Science Translational Medicine最新文献

{"title":"Inhibiting mechanotransduction prevents scarring and yields regeneration in a large animal model","authors":"Shamik Mascharak, Michelle Griffin, Heather E. Talbott, Jason L. Guo, Jennifer Parker, Annah Grace Morgan, Caleb Valencia, Maxwell Michael Kuhnert, Dayan J. Li, Norah E. Liang, Rachel M. Kratofil, Joseph A. Daccache, Ikjot Sidhu, Michael F. Davitt, Nicholas Guardino, John M. Lu, Darren B. Abbas, Nestor M. D. Deleon, Christopher V. Lavin, Sandeep Adem, Anum Khan, Kellen Chen, Dominic Henn, Amanda Spielman, Asha Cotterell, Deena Akras, Mauricio Downer, Ruth Tevlin, H. Peter Lorenz, Geoffrey C. Gurtner, Michael Januszyk, Shruti Naik, Derrick C. Wan, Michael T. Longaker","doi":"10.1126/scitranslmed.adt6387","DOIUrl":"https://doi.org/10.1126/scitranslmed.adt6387","url":null,"abstract":"Modulating mechanotransduction by inhibiting yes-associated protein (YAP) in mice yields wound regeneration without scarring. However, rodents are loose-skinned and fail to recapitulate key aspects of human wound repair. We sought to elucidate the effects of YAP inhibition in red Duroc pig wounds, the most human-like model of scarring. We show that one-time treatment with verteporfin, a YAP inhibitor, immediately after wounding is sufficient to prevent scarring and to drive wound regeneration in pigs. By performing single-cell RNA sequencing (scRNA-seq) on porcine wounds in conjunction with spatial proteomic analysis, we found perturbations in fibroblast dynamics with verteporfin treatment and the presence of putative pro-regenerative/profibrotic fibroblasts enriched in regenerating/scarring pig wounds, respectively. We also identified differences in enriched myeloid cell subpopulations after treatment and linked this observation to increased elaboration of interleukin-33 (IL-33) in regenerating wounds. Finally, we validated our findings in a xenograft wound model containing human neonatal foreskin engrafted onto nude mice and used scRNA-seq of human wound cells to draw parallels with fibroblast subpopulation dynamics in porcine wounds. Collectively, our findings provide support for the clinical translation of local mechanotransduction inhibitors to prevent human skin scarring, and they clarify a YAP/IL-33 signaling axis in large animal wound regeneration.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"14 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451584","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}

{"title":"Inhibiting mechanotransduction prevents scarring and yields regeneration in a large animal model","authors":"Shamik Mascharak,&nbsp;Michelle Griffin,&nbsp;Heather E. Talbott,&nbsp;Jason L. Guo,&nbsp;Jennifer Parker,&nbsp;Annah Grace Morgan,&nbsp;Caleb Valencia,&nbsp;Maxwell Michael Kuhnert,&nbsp;Dayan J. Li,&nbsp;Norah E. Liang,&nbsp;Rachel M. Kratofil,&nbsp;Joseph A. Daccache,&nbsp;Ikjot Sidhu,&nbsp;Michael F. Davitt,&nbsp;Nicholas Guardino,&nbsp;John M. Lu,&nbsp;Darren B. Abbas,&nbsp;Nestor M. D. Deleon,&nbsp;Christopher V. Lavin,&nbsp;Sandeep Adem,&nbsp;Anum Khan,&nbsp;Kellen Chen,&nbsp;Dominic Henn,&nbsp;Amanda Spielman,&nbsp;Asha Cotterell,&nbsp;Deena Akras,&nbsp;Mauricio Downer Jr.,&nbsp;Ruth Tevlin,&nbsp;H. Peter Lorenz,&nbsp;Geoffrey C. Gurtner,&nbsp;Michael Januszyk,&nbsp;Shruti Naik,&nbsp;Derrick C. Wan,&nbsp;Michael T. Longaker","doi":"","DOIUrl":"","url":null,"abstract":"<div >Modulating mechanotransduction by inhibiting yes-associated protein (YAP) in mice yields wound regeneration without scarring. However, rodents are loose-skinned and fail to recapitulate key aspects of human wound repair. We sought to elucidate the effects of YAP inhibition in red Duroc pig wounds, the most human-like model of scarring. We show that one-time treatment with verteporfin, a YAP inhibitor, immediately after wounding is sufficient to prevent scarring and to drive wound regeneration in pigs. By performing single-cell RNA sequencing (scRNA-seq) on porcine wounds in conjunction with spatial proteomic analysis, we found perturbations in fibroblast dynamics with verteporfin treatment and the presence of putative pro-regenerative/profibrotic fibroblasts enriched in regenerating/scarring pig wounds, respectively. We also identified differences in enriched myeloid cell subpopulations after treatment and linked this observation to increased elaboration of interleukin-33 (IL-33) in regenerating wounds. Finally, we validated our findings in a xenograft wound model containing human neonatal foreskin engrafted onto nude mice and used scRNA-seq of human wound cells to draw parallels with fibroblast subpopulation dynamics in porcine wounds. Collectively, our findings provide support for the clinical translation of local mechanotransduction inhibitors to prevent human skin scarring, and they clarify a YAP/IL-33 signaling axis in large animal wound regeneration.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 786","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447251","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}

{"title":"Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread","authors":"Felix Pahmeier, Stephanie R. Monticelli, Xinyi Feng, Christy K. Hjorth, Albert Wang, Ana I. Kuehne, Russell R. Bakken, Thomas G. Batchelor, Saeyoung E. Lee, Marissa Middlecamp, Lauren Stuart, Amaro N. Duarte-Neto, Dafna M. Abelson, Jason S. McLellan, Scott B. Biering, Andrew S. Herbert, Kartik Chandran, Eva Harris","doi":"10.1126/scitranslmed.adq5928","DOIUrl":"https://doi.org/10.1126/scitranslmed.adq5928","url":null,"abstract":"Crimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen transmitted by tick bites, with no vaccines or specific therapeutics approved to date. Severe disease manifestations include hemorrhage, endothelial dysfunction, and multiorgan failure. Infected cells release the viral glycoprotein GP38, whose extracellular function is presently unknown. GP38 is considered an important target for vaccine and therapeutic design because GP38-specific antibodies can protect against severe disease in animal models, albeit through an unknown mechanism of action. Here, we showed that GP38 induces endothelial barrier dysfunction in vitro by disrupting the endothelial glycocalyx layer and triggering hyperpermeability. We also demonstrated that GP38 alone can cause vascular leak in a mouse model. We found that CCHFV infection leads to vascular leak in vivo, which was exacerbated by exogenous administration of GP38, facilitating dissemination of CCHFV into target tissues such as the liver. Protective antibodies that recognized specific antigenic sites on GP38, but not a protective neutralizing antibody binding the structural protein Gc, potently inhibited endothelial hyperpermeability in vitro and vascular leak in vivo during CCHFV infection. This work uncovers a function of the circulating viral protein GP38 as a viral toxin in CCHFV pathogenesis and elucidates a potential mode of action of nonneutralizing yet protective GP38-specific antibodies.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"64 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451585","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}

{"title":"Gluconolactone restores immune regulation and alleviates skin inflammation in lupus-prone mice and in patients with cutaneous lupus","authors":"Wei Li, Antonios G. A. Kolios, Wenliang Pan, Catalina Burbano, Kohei Karino, Theodoros Vichos, Morgane Humbel, Vasileios C. Kyttaris, Maria G. Tsokos, George C. Tsokos","doi":"10.1126/scitranslmed.adp4447","DOIUrl":"https://doi.org/10.1126/scitranslmed.adp4447","url":null,"abstract":"Systemic lupus erythematosus (SLE) is characterized by dysfunctional regulatory T cells (T <jats:sub>regs</jats:sub> ). We previously showed that protein phosphatase 2A (PP2A) plays a critical role in maintaining the suppressive function of T <jats:sub>regs</jats:sub> . Here, we analyzed phosphoproteomics and metabolomics data from PP2A–wild type and PP2A-deficient T <jats:sub>regs</jats:sub> and demonstrated that PP2A regulates T <jats:sub>reg</jats:sub> function through the pentose phosphate pathway (PPP). Furthermore, we proved that the PPP metabolite gluconolactone (GDL) enhances in vitro induced (i)T <jats:sub>reg</jats:sub> differentiation and function by promoting forkhead box protein 3 and phosphorylated signal transducer and activator of transcription 5 expression and inhibits T helper 17 (T <jats:sub>H</jats:sub> 17) differentiation in murine cells. In short-term imiquimod-induced autoimmunity in mice, treatment with GDL alleviates inflammation by inhibiting T <jats:sub>H</jats:sub> 17 cells. GDL promotes T <jats:sub>regs</jats:sub> function and alleviates skin lesions in MRL. <jats:italic>lpr</jats:italic> lupus-prone mice in vivo. It also promotes T <jats:sub>regs</jats:sub> differentiation and function in ex vivo experiments using cells from patients with SLE. Last, in patients suffering from cutaneous lupus erythematosus, topical application of a GDL-containing cream controlled skin inflammation and improved the clinical and histologic appearance of the skin lesions within 2 weeks. Together, we have identified GDL as a PPP metabolite and showed mechanistically that it restores immune regulation in vitro and in vivo by inducing T <jats:sub>reg</jats:sub> suppressive function and inhibiting T <jats:sub>H</jats:sub> 17 cells. GDL should be considered as a treatment approach for inflammatory and autoimmune diseases.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"1 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452347","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}

{"title":"Gluconolactone restores immune regulation and alleviates skin inflammation in lupus-prone mice and in patients with cutaneous lupus","authors":"Wei Li,&nbsp;Antonios G. A. Kolios,&nbsp;Wenliang Pan,&nbsp;Catalina Burbano,&nbsp;Kohei Karino,&nbsp;Theodoros Vichos,&nbsp;Morgane Humbel,&nbsp;Vasileios C. Kyttaris,&nbsp;Maria G. Tsokos,&nbsp;George C. Tsokos","doi":"","DOIUrl":"","url":null,"abstract":"<div >Systemic lupus erythematosus (SLE) is characterized by dysfunctional regulatory T cells (T_regs). We previously showed that protein phosphatase 2A (PP2A) plays a critical role in maintaining the suppressive function of T_regs. Here, we analyzed phosphoproteomics and metabolomics data from PP2A–wild type and PP2A-deficient T_regs and demonstrated that PP2A regulates T_reg function through the pentose phosphate pathway (PPP). Furthermore, we proved that the PPP metabolite gluconolactone (GDL) enhances in vitro induced (i)T_reg differentiation and function by promoting forkhead box protein 3 and phosphorylated signal transducer and activator of transcription 5 expression and inhibits T helper 17 (T_H17) differentiation in murine cells. In short-term imiquimod-induced autoimmunity in mice, treatment with GDL alleviates inflammation by inhibiting T_H17 cells. GDL promotes T_regs function and alleviates skin lesions in MRL.<i>lpr</i> lupus-prone mice in vivo. It also promotes T_regs differentiation and function in ex vivo experiments using cells from patients with SLE. Last, in patients suffering from cutaneous lupus erythematosus, topical application of a GDL-containing cream controlled skin inflammation and improved the clinical and histologic appearance of the skin lesions within 2 weeks. Together, we have identified GDL as a PPP metabolite and showed mechanistically that it restores immune regulation in vitro and in vivo by inducing T_reg suppressive function and inhibiting T_H17 cells. GDL should be considered as a treatment approach for inflammatory and autoimmune diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 786","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adp4447","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447225","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":"β cell dedifferentiation, the underlying mechanism of diabetes in Wolfram syndrome","authors":"Kikuko Amo-Shiinoki,&nbsp;Katsuya Tanabe,&nbsp;Wataru Nishimura,&nbsp;Masayuki Hatanaka,&nbsp;Manabu Kondo,&nbsp;Syota Kagawa,&nbsp;Meng Zou,&nbsp;Shuntaro Morikawa,&nbsp;Yoshihiko Sato,&nbsp;Mitsuhisa Komatsu,&nbsp;Hiroki Mizukami,&nbsp;Naoki Nishida,&nbsp;Shun-Ichiro Asahara,&nbsp;Hiroshi Masutani,&nbsp;Yukio Tanizawa","doi":"","DOIUrl":"","url":null,"abstract":"<div >Insulin-dependent diabetes in patients with Wolfram syndrome (WS; OMIM 222300) has been linked to endoplasmic reticulum (ER) stress caused by <i>WFS1</i> gene mutations. However, the pathological process of ER stress–associated β cell failure remains to be fully elucidated. Our results indicate loss of β cell lineage and subsequent dedifferentiation as the mechanisms underlying functional and mass deficits in WS. An immunohistochemical analysis of human pancreatic sections from deceased individuals with WS revealed a near-complete loss of β cells and subsequent decrease in α cells, suggesting loss of endocrine function. <i>Wfs1</i>-deficient mice displayed dysfunction, gradual loss, and dedifferentiation of β cells, leading to permanent hyperglycemia. Impairment of the β cell lineage was observed after weaning, leading to the mixed phenotype of insulin- and glucagon-producing cells in a subset of the lineage-traced β cells. Islets of <i>Wfs1</i>-deficient mice increased the number of dedifferentiated cells that maintained general endocrine features but were no longer reactive with antisera against pancreatic hormones. Mechanistically, <i>Wfs1</i>-null islets had a lower adenosine triphosphate content and impaired oxidative glycolysis, although mitochondrial oxidative function was maintained. The functional and metabolic alterations of WS β cells were recovered by deletion of thioredoxin-interacting protein (Txnip), an ER stress–induced protein up-regulated in <i>Wfs1</i> deficiency. <i>Txnip</i> deletion preserved functional β cells and prevented diabetes progression in <i>Wfs1</i>-deficient mice. Together, this study deciphered pathological mechanisms of β cell dedifferentiation in β cell failure and has implications for Txnip inhibition in WS therapy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 786","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447246","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}

{"title":"Erratum for the Research Article \"BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure\" by Q. Duan <i>et al</i>.","authors":"","doi":"10.1126/scitranslmed.adw3692","DOIUrl":"https://doi.org/10.1126/scitranslmed.adw3692","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 786","pages":"eadw3692"},"PeriodicalIF":15.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458971","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}

{"title":"β cell dedifferentiation, the underlying mechanism of diabetes in Wolfram syndrome","authors":"Kikuko Amo-Shiinoki, Katsuya Tanabe, Wataru Nishimura, Masayuki Hatanaka, Manabu Kondo, Syota Kagawa, Meng Zou, Shuntaro Morikawa, Yoshihiko Sato, Mitsuhisa Komatsu, Hiroki Mizukami, Naoki Nishida, Shun-Ichiro Asahara, Hiroshi Masutani, Yukio Tanizawa","doi":"10.1126/scitranslmed.adp2332","DOIUrl":"https://doi.org/10.1126/scitranslmed.adp2332","url":null,"abstract":"Insulin-dependent diabetes in patients with Wolfram syndrome (WS; OMIM 222300) has been linked to endoplasmic reticulum (ER) stress caused by <jats:italic>WFS1</jats:italic> gene mutations. However, the pathological process of ER stress–associated β cell failure remains to be fully elucidated. Our results indicate loss of β cell lineage and subsequent dedifferentiation as the mechanisms underlying functional and mass deficits in WS. An immunohistochemical analysis of human pancreatic sections from deceased individuals with WS revealed a near-complete loss of β cells and subsequent decrease in α cells, suggesting loss of endocrine function. <jats:italic>Wfs1</jats:italic> -deficient mice displayed dysfunction, gradual loss, and dedifferentiation of β cells, leading to permanent hyperglycemia. Impairment of the β cell lineage was observed after weaning, leading to the mixed phenotype of insulin- and glucagon-producing cells in a subset of the lineage-traced β cells. Islets of <jats:italic>Wfs1</jats:italic> -deficient mice increased the number of dedifferentiated cells that maintained general endocrine features but were no longer reactive with antisera against pancreatic hormones. Mechanistically, <jats:italic>Wfs1</jats:italic> -null islets had a lower adenosine triphosphate content and impaired oxidative glycolysis, although mitochondrial oxidative function was maintained. The functional and metabolic alterations of WS β cells were recovered by deletion of thioredoxin-interacting protein (Txnip), an ER stress–induced protein up-regulated in <jats:italic>Wfs1</jats:italic> deficiency. <jats:italic>Txnip</jats:italic> deletion preserved functional β cells and prevented diabetes progression in <jats:italic>Wfs1</jats:italic> -deficient mice. Together, this study deciphered pathological mechanisms of β cell dedifferentiation in β cell failure and has implications for Txnip inhibition in WS therapy.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452099","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}

{"title":"A window-of-opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma","authors":"Veronica Rendo,&nbsp;Eudocia Q. Lee,&nbsp;Connor Bossi,&nbsp;Nicholas Khuu,&nbsp;Michelle A. Rudek,&nbsp;Sangita Pal,&nbsp;Narmen Azazmeh,&nbsp;Rumana Rashid,&nbsp;Jia-Ren Lin,&nbsp;Margaret Cusick,&nbsp;Abigail R. N. Reynolds,&nbsp;Auriole C. R. Fassinou,&nbsp;Georges Ayoub,&nbsp;Seth Malinowski,&nbsp;Emily Lapinskas,&nbsp;William Pisano,&nbsp;John Jeang,&nbsp;Sylwia A. Stopka,&nbsp;Michael S. Regan,&nbsp;Johan Spetz,&nbsp;Arati Desai,&nbsp;Frank Lieberman,&nbsp;Kamalakannan Palanichamy,&nbsp;Joy D. Fisher,&nbsp;Kristine Pelton,&nbsp;Raymond Y. Huang,&nbsp;Kristopher A. Sarosiek,&nbsp;Louis B. Nabors,&nbsp;Matthias Holdhoff,&nbsp;Neeraja Danda,&nbsp;Roy Strowd,&nbsp;Serena Desideri,&nbsp;Tobias Walbert,&nbsp;Xiaobu Ye,&nbsp;Arnab Chakravarti,&nbsp;Peter K. Sorger,&nbsp;Sandro Santagata,&nbsp;Nathalie Y. R. Agar,&nbsp;Stuart A. Grossman,&nbsp;Brian M. Alexander,&nbsp;Patrick Y. Wen,&nbsp;Keith L. Ligon,&nbsp;Rameen Beroukhim","doi":"","DOIUrl":"","url":null,"abstract":"<div >Inhibitors of murine double minute homolog 2 (MDM2) represent a promising therapeutic approach for the treatment of <i>TP53</i> wild-type glioblastomas (GBMs), reactivating p53 signaling to induce cancer cell death. We conducted a surgical window-of-opportunity trial (NCT03107780) of the MDM2 inhibitor navtemadlin (KRT-232) in 21 patients with <i>TP53</i> wild-type recurrent GBM to determine achievable drug concentrations within tumor tissues and biological mechanisms of response and resistance. Participants received navtemadlin at 120 mg (<i>n</i> = 10) or 240 mg (<i>n</i> = 11) for 2 days before surgical resection and after surgery until progression or unacceptable toxicity. Both 120 and 240 mg daily dosing achieved a pharmacodynamic impact, but median progression-free survival was 3.1 months. DNA sequencing of three recurrent tumors revealed an absence of <i>TP53</i>-inactivating mutations, indicating alternative mechanisms of resistance. To understand the mechanisms of response and resistance associated with navtemadlin, we conducted functional and spatial analyses of human tissue and patient-derived GBM neurosphere models. Navtemadlin induced partial tumor cell death as monotherapy, and combination with temozolomide enhanced apoptosis in GBM neurospheres while sparing normal bone marrow cells in vitro. We also observed up-regulation of oligodendrocyte differentiation genes with navtemadlin treatment and enrichment of oligodendrocyte transcription factor 2 (OLIG2)–positive cells at relapse, suggesting an unexplored mechanism of navtemadlin tolerance in GBM. Overall, these results indicated that clinically achievable doses of navtemadlin exert pharmacodynamic effects on GBM and suggest that combined treatment with temozolomide may be a route to more durable survival benefits.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 786","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447260","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}

{"title":"Dysfunctional CD11c−CD21− extrafollicular memory B cells are enriched in the periphery and tumors of patients with cancer","authors":"Ayana T. Ruffin,&nbsp;Allison N. Casey,&nbsp;Sheryl R. Kunning,&nbsp;Ian P. MacFawn,&nbsp;Zhentao Liu,&nbsp;Charu Arora,&nbsp;Anjali Rohatgi,&nbsp;Felicia Kemp,&nbsp;Caleb Lampenfeld,&nbsp;Ashwin Somasundaram,&nbsp;Giovanna Rappocciolo,&nbsp;John M. Kirkwood,&nbsp;Umamaheswar Duvvuri,&nbsp;Raja Seethala,&nbsp;Riyue Bao,&nbsp;Yufei Huang,&nbsp;Anthony R. Cillo,&nbsp;Robert L. Ferris,&nbsp;Tullia C. Bruno","doi":"","DOIUrl":"","url":null,"abstract":"<div >Many patients with recurrent and metastatic cancer fail to produce a durable response to immunotherapy, highlighting the need for additional therapeutic targets to improve the immune landscape in tumors. Recent studies have highlighted the importance of B cells in the antitumor response, with memory B cells (MBCs) being prognostic in a variety of solid tumors. MBCs are a heterogenous B cell subset and can be generated through both germinal center reactions and extrafollicular (EF) responses. EF-derived MBCs have been recently linked to poor prognosis and treatment resistance in solid tumors and thus may represent candidate biomarkers or immunotherapy targets. EF-derived MBCs, termed “double-negative” (DN) MBCs may be further classified on the basis of surface expression of CD11c and CD21 into DN1, DN2, and DN3 MBCs. CD11c⁻CD21⁺ DN1 MBCs and CD11c⁺CD21⁻ DN2 MBCs have been well studied across inflammatory diseases; however, the biology and clinical relevance of CD11c⁻CD21⁻ DN3 MBCs remain unknown. Here, we report an accumulation of DN3 MBCs in the blood and tumors of patients with head and neck squamous cell carcinoma (HNSCC) and an increase in DN3 MBCs in locally advanced HNSCC tumors. Circulating and intratumoral DN3 MBCs were hyporesponsive to antigen stimulation, had low antibody production, and failed to differentiate into antibody-secreting cells. Moreover, DN3 MBCs accumulated selectively outside of tertiary lymphoid structures. Last, circulating DN3 MBCs correlated with poor therapeutic response, advanced disease, and worse outcomes in patients with HNSCC and melanoma, supporting further assessment of EF-derived MBCs as potential biomarkers and therapeutic targets.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 786","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447236","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}