Pub Date : 2026-01-21DOI: 10.1126/scitranslmed.ady2646
Binglan Yu, Bijan Safaee Fakhr, Lynn Bry, Angela Shih, Hatus V. Wanderley, Yue Dai, Ryan W. Carroll, Dario Winterton, Talisa Buehl, Mohamed Okda, Giovanni Bruno, Eizo Marutani, Stefano Cenci, Kyle J. Medeiros, Regina Villalobos, Stefano Spina, Cristina Mietto, Edward A. Bittner, Maurizio Cereda, Mary L. Delaney, Paolo Cadringher, Carolyn LaVita, Dennis J. Stuehr, Pankaj Arora, Fumito Ichinose, Lorenzo Berra
Antibiotic resistance in respiratory infections is an escalating global concern that requires innovative antimicrobial approaches. Pseudomonas aeruginosa is a common multidrug-resistant pathogen and a major cause of hospital-acquired pneumonia. Accumulating evidence suggests that, at high doses, inhaled nitric oxide (iNO) acts as a potent antimicrobial agent. This study evaluated the efficacy and safety of iNO at 300 parts per million (iNO300) as a treatment for P. aeruginosa infection. In vitro, P. aeruginosa exhibited a dose-dependent reduction when exposed to an NO donor. In a mechanically ventilated swine model of P. aeruginosa pneumonia, intermittent iNO300 therapy resulted in a two-log reduction in bacterial burden, improved oxygenation and lung compliance, and reduced histopathological lung injury. A phase 1 clinical trial in 10 healthy individuals confirmed the safety of intermittent iNO300 therapy with no adverse events. In two critically ill patients with multidrug-resistant bacteria, who were in the intensive care unit, iNO300 was well tolerated, demonstrating clinical feasibility. Long-term follow-up of patients exposed to high-dose iNO for more than 6 years revealed no adverse outcomes. Our findings establish iNO300 as a promising antimicrobial agent against P. aeruginosa pneumonia, warranting further clinical evaluation.
{"title":"Inhaled nitric oxide at 300 ppm treats multidrug-resistant Pseudomonas pneumonia in swine and is safe in humans","authors":"Binglan Yu, Bijan Safaee Fakhr, Lynn Bry, Angela Shih, Hatus V. Wanderley, Yue Dai, Ryan W. Carroll, Dario Winterton, Talisa Buehl, Mohamed Okda, Giovanni Bruno, Eizo Marutani, Stefano Cenci, Kyle J. Medeiros, Regina Villalobos, Stefano Spina, Cristina Mietto, Edward A. Bittner, Maurizio Cereda, Mary L. Delaney, Paolo Cadringher, Carolyn LaVita, Dennis J. Stuehr, Pankaj Arora, Fumito Ichinose, Lorenzo Berra","doi":"10.1126/scitranslmed.ady2646","DOIUrl":"10.1126/scitranslmed.ady2646","url":null,"abstract":"<div >Antibiotic resistance in respiratory infections is an escalating global concern that requires innovative antimicrobial approaches. <i>Pseudomonas aeruginosa</i> is a common multidrug-resistant pathogen and a major cause of hospital-acquired pneumonia. Accumulating evidence suggests that, at high doses, inhaled nitric oxide (iNO) acts as a potent antimicrobial agent. This study evaluated the efficacy and safety of iNO at 300 parts per million (iNO<sub>300</sub>) as a treatment for <i>P. aeruginosa</i> infection. In vitro, <i>P. aeruginosa</i> exhibited a dose-dependent reduction when exposed to an NO donor. In a mechanically ventilated swine model of <i>P. aeruginosa</i> pneumonia, intermittent iNO<sub>300</sub> therapy resulted in a two-log reduction in bacterial burden, improved oxygenation and lung compliance, and reduced histopathological lung injury. A phase 1 clinical trial in 10 healthy individuals confirmed the safety of intermittent iNO<sub>300</sub> therapy with no adverse events. In two critically ill patients with multidrug-resistant bacteria, who were in the intensive care unit, iNO<sub>300</sub> was well tolerated, demonstrating clinical feasibility. Long-term follow-up of patients exposed to high-dose iNO for more than 6 years revealed no adverse outcomes. Our findings establish iNO<sub>300</sub> as a promising antimicrobial agent against <i>P. aeruginosa</i> pneumonia, warranting further clinical evaluation.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 833","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014614","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 : 2026-01-21DOI: 10.1126/scitranslmed.adv4942
Alan L. Chang, Jonathan D. Reiss, Anthony Culos, Martin Becker, Jonathan A. Mayo, Ivana Marić, Davide De Francesco, Thanaphong Phongpreecha, Camilo A. Espinosa, Samson J. Mataraso, Eloïse Berson, Yeasul Kim, Lei Xue, Feng Xie, Chi-Hung Shu, Ramin Fallahzadeh, Neda H. Bidoki, Maria Xenochristou, Miao Zhang, Jochen Profit, Henry C. Lee, Brice Gaudillière, Martin S. Angst, Steven Hawken, Kumanan Wilson, David K. Stevenson, Gary M. Shaw, Karl G. Sylvester, Nima Aghaeepour
Neonatal prematurity leads to considerable morbidity and mortality, partly because of acquired conditions such as bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and retinopathy of prematurity (ROP). Standard gestational age and birthweight-based classifications of prematurity inadequately capture the variation in newborns’ health outcomes, creating an urgent need to develop risk stratification tools for vulnerable newborn infants to initiate the most appropriate care pathways as early as possible. We hypothesized that the metabolic profiles of newborn infants capture additional risk information beyond current measures. A total of 13,536 newborn screening (NBS) blood spot tests from preterm infants in California with linked clinical outcomes of prematurity were used to develop an NBS-based metabolic health index to stratify preterm infants at risk for BPD, IVH, NEC, and ROP (12,096 cases with one or more conditions and 1440 controls) through a deep learning model that provides a single index score in tandem with subgroup discovery to identify individuals with the strongest metabolite biomarker signals for adverse outcomes of prematurity. This metabolic health index captured risk signals that were distinct from gestational age and birthweight and outperformed other machine learning algorithms and clinical risk variable-based models in stratifying at-risk individuals for adverse outcomes of prematurity. The metabolic health index was externally validated in an independent retrospective cohort of 3299 very premature newborns from Ontario, Canada (2117 cases and 1182 controls), which recapitulated common metabolic risk subgroups. In summary, combining widespread metabolite screening with deep learning established a generalizable biological risk metric of prematurity.
{"title":"Quantitative assessment of neonatal health using dried blood spot metabolite profiles and deep learning","authors":"Alan L. Chang, Jonathan D. Reiss, Anthony Culos, Martin Becker, Jonathan A. Mayo, Ivana Marić, Davide De Francesco, Thanaphong Phongpreecha, Camilo A. Espinosa, Samson J. Mataraso, Eloïse Berson, Yeasul Kim, Lei Xue, Feng Xie, Chi-Hung Shu, Ramin Fallahzadeh, Neda H. Bidoki, Maria Xenochristou, Miao Zhang, Jochen Profit, Henry C. Lee, Brice Gaudillière, Martin S. Angst, Steven Hawken, Kumanan Wilson, David K. Stevenson, Gary M. Shaw, Karl G. Sylvester, Nima Aghaeepour","doi":"10.1126/scitranslmed.adv4942","DOIUrl":"10.1126/scitranslmed.adv4942","url":null,"abstract":"<div >Neonatal prematurity leads to considerable morbidity and mortality, partly because of acquired conditions such as bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and retinopathy of prematurity (ROP). Standard gestational age and birthweight-based classifications of prematurity inadequately capture the variation in newborns’ health outcomes, creating an urgent need to develop risk stratification tools for vulnerable newborn infants to initiate the most appropriate care pathways as early as possible. We hypothesized that the metabolic profiles of newborn infants capture additional risk information beyond current measures. A total of 13,536 newborn screening (NBS) blood spot tests from preterm infants in California with linked clinical outcomes of prematurity were used to develop an NBS-based metabolic health index to stratify preterm infants at risk for BPD, IVH, NEC, and ROP (12,096 cases with one or more conditions and 1440 controls) through a deep learning model that provides a single index score in tandem with subgroup discovery to identify individuals with the strongest metabolite biomarker signals for adverse outcomes of prematurity. This metabolic health index captured risk signals that were distinct from gestational age and birthweight and outperformed other machine learning algorithms and clinical risk variable-based models in stratifying at-risk individuals for adverse outcomes of prematurity. The metabolic health index was externally validated in an independent retrospective cohort of 3299 very premature newborns from Ontario, Canada (2117 cases and 1182 controls), which recapitulated common metabolic risk subgroups. In summary, combining widespread metabolite screening with deep learning established a generalizable biological risk metric of prematurity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 833","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014615","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 : 2026-01-21DOI: 10.1126/scitranslmed.aee9871
{"title":"Erratum for Report “APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia” by G. Sienski et al.","authors":"","doi":"10.1126/scitranslmed.aee9871","DOIUrl":"10.1126/scitranslmed.aee9871","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 833","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015428","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 : 2026-01-21DOI: 10.1126/scitranslmed.adx0368
Chittampalli N. Yashaswini, Bruno Cogliati, Tianyue Qin, Tran To, Thomas Williamson, Tyler E. Papp, Kenneth Li, Raisa Rasul, Li Chen, Adi Lightstone, Haig Aghajanian, Hamideh Parhiz, Shuang Wang, Joel G. Rurik, Jonathan A. Epstein, Scott L. Friedman
Hepatic fibrosis is a key predictor of mortality in liver disease, driven by fibrogenic hepatic stellate cells (HSCs). Targeting these fibrogenic cells may therefore offer a therapeutic approach for hepatic fibrosis. We previously showed that in vivo–generated chimeric antigen receptor (CAR) T cells targeting fibroblast activation protein alpha (FAP) reduced murine cardiac fibrosis. Here, we explored the antifibrotic potential of this in vivo–generated anti-FAP CAR T cell therapy in metabolic dysfunction–associated steatohepatitis (MASH), a highly prevalent disease with no approved antifibrotic therapies. We first established that FAP expression in both human and murine MASH is specific to HSCs. We then used flow cytometry, Sirius Red morphometry, digital pathology analysis, and single nuclear RNA sequencing to assess the impact of anti-FAP CAR T cell therapy on murine MASH. Anti-CD5–targeted lipid nanoparticles carrying anti-FAPCAR messenger RNA transiently generated activated anti-FAP CAR T cells, which substantially reduced fibrosis by depleting profibrogenic HSCs. They also modulated immune cells, endothelial cells, and hepatocytes in a non–cell autonomous manner to mitigate inflammation and restore hepatic homeostasis. These findings highlight the potential of in vivo CAR T therapy to attenuate a highly morbid and pervasive liver disease, not only by directly reducing fibrosis but also through indirect effects on other cell types.
肝纤维化是肝脏疾病死亡率的关键预测因子，由纤维化性肝星状细胞（hsc）驱动。因此，靶向这些纤维化细胞可能为肝纤维化提供一种治疗方法。我们之前的研究表明，靶向成纤维细胞激活蛋白α (FAP)的体内生成嵌合抗原受体（CAR） T细胞减少了小鼠心脏纤维化。在这里，我们探索了这种体内生成的抗fap CAR - T细胞治疗代谢功能障碍相关脂肪性肝炎（MASH）的抗纤维化潜力，这是一种高度流行的疾病，没有批准的抗纤维化治疗方法。我们首先确定了人类和小鼠MASH中的FAP表达是hsc特异性的。然后，我们使用流式细胞术、天狼星红形态测定法、数字病理分析和单核RNA测序来评估抗fap CAR - T细胞治疗对小鼠MASH的影响。携带抗fapcar信使RNA的抗cd5靶向脂质纳米颗粒瞬间产生活化的抗fap CAR - T细胞，通过消耗促纤维化hsc显著减少纤维化。它们还以非细胞自主的方式调节免疫细胞、内皮细胞和肝细胞，以减轻炎症和恢复肝脏稳态。这些发现强调了体内CAR - T疗法的潜力，它不仅可以直接减少纤维化，还可以间接影响其他细胞类型，从而减轻一种高度病态和普遍存在的肝脏疾病。
{"title":"Anti-FAP CAR T cells produced in vivo reduce fibrosis and restore liver homeostasis in metabolic dysfunction–associated steatohepatitis","authors":"Chittampalli N. Yashaswini, Bruno Cogliati, Tianyue Qin, Tran To, Thomas Williamson, Tyler E. Papp, Kenneth Li, Raisa Rasul, Li Chen, Adi Lightstone, Haig Aghajanian, Hamideh Parhiz, Shuang Wang, Joel G. Rurik, Jonathan A. Epstein, Scott L. Friedman","doi":"10.1126/scitranslmed.adx0368","DOIUrl":"10.1126/scitranslmed.adx0368","url":null,"abstract":"<div >Hepatic fibrosis is a key predictor of mortality in liver disease, driven by fibrogenic hepatic stellate cells (HSCs). Targeting these fibrogenic cells may therefore offer a therapeutic approach for hepatic fibrosis. We previously showed that in vivo–generated chimeric antigen receptor (CAR) T cells targeting fibroblast activation protein alpha (FAP) reduced murine cardiac fibrosis. Here, we explored the antifibrotic potential of this in vivo–generated anti-FAP CAR T cell therapy in metabolic dysfunction–associated steatohepatitis (MASH), a highly prevalent disease with no approved antifibrotic therapies. We first established that FAP expression in both human and murine MASH is specific to HSCs. We then used flow cytometry, Sirius Red morphometry, digital pathology analysis, and single nuclear RNA sequencing to assess the impact of anti-FAP CAR T cell therapy on murine MASH. Anti-CD5–targeted lipid nanoparticles carrying anti-FAPCAR messenger RNA transiently generated activated anti-FAP CAR T cells, which substantially reduced fibrosis by depleting profibrogenic HSCs. They also modulated immune cells, endothelial cells, and hepatocytes in a non–cell autonomous manner to mitigate inflammation and restore hepatic homeostasis. These findings highlight the potential of in vivo CAR T therapy to attenuate a highly morbid and pervasive liver disease, not only by directly reducing fibrosis but also through indirect effects on other cell types.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 833","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014775","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 : 2026-01-21DOI: 10.1126/scitranslmed.adw4689
Erica M. Pimenta, Amanda E. Garza, Sabrina Y. Camp, Jihye Park, Samantha E. Hoffman, Laura Valderrábano, Jingxin Fu, Kevin Bi, Maximilian T. Carson, Julie Karam, Breanna M. Titchen, Sofia Medjahed, Melin J. Khandekar, Erin Shannon, Yun Jee Kang, Shannon Coy, Jia-Ren Lin, Anwesha Nag, Aaron R. Thorner, William J. Gibson, Sandro Santagata, Chandrajit P. Raut, Jason L. Hornick, Priscilla Merriam, Nicole L. Solimini, Suzanne George, George D. Demetri, Eliezer M. Van Allen
Sarcomas are rare cancers thought to arise from aberrant mesenchymal stem cell (MSC) differentiation. Liposarcoma (LPS) is among the most commonly diagnosed sarcomas and provides insights into dysfunctional differentiation through its well- and dedifferentiated subtypes (WDLPS and DDLPS). Despite differences in histology and clinical behavior, the molecular pathways underlying each subtype remain poorly defined, leaving patients with DDLPS reliant on empiric chemotherapies. We applied single-nucleus multiome sequencing and spatial profiling to human normal adipose, WDLPS, and DDLPS tissues and identified lineage-specific blocks in differentiation within LPS. We found that DDLPS is characterized by loss of insulin-like growth factor 1 (IGF1) signaling and activation of early mesenchymal and glucagon-like peptide-1 (GLP-1)–associated programs. IGF1 signaling loss was restricted to the DDLPS component within mixed histology tumors and correlated with poor survival in patients with LPS. In normal adipocytes, IGF1 drives differentiation through peroxisome proliferator–activated receptor gamma 2 (PPARG2). We found that DDLPS cells lack PPARG2, causing a barrier to differentiation. This defect rendered DDLPS cells unresponsive to exogenous proadipogenic signals. Restoration of PPARG2 expression alone was sufficient to reenable adipogenesis, pinpointing PPARG2 as the key molecular determinant of lineage fate. Last, IGF1 deficiency in DDLPS was associated with up-regulation of the IGF1 receptor (IGF1R), creating a selective vulnerability to IGF1R-targeted antibody-drug conjugates. In summary, we identified lineage-specific defects in DDLPS, with PPARG2 as the molecular mediator of differentiation state in LPS. More broadly, our findings demonstrate how defining lineage-specific mechanisms of tumor state can inform the development of nonchemotherapeutic treatment approaches.
{"title":"Epigenetic dysregulation of metabolic programs mediates liposarcoma cell plasticity","authors":"Erica M. Pimenta, Amanda E. Garza, Sabrina Y. Camp, Jihye Park, Samantha E. Hoffman, Laura Valderrábano, Jingxin Fu, Kevin Bi, Maximilian T. Carson, Julie Karam, Breanna M. Titchen, Sofia Medjahed, Melin J. Khandekar, Erin Shannon, Yun Jee Kang, Shannon Coy, Jia-Ren Lin, Anwesha Nag, Aaron R. Thorner, William J. Gibson, Sandro Santagata, Chandrajit P. Raut, Jason L. Hornick, Priscilla Merriam, Nicole L. Solimini, Suzanne George, George D. Demetri, Eliezer M. Van Allen","doi":"10.1126/scitranslmed.adw4689","DOIUrl":"10.1126/scitranslmed.adw4689","url":null,"abstract":"<div >Sarcomas are rare cancers thought to arise from aberrant mesenchymal stem cell (MSC) differentiation. Liposarcoma (LPS) is among the most commonly diagnosed sarcomas and provides insights into dysfunctional differentiation through its well- and dedifferentiated subtypes (WDLPS and DDLPS). Despite differences in histology and clinical behavior, the molecular pathways underlying each subtype remain poorly defined, leaving patients with DDLPS reliant on empiric chemotherapies. We applied single-nucleus multiome sequencing and spatial profiling to human normal adipose, WDLPS, and DDLPS tissues and identified lineage-specific blocks in differentiation within LPS. We found that DDLPS is characterized by loss of insulin-like growth factor 1 (IGF1) signaling and activation of early mesenchymal and glucagon-like peptide-1 (GLP-1)–associated programs. IGF1 signaling loss was restricted to the DDLPS component within mixed histology tumors and correlated with poor survival in patients with LPS. In normal adipocytes, IGF1 drives differentiation through peroxisome proliferator–activated receptor gamma 2 (PPARG2). We found that DDLPS cells lack PPARG2, causing a barrier to differentiation. This defect rendered DDLPS cells unresponsive to exogenous proadipogenic signals. Restoration of PPARG2 expression alone was sufficient to reenable adipogenesis, pinpointing PPARG2 as the key molecular determinant of lineage fate. Last, IGF1 deficiency in DDLPS was associated with up-regulation of the IGF1 receptor (IGF1R), creating a selective vulnerability to IGF1R-targeted antibody-drug conjugates. In summary, we identified lineage-specific defects in DDLPS, with PPARG2 as the molecular mediator of differentiation state in LPS. More broadly, our findings demonstrate how defining lineage-specific mechanisms of tumor state can inform the development of nonchemotherapeutic treatment approaches.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 833","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014230","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 : 2026-01-14DOI: 10.1126/scitranslmed.aee6630
{"title":"Erratum for the Research Article “Single immunizations of self-amplifying or non-replicating mRNA-LNP vaccines control HPV-associated tumors in mice” by J. Ramos da Silva et al.","authors":"","doi":"10.1126/scitranslmed.aee6630","DOIUrl":"10.1126/scitranslmed.aee6630","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 832","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964512","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}
Respiratory syncytial virus (RSV) poses a critical threat to infants, yet vaccine and antibody development remains challenged by safety risks and antigenic variability. Here, we present a prophylactic strategy leveraging two human neutralizing antibodies, 1A2 and 1B6, which target distinct, conserved epitopes on the RSV prefusion F (pre-F) protein. Cryo–electron microscopy (cryo-EM) structural analysis revealed that 1A2 binds a “waist” epitope spanning antigenic sites IV/V, whereas 1B6 engages a “head” epitope bridging sites Ø/II/V, collectively stabilizing the pre-F trimer to block conformational transitions critical for viral entry. In vitro escape mutagenesis demonstrated that the 1A2/1B6 cocktail can resist viral escape (>20 passages), contrasting with rapid resistance to nirsevimab (targeting site Ø) and single antibodies [1A2: Gly446→Glu (G446E); 1B6: Gln94→Arg (Q94R) or Gln94→Lys (Q94K)]. Fc engineering extended serum half-lives while ablating effector functions, addressing potential safety concerns. Last, prophylactic administration in rodent models conferred robust protection against RSV A and B strains, including nirsevimab-resistant variants, with a 296-fold reduction in lung viral titers. This dual-epitope approach overcomes limitations of current monotherapies by combining high conservation, synergistic potency, and escape resilience, positioning it as a valuable immunoprophylactic candidate for pediatric RSV prevention.
{"title":"An antibody cocktail targeting conserved, nonoverlapping epitopes prevents viral escape and confers protection against RSV in vivo","authors":"Yongpeng Sun, Liqin Liu, Zemin Jiang, Yizhen Wang, Jinghua Zhao, Hongsheng Qiang, Yujin Shi, Qi Lai, Li Chen, Qiangzhong Zhang, Jiahong Li, Zhihao Zhuo, Yichao Jiang, Yuhao Fu, Xiaobin Zhang, Mengxuan Zhang, Siyu Lei, Xue Lin, Min Lin, Yingbin Wang, Hai Yu, Shaowei Li, Wenxin Luo, Jun Zhang, Siling Wang, Ningshao Xia, Qingbing Zheng, Zizheng Zheng","doi":"10.1126/scitranslmed.ady2450","DOIUrl":"10.1126/scitranslmed.ady2450","url":null,"abstract":"<div >Respiratory syncytial virus (RSV) poses a critical threat to infants, yet vaccine and antibody development remains challenged by safety risks and antigenic variability. Here, we present a prophylactic strategy leveraging two human neutralizing antibodies, 1A2 and 1B6, which target distinct, conserved epitopes on the RSV prefusion F (pre-F) protein. Cryo–electron microscopy (cryo-EM) structural analysis revealed that 1A2 binds a “waist” epitope spanning antigenic sites IV/V, whereas 1B6 engages a “head” epitope bridging sites Ø/II/V, collectively stabilizing the pre-F trimer to block conformational transitions critical for viral entry. In vitro escape mutagenesis demonstrated that the 1A2/1B6 cocktail can resist viral escape (>20 passages), contrasting with rapid resistance to nirsevimab (targeting site Ø) and single antibodies [1A2: Gly<sup>446</sup>→Glu (G446E); 1B6: Gln<sup>94</sup>→Arg (Q94R) or Gln<sup>94</sup>→Lys (Q94K)]. Fc engineering extended serum half-lives while ablating effector functions, addressing potential safety concerns. Last, prophylactic administration in rodent models conferred robust protection against RSV A and B strains, including nirsevimab-resistant variants, with a 296-fold reduction in lung viral titers. This dual-epitope approach overcomes limitations of current monotherapies by combining high conservation, synergistic potency, and escape resilience, positioning it as a valuable immunoprophylactic candidate for pediatric RSV prevention.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 832","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964514","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 : 2026-01-14DOI: 10.1126/scitranslmed.adw2206
Colin Bauer, Federica Piani, Jonathan Troost, Stefano Da Sacco, Guadalupe Rojas-Sanchez, Pavel Davizon-Castillo, Laura Perin, Ilse Daehn, Md Imtiazul Islam, Audrey Fetsko, Claudia Carrera-Muñoz, Brad Rovin, Xiaolan L. Zhang, Mindy Banks, Carmen de Lucas-Collantes, Flor A. Ordóñez-Álvarez, Cristina Aparicio-López, Miguel A. Lanaspa, Ana Andres-Hernando, Alfons Segarra, Cristina Martinez, Petter Bjornstad, M. Scott Lucia, Franz Schaefer, Alev Yilmaz, Aleksandra Zurowska, Xin Wang, Phillip J. McCown, Sean Eddy, John Hartman, Laura Mariani, Matthias Kretzler, Yuwen Zhu, Antonia H. M. Bouts, Elena N. Levtchenko, Julie A. Dougherty, William E. Smoyer, Bryce A. Kerlin, Mahmoud Kallash, Danielle E. Soranno, José E. Cabrera-Sevilla, Juan David Gonzalez-Rodriguez, Bradford J. Siegele, Shoji Tsuji, Kazunari Kaneko, Christine B. Sethna, Tarak Srivastava, Markus Bitzer, Christopher L. O’Connor, Anna Dimberg, Serena Zhao, Liping Yu, Joshua M. Thurman, Richard J. Johnson, Gabriel Cara-Fuentes
Idiopathic nephrotic syndrome (INS) is a podocyte disease triggered by immune-derived factors. Endothelial activation occurs in this context, but whether the activated endothelium contributes to podocyte injury is unknown. We tested the hypothesis that CD93, a protein primarily expressed in the endothelium, is a contributory factor of podocyte injury. We studied 460 patients with INS and 150 with other podocytopathies. CD93 was analyzed in kidney tissue, urine, and serum samples. We tested the efficacy of CD93 blockade in vitro and in vivo and investigated the relationship between soluble CD93 and clinical outcomes in human INS. CD93 was highly expressed by glomerular endothelial cells (GEnCs) in human INS, and INS sera stimulated cultured human GEnCs to release CD93. Mechanistically, soluble CD93 mediated podocyte activation via β1 integrin/FAK signaling in cultured human podocytes. CD93 blockade mitigated the activation of cultured human podocytes and albumin permeability in human GEnC-podocyte cocultures as well as albuminuria, glomerulosclerosis, and podocyte loss in two models of nephrotic syndrome: podocyte-specific transforming growth factor–β1 signaling (PodTgfbr1) mice and adriamycin-treated mice. Cd93 knockout mice showed less proteinuria and glomerulosclerosis, compared with controls, after adriamycin injection. In patients with INS, soluble CD93 was high in urine in ~90% and 50% of patients in relapse and remission, respectively. High urinary CD93 was associated with faster decline in kidney function and slower response to immunosuppression. Soluble and glomerular CD93 was also elevated in other podocytopathies. We conclude that soluble CD93 contributes to podocyte injury.
{"title":"Endothelial cell–released CD93 contributes to podocyte injury in idiopathic nephrotic syndrome","authors":"Colin Bauer, Federica Piani, Jonathan Troost, Stefano Da Sacco, Guadalupe Rojas-Sanchez, Pavel Davizon-Castillo, Laura Perin, Ilse Daehn, Md Imtiazul Islam, Audrey Fetsko, Claudia Carrera-Muñoz, Brad Rovin, Xiaolan L. Zhang, Mindy Banks, Carmen de Lucas-Collantes, Flor A. Ordóñez-Álvarez, Cristina Aparicio-López, Miguel A. Lanaspa, Ana Andres-Hernando, Alfons Segarra, Cristina Martinez, Petter Bjornstad, M. Scott Lucia, Franz Schaefer, Alev Yilmaz, Aleksandra Zurowska, Xin Wang, Phillip J. McCown, Sean Eddy, John Hartman, Laura Mariani, Matthias Kretzler, Yuwen Zhu, Antonia H. M. Bouts, Elena N. Levtchenko, Julie A. Dougherty, William E. Smoyer, Bryce A. Kerlin, Mahmoud Kallash, Danielle E. Soranno, José E. Cabrera-Sevilla, Juan David Gonzalez-Rodriguez, Bradford J. Siegele, Shoji Tsuji, Kazunari Kaneko, Christine B. Sethna, Tarak Srivastava, Markus Bitzer, Christopher L. O’Connor, Anna Dimberg, Serena Zhao, Liping Yu, Joshua M. Thurman, Richard J. Johnson, Gabriel Cara-Fuentes","doi":"10.1126/scitranslmed.adw2206","DOIUrl":"10.1126/scitranslmed.adw2206","url":null,"abstract":"<div >Idiopathic nephrotic syndrome (INS) is a podocyte disease triggered by immune-derived factors. Endothelial activation occurs in this context, but whether the activated endothelium contributes to podocyte injury is unknown. We tested the hypothesis that CD93, a protein primarily expressed in the endothelium, is a contributory factor of podocyte injury. We studied 460 patients with INS and 150 with other podocytopathies. CD93 was analyzed in kidney tissue, urine, and serum samples. We tested the efficacy of CD93 blockade in vitro and in vivo and investigated the relationship between soluble CD93 and clinical outcomes in human INS. CD93 was highly expressed by glomerular endothelial cells (GEnCs) in human INS, and INS sera stimulated cultured human GEnCs to release CD93. Mechanistically, soluble CD93 mediated podocyte activation via β1 integrin/FAK signaling in cultured human podocytes. CD93 blockade mitigated the activation of cultured human podocytes and albumin permeability in human GEnC-podocyte cocultures as well as albuminuria, glomerulosclerosis, and podocyte loss in two models of nephrotic syndrome: podocyte-specific transforming growth factor–β1 signaling (<i>PodTgfbr1</i>) mice and adriamycin-treated mice. <i>Cd93</i> knockout mice showed less proteinuria and glomerulosclerosis, compared with controls, after adriamycin injection. In patients with INS, soluble CD93 was high in urine in ~90% and 50% of patients in relapse and remission, respectively. High urinary CD93 was associated with faster decline in kidney function and slower response to immunosuppression. Soluble and glomerular CD93 was also elevated in other podocytopathies. We conclude that soluble CD93 contributes to podocyte injury.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 832","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964515","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 : 2026-01-14DOI: 10.1126/scitranslmed.adz1280
Naomi Vlegels, Nicoló L. Knuth, Konstantin A. Steiner, Linjie Zhang, Apolline L. Vix, Dilara Moumin, Irem Mirzen, Nada Khalifeh, Charlotte Forster, Benno Gesierich, Franziska Müller, Philipp Lohse, Jule Filler, Rong Fang, Matthias Klein, Konstantinos Dimitriadis, Nicolai Franzmeier, Thomas Liebig, Matthias Endres, Michael Goertler, Gabor C. Petzold, Silke Wunderlich, Inga Zerr, Thalia S. Field, Mirko Pham, Richard H. Swartz, Sven Poli, Jörg Berrouschot, Atif Zafar, Hauke Schneider, Jai J. Shankar, Anne Hege Aamodt, Jens Minnerup, Jennifer L. Mandzia, Gernot Reimann, Marios-Nikos Psychogios, Sibu Mundiyanapurath, Arno Reich, Leonard L. L. Yeo, Marco Duering, Paul Reidler, DEMDAS study group, ESCAPE-NEXT biomarker substudy investigators‡, Mayank Goyal, Michael Tymianski, Michael D. Hill, Martin Dichgans, Steffen Tiedt
A specific and accurate blood test for acute brain injury could help monitor infarct growth in ischemic stroke and serve as a surrogate end point in clinical trials. Using a single-molecule detection assay, we assessed plasma brain-derived tau (BD-tau), a marker selectively quantifying tau protein from the central nervous system, in a prospective cohort of 502 patients with acute ischemic stroke with serial blood sampling from admission to day 7. Higher BD-tau concentrations at admission were associated with more extensive early brain injury on computed tomography and predicted larger final infarct volumes. BD-tau increases from admission to day 2 were related to infarct growth. BD-tau concentrations rose until day 7 and were higher in patients with secondary events, including recurrent stroke. After thrombectomy, the rise of BD-tau was smaller in patients with complete versus incomplete recanalization. BD-tau outperformed other blood markers and imaging metrics in predicting 90-day functional outcome across infarct size strata and time points. In an independent multicenter prospective cohort (N = 519), BD-tau showed higher performance than magnetic resonance imaging–derived final infarct volume in predicting functional outcomes at 3, 12, and 36 months. In the biomarker substudy of a phase 3 trial assessing nerinetide in patients with ischemic stroke (N = 193), BD-tau showed predictive performance comparable to the other cohorts, mediated the relationship between recanalization and functional outcome, and showed a 49% smaller increase in the nerinetide group versus placebo. Overall, plasma BD-tau tracked ischemic brain injury over time, outperformed other biomarkers in predicting functional outcomes, and identified possible treatment responses.
{"title":"Brain-derived tau for monitoring brain injury in acute ischemic stroke","authors":"Naomi Vlegels, Nicoló L. Knuth, Konstantin A. Steiner, Linjie Zhang, Apolline L. Vix, Dilara Moumin, Irem Mirzen, Nada Khalifeh, Charlotte Forster, Benno Gesierich, Franziska Müller, Philipp Lohse, Jule Filler, Rong Fang, Matthias Klein, Konstantinos Dimitriadis, Nicolai Franzmeier, Thomas Liebig, Matthias Endres, Michael Goertler, Gabor C. Petzold, Silke Wunderlich, Inga Zerr, Thalia S. Field, Mirko Pham, Richard H. Swartz, Sven Poli, Jörg Berrouschot, Atif Zafar, Hauke Schneider, Jai J. Shankar, Anne Hege Aamodt, Jens Minnerup, Jennifer L. Mandzia, Gernot Reimann, Marios-Nikos Psychogios, Sibu Mundiyanapurath, Arno Reich, Leonard L. L. Yeo, Marco Duering, Paul Reidler, DEMDAS study group, ESCAPE-NEXT biomarker substudy investigators‡, Mayank Goyal, Michael Tymianski, Michael D. Hill, Martin Dichgans, Steffen Tiedt","doi":"10.1126/scitranslmed.adz1280","DOIUrl":"10.1126/scitranslmed.adz1280","url":null,"abstract":"<div >A specific and accurate blood test for acute brain injury could help monitor infarct growth in ischemic stroke and serve as a surrogate end point in clinical trials. Using a single-molecule detection assay, we assessed plasma brain-derived tau (BD-tau), a marker selectively quantifying tau protein from the central nervous system, in a prospective cohort of 502 patients with acute ischemic stroke with serial blood sampling from admission to day 7. Higher BD-tau concentrations at admission were associated with more extensive early brain injury on computed tomography and predicted larger final infarct volumes. BD-tau increases from admission to day 2 were related to infarct growth. BD-tau concentrations rose until day 7 and were higher in patients with secondary events, including recurrent stroke. After thrombectomy, the rise of BD-tau was smaller in patients with complete versus incomplete recanalization. BD-tau outperformed other blood markers and imaging metrics in predicting 90-day functional outcome across infarct size strata and time points. In an independent multicenter prospective cohort (<i>N</i> = 519), BD-tau showed higher performance than magnetic resonance imaging–derived final infarct volume in predicting functional outcomes at 3, 12, and 36 months. In the biomarker substudy of a phase 3 trial assessing nerinetide in patients with ischemic stroke (<i>N</i> = 193), BD-tau showed predictive performance comparable to the other cohorts, mediated the relationship between recanalization and functional outcome, and showed a 49% smaller increase in the nerinetide group versus placebo. Overall, plasma BD-tau tracked ischemic brain injury over time, outperformed other biomarkers in predicting functional outcomes, and identified possible treatment responses.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 832","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964511","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 : 2026-01-14DOI: 10.1126/scitranslmed.adt8706
Julie R. Duffield, Xiaonan Hou, Benjamin W. Wilson, Anjali Prasad, Iman K. McKeon-Makki, Amelia M. Huehls, Xinyan Wu, Cristina Correia, Melissa C. Larson, Fergus J. Couch, Ann L. Oberg, Scott H. Kaufmann, Larry M. Karnitz, S. John Weroha, Arun Kanakkanthara
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are an important therapy for high-grade serous ovarian cancer (HGSOC). However, PARPi resistance frequently emerges, necessitating previously unrecognized approaches to improve HGSOC responses. Here, we showed that the anaplastic lymphoma kinase (ALK) inhibitor brigatinib enhances PARPi activity in HGSOC cells by disrupting an adaptive survival mechanism orchestrated by Fos-related antigen 1 (FRA1) in response to PARPi. This effect of brigatinib occurred through an ALK-independent pathway, wherein brigatinib induced a dual blockade of focal adhesion kinase (FAK) and EPH receptor A2 (EPHA2) tyrosine kinases, leading to the suppression of protein kinase B (Akt) and extracellular-regulated kinase (ERK) signaling accompanied by disruption of a phosphorylation event crucial for FRA1 protein stability. Moreover, in HGSOC patient-derived xenograft (PDX) models, brigatinib and PARPi combination therapy induced tumor regression and improved overall survival compared with PARPi alone, particularly in models with high FAK and EPHA2. These findings support dual targeting of FAK and EPHA2 as a strategy to achieve effective and durable PARPi responses and identify a promising biomarker-based combinatorial approach using brigatinib and PARPi for HGSOC, particularly the subset characterized by high FAK and EPHA2.
{"title":"Dual FAK and EPHA2 targeting by brigatinib tackles PARP inhibitor adaptive survival response in high-grade serous ovarian cancer","authors":"Julie R. Duffield, Xiaonan Hou, Benjamin W. Wilson, Anjali Prasad, Iman K. McKeon-Makki, Amelia M. Huehls, Xinyan Wu, Cristina Correia, Melissa C. Larson, Fergus J. Couch, Ann L. Oberg, Scott H. Kaufmann, Larry M. Karnitz, S. John Weroha, Arun Kanakkanthara","doi":"10.1126/scitranslmed.adt8706","DOIUrl":"10.1126/scitranslmed.adt8706","url":null,"abstract":"<div >Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are an important therapy for high-grade serous ovarian cancer (HGSOC). However, PARPi resistance frequently emerges, necessitating previously unrecognized approaches to improve HGSOC responses. Here, we showed that the anaplastic lymphoma kinase (ALK) inhibitor brigatinib enhances PARPi activity in HGSOC cells by disrupting an adaptive survival mechanism orchestrated by Fos-related antigen 1 (FRA1) in response to PARPi. This effect of brigatinib occurred through an ALK-independent pathway, wherein brigatinib induced a dual blockade of focal adhesion kinase (FAK) and EPH receptor A2 (EPHA2) tyrosine kinases, leading to the suppression of protein kinase B (Akt) and extracellular-regulated kinase (ERK) signaling accompanied by disruption of a phosphorylation event crucial for FRA1 protein stability. Moreover, in HGSOC patient-derived xenograft (PDX) models, brigatinib and PARPi combination therapy induced tumor regression and improved overall survival compared with PARPi alone, particularly in models with high FAK and EPHA2. These findings support dual targeting of FAK and EPHA2 as a strategy to achieve effective and durable PARPi responses and identify a promising biomarker-based combinatorial approach using brigatinib and PARPi for HGSOC, particularly the subset characterized by high FAK and EPHA2.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 832","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964513","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}
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