also resulted in reversal of dermatomyositis stromal and inflammatory signatures. Together, our data provide a comprehensive cross-disease characterization of lesional and nonlesional skin in dermatomyositis and implicate monocyte-mediated endothelial cell dysfunction in dermatomyositis vasculopathy. Moreover, these results suggest that JAK inhibition may offer a suitable therapeutic intervention for refractory skin disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 830","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813625","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}
The right vagus nerve is essential for cardiac homeostasis, and its intrathoracic resection can lead to postoperative cardiac complications. Strategies to restore vagal innervation after transection at the cardiac level remain lacking. Here, we show that early reconnection of the right vagus nerve using an implantable chitosan/poly-ε-caprolactone cuff-like nerve guidance conduit preserved cardiac mechanical function in adult male minipigs subjected to right cardiac vagotomy. Treated animals displayed improved global circumferential, longitudinal, and radial strains and reduced diastolic dyssynchrony. Histological analysis revealed partial repair with about 20% viable vagal fascicles, restoration of myocardial parasympathetic fibers, normalization of oxidative stress and aging markers, and prevention of interstitial fibrosis. These findings suggest that maintaining even limited vagal input prevents early cardiac remodeling by mitigating oxidative stress–induced premature senescence of cardiac cells. Reconnection of the right vagus nerve with chitosan/poly-ε-caprolactone cuff-like nerve guidance conduit may represent a therapeutic approach to preventing right vagotomy–induced heart failure after thoracic surgery or cardiothoracic transplantation.
{"title":"Reconnecting the vagus nerve to the heart through nerve conduit preserves cardiac function in a minipig model of right cardiac vagotomy","authors":"Anar Dushpanova, Eugenio Redolfi-Riva, Valentina Casieri, Letizia Brogi, Chrysanthos Grigoratos, Fabio Bernini, Domiziana Terlizzi, Khatia Gabisonia, Ciro Zinno, Filippo Agnesi, Giulia Furini, Lisa Alibrandi, Aurora Paganelli, Valentina Sassu, Alessandro Carrozzo, Sabrina Marchetti, Silvia Burchielli, Jacopo Carpaneto, Micaela Sgorbini, Antonio Paolo Beltrami, Alessandro Cellerino, Giovanni Donato Aquaro, Silvestro Micera, Vincenzo Lionetti","doi":"10.1126/scitranslmed.aea4306","DOIUrl":"10.1126/scitranslmed.aea4306","url":null,"abstract":"<div >The right vagus nerve is essential for cardiac homeostasis, and its intrathoracic resection can lead to postoperative cardiac complications. Strategies to restore vagal innervation after transection at the cardiac level remain lacking. Here, we show that early reconnection of the right vagus nerve using an implantable chitosan/poly-ε-caprolactone cuff-like nerve guidance conduit preserved cardiac mechanical function in adult male minipigs subjected to right cardiac vagotomy. Treated animals displayed improved global circumferential, longitudinal, and radial strains and reduced diastolic dyssynchrony. Histological analysis revealed partial repair with about 20% viable vagal fascicles, restoration of myocardial parasympathetic fibers, normalization of oxidative stress and aging markers, and prevention of interstitial fibrosis. These findings suggest that maintaining even limited vagal input prevents early cardiac remodeling by mitigating oxidative stress–induced premature senescence of cardiac cells. Reconnection of the right vagus nerve with chitosan/poly-ε-caprolactone cuff-like nerve guidance conduit may represent a therapeutic approach to preventing right vagotomy–induced heart failure after thoracic surgery or cardiothoracic transplantation.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 830","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813626","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}
Pub Date : 2025-12-24DOI: 10.1126/scitranslmed.adx6797
Xiao-Ting Jiang, Mei-Kuang Chen, Jiwang Lee, Xiayu Rao, Yan Wang, Linjie Luo, Jing Wang, Kelly K. Hunt, Khandan Keyomarsi
Targeting cell cycle checkpoints has emerged as a promising strategy in cancer therapy, yet single-agent inhibitors often fail because of compensatory mechanisms. Here, we demonstrate that coinhibition of ATR (RP-3500) and PKMYT1 (RP-6306) induces synthetic lethality in Rb1-deficient breast cancers by disrupting both S-G2 and G2-M checkpoints. This leads to replication stress, premature mitotic entry, and accumulation of DNA damage. In vitro, Rb1-deficient breast cancer cells exhibited marked apoptosis and loss of clonogenic survival, whereas Rb1-proficient models remained resistant to combination treatment. Genetic manipulation confirmed this dependency: Rb1 knockdown sensitized resistant models, whereas reexpression conferred protection. In vivo, patient-derived xenograft (PDX) models recapitulated these findings. Rb1-deficient tumors regressed after ATR/PKMYT1 coinhibition, whereas Rb1-proficient tumors showed only modest responses. Combination therapy was well tolerated without weight loss or measurable toxicity. Biomarker analysis revealed increased γH2AX and reduced Ki67 staining exclusively in Rb1-deficient PDX models, underscoring the specificity of this response. Mechanistically, Rb1 loss impaired double-strand DNA repair by attenuating homologous recombination and nonhomologous end joining, leading to replication fork collapse, chromosomal instability, and mitotic catastrophe. Proteogenomic analysis identified JNK/p38 stress response pathway activation as a key driver of apoptosis after ATR/PKMYT1 inhibition in Rb1-deficient cells. Clinically, a retrospective analysis of stage IV breast cancer datasets revealed that Rb1-low tumors display reduced DNA repair pathway activity in triple-negative and CDK4/6 inhibitor–resistant luminal breast cancers. These results identify Rb1 loss as a predictive biomarker for ATR/PKMYT1-targeted therapy, offering a potential precision treatment strategy for advanced breast cancers.
{"title":"Rb1 deficiency induces synthetic lethality with ATR and PKMYT1 coinhibition in breast cancer cell lines and patient-derived xenografts","authors":"Xiao-Ting Jiang, Mei-Kuang Chen, Jiwang Lee, Xiayu Rao, Yan Wang, Linjie Luo, Jing Wang, Kelly K. Hunt, Khandan Keyomarsi","doi":"10.1126/scitranslmed.adx6797","DOIUrl":"10.1126/scitranslmed.adx6797","url":null,"abstract":"<div >Targeting cell cycle checkpoints has emerged as a promising strategy in cancer therapy, yet single-agent inhibitors often fail because of compensatory mechanisms. Here, we demonstrate that coinhibition of ATR (RP-3500) and PKMYT1 (RP-6306) induces synthetic lethality in Rb1-deficient breast cancers by disrupting both S-G<sub>2</sub> and G<sub>2</sub>-M checkpoints. This leads to replication stress, premature mitotic entry, and accumulation of DNA damage. In vitro, Rb1-deficient breast cancer cells exhibited marked apoptosis and loss of clonogenic survival, whereas Rb1-proficient models remained resistant to combination treatment. Genetic manipulation confirmed this dependency: Rb1 knockdown sensitized resistant models, whereas reexpression conferred protection. In vivo, patient-derived xenograft (PDX) models recapitulated these findings. Rb1-deficient tumors regressed after ATR/PKMYT1 coinhibition, whereas Rb1-proficient tumors showed only modest responses. Combination therapy was well tolerated without weight loss or measurable toxicity. Biomarker analysis revealed increased γH2AX and reduced Ki67 staining exclusively in Rb1-deficient PDX models, underscoring the specificity of this response. Mechanistically, Rb1 loss impaired double-strand DNA repair by attenuating homologous recombination and nonhomologous end joining, leading to replication fork collapse, chromosomal instability, and mitotic catastrophe. Proteogenomic analysis identified JNK/p38 stress response pathway activation as a key driver of apoptosis after ATR/PKMYT1 inhibition in Rb1-deficient cells. Clinically, a retrospective analysis of stage IV breast cancer datasets revealed that Rb1-low tumors display reduced DNA repair pathway activity in triple-negative and CDK4/6 inhibitor–resistant luminal breast cancers. These results identify Rb1 loss as a predictive biomarker for ATR/PKMYT1-targeted therapy, offering a potential precision treatment strategy for advanced breast cancers.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 830","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145813642","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号