Science Translational Medicine最新文献

{"title":"Synchronized dynamics of dengue across the Americas","authors":"Talia M. Quandelacy,&nbsp;Maria F. Vincente-González,&nbsp;Maria Eugenia Grillet,&nbsp;Manuel Colomé-Hidalgo,&nbsp;Demian Herrera,&nbsp;Jomil M. Torres Aponte,&nbsp;Melissa Marzán Rodríguez,&nbsp;Laura E. Adams,&nbsp;Gabriela Paz-Bailey,&nbsp;Dania M. Rodriguez,&nbsp;César Munayco,&nbsp;Laura Figueroa,&nbsp;Rolando Masis,&nbsp;Mercy Borbor-Cordova,&nbsp;Esteban Ortiz-Prado,&nbsp;Matias Piaggio,&nbsp;Leslie Rollock,&nbsp;Guillermo Barrenechea,&nbsp;Aníbal Carbajo,&nbsp;Elizabet L. Estallo,&nbsp;Thais dos Santos,&nbsp;Michael A. Robert,&nbsp;Isabel Rodriguez-Barraquer,&nbsp;Rachel Lowe,&nbsp;Anna M. Stewart-Ibarra,&nbsp;Bernardo Garcia-Carreras,&nbsp;Derek Cummings,&nbsp;Michael A. Johansson","doi":"10.1126/scitranslmed.adq4326","DOIUrl":"10.1126/scitranslmed.adq4326","url":null,"abstract":"<div >Dengue is endemic throughout the tropical areas of the Americas, but little is known about its regional dynamics. We examined seasonal and multiannual dengue trends across the Americas and possible underlying mechanisms using monthly dengue surveillance data from 14 countries. We collected monthly dengue case data from 241 subnational locations in 14 countries, ranging from 1985 to 2018 (6 to 22 years), and used wavelet analysis to isolate seasonal (8 to 16 months) and multiannual (17+ months) patterns. For each location, we assessed seasonal and multiannual dynamics as well as coherence and differences in timing of dengue cycles between 22,578 location pairs. We assessed patterns in coherence over time and space and compared these patterns to variations in temperature, rainfall, and El Niño Southern Oscillation patterns. Strong synchrony in dengue dynamics was identified across the region at the seasonal and multiannual scales. Seasonal dengue dynamics were associated with local climate patterns and dengue dynamics in nearby locations. High synchrony at multiannual scales indicated that large dengue epidemics were shared across the region, with an average temporal lag of only 6 months at distances of up to 10,000 kilometers. Synchrony of these epidemics likely reflects both regional climate variability and human movement. Observed dengue dynamics were not unique to individual countries in the Americas but rather extended across the region reflecting climatic and nonclimatic drivers. These findings can support the development of better early warning tools to support epidemic preparedness and response and underscore the importance of working collaboratively across borders.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 812","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881574","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":"CAR Treg cells mediate linked suppression and infectious tolerance in islet transplantation in mice","authors":"Christine M. Wardell,&nbsp;Vivian C. W. Fung,&nbsp;Eleanor Chen,&nbsp;Manjurul Haque,&nbsp;David F. H. Tan,&nbsp;Monica Leca,&nbsp;Jana Gillies,&nbsp;Justin A. Spanier,&nbsp;Majid Mojibian,&nbsp;Brian T. Fife,&nbsp;Megan K. Levings","doi":"10.1126/scitranslmed.adp6519","DOIUrl":"10.1126/scitranslmed.adp6519","url":null,"abstract":"<div >Regulatory T cells (T_reg cells) have potential as a cell-based therapy to prevent or treat transplant rejection and autoimmunity. Using a human leukocyte antigen (HLA)–A2-specific chimeric antigen receptor (A2-CAR), we previously showed that adoptive transfer of A2-CAR T_reg cells can limit anti–HLA-A2 alloimmunity. However, it was unknown whether A2-CAR T_reg cells could also limit immunity to autoantigens. Using a model of HLA-A2⁺ islet transplantation into immunodeficient nonobese diabetic mice, we investigated whether A2-CAR T_reg cells could control hyperglycemia induced by diabetogenic BDC2.5 effector T cells. In mice transplanted with HLA-A2⁺ islets, A2-CAR T_reg cells reduced BDC2.5 T cell engraftment, proliferation, and cytokine production and protected mice from diabetes. Islet tolerance was systemic, including protection of the HLA-A2^negative endogenous pancreas. Treated mice remained euglycemic even after removal of the HLA-A2⁺ islet graft and A2-CAR T_reg cells. Thus, A2-CAR T_reg cells can induce linked suppression and long-lasting tolerance to a distinct autoimmune antigen. Tolerance to the autoantigen does not require A2-CAR T_reg persistence, indicating the presence of infectious tolerance. Overall, these data demonstrate that A2-CAR T_reg cells have potential therapeutic use to simultaneously control both allo- and autoimmunity in islet transplantation.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 812","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881616","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 epitope vaccine derived by analyzing clinical trial samples safeguards hosts with prior exposure to S. aureus against reinfection","authors":"Xiaokai Zhang,&nbsp;Shuang Ge,&nbsp;Yu Wang,&nbsp;Miao Wang,&nbsp;Yanyan Xu,&nbsp;Yulu Chen,&nbsp;Zhen Song,&nbsp;Liqun Zhao,&nbsp;Jinyong Zhang,&nbsp;Jianxun Qi,&nbsp;Yeping Sun,&nbsp;Jiang Gu,&nbsp;Zhuo Zhao,&nbsp;Xieyuan Jiang,&nbsp;Maoqi Gong,&nbsp;Yejun Zha,&nbsp;Yun Yang,&nbsp;Haiming Jing,&nbsp;Feng Yang,&nbsp;Ni Zeng,&nbsp;Xin Xia,&nbsp;Yanhao Zhang,&nbsp;Ping Luo,&nbsp;Weijun Zhang,&nbsp;Ping Cheng,&nbsp;Hao Zeng,&nbsp;Quanming Zou","doi":"10.1126/scitranslmed.adr7464","DOIUrl":"10.1126/scitranslmed.adr7464","url":null,"abstract":"<div >Humans, as natural carriers of <i>Staphylococcus aureus</i> (SA), have developed nonprotective immune imprints that can be reactivated by SA antigen vaccination and that contribute to the failure of SA vaccine trials. To test whether an epitope-focused vaccine strategy can overcome this issue, we explored the protective epitope of the notable SA antigen MntC. A surface loop of MntC (Loop101) was found to be essential for SA to absorb manganese(II) ion and survive oxidative stress. Our Loop101-deficient versus -competent MntC-based differential screening identified a Loop101-specific human monoclonal antibody (Hm0686). Hm0686 blocked SA from absorbing manganese(II) ion and exhibited a strong opsonophagocytic activity, suggesting that Hm0686-targeted Loop101 may be a protective epitope. A Loop101 epitope vaccine but not the whole MntC antigen protected against SA infection in mice with prior exposure–induced nonprotective imprints. Thus, this effective protective epitope–based vaccine strategy may be explored to overcome nonprotective immune imprints in humans.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 812","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adr7464","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881601","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":"Bezafibrate improves mitochondrial function, blood-brain barrier integrity, and social deficits in models of 22q11.2 deletion syndrome","authors":"Alexis M. Crockett,&nbsp;Maria C. Vélez Colόn,&nbsp;Hanna Kebir,&nbsp;Frances M. Smith,&nbsp;Daniel M. Iascone,&nbsp;Brianna Ciesielski,&nbsp;Sergei Koshkin,&nbsp;Andrew D. Patterson,&nbsp;Adam J. Rossano,&nbsp;Amita Sehgal,&nbsp;Stewart A. Anderson,&nbsp;Jorge Ivan Alvarez","doi":"10.1126/scitranslmed.ads2116","DOIUrl":"10.1126/scitranslmed.ads2116","url":null,"abstract":"<div >Maintenance of blood-brain barrier (BBB) integrity is critical to optimal brain function, and its impairment has been linked to multiple neurological disorders. A notable feature of the BBB is its elevated mitochondrial content compared with peripheral endothelial cells, although the functional implications of this phenomenon are unclear. Here, we studied BBB mitochondrial function in the context of 22q11.2 deletion syndrome (22qDS), a condition associated with a highly increased risk for neuropsychiatric disease. Because the 22q11.2 deletion includes six mitochondrial genes, and because we have previously identified BBB impairment in 22qDS, we addressed the hypothesis that mitochondrial deficits contribute to BBB dysfunction and affect behavior in this condition. We report mitochondrial impairment in human induced pluripotent stem cell (iPSC)–derived brain microvascular endothelial cells (iBMECs) from people with 22qDS and in BBB endothelial cells from a mouse model of 22qDS. We found that treatment with bezafibrate, an activator of mitochondrial biogenesis, attenuates mitochondrial deficits and enhances BBB function in both the iBMECs and a mouse model of 22qDS. This treatment also corrects social memory in the mouse model, a deficit previously associated with BBB dysfunction. Given that BBB integrity correlated with social memory performance, our findings suggest that mitochondrial dysfunction in the BBB influences barrier integrity and behavior.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 812","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881575","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":"Ultrahigh-concentration biologic therapeutics enabled by spray drying with a glassy surfactant excipient","authors":"Carolyn K. Jons,&nbsp;Alexander N. Prossnitz,&nbsp;Noah Eckman,&nbsp;Changxin Dong,&nbsp;Ashley Utz,&nbsp;Eric A. Appel","doi":"10.1126/scitranslmed.adv6427","DOIUrl":"10.1126/scitranslmed.adv6427","url":null,"abstract":"<div >Biopharmaceuticals such as peptides and antibodies have become critical to health care. Despite their exceptional potency and specificity, biopharmaceuticals are prone to aggregation, which can limit efficacy. These therapies therefore often require low-concentration formulations as well as cold storage to maintain stability; however, high doses are required to treat many diseases. Most approved protein drug products are administered intravenously, imposing excessive burdens on patients. New approaches are needed to formulate proteins at high concentrations to enable less burdensome subcutaneous injection, preferably with an autoinjector that can be used directly by patients. To address this challenge, we report a subcutaneously injectable protein delivery platform composed of spray-dried protein microparticles suspended in a nonsolvent liquid carrier. These microparticles contain only biopharmaceuticals and a high–glass transition temperature polyacrylamide-derived copolymer excipient that affords key benefits over traditional excipients. First, the excipient improved stabilization of biopharmaceuticals through the spray-drying process, and second, it improved morphology and properties of the spray-dried particles, enhancing suspension injectability. We demonstrated with albumin, human immunoglobulin G, and an anti-COVID monoclonal antibody (IDBiologics) that this technology enables ultrahigh-concentration protein formulations (exceeding 500 milligrams per milliliter) that are injectable through standard needles with clinically relevant injection forces. In addition, experiments with two clinically relevant antibody drugs show that these ultrahigh-concentration formulations reduce required injection volumes without altering pharmacokinetics or efficacy in mice. This approach could nearly triple the number of commercial protein drugs amenable to subcutaneous administration, improving access to these critical biopharmaceuticals.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 812","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881578","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":"High binding potency overcomes the requirement of Fc effector functions for broadly reactive anti-alphavirus antibodies","authors":"Victoria Callahan,&nbsp;Matthew S. Sutton,&nbsp;Christina L. Gardner,&nbsp;Jessica Prado-Smith,&nbsp;Doreswamy Kenchegowda,&nbsp;Megan M. Dunagan,&nbsp;Mrunal Gosavi,&nbsp;Aizan Embong,&nbsp;Courtney Green,&nbsp;Hannah Kamphaugh,&nbsp;Tammy Y. Chen,&nbsp;Daniel Long,&nbsp;Jodi L. Vogel,&nbsp;Ivan Kosik,&nbsp;Jonathan W. Yewdell,&nbsp;Thomas M. Kristie,&nbsp;Chad S. Clancy,&nbsp;Crystal W. Burke,&nbsp;Mario Roederer,&nbsp;Julie M. Fox","doi":"10.1126/scitranslmed.adt9853","DOIUrl":"10.1126/scitranslmed.adt9853","url":null,"abstract":"<div >Alphaviruses are emerging public health threats. Broadly reactive anti-alphavirus monoclonal antibodies (mAbs) have been shown to be protective in mouse models of infection. However, the antibody characteristics that promote in vivo efficacy and dependency on Fc effector functions remain ill defined. Here, we used two vaccine-elicited, broadly reactive, anti-alphavirus mAbs, SKT05 and SKT20, to establish correlates of mAb-mediated protection during Venezuelan equine encephalitis virus (VEEV) challenge. SKT20 required Fc effector functions to prevent lethality. The necessity of Fc effector functions for SKT20 was dose dependent and related to mAb binding potency and pseudovirus neutralization rather than epitope specificity. In contrast, survival mediated by SKT05 when given prophylactically was independent of Fc effector functions and rather was linked to early viral control through egress inhibition. However, control of virus replication and spread with SKT05 at later time points was Fc dependent. Therapeutic administration of SKT05 required Fc effector functions only at 3 days after infection. These findings extended to additional in vivo infection models with alternative VEEV subtypes and with chikungunya virus. Collectively, this study identified binding potency and pseudoviral neutralization as correlates for in vivo efficacy of mAbs and demonstrated that Fc-dependent mechanisms can be leveraged for development of therapeutic mAbs against emerging alphaviruses.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 812","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881609","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":"Proviruses in CD4+ T cells reactive to autologous antigens contribute to nonsuppressible HIV-1 viremia","authors":"Fengting Wu,&nbsp;Milica Moskovljevic,&nbsp;Filippo Dragoni,&nbsp;Sahana Jayaraman,&nbsp;Nathan L. Board,&nbsp;Angelica Camilo-Contreras,&nbsp;Silvia Bernal,&nbsp;Vivek Hariharan,&nbsp;Hao Zhang,&nbsp;Jun Lai,&nbsp;Anushka Singhal,&nbsp;Sebastien Poulin,&nbsp;Frederic Chano,&nbsp;Annie Chamberland,&nbsp;Cecile Tremblay,&nbsp;Meredith Zoltick,&nbsp;Christopher J. Hoffmann,&nbsp;Joyce L. Jones,&nbsp;H. Benjamin Larman,&nbsp;Luis J. Montaner,&nbsp;Janet D. Siliciano,&nbsp;Robert F. Siliciano,&nbsp;Francesco R. Simonetti","doi":"10.1126/scitranslmed.adu4643","DOIUrl":"10.1126/scitranslmed.adu4643","url":null,"abstract":"<div >Antiretroviral therapy (ART) halts human immunodeficiency virus–1 (HIV-1) replication, reducing plasma virus concentrations to below the limit of detection, but it is not curative because of a reservoir of latently infected CD4⁺ T cells. In some people living with HIV-1 (PLWH), plasma HIV-1 RNA becomes persistently detectable despite optimal ART. This nonsuppressible viremia (NSV) is characterized by identical, nonevolving HIV-1 RNA variants expressed from infected CD4⁺ T cell clones. The mechanisms driving persistent virus production from a specific population of infected cells are poorly understood. We hypothesized that proviruses in cells responding to chronic immunologic stimuli, including self-associated antigens, may drive viral gene expression and NSV. Here, we demonstrate that stimulation of CD4⁺ T cells with autologous cell lysates induced virus production in a major histocompatibility complex class II–dependent manner. In seven of eight participants with NSV, we recovered viral RNA released ex vivo in response to autologous cell lysates that matched plasma virus. This process involved both defective and replication-competent proviruses residing in conventional CD4⁺ T cells and was also observed in PLWH with undetectable viremia. These findings suggest that recognition of self-associated antigens is a potentially important cause of HIV-1 reservoir expression, which can contribute to persistent systemic inflammation and rebound upon ART interruption.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 811","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833374","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 mRNA-based broad-spectrum antiviral inspired by ISG15 deficiency protects against viral infections in vitro and in vivo","authors":"Yemsratch T. Akalu,&nbsp;Roosheel S. Patel,&nbsp;Justin Taft,&nbsp;Rodrigo Canas-Arranz,&nbsp;Rachel Geltman,&nbsp;Ashley Richardson,&nbsp;Sofija Buta,&nbsp;Marta Martin-Fernandez,&nbsp;Christos Sazeides,&nbsp;Rebecca L. Pearl,&nbsp;Gayatri Mainkar,&nbsp;Andrew P. Kurland,&nbsp;Haylen Rosberger,&nbsp;Diana D. Kang,&nbsp;Ann Anu Kurian,&nbsp;Keerat Kaur,&nbsp;Jennie Altman,&nbsp;Yizhou Dong,&nbsp;Jeffrey R. Johnson,&nbsp;Lior Zangi,&nbsp;Jean K. Lim,&nbsp;Randy A. Albrecht,&nbsp;Adolfo García-Sastre,&nbsp;Brad R. Rosenberg,&nbsp;Dusan Bogunovic","doi":"10.1126/scitranslmed.adx5758","DOIUrl":"10.1126/scitranslmed.adx5758","url":null,"abstract":"<div >Type I interferons (IFN-Is) are cytokines with potent antiviral and inflammatory capacities. IFN-I signaling drives the expression of thousands of IFN-I–stimulated genes (ISGs), whose aggregate function results in the control of viral infections. A few of these ISGs are tasked with negatively regulating the IFN-I response to prevent overt inflammation. ISG15 is a negative regulator whose absence leads to persistent, low-grade elevation of ISG expression and concurrent, often self-resolving, mild autoinflammation. The limited breadth and low-grade persistence of ISGs expressed in ISG15 deficiency are sufficient to confer broad-spectrum antiviral resistance. Inspired by the antiviral state of humans with ISG15 deficiency, we identified a nominal collection of 10 ISGs that recapitulated the broad antiviral potential of the IFN-I system, which typically induces the expression of thousands of ISGs. The expression of this 10-ISG collection in an IFN-I–nonresponsive cell line increased cellular resistance to Zika virus, vesicular stomatitis virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A lipid nanoparticle–encapsulated messenger RNA (mRNA) formulation of this 10-ISG collection reduced influenza A virus plaque size in samples collected from infected mice when given prophylactically. Moreover, when used collectively and delivered prophylactically, the 10-ISG collection was able to protect hamsters against a lethal SARS-CoV-2 challenge, in contrast with the lack of efficacy when mRNAs were delivered individually. These findings suggest that these 10 ISGs have potential as a broad-spectrum antiviral prophylactic.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 811","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833376","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":"PIEZO1-activated donor lymphatic remodeling integrates with autologous lymphangiogenesis to enhance vein graft patency in mice","authors":"Kai Chen,&nbsp;Rong Mou,&nbsp;Ziyin Guan,&nbsp;Peng Teng,&nbsp;Muladili Aihemaiti,&nbsp;Junning Cheng,&nbsp;Simon Xu,&nbsp;Pengwei Zhu,&nbsp;Xiaosheng Hu,&nbsp;Donglin Li,&nbsp;Junru Wu,&nbsp;Yao Lu,&nbsp;Hong Yuan,&nbsp;Shilong Sun,&nbsp;Xiangyuan Pu,&nbsp;Yanhua Hu,&nbsp;Liang Ma,&nbsp;Jingjing Cai,&nbsp;Haige Zhao,&nbsp;Qingbo Xu","doi":"10.1126/scitranslmed.ads7438","DOIUrl":"10.1126/scitranslmed.ads7438","url":null,"abstract":"<div >The great saphenous vein is the most commonly used conduit in coronary artery bypass grafting; however, the high vein graft failure rates remain an unresolved issue. Here, we compared different harvesting techniques for mouse vein grafts and found that the construction of a denser lymphatic network contributed to improved vein graft patency. Dual lymphatic tracing strategies using <i>Lyve1</i>-Cre^ER;R26-tdTomato/zsGreen mice uncovered a heterogeneous lymphatic network in mouse vein grafts. The anastomotic delivery of a lymphangiogenic signal, vascular endothelial growth factor–C_156S, upon surgical completion promoted autologous lymphangiogenesis. The preservation of surrounding tissue led to donor-derived lymphatic remodeling dependent on PIEZO1-induced CD44 cleavage. The autologous and donor-derived lymphatic structures integrated with each other in the anastomotic area, and the loss of either component aggravated inflammation-associated neointima formation. Obesity was identified as an independent factor in mouse- and patient-derived venous samples, contributing to the perivenous macrophage accumulation and functional lymphatic remodeling, which intensified the vein graft benefits induced by surrounding tissue preservation. Collectively, this study provides both preoperative and perioperative therapeutic strategies to improve vein grafts and shows that preserving perivenous lymphatic vessels or promoting autologous lymphangiogenesis could enhance vein graft patency.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 811","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833389","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":"Sequential treatment with PARPi and WEE1i enhances antitumor immune responses in preclinical models of ovarian cancer","authors":"Xiaofei Jiao,&nbsp;Jiahao Liu,&nbsp;Yijie Wu,&nbsp;Qing Zhong,&nbsp;Li Zhu,&nbsp;Linghui Wang,&nbsp;Huayi Li,&nbsp;Minghua Xiang,&nbsp;Xuejiao Zhao,&nbsp;Guangnian Zhao,&nbsp;Gordon B. Mills,&nbsp;Ding Ma,&nbsp;Qinglei Gao,&nbsp;Yong Fang","doi":"10.1126/scitranslmed.adu6989","DOIUrl":"10.1126/scitranslmed.adu6989","url":null,"abstract":"<div >The antitumor activity demonstrated by DNA damage response inhibitors (DDRis) can be partially attributed to their capacity to enhance immune responses. However, the toxicity of DDRis to lymphocytes, particularly when a DDRi is combined with other treatments targeting cell cycle checkpoint kinases, indicates a need for the development of different DDRi treatment schedules. Here, we systematically assessed changes to the tumor immune microenvironment (TIME) in response to DDRis across various treatment timelines in ovarian cancer. Using single-cell analysis, we found that the sequential treatment with an inhibitor of poly(ADP-ribose) polymerase (PARPi), followed by an inhibitor of the cell cycle checkpoint kinase WEE1 (WEE1i), resulted in more effective cancer eradication and stronger antitumor immune responses in vivo, compared with mono- and concurrent therapy. Both sequential and concurrent treatment schedules could induce lethal DNA damage and activate the cGAS-STING pathway in cancer cells, but T cell viability was greater under sequential treatment. Proteomic analysis showed that T cells more quickly recovered from DNA damage after DDRi treatment compared with cancer cells. Both immune checkpoint therapy and CAR T cells were more effective when combined with sequential treatment compared with monotherapy treatment in a syngeneic high-grade serous ovarian cancer mouse model and in a treatment-resistant ovarian cancer patient-derived xenograft model. Our study demonstrated that sequential treatment with PARPi and WEE1i spared T cells from severe DNA damage and activated the cGAS-STING pathway in cancer cells, suggesting that antitumor immunity and control of tumor growth can be optimized through changes in treatment schedules.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 811","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833392","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}