tbuckley/cabot-search huggingface dataset:
Exposure to Sucralose and Its Effects on Testicular Damage and Male Infertility: Insights into Oxidative Stress and Autophagy
Authors: Yi-Fen Chiang, Yang-Ching Chen, Ko-Chieh Huang, Mohamed Ali, Shih-Min Hsia
Journal: Environmental Health Perspectives (2025)

The impact of non-nutritive sweeteners on male reproductive health, particularly at the cellular level, remains insufficiently explored. Sucralose's high stability and resistance to degradation during wastewater treatment raises concerns about its long-term environmental and health impacts. Whether sucralose consumption correlates with reduced reproductive hormone levels and testicular damage remains unclear, and the underlying mechanisms require further investigation. This study aims to investigate the influence of sucralose on cell damage and reproductive health in male. The male mouse Leydig cell line TM3 and Sertoli cell line TM4 were used to evaluate sucralose-associated cellular damage. In vitro experiments assessed cell survival rates and the potential disruption of autophagy. Additionally, male SD rats were exposed to sucralose via oral gavage for two months at doses reflecting the acceptable daily intake (ADI) to evaluate sperm viability and reproductive health. In vitro experiments demonstrated cells exposed to sucralose had significantly lower cell survival rates. Sucralose exposure significantly reduced cell viability in TM3 and TM4 cells, induced oxidative stress, and disrupted autophagic flux by impairing autophagosome-lysosome fusion. Additionally, sucralose downregulated T1R3 protein expression, suggesting a role for sweet taste receptor signaling in testicular cell regulation. In vivo, chronic oral exposure to sucralose led to decreased sperm viability and dysregulated reproductive function, including altered testicular morphology and suppressed steroidogenesis. These findings provide new insights into the adverse effects of sucralose on male reproductive physiology, highlighting its role in disrupting autophagy, inducing oxidative stress, and impairing reproductive function. The environmental persistence of sucralose and its potential leakage into wastewater systems present broader implications for public health and ecological stability. This study underscores the importance of carefully evaluating non-nutritive sweeteners in the diet and calls for stricter food safety regulations and wastewater management practices to mitigate potential risks.. https://doi.org/10.1289/EHP15919.
AI-based volumetric six-tissue body composition quantification from CT cardiac attenuation scans for mortality prediction: a multicentre study
Authors: Jirong Yi, Anna M Marcinkiewicz, Aakash Shanbhag, Robert J H Miller, Jolien Geers, Wenhao Zhang, Aditya Killekar, Nipun Manral, Mark Lemley, Mikolaj Buchwald, Jacek Kwiecinski, Jianhang Zhou, Paul B Kavanagh, Joanna X Liang, Valerie Builoff, Terrence D Ruddy, Andrew J Einstein, Attila Feher, Edward J Miller, Albert J Sinusas, Daniel S Berman, Damini Dey, Piotr J Slomka
Journal: The Lancet Digital Health (2025)

CT attenuation correction (CTAC) scans are routinely obtained during cardiac perfusion imaging, but currently only used for attenuation correction and visual calcium estimation. We aimed to develop a novel artificial intelligence (AI)-based approach to obtain volumetric measurements of chest body composition from CTAC scans and to evaluate these measures for all-cause mortality risk stratification. We applied AI-based segmentation and image-processing techniques on CTAC scans from a large international image-based registry at four sites (Yale University, University of Calgary, Columbia University, and University of Ottawa), to define the chest rib cage and multiple tissues. Volumetric measures of bone, skeletal muscle, subcutaneous adipose tissue, intramuscular adipose tissue (IMAT), visceral adipose tissue (VAT), and epicardial adipose tissue (EAT) were quantified between automatically identified T5 and T11 vertebrae. The independent prognostic value of volumetric attenuation and indexed volumes were evaluated for predicting all-cause mortality, adjusting for established risk factors and 18 other body composition measures via Cox regression models and Kaplan-Meier curves. The end-to-end processing time was less than 2 min per scan with no user interaction. Between 2009 and 2021, we included 11 305 participants from four sites participating in the REFINE SPECT registry, who underwent single-photon emission computed tomography cardiac scans. After excluding patients who had incomplete T5-T11 scan coverage, missing clinical data, or who had been used for EAT model training, the final study group comprised 9918 patients. 5451 (55%) of 9918 participants were male and 4467 (45%) of 9918 participants were female. Median follow-up time was 2·48 years (IQR 1·46-3·65), during which 610 (6%) patients died. High VAT, EAT, and IMAT attenuation were associated with an increased all-cause mortality risk (adjusted hazard ratio 2·39, 95% CI 1·92-2·96; p<0·0001, 1·55, 1·26-1·90; p<0·0001, and 1·30, 1·06-1·60; p=0·012, respectively). Patients with high bone attenuation were at reduced risk of death (0·77, 0·62-0·95; p=0·016). Likewise, high skeletal muscle volume index was associated with a reduced risk of death (0·56, 0·44-0·71; p<0·0001). CTAC scans obtained routinely during cardiac perfusion imaging contain important volumetric body composition biomarkers that can be automatically measured and offer important additional prognostic value. The National Heart, Lung, and Blood Institute, National Institutes of Health.
Genomic Analyses Reveal the Evolving Characteristics of Intestinal Metaplasia and Gastric Cancer
Authors: Xianfeng Xu, Caiwang Yan, Lijun Bian, Zhe Li, Yuhui Yu, Xia Zhu, Yun Gao, Hao Xu, Fengyuan Li, Yao Liu, Ping Sun, Zheng Wang, Yao Fu, Yue Jiang, Juncheng Dai, Hongxia Ma, Zhibin Hu, Hongbing Shen, Gang Li, Cheng Wang, Guangfu Jin
Journal: Cancer Research (2025)

Abstract Intestinal metaplasia (IM) represents a precancerous condition associated with an increased gastric cancer (GC) risk. A better understanding of whether and how precancerous lesions progress to GC is crucial for patient stratification and personalized prevention. Here, we reconstruct evolutionary trajectories of genomic alterations in 330 multi-region matched samples of IM and tumors from 93 GC patients. Intestinal-type gastric cancer (IGC) exhibited a higher mutation burden than diffuse-type gastric cancer (DGC), notably in genomically stable (GS) patients. IM from GS patients carried more mutations associated with alcohol consumption. The 20 significantly mutated genes identified were classified into three evolutionary patterns. "Maintained" genes (TP53, APC, and PIK3CA) were commonly altered in IM and matched GC samples in both IGC and DGC, while CDH1 mutations were specific to DGC. "Maintained" mutations in IM accelerated GC progression. Alterations in "IM favored" genes (MUC6, CFTR, BMP6, and MTRR) were associated with IM development but were negatively selected in GC. Interestingly, MUC6 mutations were enriched in specific pit cells with upregulation of GKN1 and GKN2. The remaining genes were "GC favored" and showed high heterogeneity in GC. These findings illuminate the genomic evolution from IM to IGC or DGC, providing insights that could guide precancerous lesion surveillance and early prevention strategies.
Cells keep diverse company in diseased tissues
Authors: Kieran R. Campbell, Aleksandrina Goeva
Journal: Cancer Research (2025)

Abstract Emerging spatial profiling technologies have revolutionized our understanding of how tissue architecture shapes disease progression, yet the contribution of cellular diversity remains underexplored. Here, Ding and colleagues introduce multiomics and ecological spatial analysis (MESA), an ecology-inspired framework that integrates spatial and single-cell expression data to quantify tissue diversity across multiple scales. MESA both identifies distinct cellular neighborhoods and computes a variety of diversity metrics alongside the identification of diversity “hotspots”. Applied to human tonsil tissue, MESA revealed previously undetected germinal center organization, while in spleen tissue of a murine lupus model, MESA highlights increasing cellular diversity with disease progression. Importantly, diversity hotspots do not correspond to conventional compartments identified by existing methods, presenting an orthogonal metric of spatial organization. In colorectal cancer, MESA’s diversity metrics outperformed established subtypes at predicting patient survival, while in hepatocellular carcinoma, multi-omic integration identified significantly more ligand-receptor interactions between immune cells compared to single-modality analysis. This work establishes cellular diversity within tissues as a critical correlate of disease progression and underscores the value of multi-omic integration in spatial biology.
Hemodynamic response of normal aortic valves to stress using invasive, non-invasive, and computational techniques
Authors: Rob Eerdekens, Vijay Govindarajan, Nils P Johnson, Jesse P A Demandt, Mohamed El Farissi, Fabienne E Vervaat, Daniel T Johnson, Richard L Kirkeeide, Pim A L Tonino
Journal:  (2025)

Abstract Background The hemodynamic physiology of the aortic valve has attracted renewed attention after the introduction of transcatheter aortic valve implantation (TAVI). Understanding normal valve function, especially under stress conditions, permits identification of early pathology and quantification of the extent to which TAVI restores normalcy. We aimed to describe the hemodynamic behavior of a normal aortic valve during stress via invasive, non-invasive, and computational techniques. Methods Our cohort included subjects already undergoing invasive coronary angiography for clinical indications. Hemodynamic measurements were made invasively and non-invasively along with dobutamine infusion. Additionally, patient-specific anatomy from computed tomographic imaging served as input to a computational fluid dynamics model using fluid-structure interaction (FSI) analysis. Results We studied 10 subjects with simultaneous invasive sensors and non-invasive echocardiography during dobutamine administration. The majority of normal valves (7 of 10) demonstrated a fall in the invasive gradient during stress, in contrast to the increase noted by Doppler assessment. The stress aortic valve index (SAVI), a relative measure of pressure loss over the valve during ejection, uniformly exceeded 0.90 with median value of 0.96 and interquartile range 0.94 to 1.00. Simulation of increased transvalvular flow via faster heart rates produced a highly linear relationship (coefficient of determination R2 equal to 0.95) with the mean transvalvular pressure gradient. Conclusion Normal aortic valves demonstrated minimal pressure loss even during the high transvalvular flow generated by dobutamine infusion. Computational simulation using anatomy from a normal aortic valve behaved like a resistor, since mean gradient scaled directly with transvalvular flow.
C/EBPα activates <i>Irf8</i> expression in myeloid progenitors at the +56-kb enhancer to initiate cDC1 development
Authors: Jing Chen, Tian-Tian Liu, Feiya Ou, Ray A. Ohara, Suin Jo, Joshua Luke Postoak, Takeshi Egawa, Ryan B. Day, Theresa L. Murphy, Kenneth M. Murphy, Sunkyung Kim
Journal: Science Immunology (2025)

Development of type 1 conventional dendritic cells (cDC1s) underlies the capacity to generate antiviral and antitumor immune responses. Here, we identify the basis for cDC1 development from its earliest progenitors, determining the hierarchy of several required transcription factors and uncovering a series of mandatory cis interactions between constituent enhancers within the Irf8 superenhancer. We produced in vivo mutations of two C/EBPα binding sites that comprise the Irf8 +56–kilobase (kb) enhancer that markedly reduced IRF8 expression in all myeloid progenitors and impaired cDC1 development. These sites did not bind RUNX1 or RUNX3, and C/EBPα expression was instead regulated by their action at the Cebpa +37-kb enhancer, placing RUNX factors upstream of Cebpa in regulating Irf8 . Last, we demonstrate that cis interactions between the +56-kb Irf8 enhancer and the previously reported +41- and +32-kb Irf8 enhancers are mandatory in the sequential progression of these stage-specific constituent elements.
ILC3s promote intestinal tuft cell hyperplasia and anthelmintic immunity through RANK signaling
Authors: Hongkai Xu, Yibo Wang, Wenyan Wang, Yang-Xin Fu, Ju Qiu, Yan Shi, Lei Yuan, Chen Dong, Xiaoyu Hu, Ye-Guang Chen, Xiaohuan Guo
Journal: Science Immunology (2025)

Helminth infections, particularly in developing countries, remain a notable health burden worldwide. Group 3 innate lymphoid cells (ILC3s) are enriched in the intestine and play a critical role in immunity against extracellular bacteria and fungi. However, whether ILC3s are involved in intestinal helminth infection is still unclear. Here, we report that helminth infection reprograms ILC3s, which, in turn, promote anthelmintic immunity. ILC3-derived RANKL [receptor activator of NF-κB (nuclear factor κB) ligand] synergizes with interleukin-13 (IL-13) to facilitate intestinal tuft cell expansion after helminth infection, which further activates the tuft cell–group 2 innate lymphoid cell (ILC2) circuit to control helminth infection. Deletion of RANKL in ILC3s or deletion of RANK or its downstream adaptor RelB in intestinal epithelial cells substantially diminishes tuft cell hyperplasia and dampens anthelmintic immunity. Thus, ILC3s play an indispensable role in protecting against helminth infection through the regulation of intestinal tuft cell hyperplasia and type 2 immunity.
Subaqueous acoustic pressure system based one day heterotypic pseudo-islet spheroid formation with adipose derived stem cells for graft survival-related function enhancement
Authors: Jiyu Hyun, Junhyeung Park, Jihun Song, Chaerim Yoo, Seonmi Jang, Sang Yoon Lee, Jiseon An, Hyun Su Park, Seunghyuk Jung, Dasom Kong, Ji Hyeon Cho, Tae Il Lee, Ki Dong Park, Gwang-Bum Im, Jee-Heon Jeong, Hyun-Ji Park, Dong Yun Lee, Suk Ho Bhang
Journal: Bioactive Materials (2025)
Lineages and sublineages of high-risk HPV types associated with cervical cancer and precancer: a systematic review and meta-analysis
Authors: Eef Van Den Borst, Margo Bell, Ken Op De Beeck, Guy Van Camp, Severien Van Keer, Alex Vorsters
Journal: JNCI Journal of the National Cancer Institute (2025)

Abstract BACKGROUND Infection with high-risk types of the human papillomavirus (hrHPV) is known to cause cervical cancer. Cervical cancer risk varies greatly by genotype, which is therefore used in screening algorithms. A significant amount of research has also focused on the differential pathogenicity of hrHPV subtypes called lineages and sublineages (resp. 1.0-10% and 0.5-1.0% genetic difference), albeit with inconclusive and contradictory results. Therefore, the topic is systematically reviewed for the first time to determine whether the clinical use of (sub)lineage detection is supported. METHODS Three databases for health sciences (PubMed, Web of Science, and Scopus) were searched for relevant papers. Meta-analysis was performed for HPV16 positive cancers and controls using random effects models. RESULTS The search yielded 1,535 records and 93 papers were included after the selection process. Although some trends in disease association were detected, 46 studies did not find significant differences between (sub)lineages in cases and controls. Additionally, the reports are heterogeneous in terms of study design and often characterized by a small sample size. The meta-analysis found odds ratios of 2.2 [95% CI: 1.49-3.15] for HPV16 A4, 2.1 [95% CI: 1.25-3.40] for HPV16 D and 0.48 [95% CI: 0.33-0.68] for HPV16 A1-3 with significant heterogeneity (38-77%). CONCLUSION This systematic review and meta-analysis provides an overview of the hrHPV (sub)lineages and association with cervical disease. Although some (sub)lineages marginally correlate with cervical malignancy, there is great variability. Unlike genotyping, this study demonstrates insufficient association between hrHPV (sub)lineages and cervical malignancy for clinical use to date.
Corrigendum to “Advancing neural regeneration via adaptable hydrogels: Enriched with Mg2+and silk fibroin to facilitate endogenous cell infiltration and macrophage polarization” [Bioact. Mater. 33 (2024) 100–113]
Authors: Yisheng Gao, Yingyu Wang, Jianye Zhang, Miao Zhang, Chaolun Dai, Yang Zhang, Luzhong Zhang, Liming Bian, Yumin Yang, Kunyu Zhang, Yahong Zhao
Journal: Bioactive Materials (2025)
Multiple horizontal transfers of immune genes between distantly related teleost fishes
Authors: Maxime Policarpo, Walter Salzburger, Florian Maumus, Clément Gilbert
Journal: Molecular Biology and Evolution (2025)

Abstract Horizontal gene transfer (HGT) is less frequent in eukaryotes than in prokaryotes, yet can have strong functional implications and was proposed as causal factor for major adaptations in several eukaryotic lineages. Most cases of eukaryote HGT reported to date are inter-domain transfers and few studies have investigated eukaryote-to-eukaryote HGTs. Here, we performed a large-scale survey of HGT among 242 species of ray-finned fishes. We found multiple lines of evidence supporting 19 teleost-to-teleost HGT events that involve 17 different genes in 11 teleost fish orders. The genes involved in these transfers show lower synonymous divergence than expected under vertical transmission, their phylogeny is inconsistent with that of teleost fishes, and they occur at non syntenic positions in donor and recipient lineages. The distribution of HGT events in the teleost tree is heterogenous, with eight of the 19 transfers occurring between the same two orders (Osmeriformes and Clupeiformes). Though we favor a scenario involving multiple HGT events, future work should evaluate whether hybridization between species belonging to different teleost orders may generate HGT-like patterns. Besides the previously reported transfer of an antifreeze protein, most transferred genes play roles in immunity or are pore forming proteins, suggesting that such genes may be more likely than others to confer strong selective advantage to the recipient species. Overall, our work shows that teleost-to-teleost HGT has occurred on multiple occasions, and it will be worth further quantifying these transfers and evaluating their impact on teleost evolution as more genomes are sequenced.
Cross-regulation between the nervous system and type 2 immunity
Authors: Nicholas M. Mroz, Pailin Chiaranunt, Anna V. Molofsky, Ari B. Molofsky
Journal: Science Immunology (2025)

Interactions between the nervous and immune systems are critical to healthy physiology and are altered in many human diseases. Many of the major players in type 2 immune responses, including type 2 lymphocytes and cytokines, mast cells, and immunoglobulin E, have been implicated in neuronal function and behavior. Conversely, neurons in both the central and peripheral nervous systems can affect type 2 immune responses and behaviors relevant to allergy, such as food avoidance. Defining this complex circuitry and its molecular intermediates in physiology may reveal type 2 immunomodulators that can be harnessed for therapeutic benefit in neurologic diseases including Alzheimer’s disease, brain injury, and neurodevelopmental disorders. Conversely, modulation of the nervous system may be an important adjunct to treating immunologic disorders including atopic dermatitis, asthma, and food allergy. This Review covers recent work defining how the nervous system can both regulate and be regulated by type 2 immune responses.
A single arm phase 2 trial of doxorubicin plus zalifrelimab (anti-CTLA-4 antibody) and balstilimab (anti-PD-1 antibody) in advanced/metastatic soft tissue sarcomas
Authors: Breelyn A. Wilky, Katherine A. Julian, Alessandra Maleddu, Anne C. Mailhot, Chelsey R. Cartwright, Dexiang Gao, Cristiam Moreno Tellez, Lindsey E. Kemp, Nicholas R. Therrien, Sumra S. Chaudhry, Jeffrey D. Rytlewski, Qierra R. Brockman, Eduardo Davila, Anthony D. Elias
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Doxorubicin is standard chemotherapy for metastatic soft tissue sarcomas (STSs) but also enhances innate/adaptive immune responses by inducing immunogenic cell death. Most STSs are immune “cold” tumors that do not respond to immune checkpoint inhibitors (ICIs) blocking PD-1 and CTLA-4. We hypothesized that concurrent doxorubicin would improve tumor immunogenicity and boost efficacy of ICIs in STS. Patients and Methods: We conducted a single arm, phase 2 trial of doxorubicin plus zalifrelimab (anti-CTLA-4 antibody) and balstilimab (anti-PD-1 antibody) for advanced/metastatic STS patients without prior doxorubicin or ICIs (NCT04028063). The study was a Simon minimax two-stage design to accrue 28 patients evaluable for primary endpoint of progression-free survival rate at six months (PFS6mo) by RECIST 1.1. The study aimed to improve PFS6mo by 20% over historical null rate of 43.4% with doxorubicin monotherapy. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), duration of response (DOR), and adverse events (AEs). Results: PFS6mo for 28 evaluable patients was 46.4% [95% CI 27.5-66.1] and not superior to null rate, with median PFS of 25.3 weeks [95% CI 24.0-42]. Best ORR was 33.3% [95% CI 17.3-52.8] with DCR of 80.0% [95% CI 61.4-92.3], including STS types unlikely to respond to doxorubicin or ICIs alone. Grade 3/4 treatment-related AEs occurred in 45% of patients, with immune-mediated AEs requiring immunosuppression in 9%. Conclusions: Although the study did not meet the predefined endpoint for PFS improvement, promising signals of efficacy warrant future investigation including response/resistance biomarkers to inform patient selection.
Phase I/II Study of Tifcemalimab, an Anti-B and T-lymphocyte Attenuator Antibody, in Combination with Toripalimab in Previously Treated Advanced Lung Cancer
Authors: Ying Cheng, Jie Wang, Yan Yu, QiMing Wang, Runxiang Yang, Bing Xia, Chong Li, Dongqing Lv, Tienan Yi, Liang Han, Xiao-Qing Liu, Xi-Cheng Wang, Wei Zhang, Man Su, Minjie Shen, Jing Xu, Bang.an Peng
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Tifcemalimab is a recombinant humanized IgG4k monoclonal antibody targeting B and T-lymphocyte attenuator (BTLA). Co-blockade of BTLA and programmed death-1 pathways improved outcomes in non-clinical models. This phase I/II trial evaluated the safety and preliminary efficacy of tifcemalimab plus toripalimab in advanced lung cancer. Patients and Methods: Eligible patients with pathologically confirmed advanced non-small cell lung cancer (NSCLC) without sensitive epidermal growth factor receptor variation and anaplastic lymphoma kinase fusion who failed standard treatment including one programmed death-(ligand) 1 inhibitor, or refractory extensive-stage small cell lung cancer (SCLC) received tifcemalimab (200 mg) and toripalimab (240 mg) every 3 weeks intravenously until disease progression or intolerable toxicity. Simon’s two-stage optimal design was used in expansion part. The primary endpoints included safety and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Results: Totally, 24 patients with NSCLC and 43 with SCLC were enrolled (median age of all patients, 60.0 years). All patients with NSCLC and 14 (32.6%) with SCLC had received previous immunotherapy. Fifty-five (82.1%) patients experienced treatment-related adverse events (AEs), and 5 (7.5%) patients reported grade ≥3 immune-related AEs. For NSCLC, ORR was 4.3%, and disease control rate (DCR) was 47.8%; median progression-free survival (PFS) and overall survival (OS) was 1.5 and 18.9 months, respectively. For SCLC, ORR and DCR were 35.0% and 55.0%, respectively; median duration of response, PFS, and OS were 5.7, 2.8, and 12.3 months, respectively. Conclusions: Tifcemalimab plus toripalimab showed promising antitumor activities with acceptable safety, especially, in advanced refractory SCLC.