Science Translational Medicine最新文献

{"title":"Dengue virus controlled human challenge reveals that preexisting immunity shapes viral replication and broadly protective responses","authors":"Camila D. Odio, Rosemary A. Aogo, Saba Firdous, Charlie Voirin, Silvia Blanco-Rivera, Kelsey E. Lowman, Nhyira Asante, Ysabelle Broderson, Keerthi Konda, Chloe M. Hasund, Amparo Martinez-Perez, Patrick I. Mpingabo, Melissa Law, Caitlin Jarvis, Viviane Callier, Sally Hunsberger, Maria Abad Fernandez, Aravinda de Silva, Robbie Kattappuram, Gitanjali Bhushan, Christina Yek, Jessica Manning, Anna P. Durbin, Jeffrey I. Cohen, Daniela Weiskopf, Stephen S. Whitehead, Leah C. Katzelnick","doi":"10.1126/scitranslmed.aei5117","DOIUrl":"https://doi.org/10.1126/scitranslmed.aei5117","url":null,"abstract":"Dengue is the canonical viral disease for which immune history is a determinant of protective versus pathogenic responses and immunogenicity. Yet, because of limitations in animal models and clinical presentation after peak viremia, how preinfection and early immune responses affect dengue outcome is not confirmed. We conducted a phase 1 clinical trial with 45 healthy adults to test whether secondary infection challenge with a heterotypic, full-length, attenuated virus increases viremia and immunogenicity compared with primary and tertiary infection. Viremia was associated with more, but still mild, clinical signs and symptoms, and secondary infection resulted in greater viremia, neutralizing antibodies, and protective T cell responses. However, those whose baseline antibodies most efficiently increased dengue virus replication in an in vitro assay experienced delayed inflammatory and adaptive immune activation, the highest viremia, strong acute immune responses, and waning of potent CD8 <jats:sup>+</jats:sup> T cells and antibodies. In contrast, higher baseline antibodies against the nonstructural protein 1 of multiple serotypes predicted early interferon and balanced immune activation, viremia control, and development of enduring, potent B and T cells, revealing how vaccines can induce broad, long-lasting protection. Last, individuals with potent and neutralizing antibodies and IFN-γ <jats:sup>+</jats:sup> T cells at baseline experienced minimal viral replication. Together, these findings demonstrate that controlled human challenge with dengue virus can delineate coordinated versus dysregulated acute immune responses and their effects on immunogenicity, informing therapeutic and vaccine strategies for dengue and other viral diseases.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"7 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149274954","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":"B cell subsets are associated with durable responses in distinct cancer types after immune checkpoint inhibition","authors":"Sangwoo Shawn Kim, Sayuri Miyauchi, Riley N. Jones, Elizabeth Weihe, Lin Zhang, Jamillah Murtadha, Stephen T. Ryan, Shumei Kato, Razelle Kurzrock, Jason K. Sicklick, Ezra E. W. Cohen, Sandip P. Patel, Sarah G. Boles, Kathryn A. Gold, Gregory P. Botta, Hitendra Patel, Rebecca A. Shatsky, Susan M. Kaech, Souvick Roy, P. Dominick Sanders, James D. Murphy, Christopher J. Kane, Emily I. Pittman, Jingjing Zou, Minya Pu, Natalie E. Quach, J. Silvio Gutkind, Karen Messer, Diane Simeone, Loren K. Mell, Joseph A. Califano, Christina Jamieson, Arno J. Mundt, Andrew B. Sharabi","doi":"10.1126/scitranslmed.adv7928","DOIUrl":"https://doi.org/10.1126/scitranslmed.adv7928","url":null,"abstract":"B cells are a critical arm of the adaptive immune system. However, the impact of B cells and antibody responses on overall cancer survival remains understudied. Here, we report results from a prospective randomized phase 2 trial of 106 patients treated with immune checkpoint inhibitors (ICIs) and identify that B cell antibody responses are associated with exceptional complete responses to ICI in certain cancer types. To further dissect the impact of B cell subtypes, we generated a comprehensive single-cell RNA sequencing database of intratumoral B cells in 12 tumor types from 152 patients. We found a context-dependent role for B cells, in which they are beneficial in certain cancer types and potentially unfavorable in others, with germinal center and memory B cells enriched in favorable prognosis cohorts and immunoglobulin A–positive plasma cells enriched in unfavorable prognosis cohorts. Depletion of B cells using rituximab in patients before surgery affected intratumoral T cell frequency and diversity. Furthermore, we show that B cells improve long-term overall survival even when T cell infiltrates are already high, indicating that a coordinated dual-arm T cell and B cell adaptive immune response is key to long-term tumor control. Overall, these results demonstrate that B cells and antibody responses in the proper context play an important role in durable complete responses in multiple tumor types.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149274957","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":"MIF-CD74 orchestrates synovial macrophage metabolic-inflammatory reprogramming by ENO2 interaction to drive osteoarthritis pathogenesis","authors":"Rui Peng, Bo Yu, Yulong Wei, Lutian Yao, Zhaowen Xue, Lei Zhang, Guihong Liang, Huajun Wang, Yongpeng Lin, Jianke Pan, Zhengang Zha, Xiaofei Zheng, Weiyi Yang, Bolai Chen, Tao Gui","doi":"10.1126/scitranslmed.adz4081","DOIUrl":"https://doi.org/10.1126/scitranslmed.adz4081","url":null,"abstract":"Synovitis is a central driver of osteoarthritis (OA) progression, yet the cellular and molecular mechanisms sustaining inflammatory circuits in the synovium remain incompletely understood. Through integrative analysis of time-resolved single-cell RNA sequencing in murine synovium and spatial transcriptomics of human OA tissues, we identified a pathogenic CD74 <jats:sup>+</jats:sup> macrophage subset that expands in OA and localizes at the synovial-cartilage interface. This subset exhibits a proinflammatory, nonclassical polarization and displays a metabolic dependency on glycolysis. Multiomics and mechanistic studies revealed that CD74 interacts with the glycolytic enzyme enolase 2 (ENO2). This interaction orchestrates a feed-forward signaling axis wherein CD74/ENO2 facilitates the nuclear translocation of hypoxia-inducible factor 1-α (HIF-1α)/β-catenin dimers, which coactivate glycolytic and inflammatory gene programs, thereby sustaining a metabolically driven inflammatory state. Genetic ablation of CD74 in myeloid cells or its pharmacological blockade mitigated synovitis and cartilage degradation in murine OA models. To translate this axis therapeutically, we developed synovium-targeted cationic lipid nanoparticles decorated with MIF-mimetic peptides (PcLNPs) for the delivery of CD74 siRNA. Intra-articular administration of PcLNPs efficiently targeted CD74 <jats:sup>+</jats:sup> macrophages, attenuated their inflammatory and glycolytic phenotypes, and ameliorated murine OA progression in vivo. Our findings establish the CD74/ENO2/HIF-1α/β-catenin axis as a critical integrator of metabolic reprogramming and inflammation in OA synovitis and present a potential targeted nanotherapeutic strategy for disease modification.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149274851","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":"Acute kidney injury as a systemic disease","authors":"Hannah M. M. Preston, Richard Shemilt, Fiona A. Chapman, David E. Newby, Nicholas M. Selby, Neeraj Dhaun","doi":"10.1126/scitranslmed.aeh0442","DOIUrl":"https://doi.org/10.1126/scitranslmed.aeh0442","url":null,"abstract":"Acute kidney injury (AKI) affects ∼20% of hospitalized patients and is traditionally viewed as a transient complication of acute illness. Evidence suggests that AKI can initiate long-term renal and cardiovascular disease, even when kidney function appears to recover. Survivors of AKI face increased risks of CKD, heart failure, myocardial infarction, and premature mortality, yet post-AKI care remains poorly defined. We synthesize emerging mechanistic and clinical evidence linking AKI to systemic cardiorenal disease and discuss how biomarkers, imaging, and clinical risk prediction may enable identification of high-risk patients and support translational strategies to prevent progression to chronic disease.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"4 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149275202","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":"Keratinocyte-derived CHI3L2 reprograms phospholipid metabolism to promote skin inflammation in psoriasis","authors":"Fei Li, Wentao Zhang, Wenxian Ma, Yanglong Guan, Yu Wang, Yuanyuan Cheng, Dongxia Liang, Yudan Wang, Xiangyu Xu, Leyao Feng, Bo Wang, Jing Xu, Lingfei Mo, Jingyuan Wang, Dan Han, Kuanhou Mou, Yan Zhou, Shemin Lu, Rikard Holmdahl, Liesu Meng, Wenhua Zhu","doi":"10.1126/scitranslmed.aef3967","DOIUrl":"https://doi.org/10.1126/scitranslmed.aef3967","url":null,"abstract":"Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferative keratinocytes and a dysregulated cytokine milieu, perpetuating a self-reinforcing inflammatory cycle. Despite the key involvement of keratinocytes in this pathogenic loop, the molecular pathogenesis remains incompletely understood. Here, we identify chitinase-like protein CHI3L2 as a key mediator. Elevated CHI3L2 levels were detected in serum and lesional skin from patients with psoriasis, predominantly in keratinocytes, as also verified by single-cell RNA sequencing and spatial transcriptomic analyses. In vitro stimulation of keratinocytes with M5 cytokine cocktail (IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α) increased CHI3L2 expression, demonstrating that CHI3L2 is inducible under inflammatory conditions. Transgenic mice expressing human CHI3L2 exhibited aggravated psoriasis-like phenotypes in both imiquimod- and mannan-induced psoriasis models, characterized by epidermal hyperplasia and scaling. To dissect the role of CHI3L2, we used recombinant protein injection, parabiosis, and bone marrow transplantation, identifying keratinocytes as the primary source of pathogenic CHI3L2. This was further confirmed by keratinocyte-specific CHI3L2 knockin mice. CHI3L2 functions in the HaCaT cell line and primary keratinocytes were investigated by recombinant CHI3L2 administration or CHI3L2 knockout. CHI3L2 disrupted phospholipid homeostasis, leading to altered inflammatory responses, proliferation, and differentiation of keratinocytes. CHI3L2 activated secretory phospholipase A2, elevating lysophosphatidylcholine, thereby establishing an autocrine loop perpetuating keratinocyte inflammation and reshaping the immune microenvironment. Therapeutic neutralization of CHI3L2 with antibodies or intervention of phospholipid pathway ameliorated skin inflammation in mouse psoriasis models. Our findings reveal CHI3L2 as an important regulator of keratinocyte-driven lipid remodeling and inflammation in psoriasis, highlighting potential as a therapeutic target.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"13 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149274995","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":"T cell–mediated depletion of intratumoral regulatory T cells using a CCR8xCD3 T cell–engaging bispecific antibody (TCB) promotes antitumor immunity in preclinical mouse models","authors":"Baomei Wang, Isabel Ishizuka, Emel Esen, Ji Li, Cecilia Chiu, Yonglian Sun, Zhonghua Lin, Dhaya Seshasayee, Aija Kusi, Yu Zhong, Wendy Halpern, Adeyemi O. Adedeji, Lanlan Yu, Peter Tran, Zhaojun Yin, Shang-Fan Yu, Geoff Del Rosario, Yoko Oei, Yagai Yang, Jill Schartner, Mary Ann Go, Giulia Protti, Soren Muller, Cong Wu, Ran Li, Genee Lee, James T. Koerber, Sascha Rutz, Teemu T. Junttila","doi":"10.1126/scitranslmed.aea7127","DOIUrl":"https://doi.org/10.1126/scitranslmed.aea7127","url":null,"abstract":"T cell–engaging bispecific antibodies (TCBs) have seen notable successes in hematologic malignancies, and emerging data demonstrate their potential for the treatment of solid tumors. Most oncology applications of TCBs have focused on targeting tumor cells via tumor-specific antigens; however, TCBs have been underutilized for strategic depletion of immunosuppressive cells in the TME. Regulatory T cells (T <jats:sub>reg</jats:sub> cells) play a crucial role in suppressing antitumor immune responses, making them an attractive target for immune-based therapies. T <jats:sub>reg</jats:sub> cells express several surface markers that can serve as potential targets for antibody-mediated depletion, including C-C chemokine receptor type 8 (CCR8), which is highly enriched on tumor-infiltrating T <jats:sub>reg</jats:sub> cells. Monoclonal antibody (mAb)–mediated T <jats:sub>reg</jats:sub> cell depletion relies on natural killer (NK) cells, which can be scarce in some solid tumors, whereas TCBs can broadly engage the T cell compartment by overwriting antigen specificity and redirecting potent T cell cytotoxicity against target cells. Here, we have developed a CCR8xCD3 TCB and show that it effectively depletes CCR8-expressing T <jats:sub>reg</jats:sub> cells in a T cell–mediated manner. CCR8xCD3 TCB led to the selective depletion of intratumoral T <jats:sub>reg</jats:sub> cells from human solid tumor samples in vitro and mediated inhibition of tumor growth in multiple syngeneic tumor models with variable levels of T cell infiltration alone or in combination with anti–PD-L1. In cynomolgus monkeys, CCR8xCD3 TCB was well tolerated without evidence of acute phase inflammation or cytokine release syndrome and led to effective and durable depletion of the CCR8-expressing subset of T <jats:sub>reg</jats:sub> cells.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"43 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149274953","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":"Brain-sensing synNotch–CAR T cells enable precise targeting and clearance of diffuse midline glioma in multiple preclinical models","authors":"Senthilnath Lakshmanachetty, Milos S. Simic, Payal B. Watchmaker, Robert Zhu, Takahide Nejo, Maggie Colton Cove, Jeffrey Haegelin, Haoyu Long, Aishi Zhao, Alejandra Bergquist, Wei Yu, Brianna Wong, Marco Gallus, Ricardo Almeida, Joanna P. Phillips, Wendell A. Lim, Hideho Okada","doi":"10.1126/scitranslmed.aed9994","DOIUrl":"https://doi.org/10.1126/scitranslmed.aed9994","url":null,"abstract":"Diffuse midline glioma (DMG) is a lethal pediatric brain tumor with limited therapeutic options and a poor prognosis. The success of chimeric antigen receptor (CAR) T cell therapy requires both improving T cell tumor infiltration and persistence and reducing the risk of on-target/off-tumor toxicity. Here, we adapted and advanced a brain-restricted CAR T cell platform previously validated in glioblastoma to address the anatomical and biological challenges of DMG. We engineered a T cell circuit in which a brain-specific synthetic Notch (synNotch) receptor recognizing brevican (BCAN) induced CAR expression against EphA2 or IL-13Rα2 (“B-SYNC”), thereby restricting CAR expression to the central nervous system (CNS). In immunodeficient DMG models, a single infusion of intravenous (iv) or intracerebroventricular (icv) B-SYNC circuit T cells led to tumor infiltration, sustained persistence, antitumor activity, and extended survival. An alternative BCAN-primed CAR targeting B7-H3 or IL-13Rα2 (“B-SYNC–B/I”) similarly improved therapeutic efficacy when delivered intravenously. However, icv administration triggered fatal neurotoxicity because of low-level B7-H3 expression in nontumor CNS regions, indicating that rapid CNS exposure via icv delivery can amplify off-tumor toxicity. In contrast, in an immunocompetent syngeneic DMG model, both iv and icv delivery of a murinized BCAN-gated B7-H3 CAR (mB-SYNC–B7-H3) achieved durable tumor clearance and resistance to rechallenge without any detectable neurotoxicity. Mechanistically, synNotch-primed CAR T cells exhibited reduced exhaustion, enhanced activation, and enrichment of naïve and stem cell memory–like subsets. These findings demonstrate that brain-sensing synNotch CAR T circuits represent a generalizable and translatable strategy for targeting multiple CNS malignancies, including DMG.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"34 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149274773","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":"Graft-versus-host disease prophylaxis shapes T cell biology and immune reconstitution after hematopoietic cell transplant","authors":"Susan DeWolf,&nbsp;Steven J. Siegel,&nbsp;Joseph Schmalz,&nbsp;Wael Saber,&nbsp;Alexandre Albanese,&nbsp;Jiayi Dong,&nbsp;Michael J. Martens,&nbsp;Brent Logan,&nbsp;Lorenzo Iovino,&nbsp;Kayleigh Ingersoll-Ohmdahl,&nbsp;Nicholas Winn,&nbsp;Edward Chen,&nbsp;James Kaminski,&nbsp;Donna Neuberg,&nbsp;Kyle Hebert,&nbsp;Paula Keskula,&nbsp;Jillian Zavistaski,&nbsp;Lea Steinberg,&nbsp;Isabella Schichter,&nbsp;Zoe Katsamakis,&nbsp;Lorenzo Cagnin,&nbsp;Vanessa Hernandez,&nbsp;Makya Warren,&nbsp;Kristy Applegate,&nbsp;Merav Bar,&nbsp;Saurabh Chhabra,&nbsp;Sung Won Choi,&nbsp;William Clark,&nbsp;Suman Das,&nbsp;Robert Jenq,&nbsp;Richard J. Jones,&nbsp;John E. Levine,&nbsp;Hemant Murthy,&nbsp;Armin Rashidi,&nbsp;Marcie Riches,&nbsp;Karamjeet Sandhu,&nbsp;Anthony D. Sung,&nbsp;Karilyn Larkin,&nbsp;Monzr M. Al Malki,&nbsp;Mahasweta Gooptu,&nbsp;Hany Elmariah,&nbsp;Amin Alousi,&nbsp;Lyndsey Runaas,&nbsp;Brian Shaffer,&nbsp;Andrew Rezvani,&nbsp;Najla El Jurdi,&nbsp;Alison W. Loren,&nbsp;Danielle Scheffey,&nbsp;Catherine Sanders,&nbsp;Mehdi Hamadani,&nbsp;Jarrod A. Dudakov,&nbsp;Stephanie Bien,&nbsp;Harlan Robins,&nbsp;Mary Horowitz,&nbsp;Javier Bolaños-Meade,&nbsp;Shernan Holtan,&nbsp;Ami S. Bhatt,&nbsp;Miguel-Angel Perales,&nbsp;Leslie S. Kean","doi":"10.1126/scitranslmed.aef7406","DOIUrl":"10.1126/scitranslmed.aef7406","url":null,"abstract":"<div >Successful hematopoietic cell transplant requires immunosuppression to prevent graft-versus-host disease (GVHD), a lethal, T cell–mediated complication. The phase 3 BMT CTN 1703 trial demonstrated superior GVHD-free/relapse-free survival for posttransplant cyclophosphamide (PT-Cy)–based GVHD prophylaxis versus tacrolimus/methotrexate (Tac/MTX), but the T cell biology underpinning these outcomes remains unknown. To determine this, 324 patients were coenrolled onto BMT CTN 1801 to investigate the distinct T cell immune reconstitution pathways of these regimens, including extensive evaluation of T cell receptor (TCR) repertoire, via sequencing of 2359 longitudinal samples and 180,432,350 T cells. Multimodal T cell analysis revealed that PT-Cy was associated with pan–T cell deletion followed by delayed T cell expansion from a smaller founder population compared with Tac/MTX. This created a T cell diversity bottleneck, leading to reduced TCR repertoire diversity for 2 years posttransplant. Reduced TCR diversity, more common in patients receiving PT-Cy, was linked to protection against chronic GVHD when patients were analyzed without regard to study arm. Leveraging donor- and host-specific TCR clonal analysis, we determined that PT-Cy–mediated T cell depletion also depleted pathogen-specific TCRs, rendering PT-Cy patients more likely to lack detectable graft-derived pathogen-specific TCRs early after transplant, which was associated with an increased risk of severe infection. This study reveals how distinct immunosuppression strategies uniquely remodel T cell immunity and shape divergent transplant outcomes.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 872","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149226263","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":"A fluorescent choline kinase alpha inhibitor for intraoperative molecular imaging during resection of canine NSCLC tumors","authors":"Sofya A. Osharovich,&nbsp;David E. Holt,&nbsp;Michael C. Hart,&nbsp;Ritesh K. Isuri,&nbsp;Jennifer L. Huck,&nbsp;Stefan Harmsen,&nbsp;Charles-Antoine Assenmacher,&nbsp;Enrico Radaelli,&nbsp;Sean Carlin,&nbsp;Alex C. Watts,&nbsp;Maureen A. Griffin,&nbsp;Heather Scavello,&nbsp;Wei-Ting Hwang,&nbsp;Anatoliy V. Popov,&nbsp;Sunil Singhal,&nbsp;Edward J. Delikatny","doi":"10.1126/scitranslmed.aea4947","DOIUrl":"10.1126/scitranslmed.aea4947","url":null,"abstract":"<div >Choline kinase α (ChoKα) is a biomarker of lung cancer, is overexpressed in 60% of human pulmonary malignancies, and is associated with an aggressive phenotype and poor clinical outcome. Patients with lung cancer who undergo surgery have a recurrence rate of 30 to 50%, indicating a potential need for better tumor detection modalities. A near-infrared fluorescent ChoKα-targeting imaging agent, JAS239 (λ_ex, λ_em: 745, 775 nanometers), was developed for intraoperative identification of tumors, their margins, and local metastases. In lung cancer cells, JAS239 inhibited phosphocholine production, reduced viability in a dose-dependent manner, and accumulated in the cytoplasm where ChoKα is active. JAS239 had favorable pharmacokinetics and pharmacodynamics for imaging metastatic lung lesions in mice. In situ and ex vivo fluorescence imaging of primary lung tumors in a canine clinical trial showed distinct tumor identification and margin delineation with a tumor-to-background ratio of 5.0 ± 0.6 and a contrast-to-variance ratio of 2.0 ± 0.2 at 0.5 milligram/kilogram. Fluorescence imaging identified a clinically significant event where an occult lesion was found after primary tumor resection. Fluorescence imaging also identified a close surgical margin, which prompted further investigation. Immunohistochemistry for ChoKα showed overexpression in canine lung tumors proportional to tumor fluorescence. Ex vivo human tumor painting demonstrated preferential JAS239 localization with a tumor-to-background ratio of 1.5 ± 0.1 and a contrast-to-variance ratio of 0.9 ± 0.1. These studies establish JAS239 as a safe and effective imaging agent for intraoperative lung tumor detection, warranting further evaluation for human patients with lung cancer.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 872","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149226562","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":"A 5 + 1 polyene scaffold that selectively recognizes ergosterol’s conjugated diene uncouples antifungal potency from host toxicity","authors":"Wei Liu,&nbsp;Qisen Deng,&nbsp;Feng Tang,&nbsp;Wenbo Zhu,&nbsp;Han Zhang,&nbsp;Tao Chen,&nbsp;Wen Xiao,&nbsp;Wenyan He,&nbsp;Nan Liu,&nbsp;Zongqiang Wang","doi":"10.1126/scitranslmed.aei5968","DOIUrl":"10.1126/scitranslmed.aei5968","url":null,"abstract":"<div >Amphotericin B remains the gold-standard therapy for invasive fungal infections, but its clinical utility is limited by toxicity arising from poor selectivity for fungal ergosterol over mammalian cholesterol, a challenge that decades of medicinal chemistry have failed to fully overcome. Here, we report mandimycin M16, a polyene macrolide engineered from a unique 5 + 1 polyene scaffold that uncouples antifungal potency from host toxicity. Mandimycin M16 exhibited potent, broad-spectrum activity against 11 tested World Health Organization (WHO) priority fungal pathogens. Unlike amphotericin B, which binds cholesterol, M16 exhibited no detectable cholesterol binding and showed no detectable hemolysis, cytotoxicity, or nephrotoxicity at concentrations up to 128 micrograms per milliliter in vitro and after up to seven daily intravenous doses in mice. Mechanistic studies revealed that mandimycin M16 exerted rapid fungicidal activity through selective recognition of the conjugated C5–C8 diene system present in ergosterol but absent in cholesterol, a mode of sterol discrimination fundamentally different from classical polyenes. In multiple disseminated murine infection models, M16 outperformed liposomal amphotericin B at equivalent doses, achieving up to 3.4 log reduction in fungal burden and 100% survival without detectable renal injury by biomarkers or histopathology. These findings establish that the 5 + 1 polyene architecture enables complete sterol selectivity and molecularly uncouples antifungal potency from host toxicity, providing a next-generation antifungal candidate for the treatment of invasive fungal infections.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"18 872","pages":""},"PeriodicalIF":15.6,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149226261","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}