Science Translational Medicine最新文献

{"title":"Icosapent ethyl reduces arterial thrombosis by inhibition of cyclooxygenase-1–induced platelet reactivity","authors":"Philipp Mourikis,&nbsp;Marcel Benkhoff,&nbsp;Laura Wildeis,&nbsp;Maike Barcik,&nbsp;Carolin Helten,&nbsp;Cristina Coman,&nbsp;Fiorella A. Solari,&nbsp;Daniel Krahn,&nbsp;Lisa Dannenberg,&nbsp;Samantha Ahlbrecht,&nbsp;Dorothee Zikeli,&nbsp;Amelie Utz,&nbsp;Kajetan Trojovsky,&nbsp;Hannah Richter,&nbsp;Gabrielle Al Kassis,&nbsp;René M’Pembele,&nbsp;Saif Zako,&nbsp;Tim Huckenbeck,&nbsp;Sofia Bauer,&nbsp;Danny Schmitz,&nbsp;Susanne Pfeiler,&nbsp;Norbert Gerdes,&nbsp;Christof Dücker,&nbsp;Joachim Pircher,&nbsp;Zhang Zhe,&nbsp;Manuela Thienel,&nbsp;Qurrat Ul Ain,&nbsp;Petra Keul,&nbsp;Nicholas Kirkby,&nbsp;Dennis Sohn,&nbsp;Wilfried Budach,&nbsp;Thomas Hohlfeld,&nbsp;Karsten Schrör,&nbsp;Bodo Levkau,&nbsp;Tobias Zeus,&nbsp;Steven H. L. Verhelst,&nbsp;Robert Ahrends,&nbsp;Albert Sickmann,&nbsp;Jane Mitchell,&nbsp;Samia Mora,&nbsp;JoAnn E. Manson,&nbsp;Deepak L. Bhatt,&nbsp;Ulf Landmesser,&nbsp;Steffen Massberg,&nbsp;Malte Kelm,&nbsp;Tobias Petzold,&nbsp;Amin Polzin","doi":"10.1126/scitranslmed.ado0610","DOIUrl":"10.1126/scitranslmed.ado0610","url":null,"abstract":"<div >Large, randomized trials testing omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation to reduce cardiovascular events have reported contradictory results. Interpretation of these trials is challenging, because different dosages and formulations of ω-3 PUFA were tested. Furthermore, the exact mechanisms for the reduction in cardiovascular events are unclear. In this study, we investigated the effects of ω-3 PUFA on platelet adhesion, degranulation, and aggregation in vitro and in patients with cardiovascular disease using different formulations of ω-3 PUFA. We also investigated the effects of ω-3 PUFA in rodent models of arterial thrombosis and in tail bleeding assays, including in cyclooxygenase-1 (COX-1)–deficient animals. The ω-3 PUFA eicosapentaenoic acid (EPA) dose-dependently reduced platelet adhesion, degranulation, and aggregation in vitro. Moreover, arterial thrombus formation in wild-type mice was inhibited by oral EPA administration before thrombus formation. Photoaffinity labeling and in silico docking analyses suggested a direct, competitive interaction of EPA and arachidonic acid at the level of COX-1. The COX-1 dependency of EPA’s inhibitory effects was confirmed by platelet-specific COX-1–deficient animals that had no reduction of thrombus burden by EPA. In patients with cardiovascular disease, switching from 2 grams of EPA twice daily to 1 gram of docosahexaenoic acid (DHA) (460 milligrams of EPA and 380 milligrams of DHA) once daily completely blunted the platelet inhibition achieved by EPA. Our results may partially explain contradictory results with different ω-3 PUFA formulations in clinical trials.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 799","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104216","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":"In vivo CRISPR activation screen identifies acyl-CoA–binding protein as a driver of bone metastasis","authors":"Hongqi Teng,&nbsp;Qinglei Hang,&nbsp;Caishang Zheng,&nbsp;Yuelong Yan,&nbsp;Shaomin Liu,&nbsp;Yang Zhao,&nbsp;Yalan Deng,&nbsp;Litong Nie,&nbsp;Weiche Wu,&nbsp;Marisela Sheldon,&nbsp;Zachary Yu,&nbsp;Wei Shi,&nbsp;Jianxuan Gao,&nbsp;Chenling Meng,&nbsp;Consuelo Martinez,&nbsp;Jie Zhang,&nbsp;Fan Yao,&nbsp;Yutong Sun,&nbsp;Di Zhao,&nbsp;Boyi Gan,&nbsp;Tong Meng,&nbsp;Li Ma","doi":"10.1126/scitranslmed.ado7225","DOIUrl":"10.1126/scitranslmed.ado7225","url":null,"abstract":"<div >One of the most common sites of cancer metastasis is to the bone. Bone metastasis is associated with substantial morbidity and mortality, and current therapeutic interventions remain largely palliative. Metastasizing tumor cells need to reprogram their metabolic states to adapt to the nutrient environment of distant organs; however, the role and translational relevance of lipid metabolism in bone metastasis remain unclear. Here, we used an in vivo CRISPR activation screening system coupled with positive selection to identify acyl–coenzyme A (CoA) binding protein (ACBP) as a bone metastasis driver. In nonmetastatic and weakly metastatic cancer cells, overexpression of wild-type ACBP, but not the acyl-CoA–binding deficient mutant, stimulated fatty acid oxidation (FAO) and bone metastasis. Conversely, knockout of ACBP in highly bone metastatic cancer cells abrogated metastatic bone colonization. Mechanistically, ACBP-mediated FAO increased ATP and NADPH production, reduced reactive oxygen species, and inhibited lipid peroxidation and ferroptosis. We found that ACBP expression correlated with metabolic signaling, bone metastatic ability, and poor clinical outcomes. In mouse models, pharmacological blockade of FAO or treatment with a ferroptosis inducer inhibited bone metastasis. Together, our findings reveal the role of lipid metabolism in tumor cells adapting and thriving in the bone and identify ACBP as a key regulator of this process. Agents that target FAO or induce ferroptosis represent a promising therapeutic approach for treating bone metastases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 799","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104223","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":"An AAV variant selected through NHP screens robustly transduces the brain and drives secreted protein expression in NHPs and mice","authors":"Luis Tecedor,&nbsp;Yong Hong Chen,&nbsp;David E. Leib,&nbsp;Paul T. Ranum,&nbsp;Megan S. Keiser,&nbsp;Brian C. Lewandowski,&nbsp;Elli M. Carrell,&nbsp;Elena Lysenko,&nbsp;Icnelia Huerta-Ocampo,&nbsp;Sakshi Arora,&nbsp;Congsheng Cheng,&nbsp;Xueyuan Liu,&nbsp;Beverly L. Davidson","doi":"10.1126/scitranslmed.adr2531","DOIUrl":"10.1126/scitranslmed.adr2531","url":null,"abstract":"<div >Recent work has shown that prolonged expression of recombinant proteins after adeno-associated virus (AAV)–mediated delivery of gene therapy to long-lived, ventricle-lining ependymal cells can profoundly affect disease phenotypes in animal models of neurodegenerative diseases. Here, we performed in vivo screens of millions of peptide-modified capsid variants of AAV1, AAV2, and AAV9 parental serotypes in adult nonhuman primates (NHPs) to identify capsids with potent transduction of key brain tissues, including ependyma, after intracerebroventricular injection. Through these screens, we identified an AAV capsid, AAV-Ep⁺, with markedly increased potency in transducing ependymal cells and cerebral neurons in NHPs. AAV-Ep⁺’s potency was conserved in three species of NHP, two mouse strains, and human neurons derived from induced pluripotent stem cells. To apply AAV-Ep⁺ to the treatment of ceroid lipofuscinosis type 2 disease, a lysosomal storage disorder caused by loss-of-function mutations in <i>tripeptidyl-peptidase 1</i> (<i>TPP1</i>), we used the capsid to package the human <i>TPP1</i> transgene (AAV-Ep⁺.hTPP1) and delivered the construct by intracerebroventricular injection into mice lacking TPP1 activity. AAV-Ep⁺ provided robust and therapeutically relevant TPP1 protein concentrations in these mice, significantly improving tremor and life span. In NHPs, high cerebrospinal fluid (CSF) TPP1 concentrations were achieved after intracerebroventricular delivery of AAV-Ep⁺.hTPP1 at a total dose of 1 × 10¹² viral genomes, which was more than 30× lower than previously reported doses in NHPs. These results suggest that AAV-Ep⁺ may be a potent vector for gene therapy applications where CSF protein expression is required.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 798","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950620","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":"Intra-amniotic antisense oligonucleotide treatment improves phenotypes in preclinical models of spinal muscular atrophy","authors":"Beltran Borges,&nbsp;Stephen M. Brown,&nbsp;Wan-Jin Chen,&nbsp;Maria T. Clarke,&nbsp;Akos Herzeg,&nbsp;Jae Hong Park,&nbsp;Joshua Ross,&nbsp;Lingling Kong,&nbsp;Madeline Denton,&nbsp;Amy K. Smith,&nbsp;Tony Lum,&nbsp;Fareha Moulana Zada,&nbsp;Marco Cordero,&nbsp;Nalin Gupta,&nbsp;Sarah E. Cook,&nbsp;Heather Murray,&nbsp;John Matson,&nbsp;Stephanie Klein,&nbsp;C. Frank Bennett,&nbsp;Adrian R. Krainer,&nbsp;Tippi C. MacKenzie,&nbsp;Charlotte J. Sumner","doi":"10.1126/scitranslmed.adv4656","DOIUrl":"10.1126/scitranslmed.adv4656","url":null,"abstract":"<div >Neurological disorders with onset before or at birth are a leading cause of morbidity and mortality in infants and children. Prenatal treatment has the potential to reduce or prevent irreversible neuronal loss and facilitate normal neurodevelopment. We hypothesized that antisense oligonucleotides (ASOs) delivered to the amniotic fluid by intra-amniotic (IA) injection could safely distribute to the fetal central nervous system (CNS) and provide therapeutic benefit in the motor neuron disease spinal muscular atrophy (SMA), caused by mutations of the survival of motor neuron 1 gene (<i>SMN1</i>), leading to deficiency of SMN protein. Although the splice-switching ASO nusinersen ameliorates SMA when delivered postnatally, substantial deficits can remain in severely affected infants. Here, IA injection of ASOs into two mouse models of severe SMA increased SMN expression in the CNS. In SMAΔ7 mice, which manifest pathology in utero, prenatal treatment improved motor neuron numbers, motor axon development, motor behavioral tests, and survival when compared with those in mice treated postnatally (between P1 and P3). To assess the feasibility of prenatal treatment in a large-animal model, ASOs were delivered midgestation to fetal sheep by IA or intracranial injection. ASOs delivered by IA injection distributed to the spinal cord at therapeutic concentrations and to multiple peripheral tissues without evidence of substantial toxicity to the fetus or mother. These data demonstrated that IA delivery of ASOs holds potential as a minimally invasive approach for prenatal treatment of SMA and possibly other severe, early-onset neurological disorders.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 798","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950590","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":"MEK1/2 inhibitors suppress pathological α-synuclein and neurotoxicity in cell models and a humanized mouse model of Parkinson’s disease","authors":"Huilan Wang,&nbsp;Qing Wang,&nbsp;Haoxiang Xu,&nbsp;Yuanzheng Wu,&nbsp;Siulam Cheung,&nbsp;Qianhui Xu,&nbsp;Chengfang Pan,&nbsp;Jingyu Cao,&nbsp;Zhiyuan Cao,&nbsp;Ruonan Yang,&nbsp;Yu Ding,&nbsp;Yiyan Fei,&nbsp;Yongfeng Chen,&nbsp;Jian Wang,&nbsp;Cong Liu,&nbsp;Boxun Lu","doi":"10.1126/scitranslmed.adp4625","DOIUrl":"10.1126/scitranslmed.adp4625","url":null,"abstract":"<div >The abnormal accumulation of misfolded proteins is a common hallmark of many neurodegenerative disorders. Among these proteins, α-synuclein (αsyn) is a well-characterized pathogenic protein in Parkinson’s disease (PD) and other synucleinopathies. αsyn can be hyperphosphorylated and form pathological aggregates, leading to neurodegeneration. Thus, chemical modulators of pathological αsyn may suppress its downstream toxicity and provide entry points to therapeutic intervention. Here, we identified mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitors as negative modulators of basal αsyn in wild-type cells and that pathological αsyn in αsyn preformed fibrils (αsyn-PFF) induced the neuroblastoma cell line SHSY-5Y, PC12 cells, and primary cultured neurons. We further demonstrated that these inhibitors suppressed Ser¹²⁹ phosphorylated αsyn (p-αsyn) through the kinase PLK2 downstream of MEK1/2-ERK2 in PD cell models. We established a humanized PD mouse model by injecting human αsyn-PFF into mice with homozygous knock-in of human <i>SNCA</i>. Oral administration of blood-brain barrier–penetrable MEK1/2 inhibitors lowered pathological αsyn and rescued PD-relevant phenotypes with an acceptable safety profile in these mice. Collectively, these data highlight MEK1/2 inhibitors as a potential therapeutic strategy for PD.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 798","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950611","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":"An oral norovirus vaccine generates mucosal immunity and reduces viral shedding in a phase 2 placebo-controlled challenge study","authors":"Becca A. Flitter,&nbsp;Joshua Gillard,&nbsp;Susan N. Greco,&nbsp;Maria D. Apkarian,&nbsp;Nick P. D’Amato,&nbsp;Lam Quynh Nguyen,&nbsp;Elena D. Neuhaus,&nbsp;Darreann Carmela M. Hailey,&nbsp;Marcela F. Pasetti,&nbsp;Mallory Shriver,&nbsp;Christina Quigley,&nbsp;Robert W. Frenck Jr.,&nbsp;Lisa C. Lindesmith,&nbsp;Ralph S. Baric,&nbsp;Lee-Jen Wei,&nbsp;Sean N. Tucker,&nbsp;James F. Cummings","doi":"10.1126/scitranslmed.adh9906","DOIUrl":"10.1126/scitranslmed.adh9906","url":null,"abstract":"<div >There are currently no licensed vaccines for norovirus, a leading cause of epidemic and endemic gastroenteritis worldwide. Clinical advancement of promising vaccine candidates from phase 2 studies to phase 3 field trials has been hampered by the lack of robust immunological correlates of protection. Here, we conducted a phase 2b randomized, placebo-controlled vaccination and challenge study to assess the safety, efficacy, immunogenicity, and correlates of protection of VXA-G1.1-NN, an oral tablet norovirus vaccine. VXA-G1.1-NN was safe and well tolerated, conferred protection against norovirus GI.1 challenge, and reduced viral shedding in stool and emesis. Norovirus VP1-specific serum immunoglobulin A (IgA), IgG, and functional blocking antibody titers increased substantially after oral vaccination. Moreover, oral immunization stimulated VP1-specific IgA antibodies in nasal lining fluid, saliva, and fecal samples. Serum and mucosal antibody responses 7 days after vaccination were correlated with the induction of antibody-secreting, α4β7⁺ mucosal-homing B cells. Machine learning analyses of vaccine-stimulated immune components identified serum functional blocking antibody and fecal IgA as robust correlates of protection. These results demonstrate the potential of VXA-G1.1-NN as a safe and effective oral norovirus vaccine and reveal critical immunological features underpinning vaccine efficacy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 798","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adh9906","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950615","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":"Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease","authors":"Mandeep Singh,&nbsp;Raymond H. Y. Louie,&nbsp;Jerome Samir,&nbsp;Matthew A. Field,&nbsp;Claire Milthorpe,&nbsp;Thiruni Adikari,&nbsp;Joseph Mackie,&nbsp;Ellise Roper,&nbsp;Megan Faulks,&nbsp;Katherine J. L. Jackson,&nbsp;Andrew Calcino,&nbsp;Melinda Y. Hardy,&nbsp;Piers Blombery,&nbsp;Timothy G. Amos,&nbsp;Ira W. Deveson,&nbsp;Helen Vander Wende,&nbsp;Stephen N. Floor,&nbsp;Scott A. Read,&nbsp;Dmitri Shek,&nbsp;Antoine Guerin,&nbsp;Cindy S. Ma,&nbsp;Stuart G. Tangye,&nbsp;Antonio Di Sabatino,&nbsp;Marco V. Lenti,&nbsp;Alessandra Pasini,&nbsp;Rachele Ciccocioppo,&nbsp;Golo Ahlenstiel,&nbsp;Dan Suan,&nbsp;Jason A. Tye-Din,&nbsp;Christopher C. Goodnow,&nbsp;Fabio Luciani","doi":"10.1126/scitranslmed.adp6812","DOIUrl":"10.1126/scitranslmed.adp6812","url":null,"abstract":"<div >Intestinal inflammation continues in a subset of patients with celiac disease despite a gluten-free diet. Here, by applying multi-omic single-cell analysis to duodenal biopsies, we found that low-grade malignancies with lymphoma driver mutations in patients with refractory celiac disease type 2 (RCD2) are comprised by surface CD3-negative (sCD3⁻) lymphocytes stalled at an innate lymphoid cell (ILC)–progenitor T cell stage undergoing extensive <i>TRA</i>, <i>TRB</i>, and <i>TRD</i> TCR recombination. In people with refractory celiac disease type 1 (RCD1), a disease currently lacking explanation, we identified sCD3⁺ T cells with lymphoma driver mutations in 6 of 10 individuals with RCD1 and in one of the patients with active, recently diagnosed celiac disease. Furthermore, the mutant T cells formed large TCRαβ clones and displayed inflammatory and cytotoxic molecular profiles. Thus, accumulation of lymphoma driver–mutated T cells and sCD3⁻ progenitors may contribute to chronic, nonresponsive celiac disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 798","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950624","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":"Rapid closure and hemostasis of ruptured soft tissues using a modified human tropoelastin-based sealant in preclinical models","authors":"Mahsa Ghovvati,&nbsp;Saumya Jain,&nbsp;George Z. Cheng,&nbsp;Naoki Kaneko,&nbsp;Joshua A. Boys,&nbsp;Taichiro Imahori,&nbsp;Tess De Maeseneer,&nbsp;Reihaneh Haghniaz,&nbsp;Robert B. Cameron,&nbsp;Anthony S. Weiss,&nbsp;Nasim Annabi","doi":"10.1126/scitranslmed.adr6458","DOIUrl":"10.1126/scitranslmed.adr6458","url":null,"abstract":"<div >Treatment of injuries to soft elastic organs is often hindered by challenging anatomical features and limitations of existing sealant materials, which may lack adequate tissue adhesion, elasticity, biocompatibility, and effective hemostatic properties. To address these clinical challenges, we developed an injectable elastic sealant formulated with methacryloyl-modified human recombinant tropoelastin (MeTro) and Laponite silicate nanoplatelets (SNs). We optimized the hydrogel formulation for mechanical properties, adhesion, biocompatibility, and hemostatic properties and used visible light for cross-linking to improve safety. MeTro/SN hydrogels had increased tissue adhesion strength and burst pressure in vitro and ex vivo compared with MeTro alone or commercial sealants. The addition of SNs to the hydrogels facilitated faster blood clotting in vitro without increasing hemolysis. Applied to incisional injuries on rat lungs or aortas, MeTro/SN had burst pressures comparable to those of native tissue and greater than those of MeTro after a 7-day in vivo application. On porcine lungs, MeTro/SN also supported effective lung sealing and burst pressure similar to native lung 14 days after injury sealing. In a rodent tail hemostasis model, MeTro/SN reduced bleeding compared with MeTro. In an injured porcine lung model, early hemostasis was better than the tested commercial sealants. The results demonstrated that MeTro/SN provided effective tissue sealing and promoted hemostasis in a time frame that minimized blood loss without causing a major inflammatory response. These findings highlight the translational potential of our engineered sealant with biomimetic mechanics, durable tissue adhesion, and rapid hemostasis as a multipronged approach for the sealing and repair of traumatic injuries to soft organs.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 798","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950604","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":"Mitigating T cell DNA damage during PARP inhibitor treatment enhances antitumor efficacy","authors":"Jiahao Liu,&nbsp;Xiaofei Jiao,&nbsp;Wei Mu,&nbsp;Huayi Li,&nbsp;Yu Xia,&nbsp;Yijie Wu,&nbsp;Li Zhu,&nbsp;Qing Zhong,&nbsp;Wen Pan,&nbsp;Xingzhe Liu,&nbsp;Minghua Xiang,&nbsp;Jiali Cheng,&nbsp;Haolong Lin,&nbsp;Xuejiao Zhao,&nbsp;Zhiyong Ding,&nbsp;Guang Hu,&nbsp;Gordon B. Mills,&nbsp;Ding Ma,&nbsp;Qinglei Gao,&nbsp;Yong Fang","doi":"10.1126/scitranslmed.adr5861","DOIUrl":"10.1126/scitranslmed.adr5861","url":null,"abstract":"<div >Poly(ADP-ribose) polymerase inhibitors (PARPis) are a class of agents targeting DNA damage repair that have become standard therapy for epithelial ovarian cancer (EOC) and multiple other solid tumors. In addition to targeting DNA damage repair, PARPis actively modulate antitumor immune responses, with efficacy being partially dependent on T cell activity. Here, we found that patient T cells sustain DNA damage during PARPi treatment, which reduces treatment efficacy. Leveraging paired pre- and posttreatment tumor samples from a clinical trial of patients with EOC treated with neoadjuvant niraparib as monotherapy, we showed that the PARPi caused DNA damage, slowed proliferation, and increased apoptosis in T cells, which we validated both in vitro and in mouse models. A genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) knockout screen in primary human T cells identified PARP1 as the principal mediator of PARPi-induced T cell death. T cell–specific deletion of <i>PARP1</i> or mutating <i>Parp1</i> at its binding sites in transgenic mice led to reduced T cell DNA damage during PARPi treatment, resulting in improved efficacy of PARPis, alone or in combination with immune checkpoint inhibition. We then engineered PARPi-tolerant CAR T cells using cytosine base editing, which decreased PARPi-induced PARP1 trapping and led to reduced PARPi-induced DNA damage, resulting in superior antitumor efficacy in xenograft models compared with parental CAR T cells. This study highlights the relevance of PARPi-induced DNA damage to T cells and suggests opportunities to improve the efficacy of PARPis as monotherapy or in combination with immunotherapy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 797","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adr5861","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916022","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":"Splicing regulatory dynamics for precision analysis and treatment of heterogeneous leukemias","authors":"Meenakshi Venkatasubramanian,&nbsp;Leya Schwartz,&nbsp;Nandini Ramachandra,&nbsp;Joshua Bennett,&nbsp;Krithika R. Subramanian,&nbsp;Xiaoting Chen,&nbsp;Shanisha Gordon-Mitchell,&nbsp;Ariel Fromowitz,&nbsp;Kith Pradhan,&nbsp;David Shechter,&nbsp;Srabani Sahu,&nbsp;Diane Heiser,&nbsp;Peggy Scherle,&nbsp;Kashish Chetal,&nbsp;Aishwarya Kulkarni,&nbsp;Davy Lee,&nbsp;Jeff Zhou,&nbsp;Kasiani C. Myers,&nbsp;Elizabeth Tseng,&nbsp;Matthew T. Weirauch,&nbsp;H. Leighton Grimes,&nbsp;Daniel T. Starczynowski,&nbsp;Amit Verma,&nbsp;Nathan Salomonis","doi":"10.1126/scitranslmed.adr1471","DOIUrl":"10.1126/scitranslmed.adr1471","url":null,"abstract":"<div >The role of splicing dysregulation in cancer is underscored by splicing factor mutations; however, its impact in the absence of such rare mutations remains poorly understood. Prompted by the finding that splicing uniquely resolved genetic subtypes of cancer, we developed an unsupervised computational workflow called OncoSplice to comprehensively define tumor molecular landscapes. In adult and pediatric acute myeloid leukemia (AML), OncoSplice identified the spectrum of driver genetics from splicing profiles alone, defined more than a dozen previously unreported molecular subtypes recurrent across AML cohorts, and discovered a dominant splicing subtype that partially phenocopies <i>U2AF1</i>-mutant splicing. Although pediatric leukemias lack splicing factor mutations, this <i>U2AF1</i>-like subtype similarly spanned pediatric and adult AML genetics and consistently predicted poor prognosis. Using long-read single-cell RNA sequencing, we confirmed that discovered <i>U2AF1</i>-like splicing was shared across cell states, co-opted a healthy circadian gene program, was stable through relapse, and induced a leukemic stem cell program. Pharmacological inhibition of an implicated <i>U2AF1</i>-like splicing regulator, PRMT5, rescued leukemia missplicing and inhibited leukemic cell growth. Finally, genetic deletion of <i>IRAK4</i>, a common target of <i>U2AF1</i>-like and PRMT5 treatment, blocked leukemia development in xenograft models and induced differentiation. This work suggests that broad splicing dysregulation, in the absence of select mutations, is a therapeutic target in heterogeneous leukemias.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 797","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916024","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}