tbuckley/cabot-search huggingface dataset:
Prognostic Impact of Fluorescent Lymphography on Gastric Cancer After Neoadjuvant Chemotherapy
Authors: Yi-Hui Tang, Ze-Ning Huang, Yu-Qin Sun, Ya-Qi Zhao, Wen-Wu Qiu, Ji-Xun He, Ping Li, Jian-Wei Xie, Jia-Bin Wang, Qi-Yue Chen, Long-Long Cao, Chao-Hui Zheng, Jian-Xian Lin, Su Yan, Chang-Ming Huang
Journal: JAMA Surgery (2025)

Importance Indocyanine green (ICG)–guided lymphadenectomy has been increasingly used to treat gastric cancer. However, its oncologic impact remains unclear. Objective To investigate the effect of ICG tracing on long-term outcomes in patients diagnosed with locally advanced gastric cancer undergoing neoadjuvant chemotherapy (NAC) followed by laparoscopic radical gastrectomy. Design, Settings, and Participants This retrospective cohort study included patients diagnosed with cT2-4N0/+M0 gastric adenocarcinoma who underwent NAC and laparoscopic radical gastrectomy at 3 teaching hospitals in China between January 2015 and June 2021, with follow-up data examined until June 2024. Overlap weighting (OW) was used to compare outcomes between the ICG and non–ICG groups. Results were tested for robustness using propensity score matching (PSM) and instrumental variable analysis. Exposure ICG–guided lymphadenectomy during laparoscopic gastrectomy. Main Outcomes and Measures The primary end points were 3-year survival outcomes, including overall survival (OS) and recurrence-free survival (RFS). Results Data from 459 patients (338 men [73.6%] and 121 women [26.4%]; mean [SD] age, 60.8 [9.9] years), of whom 119 underwent ICG–guided lymphadenectomy, were included. After OW adjustment, the ICG group exhibited a higher number of lymph nodes harvested (47.4 vs 38.3; P &amp;amp;lt; .001) and better 3-year OS (78.6% vs 66.6%; P = .04) and RFS (74.0% vs 57.0%; P = .03) compared with the non–ICG group. Multivariable Cox regression analysis revealed that ICG tracing was an independent prognostic factor for both OS (hazard ratio, 0.59; 95% CI, 0.39-0.90; P = .02) and RFS (hazard ratio, 0.59; 95% CI, 0.40-0.87; P = .01), with the results remaining significant in both doubly robust and instrumental variable-adjusted models. Furthermore, in the OW–adjusted population, the OS benefit of ICG tracing was more pronounced in subgroups with ypN2/3 gastric adenocarcinoma (70.3% vs 36.2%; P = .01) and those achieving major pathological response (97.7% vs 77.6%; P = .04) (both P for interaction = .04). Similar results were obtained after adjusting for PSM. Conclusion and Relevance In this study, ICG tracing was associated with enhanced lymphadenectomy and improved survival outcomes in patients with locally advanced gastric cancer after NAC. A prospective randomized clinical trial is needed to verify these findings.
Exercise and Psychosexual Education to Improve Sexual Function in Men With Prostate Cancer
Authors: Daniel A. Galvão, Robert U. Newton, Dennis R. Taaffe, Prue Cormie, Oliver Schumacher, Christian J. Nelson, Robert A. Gardiner, Nigel Spry, David Joseph, Colin Tang, Hao Luo, Raphael Chee, Dickon Hayne, Suzanne K. Chambers
Journal: JAMA Network Open (2025)

Importance Sexual dysfunction is a common adverse effect of prostate cancer treatment, and current management strategies do not adequately address physical and psychological causes. Exercise is a potential therapy in the management of sexual dysfunction. Objective To investigate the effects of supervised, clinic-based, resistance and aerobic exercise with and without a brief psychosexual education and self-management intervention (PESM) on sexual function in men with prostate cancer compared with usual care. Design, Setting, and Participants A 3-arm, parallel-group, single-center randomized clinical trial was undertaken at university-affiliated exercise clinics between July 24, 2014, and August 22, 2019. Eligible participants were men with prostate cancer who had previously undergone or were currently undergoing treatment and were concerned about sexual dysfunction. Data analysis was undertaken October 8 to December 23, 2024. Interventions Participants were randomized to (1) 6 months of supervised, group-based resistance and aerobic exercise (n = 39 [34.8%]), (2) the same exercise program plus PESM (n = 36 [32.1%]), or (3) usual care (n = 37 [33.0%]). Exercise was to be undertaken 3 days per week. Main Outcomes and Measures The primary outcome was sexual function assessed with the International Index of Erectile Function (IIEF). Secondary outcomes included body composition, physical function, and muscle strength. Analyses were undertaken using an intention-to-treat approach. Results In total, 112 participants (mean [SD] age, 66.3 [7.1] years) were randomized. Mean adjusted difference in IIEF score at 6 months favored exercise compared with usual care (3.5; 95% CI, 0.3-6.6; P = .04). The mean adjusted difference for intercourse satisfaction was not significant (1.7; 95% CI, 0.1-3.2; P = .05). PESM did not result in additional improvements. Compared with usual care, exercise also significantly improved fat mass (mean adjusted difference, −0.9 kg; 95% CI, −1.8 to −0.1 kg; P = .02), chair rise performance (mean adjusted difference, −1.8 seconds; 95% CI, −3.2 to −0.5 seconds; P = .002), and upper (mean adjusted difference, 9.4 kg; 95% CI, 6.9-11.9 kg; P &amp;amp;lt; .001) and lower (mean adjusted difference, 17.9 kg; 95% CI, 7.6-28.2 kg; P &amp;amp;lt; .001) body muscle strength. Conclusions and Relevance In this randomized clinical trial of supervised exercise, erectile function in patients with prostate cancer was improved. PESM resulted in no additional improvements. Patients with prostate cancer should be offered exercise following treatment as a potential rehabilitation measure. Trial Registration ANZCTR Identifier: ACTRN12613001179729
Circulating Blood-Based Proteins in Psychopathology and Cognition
Authors: Upasana Bhattacharyya, Jibin John, Max Lam, Jonah Fisher, Benjamin Sun, Denis Baird, Stephen Burgess, Chia-Yen Chen, Todd Lencz
Journal: JAMA Psychiatry (2025)

Importance Peripheral (blood-based) biomarkers for psychiatric illness could benefit diagnosis and treatment, but research to date has typically been low throughput, and traditional case-control studies are subject to potential confounds of treatment and other exposures. Large-scale 2-sample mendelian randomization (MR) can examine the potentially causal impact of circulating proteins on neuropsychiatric phenotypes without these confounds. Objective To identify circulating proteins associated with risk for schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) as well as cognitive task performance (CTP). Design, Setting, and Participants In a 2-sample MR design, significant proteomic quantitative trait loci were used as candidate instruments, obtained from 2 large-scale plasma proteomics datasets: the UK Biobank Pharma Proteomics Project (2923 proteins per 34 557 UK individuals) and deCODE Genetics (4719 proteins per 35 559 Icelandic individuals). Data analysis was performed from November 2023 to November 2024. Exposure Genetic influence on circulating levels of proteins in plasma. Main Outcomes and Measures Outcome measures were summary statistics drawn from recent large-scale genome-wide association studies for SCZ (67 323 cases and 93 456 controls), BD (40 463 cases and 313 436 controls), MDD (166 773 cases and 507 679 controls), and CTP (215 333 individuals). MR was carried out for each phenotype, and proteins that showed statistically significant (Bonferroni-corrected P &amp;amp;lt; .05) associations from MR analysis were used for pathway, protein-protein interaction, drug target enrichment, and potential druggability analysis for each outcome phenotype separately. Results MR analysis revealed 113 Bonferroni-corrected associations (46 novel) involving 91 proteins across the 4 outcome phenotypes. Immune-related proteins, such as interleukins and complement factors, showed pleiotropic effects across multiple outcome phenotypes. Drug target enrichment analysis provided support for repurposing of anti-inflammatory agents for SCZ, amantadine for BD, retinoic acid for MDD, and duloxetine for CTP. Conclusions and Relevance Identifying potentially causal effects of circulating proteins on neuropsychiatric phenotypes suggests potential biomarkers and offers insights for the development of innovative therapeutic strategies. The study also reveals pleiotropic effects of many proteins across different phenotypes, indicating shared etiology among serious psychiatric conditions and cognition.
Lymphatic system is the mainstream for breast cancer dissemination and metastasis revealed by single-cell lineage tracing
Authors: Kai Miao, Aiping Zhang, Xiaodan Yang, Yipeng Zhang, Anqi Lin, Lijian Wang, Xin Zhang, Heng Sun, Jun Xu, Jingyao Zhang, Yuzhao Feng, Fangyuan Shao, Sen Guo, Zhihui Weng, Peng Luo, Dong Wang, Shuai Gao, Xiao-Yang Zhao, Xiaoling Xu, Chu-Xia Deng
Journal: Molecular Cancer (2025)

Cancer metastasis is the primary cause of cancer-related death, yet the forces that drive cancer cells through various steps and different routes to distinct target organs/tissues remain elusive. In this study, we applied a barcoding system based single-cell lineage tracing approach to study the metastasis rate and route of breast cancer cells and their interactions with the tumor microenvironment (TME) during metastasis. The results indicate that only a small fraction of cells, accounting for fewer than 3% of total barcodes, can intravasate from the primary site into the blood circulation, whereas more cells disseminate through the lymphatic system to different organs. Tumor cells derived from the same progenitor cell exhibit different gene expression patterns in different soils, and the cancer cell-TME communication paradigm varies significantly between primary and metastatic tumors. Furthermore, metastable cells require a prewired particular cytokine expression ability which may be specific for lymph metastasis route although the underlying mechanism requires further investigation. In summary, leveraging a single-cell lineage tracing system, we demonstrate that the crosstalk between tumor cells and the TME is the driving force controlling the preferential metastatic fate of cancer cells through the lymphatic system.
Heterogeneous cellular responses to hyperthermia support combined intraperitoneal hyperthermic immunotherapy for ovarian cancer mouse models
Authors: Xingyuan Hu, Xiaoyan Kang, Faming Zhao, Yaoyuan Cui, Yu Fu, Xiaohang Yang, Jingjing Yin, Wenting Li, Junpeng Fan, Bin Yang, Zixuan Fang, Tianyu Qin, Xucui Zhuang, Yiting Liu, Chenzhao Feng, Yunyi Yang, Funian Lu, Li Zhang, Weihao Chen, Miaofang Wu, Ning Du, Xia Sheng, Xin Zhou, Jing Li, Gang Chen, Chaoyang Sun
Journal: Science Translational Medicine (2025)

The benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer remains controversial, hindering the development of rational combination therapies based on hyperthermia (HT). This study reports the preliminary results of the neoadjuvant HIPEC (NHIPEC) trial (ChiCTR2000038173), demonstrating enhanced tumor response in high-grade serous ovarian cancer with NHIPEC. Through single-cell RNA sequencing analysis, we identified both homogeneous and heterogeneous cellular responses to HT within the tumor and microenvironment. Epithelial-mesenchymal transition–activated tumor cells and matrix metallopeptidase 11 (MMP-11) + cancer-associated fibroblasts (CAFs) exhibited greater reductions and higher sensitivity to HT. CUT&amp;Tag and RNA sequencing integration unveiled the differential binding programs and transcriptional regulatory mechanisms of HSF1 under normothermia (NT) and HT in tumor cells and CAFs. Furthermore, HT ameliorated the immunosuppressive tumor microenvironment, and in vivo mouse models confirmed the combined antitumor effects of HT and programmed cell death ligand 1 blockade. These findings provide an innovative strategy for rational combination therapy with HT in ovarian cancer.
Itaconate restrains acute proinflammatory activation of microglia MG after traumatic brain injury in mice
Authors: Ning Liu, Yinghua Jiang, Yuwen Xiu, Giovane G. Tortelote, Winna Xia, Yingjie Wang, Yadan Li, Samuel Shi, Jinrui Han, Charles Vidoudez, Aim Niamnud, Mitchell D. Kilgore, Di Zhou, Mengxuan Shi, Stephen A. Graziose, Jia Fan, Prasad V. G. Katakam, Aaron S. Dumont, Xiaoying Wang
Journal: Science Translational Medicine (2025)

Traumatic brain injury (TBI) rapidly triggers proinflammatory activation of microglia, contributing to secondary brain damage post-TBI. Although the governing role of energy metabolism in shaping the inflammatory phenotype and function of immune cells has been increasingly recognized, the specific alterations in microglial bioenergetics post-TBI remain poorly understood. Itaconate, a metabolite produced by the enzyme aconitate decarboxylase 1 [IRG1; encoded by immune responsive gene 1 ( Irg1 )], is a pivotal metabolic regulator in immune cells, particularly in macrophages. Because microglia are macrophages of the brain parenchyma, the IRG1/itaconate pathway likely modulates microglial inflammatory responses. In this study, we explored the role of the IRG1/itaconate pathway in regulating microglial bioenergetics and inflammatory activation post-TBI using a mouse controlled cortical impact (CCI) model. We isolated microglia before and 4 and 12 hours after TBI and observed a swift but transient increase in glycolysis coupled with a prolonged disruption of mitochondrial metabolism after injury. Despite an up-regulation of Irg1 expression, itaconate in microglia declined after TBI. Microglia-specific Irg1 gene knockout ( Irg1 -Mi-KO) exacerbated metabolic changes, intensified proinflammatory activation and neurodegeneration, and worsened certain long-term neurological deficits. Supplementation with 4-octyl itaconate (OI) reinstated the use and oxidative metabolism of glucose, glutamine, and fatty acid, thereby enhancing microglial bioenergetics post-TBI. OI supplementation also attenuated proinflammatory activation and neurodegeneration and improved long-term neurological outcomes. These results suggest that therapeutically targeting the itaconate pathway could improve microglial energy metabolism and neurological outcomes after TBI.
A humanized antibody against mucormycosis targets angioinvasion and augments the host immune response
Authors: Yiyou Gu, Shakti Singh, Abdullah Alqarihi, Sondus Alkhazraji, Teclegiorgis Gebremariam, Eman G. Youssef, Hong Liu, Xiaomin Fan, Wen-Rong Jiang, David Andes, Terrence R. Cochrane, Julie A. Schwartz, Scott G. Filler, Priya Uppuluri, Ashraf S. Ibrahim
Journal: Science Translational Medicine (2025)

Mucormycosis is a fungal infection caused by Mucorales fungi that cause severe disease and fatality, especially in immunocompromised individuals. Although vaccines and immunotherapeutics have been successful in combating viral and bacterial infections, approved antifungal immunotherapies are yet to be realized. To address this gap, monoclonal antibodies targeting invasive fungal infections have emerged as a promising approach, particularly for immunocompromised patients who are unlikely to maximally benefit from vaccines. The Mucorales spore coat (CotH) proteins have been identified as crucial fungal invasins that bind to glucose-regulated protein 78 (GRP78) and integrins of host barrier cells. Previously, we described a murine monoclonal antibody, anti-CotH C2, which protected diabetic ketoacidosis (DKA) and neutropenic mice from mucormycosis. Here, we advanced the development of the C2 immunoglobulin G1 (IgG1) by humanizing it, establishing a stable Chinese hamster ovary cell line producing the antibody at commercial yields, and carried out optimization of the upstream and downstream manufacturing processes. The resultant humanized IgG1 (VX-01) exhibited a 10-fold increase in binding affinity to CotH proteins and conferred comparable in vitro and in vivo efficacy when compared to C2 antibody. The mechanism of protection was reliant on prevention of angioinvasion and enhancing opsonophagocytic killing. VX-01 demonstrated acceptable safety profiles with no detectable damage to host cells in vitro and weak or moderate binding to only cytoplasmic proteins in ex vivo good laboratory practice–human tissue cross-reactivity studies. Our studies warrant continued development of VX-01 as a promising adjunctive immunotherapy.
Upadacitinib outperforms dupilumab in restoring the fungal microbiome in atopic dermatitis
Authors: Tingting Li, Rong Tao, Li Yang, Zhe Wan, Ruoyu Li, Ruojun Wang
Journal: British Journal of Dermatology (2025)

Our study is the first to compare fungal microbiome changes in atopic dermatitis (AD) patients before and after treatment with upadacitinib and dupilumab. We found that upadacitinib more effectively restores the fungal microbiome to levels observed in healthy individuals, which may contribute to its superior efficacy in head and neck dermatitis (a subtype of AD). The results enhance understanding of how JAK inhibitors influence the skin microbiome in AD.
The pentameric complex is not required for congenital CMV transmission in seronegative rhesus macaques
Authors: Hsuan-Yuan Wang, Husam Taher, Craig N. Kreklywich, Kimberli A. Schmidt, Elizabeth A. Scheef, Richard Barfield, Claire E. Otero, Sarah M. Valencia, Ke Zhang, Claire Callahan, Francesco Monticolo, Yueqing Qiao, Roxanne M. Gilbride, Chelsea M. Crooks, Anne Mirza, Kelsey Knight, Matilda J. Moström, Tabitha D. Manuel, Lesli Sprehe, Savannah Kendall, Nathan Vande Burgt, Timothy F. Kowalik, Peter A. Barry, Scott G. Hansen, Jian Shu, Alice F. Tarantal, Cliburn Chan, Daniel N. Streblow, Louis J. Picker, Amitinder Kaur, Klaus Früh, Sallie R. Permar, Daniel Malouli
Journal: Science Translational Medicine (2025)

Congenital cytomegalovirus (cCMV) is the leading infectious cause of neonatal neurological impairment worldwide, but the viral factors enabling vertical spread across the placenta remain undetermined. The pentameric complex (PC), composed of the subunits gH/gL/UL128/UL130/UL131A, has been demonstrated to be important for entry into nonfibroblast cells in vitro. These findings link the PC to broad cell tropism and virus dissemination in vivo, denoting all subunits as potential targets for intervention strategies and vaccine development. To determine the relevance of the PC for congenital transmission in a translational nonhuman primate model, we engineered a rhesus CMV (RhCMV) mutant lacking the orthologs of UL128 and UL130, which demonstrated diminished infection of epithelial cells in vitro. However, intravenous inoculation of either CD4 + T cell–depleted or immunocompetent RhCMV-seronegative pregnant rhesus macaques (RMs) in the early second trimester with the PC-deficient mutant resulted in maternal RhCMV peak plasma viremia similar to inoculations with PC-intact RhCMV, although virus shedding in saliva and urine was limited. Infections with the PC-intact virus induced IgG responses that neutralized RhCMV entry into epithelial cells in tissue culture. These responses were reduced, but not absent, from animals infected with the PC-deficient virus, which also induced IgG responses against gH. Moreover, congenital CMV transmission was confirmed in multiple animals infected with PC-deficient virus by detecting viral DNA in the amniotic fluid, indicating that transplacental transmission in RMs is not contingent on the PC.
Postoperative adhesions are abrogated by a sustained-release anti-JUN therapeutic in preclinical models
Authors: Deshka S. Foster, Jason L. Guo, Emily Meany, Charlotte E. Berry, Mahsa Fallah, Maria Korah, Michael Januszyk, Khristian Erich Bauer-Rowe, David M. Lopez, Christian M. Williams, Rachel Song, Michelle Griffin, Alexia Kim, Malini S. Chinta, Clement D. Marshall, Derrick C. Wan, Jeong S. Hyun, Gerlinde Wernig, Jeffrey A. Norton, Eric A. Appel, Daniel Delitto, Michael T. Longaker
Journal: Science Translational Medicine (2025)

Postoperative abdominal adhesions are the leading cause of bowel obstruction and a cause of chronic pain and infertility. Adhesion formation occurs after 50 to 90% of abdominal operations and has no proven preventative or treatment strategy. Abdominal adhesions derive primarily from the visceral peritoneum and are composed of polyclonally proliferating tissue-resident fibroblasts. We have previously shown that signaling of the transcription factor JUN regulates adhesiogenesis and that a small-molecule JUN inhibitor (T-5224) decreases adhesion formation. Here, we encapsulated T-5224 in a shear-thinning hydrogel with antiadhesion properties for intraperitoneal postoperative delivery and sustained release of a JUN inhibitor for adhesion prevention. The material properties of the T-5224–hydrogel support its use for open or minimally invasive surgical application. We found this therapeutic system to be safe, well tolerated, and efficacious in murine and porcine preclinical models. T-5224–hydrogel minimized adhesion quantity and also diminished adhesion fibrosis at an ultrastructural level. Moving toward clinical translation, we developed a large mammal adhesion model in pigs with bowel resection. Single-cell transcriptomic analysis showed that JUN and associated pathway signaling were diminished in adhesion-derived fibroblasts treated with T-5224–hydrogel. The JUN-inhibiting T-5224–hydrogel provided robust prevention of adhesion without deleterious effects on bowel anastomosis or abdominal wall healing. Adhesion biology is similar across surgical sites, and, therefore, this formulation has potential for applicability across the body. The development of therapeutics to prevent adhesions is of paramount importance with potential for high-impact translation to patient care to address a common, unmet clinical need.
A human histidyl-tRNA synthetase splice variant therapeutic targets NRP2 to resolve lung inflammation and fibrosis
Authors: Leslie A. Nangle, Zhiwen Xu, David Siefker, Christoph Burkart, Yeeting E. Chong, Liting Zhai, Yanyan Geng, Clara Polizzi, Lauren Guy, Lisa Eide, Yao Tong, Sofia Klopp-Savino, Michaela Ferrer, Kaitlyn Rauch, Annie Wang, Kristina Hamel, Steve Crampton, Suzanne Paz, Kyle P. Chiang, Minh-Ha Do, Luke Burman, Darin Lee, Mingjie Zhang, Kathleen Ogilvie, David King, Ryan A. Adams, Paul Schimmel
Journal: Science Translational Medicine (2025)

Interstitial lung disease (ILD) consists of a group of immune-mediated disorders that can cause inflammation and progressive fibrosis of the lungs, representing an area of unmet medical need given the lack of disease-modifying therapies and toxicities associated with current treatment options. Tissue-specific splice variants (SVs) of human aminoacyl-tRNA synthetases (aaRSs) are catalytic nulls thought to confer regulatory functions. One example from human histidyl-tRNA synthetase (HARS), termed HARS WHEP because the splicing event resulted in a protein encompassing the WHEP-TRS domain of HARS (a structurally conserved domain found in multiple aaRSs), is enriched in human lung and up-regulated by inflammatory cytokines in lung and immune cells. Structural analysis of HARS WHEP confirmed a well-organized helix-turn-helix motif. This motif bound specifically and selectively to neuropilin-2 (NRP2), a receptor expressed by myeloid cells in active sites of inflammation, to inhibit expression of proinflammatory receptors and cytokines and to down-regulate inflammatory pathways in primary human macrophages. In animal models of lung injury and ILD, including bleomycin treatment, silicosis, sarcoidosis, chronic hypersensitivity pneumonitis, systemic sclerosis, and rheumatoid arthritis–ILD, HARS WHEP reduced lung inflammation, immune cell infiltration, and fibrosis. In patients with sarcoidosis, efzofitimod treatment resulted in down-regulation of gene expression for inflammatory pathways in peripheral immune cells and stabilization of inflammatory biomarkers in serum after steroid tapering. We demonstrate the immunomodulatory activity of HARS WHEP and present preclinical data supporting ongoing clinical development of the biologic efzofitimod based on HARS WHEP in ILD.