tbuckley/cabot-search huggingface dataset:
Targeting the Galectin‐7/<scp>TRPM2</scp>/Zn<sup>2+</sup>/<scp>DRP</scp>‐1 Signaling Pathway: A Potential Therapeutic Intervention in the Pathogenesis of <scp>SJS</scp>/<scp>TEN</scp>
Authors: Chen Zhang, BingYu Pang, YiXin Luo, Zipeng Cao, Pei Qiao, ZhenLai Zhu, Hui Fang, JianKang Yang, ErLe Dang, ShengXian Shen, Pan Kang, Qingqing Jiao, Akito Hasegawa, Riichiro Abe, HongJiang Qiao, Gang Wang, Meng Fu
Journal: Allergy (2025)

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a spectrum of severe drug-induced cutaneous reactions. These conditions are characterized by widespread and confluent keratinocyte apoptosis, which differentiates them from erythema multiforme (EM). Mounting evidence has implicated the mitochondrial-dependent apoptosis pathway in the pathogenesis of SJS/TEN, but the potential roles and specific mechanisms of these pathways in SJS/TEN remain largely unexplored. Proteomic analyses were conducted to investigate differential protein expression in blister fluid (BF)-derived exosomes from suction surgery in healthy individuals (Con Exo) or patients with EM (EM Exo) or SJS/TEN (TEN Exo). Further analysis involved glutathione S-transferase (GST) pull-down assay, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, and validation of MS results through proximity ligation assay (PLA) and coimmunoprecipitation (co-IP). Phenotypic and mechanistic analyses were performed using immunohistochemistry (IHC) staining, enzyme-linked immunosorbent assay (ELISA), western blotting, reverse transcription-polymerase chain reaction (RT-PCR), co-IP, CCK-8 assay, adenosine triphosphate (ATP) level measurements, and flow cytometry. Galectin-7 was markedly upregulated in BF-derived exosomes from SJS/TEN patients and showed a correlation with disease severity. Further analysis confirmed the interaction between galectin-7 and transient receptor potential (melastatin) 2 (TRPM2). BF-derived exosomes from SJS/TEN patients induced an imbalance in mitochondrial dynamics via galectin-7/TRPM2 upregulation. Activation of TRPM2 led to an elevation in mitochondrial Zn2+, which facilitated the recruitment of the fission factor dynamin-related protein-1 (DRP-1) to mitochondria to trigger mitochondrial fission in the keratinocyte. In addition, the recruitment of DRP-1-dependent mitochondrial fission via the voltage-dependent anion channel 1 (VDAC1)/hexokinase 2 (HK2)-mediated opening of the mitochondrial permeability transition pore (mPTP)-triggered cytochrome c release. These effects ultimately induce activation of the intrinsic mitochondrial apoptotic pathway and contribute to the pathogenesis of SJS/TEN. Targeting the galectin-7/TRPM2/Zn2+/DRP-1 signaling pathway in keratinocytes presents a prospective therapeutic strategy for mitigating SJS/TEN in the future.
Vasoconstriction-inhibiting factor: an endogenous inhibitor of vascular calcification as a calcimimetic of calcium-sensing receptor
Authors: Sofía de la Puente-Secades, Dustin Mikolajetz, Nathalie Gayrard, Juliane Hermann, Vera Jankowski, Shruti Bhargava, Amina Meyer, Àngel Argilés, Turgay Saritas, Emiel P C van der Vorst, Zhuojun Wu, Heidi Noels, Martin Tepel, Khaleda Alghamdi, Donald Ward, Walter Zidek, Michael Wolf, Jürgen Floege, Leon Schurgers, Setareh Orth-Alampour, Joachim Jankowski
Journal: Cardiovascular Research (2025)

Patients with chronic kidney disease (CKD) show a high risk of cardiovascular diseases, predominantly caused by accelerated vascular calcification. Vascular calcification is a highly regulated process with no current treatment. The vasoconstriction-inhibiting factor (VIF) peptide was recently discovered with vasoregulatory properties, but no information regarding calcification has been described. In the present work, the inhibitory calcification effect of the VIF peptide was analysed in vitro in vascular smooth muscle cells (VSMCs), ex vivo in rat aortic rings, as well as in vivo in rats treated with vitamin D and nicotine (VDN). The VIF peptide inhibits vascular calcification by acting as a calcimimetic for the calcium-sensing receptor, increasing carboxylated matrix Gla protein production and blocking the activation of calcification pathways. The VIF peptide decreased calcium influx, the production of reactive oxygen species, and the activation of multiple kinases in VSMCs. Furthermore, calcium deposition in the aortas of patients with CKD negatively correlates with the VIF peptide concentration. Moreover, we show the cleavage of the VIF peptide from chromogranin-A by 'proprotein convertase subtilisin/kexin type 2' and 'carboxypeptidase E' enzymes. In addition, 'cathepsin K' degrades the VIF peptide. The active site of the native 35 amino acid-sequence long VIF peptide was identified with seven amino acids, constituting a promising drug candidate with promise for clinical translation. The elucidation of the underlying mechanism by which the VIF peptide inhibits vascular calcification, as well as the active sequence and the cleavage and degradation enzymes, forms the basis for developing preventive and therapeutic measures to counteract vascular calcification.
Select Airway Specialized Pro-Resolving Mediators Are Associated with Recovery from Non-Viral COPD Exacerbations
Authors: Lydia J. Finney, Jordina Mah, Melody Duvall, Dexter Wiseman, Faisal Kamal, Peter Fenwick, Andrew I Ritchie, Tata Kebadze, Christopher Orton, Pankaj Bhavsar, James P. Allinson, Mairi Macleod, Alexander J Mackay, Federico Baraldi, Samuel Kemp, Aran Singanayagam, Sebastian L Johnston, Adam Byrne, Bruce D. Levy, Jadwiga A. Wedzicha
Journal: American Journal of Respiratory and Critical Care Medicine (2025)

Recovery from chronic obstructive pulmonary disease (COPD) exacerbations is heterogeneous and has a profound impact on disease trajectories. Resolution of airway inflammation is an active process which may be driven by Specialized Pro-resolving Mediators (SPMs). To characterize the temporal change in SPMs in the sputum of COPD patients during COPD exacerbations, their association with exacerbation triggers and exacerbation recovery. Participants were recruited from the London COPD Exacerbation Cohort between 01/11/2016 and 01/04/2018. Participants were reviewed at baseline, exacerbation onset, 1 week, 2 weeks and 6 weeks during their exacerbation recovery. Sputum, nasopharyngeal swabs, phlebotomy, quality of life questionnaires and spirometry were performed at each visit. SPMs were measured in sputum by liquid chromatography tandem mass spectrometry. Respiratory viruses were measured by quantitative PCR and bacteria by microbiological culture. There were 68 exacerbations during the study period. Median time to symptomatic recovery was 21 days for viral exacerbations compared to 13 days in non-viral exacerbations (P<0.001). There was a significant increase in Resolvin D1 (RvD1) at exacerbation onset in bacterial exacerbations but not viral exacerbations. Lower levels of RvD1 were associated with prolonged respiratory symptoms during the 1-week and 2-week recovery time points. Exogenous RvD1 significantly reduced IL-6 and CXCL8 response to rhinovirus infection in COPD bronchial epithelial cells. There is a dynamic temporal change in airway SPMs during COPD exacerbations. Reduced levels of RvD1 were associated with prolonged respiratory symptoms. SPMs may be a potential therapeutic approach to promote exacerbation recovery.
Prenatal and childhood exposure to fluoride and cognitive development: findings from the longitudinal MINIMat cohort in rural Bangladesh
Authors: Taranbir Singh, Klara Gustin, Syed Moshfiqur Rahman, Shamima Shiraji, Fahmida Tofail, Marie Vahter, Mariza Kampouri, Maria Kippler
Journal: Environmental Health Perspectives (2025)

There are indications that fluoride exposure considered to be beneficial for dental health may not be safe from a neurodevelopmental perspective. To assess the impact of prenatal and childhood fluoride exposure on cognitive abilities at 5 and 10 years of age. We studied 500 mother-child pairs from the MINIMat (Maternal and Infant Nutrition Interventions in Matlab) birth cohort in rural Bangladesh. Urinary fluoride concentrations were measured in the pregnant women at gestational week 8 and in their children at 5 and 10 years, using an ion-selective electrode and adjusting for specific gravity. Cognitive abilities were assessed using the Wechsler Preschool and Primary Scale for Intelligence-Third Edition and the Wechsler Intelligence Scale-Fourth Edition at age 5 and 10 years, respectively. Associations of urinary fluoride concentrations (log2-transformed) with cognitive abilities (raw scores) were assessed with multivariable-adjusted linear or spline regression models. Water fluoride concentrations were measured at the 10-year-old visit. Maternal urinary fluoride concentrations (median: 0.63 mg/L, 5th-95th percentiles: 0.26-1.41 mg/L) were inversely associated with full-scale raw scores at 5 and 10 years (B [95% confidence interval]: -2.8 [-5.1, -0.6] and -4.9 [-8.0, -1.8], respectively, by exposure doubling). In cross-sectional analysis at 10 years, child urinary fluoride (overall median: 0.66 mg/L, 5th-95th percentiles: 0.34-1.26 mg/L) above -0.47 on the log2-scale (corresponding to 0.72 mg/L) was inversely associated with full-scale raw scores (B [95% CI]: -12.1 [-21.2, -3.0]). The association at 5 years was also negative but non-significant. For both prenatal and childhood exposure, associations were most noticeable with perceptual reasoning, but also verbal scores. The estimate for the association between urinary fluoride at 10 years and perceptual reasoning became 18% lower after adjustment for prenatal exposure. Non consistent sex-specific differences were observed. Urinary fluoride concentrations measured prenatally and during childhood (child urinary fluoride concentrations above -0.47 on the log2 scale (corresponding to 0.72 mg/L) were associated with lower cognitive abilities, especially perceptual reasoning and verbal abilities, in Bangladeshi children. https://doi.org/10.1289/EHP14534.
Trends in Young-Onset Cancer Incidence: A Modeling Perspective
Authors: Lukas Owens, Allison Fung, Jonathan Shuhendler, Joseph Glick, Marc D Ryser, Roman Gulati, Ruth Etzioni
Journal: JNCI Journal of the National Cancer Institute (2025)

Recent increases in the diagnosis of certain cancers among younger individuals are generating intense concern. Many studies attribute the increase in so-called "young-onset" cancer to an etiologic cause but questions have also arisen about the role of earlier diagnosis. We simulate incidence trends from a natural history model that includes healthy, preclinical, and clinical disease states, where transitions from a healthy to a preclinical state represent disease onset and transitions from the preclinical to the clinical state represent diagnosis. We superimpose birth cohort effects on the rate of disease onset and period effects on the rate of disease diagnosis to identify those that match patterns of relative incidence by age group and five-year calendar interval from 2000-2019 for six "young-onset" cancers (colon, rectum, female breast, gastric, pancreas, kidney). Two types of effects are broadly consistent with the observed increasing incidence trends in younger individuals: (1) A birth-cohort effect on disease onset that begins around 1970 and becomes more pronounced in later birth years, or (2) A period effect consistent with progressive reduction over time in the duration of preclinical disease. An earlier, protective birth cohort effect is consistent with recent declining trends in incidence in older individuals for colon, rectal, and gastric cancers. A disease model provides clues about the possible drivers of cancer incidence trends, suggests constraints on the patterns of exposures that might be implicated etiologically, and indicates that the role of diagnostic changes warrants consideration alongside potential etiologic explanations.
Neoadjuvant Semaglutide, Bariatric Surgery Weight Loss, and Overall Outcomes
Authors: Vasundhara Mathur, Katherine Wasden, Thomas H. Shin, Pourya Medhati, Abdelrahman A. Nimeri, Ali Tavakkoli, Eric G. Sheu
Journal: JAMA Surgery (2025)

This case-control study examines the use of glucagon-like peptide-1 receptor agonist before metabolic and bariatric surgery and its postoperative outcome.
Developing an adaptive platform trial for evaluation of medical treatments for Crohn’s disease
Authors: Nurulamin M Noor, Shellie J Radford, Babak Choodari-Oskooei, Morris Gordon, Ailsa L Hart, Trish Hepburn, Ed Juszczak, James O Lindsay, Nicholas A Kennedy, Mahesh K B Parmar, Vipul Jairath, Gordon W Moran
Journal: Nature Reviews Gastroenterology & Hepatology (2025)
PCK1 inhibits cGAS-STING activation by consumption of GTP to promote tumor immune evasion
Authors: Wenxing Qin, Yuran Duan, Zhiqiang Hu, Yueru Hou, Ting Wen, Yuan Ouyang, Zheng Wang, Xue Sun, Xiaohan Chen, Katherine L. Wang, Shudi Luo, Guimei Ji, Yuli Shen, Bofei Dong, Yanni Lin, Qi Tian, Zhanpeng Guo, Shiqi Wu, Ling Xiao, Min Li, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Wuchang Zhang, Shengzhong Duan, Xueli Bai, Tong Liu, Jie He, Zhimin Lu, Daqian Xu
Journal: The Journal of Experimental Medicine (2025)

Hypoxia induces immunosuppressive phenotypes in tumor cells even in the presence of cytosolic DNA accumulation. The mechanisms by which tumor cells suppress hypoxia-induced cGAS-STING activation for immune evasion remain largely unclear. Here, we demonstrate that hypoxic stimulation induces JNK1/2-mediated S151 phosphorylation of phosphoenolpyruvate carboxykinase 1 (PCK1), a rate-limiting enzyme in gluconeogenesis. This phosphorylation triggers the interaction between PCK1 and cGAS. The PCK1 associated with cGAS competitively consumes GTP, a substrate shared by both PCK1 and cGAS. Consequently, PCK1 inhibits GTP-dependent cGAS activation and subsequent STING-promoted immune cell infiltration and activation in the tumor microenvironment, leading to promoted tumor growth in mice. The blockade of PCK1 function, in combination with anti–PD-1 antibody treatment, exhibits an additive therapeutic effect on tumor growth. Additionally, PCK1 S151 phosphorylation is inversely correlated with cGAS-STING activation in human breast cancer specimens and patient survival. These findings reveal a novel regulation of cGAS-STING pathway and uncover the metabolic control of immune response in tumor cells.
Scarlett McNally: Unleashing the talent of women doctors can improve everyone’s health
Authors: Scarlett McNally
Journal: BMJ (2025)

<h3>Abstract</h3> Cell-to-cell communication via Delta-Notch signaling is widely used in various tissues and organs to regulate development and patterning; however, the mechanisms regulating Notch signaling for precise cell fate decisions remain poorly understood. Similar to mammals, the intestinal stem cells (ISCs) in the adult <i>Drosophila</i> midgut generate both absorptive and secretory cell progeny, guided by differential levels of Notch activation. Here we performed a forward genetic screen in <i>Drosophila</i> and identified glucosylceramide synthase (GlcT), a rate-limiting enzyme for glycosphingolipid (GSL) production, whose mutation causes the development of secretory cell tumors. Genetic analysis of the GSL synthesis pathway, combined with metabolite rescue experiments, revealed that the tumor formation is linked to a deficiency in Mactosylceramide/Lactosylceramide. This deficiency impaired the endocytic recycling of the Delta, subsequently reducing Notch signaling activation. Conditional knockout of <i>UGCG</i>, the mammalian ortholog of <i>GlcT</i>, in mouse small intestine caused an excessive differentiation of goblet cells, phenotypes similar to these caused by Notch inhibition. Our study suggests an evolutionarily conserved role for a specific GSL metabolite in modulating Notch signaling during stem cell fate decisions and provides a molecular connection between ceramide metabolism and Notch signaling in regulating tissue homeostasis and tumor formation.
Silk Nonwoven Fabric‐Based Dressing with Antibacterial and ROS‐Scavenging Properties for Modulating Wound Microenvironment and Promoting Diabetic Wound Healing
Authors: Zhao‐Xi Zhou, Yanbin Chen, Jingyi Li, Jie Shen, Huaqiang Zeng
Journal: Advanced Healthcare Materials (2025)

The microenvironment of diabetic wounds is exceptionally complex, characterized notably by persistent bacterial infections and the excessive production of reactive oxygen species (ROS). Traditional treatment methods often fall short of achieving ideal results. Consequently, there is an urgent need to develop and implement more advanced and efficient treatment strategies to effectively address the complexity and recalcitrance of diabetic wounds. This study pioneers a novel approach by fabricating a silk fibroin-based nonwoven dressing (SF-Ag-HCA) under neutral conditions, integrating silver ions with dihydrocaffeic acid-modified silk fibroin. Uniquely, this dressing achieves dual functionality: exceptional antibacterial efficacy against common pathogens (E. coli, S. aureus, P. aeruginosa) and robust ROS-scavenging capabilities, effectively mitigating oxidative stress and promoting immune homeostasis. The SF-Ag-HCA dressing not only surpasses conventional materials in regulating the wound microenvironment but also accelerates re-epithelialization and collagen deposition. Animal studies further validate its superior performance in healing diabetic and infected wounds compared to commercial alternatives. This innovative dressing represents a significant advancement in wound care, offering an integrated, cost-effective solution tailored for complex chronic wound management.
Maternal urinary fluoride levels of a large pregnancy cohort in the United States: findings from the ADORE study
Authors: Adrianne K Griebel-Thompson, Scott Sands, Lynn Chollet-Hinton, Danielle Christifano, Debra K Sullivan, Holly Hull, Juliana Teruel Camargo, Susan E Carlson
Journal: Environmental Health Perspectives (2025)

Emerging evidence has suggested negative associations between maternal urinary fluoride adjusted for specific gravity (MUFsg) and offspring IQ. Two prior studies report the MUFsg of pregnant women in the US, both in California, and more information is needed on population levels of MUFsg. The primary objective was to measure MUFsg in a large pregnancy cohort of women recruited from health departments and academic hospitals in Ohio and Kansas. A secondary objective was to compare associations between water fluoridation level and estimated fluoride intake from tap water, and MUFsg. Pregnant women (n=965) from the ADORE (Assessment of DHA on Reducing Early Preterm Birth) cohort provided a urine sample and dietary assessment, at enrollment, between 14-20 weeks gestation. MUFsg was measured by fluoride-sensitive electrode and corrected for specific gravity. Water fluoridation levels were obtained for public water systems (PWS), matched to participant residence, and multiplied by their tap water intake from dietary assessment. The association between MUFsg and water fluoridation level was estimated using a generalized linear model with gamma distribution and log link. MUFsg (median: 1.0 mg/L, Q1, Q3: 0.6, 1.5) was correlated with PWS fluoridation (rs=0.30, p<0.01) and self-reported tap water consumption (rs=0.29, p<0.01). For 87% of the cohort, MUFsg was above the 0.45 mg/L safety benchmark for pregnancy proposed in a previous study. Similarly, 76.7% lived in areas with PWS fluoridation ≥0.7 mg/L. The median MUFsg (1.0 mg/L; Q1, Q3: 0.7, 1.5) of those living in areas with PWS fluoridation level ≥0.7 mg/L was higher than the median MUFsg (0.8 mg/L; Q1, Q3: 0.5, 1.2) of women living in areas with PWS fluoridation <0.7 mg/L (p<0.01). MUFsg in this population of midwestern US women exceeds the safety benchmark for pregnancy. While we cannot account for all sources of fluoride, MUFsg was correlated to PWS fluoridation. Because so many exceeded the safety benchmark for MUFsg, there is a need for MUFsg evaluation in other US regions, especially where the PWS fluoridation exceeds US Department of Health and Human Services recommendations (≥0.7 mg/L). https://doi.org/10.1289/EHP14711.
Self‐Healing Hydrogel Dressing with Solubilized Flavonoids for Whole Layer Regeneration of Diabetic Wound
Authors: Qiang Zeng, Sa Du, Rui Yuan, Yuan Zeng, Xuefen Li, Yu‐Wei Wu, Ke Chen, Lei Tao, Zhihui Tang, Xuliang Deng
Journal: Advanced Healthcare Materials (2025)

Hydrogels are soft, tissue-like materials that have great potential as wound dressings. However, most hydrogels are unsatisfactory in achieving whole-layer regeneration of diabetic wounds due to the complex pathological microenvironment and irregular wound shapes. Here, a glucose-responsive and self-adaptive phenylboronic acid (PBA) hydrogel solubilized strong antioxidant flavonoids (Gel-Flavonoids) is developed via dynamic borate bonds. The Gel-Flavonoids system can spontaneously confirm to the irregular wound shape and release flavonoids in a high-glucose microenvironment to effectively eliminate reactive oxygen species (ROS). The optimized Gel-Flavonoids demonstrate remarkable efficacy in inhibiting inflammation and activating fibroblasts and endothelial cells through CD36-activated lipid metabolism in macrophages and is significantly superior to commercial dressings (3M) in healing rate (> 93%, 14 days) and whole-layer regeneration effect. This study obtained a multidimensional Gel-Flavonoids system to effectively repair diabetic wounds, and reveal the underlying therapeutic mechanisms, offering a promising insight to guide the development of medical materials to treat diabetic wounds.
Unveiling the Unforeseen
Authors: Maria Alejandra Mendoza, Jennifer E Fugate, Aleksandra Kukla, Raymund R Razonable, Supavit Chesdachai
Journal: New England Journal of Medicine (2025)

A 57-year-old woman presented with a 3-day history of altered mental status. Three weeks earlier, fever, weakness, cough, and diarrhea had developed, followed by intermittent visual hallucinations, tremors, and unsteadiness.