tbuckley/cabot-search huggingface dataset:
Dysregulation of Astrocytic ATP/Adenosine Release in the Hippocampus Cause Cognitive and Affective Disorders: Molecular Mechanisms, Diagnosis, and Therapy
Authors: Peter Illes, Patrizia Rubini, Henning Ulrich, Hai‐Yan Yin, Yong Tang
Journal: MedComm (2025)

ABSTRACT The gliotransmitter adenosine 5'‐triphosphate (ATP) and its enzymatic degradation product adenosine play a major role in orchestrating in the hippocampus cognitive and affective functions via P2 purinoceptors (P2X, P2Y) and P1 adenosine receptors (A1, A2A). Although numerous reviews exist on purinoceptors that modulate these functions, there is an apparent gap relating to the involvement of astrocyte‐derived extracellular ATP. Our review focuses on the following issues: An impeded release of ATP from hippocampal astrocytes through vesicular mechanisms or connexin hemichannels and pannexin channels interferes with spatial working memory in rodents. The pharmacological blockade of P2Y1 receptors (P2Y1Rs) reverses the deficits in learning/memory performance in mouse models of familial Alzheimer's disease (AD). Similarly, in mouse models of major depressive disorder (MDD), based on acute or chronic stress‐induced development of depressive‐like behavior, a reduced exocytotic/channel‐mediated ATP release from hippocampal astrocytes results in the deterioration of these behavioral responses. However, on the opposite, the increased stimulation of the microglial/astrocytic P2X7R‐channel by ATP causes neuroinflammation and in consequence depressive‐like behavior. In conclusion, there is strong evidence for the assumption that gliotransmitter ATP is intimately involved in the pathophysiology of cognitive and affective neuron/astrocyte‐based human illnesses opening new diagnostic and therapeutic vistas for AD and MDD.
Factor XII–driven coagulation traps bacterial infections
Authors: Katrin F. Nickel, Anne Jämsä, Sandra Konrath, Praveen Papareddy, Lynn M. Butler, Evi X. Stavrou, Maike Frye, Mathias Gelderblom, Bernhard Nieswandt, Sven Hammerschmidt, Heiko Herwald, Thomas Renné
Journal: The Journal of Experimental Medicine (2025)

Blood coagulation is essential for stopping bleeding but also drives thromboembolic disorders. Factor XII (FXII)–triggered coagulation promotes thrombosis while being dispensable for hemostasis, making it a potential anticoagulant target. However, its physiological role remains unclear. Here, we demonstrate that FXII-driven coagulation enhances innate immunity by trapping pathogens and restricting bacterial infection in mice. Streptococcus pneumoniae infection was more severe in FXII-deficient (F12−/−) mice, with increased pulmonary bacterial burden, systemic spread, and mortality. Similarly, Staphylococcus aureus skin infections and systemic dissemination were exacerbated in F12−/− mice. Reconstitution with human FXII restored bacterial containment. Plasma kallikrein amplifies FXII activation, and its deficiency aggravated S. aureus skin infections, similarly to F12−/− mice. FXII deficiency impaired fibrin deposition in abscess walls, leading to leaky capsules and bacterial escape. Bacterial long-chain polyphosphate activated FXII, triggering fibrin formation. Deficiency in FXII substrate factor XI or FXII/factor XI co-deficiency similarly exacerbated S. aureus infection. The data reveal a protective role for FXII-driven coagulation in host defense, urging caution in developing therapeutic strategies targeting this pathway.
Microbiota-centered interventions to boost immune checkpoint blockade therapies
Authors: Andrew A. Almonte, Simon Thomas, Laurence Zitvogel
Journal: The Journal of Experimental Medicine (2025)

Immune checkpoint blockade therapies have markedly advanced cancer treatment by invigorating antitumor immunity and extending patient survival. However, therapeutic resistance and immune-related toxicities remain major concerns. Emerging evidence indicates that microbial dysbiosis diminishes therapeutic response rates, while a diverse gut ecology and key beneficial taxa correlate with improved treatment outcomes. Therefore, there is a growing understanding that manipulating the gut microbiota could boost therapy efficacy. This review examines burgeoning methods that target the gut microbiome to optimize therapy and innovative diagnostic tools to detect dysbiosis, and highlights challenges that remain to be addressed in the field.
Circulating glycerate predicts resilience to fructose-induced hepatic steatosis
Authors: Cuauhtemoc B Ramirez, In Sook Ahn, Varvara I Rubtsova, Ingrid Cely, Johnny Le, Joohwan Kim, Sunhee Jung, Miranda E Kelly, Yeojin Kim, Hosung Bae, Won-Suk Song, Yasmine H Alam, Guanglin Zhang, Graciel Diamante, Alina Chao, Lauren Hoffner, Alexis Anica, Izabelle Le, Miranda L Lopez, Ian J Tamburini, Elena M Moyer, Ariel Tsai, Qin Yang, Xing Dai, Daniele Piomelli, Gina Lee, Xia Yang, Cholsoon Jang
Journal: Cell Metabolism (2025)

Excessive intake of dietary fructose increases the risk of metabolic-dysfunction-associated steatotic liver disease (MASLD), cirrhosis, and cancers. However, what host factors determine disease vulnerability is incompletely understood. Here, we leverage genetically divergent mouse strains, mass spectrometry-based metabolomics, and in vivo isotope tracing, identifying circulating glycerate as a biomarker that predicts resilience to fructose-induced hepatic steatosis in both sexes. We found that the surge of circulating glycerate after an oral fructose provision reflects strong small-intestinal fructose catabolism. Such fructose clearance by the small intestine is linked to a weaker induction of hepatic de novo lipogenesis and steatosis upon chronic fructose exposure across strains. These data indicate the potential utility of an oral fructose tolerance test and circulating glycerate measurements to predict an individual's susceptibility to fructose-elicited steatotic liver and provide personalized dietary recommendations.
CD47-blocking antibody confers metabolic benefits against obesity
Authors: Yajuan Su, Jingyu Sun, Xiaobo Li, Feier Huang, Yunhui Kong, Zian Chen, Jingzhi Zhang, Duran Qin, Xiangyi Chen, Zhaoyue Wang, Yu Pei, Mengting Gong, Kaijiang Yang, Minglu Xu, Yu Dong, Qing He, Zhen-Ning Zhang, Zhejin Sheng, Qiaolin Deng, Hong Wang, Gaowei Wang, Ping Hu, Rongrong Le, Shaorong Gao, Weida Li
Journal: Cell Reports Medicine (2025)

CD47-blocking antibody is a well-known potential antibody drug for tumor immunotherapy. However, it is unclear whether CD47-blocking antibody can protect against metabolic disorders. We report that high-fat diet (HFD)-induced obesity increases CD47 expression, while exercise downregulates it in skeletal muscle. Administration of CD47-blocking antibody in mice prevents HFD-induced weight gain and glucose intolerance, enhances exercise capacity, and improves body composition and skeletal muscle mitochondrial function. Mechanistically, the protective effects conferred by CD47-blocking antibody are mediated through activation of AMP-activated protein kinase (AMPK) in skeletal muscle. Consistently, muscle-specific CD47-knockout mice show similar metabolic improvements, indicating a direct muscle-specific role of CD47 in regulating AMPK activation in vivo. Furthermore, the CD47-blocking antibody reduces the phosphorylation of heat shock protein 90α (HSP90α) to activate AMPK in skeletal muscle. In conclusion, CD47-blocking antibody confers metabolic benefits by activating the AMPK pathway in skeletal muscle.
Core GRADE 1: overview of the Core GRADE approach
Authors: Gordon Guyatt, Thomas Agoritsas, Romina Brignardello-Petersen, Reem A Mustafa, Jamie Rylance, Farid Foroutan, Manya Prasad, Arnav Agarwal, Hans De Beer, M Hassan Murad, Stefan Schandelmaier, Alfonso Iorio, Liang Yao, Roman Jaeschke, Per Olav Vandvik, Linan Zeng, Sameer Parpia, Rohan D'Souza, David Rind, Derek K Chu, Prashanti Eachempati, Kameshwar Prasad, Monica Hultcrantz, Victor M Montori
Journal: BMJ (2025)
Illuminating the Noncoding Genome in Cancer using Artificial Intelligence.
Authors: Maria del Mar Alvarez-Torres, Xi Fu, Raul Rabadan
Journal: Cancer Research (2025)

Abstract Understanding the vast noncoding cancer genome requires cutting-edge, high-resolution, and accessible strategies. Artificial intelligence (AI) is revolutionizing cancer research, enabling advanced models to analyze genome regulation. This review examines illustrative examples of noncoding mutations in cancer, focusing on both key regulatory elements and risk-associated variants that remain poorly understood, and compares key AI models developed over the last decade for identifying functional noncoding variants, predicting gene expression impacts, and uncovering cancer-associated mutations. The discussion of the goals, data requirements, features, and outcomes of the models offers practical insights to help cancer researchers integrate these technologies into their work, regardless of computational expertise.
Genomic and Single-Cell Analyses Characterize Patient-Derived Tumor Organoids to Enable Personalized Therapy for Head and Neck Squamous Cell Carcinoma
Authors: Jung Hyun Um, Yueyuan Zheng, Qiong Mao, Chehyun Nam, Hua Zhao, Yoon Woo Koh, Su-Jin Shin, Young Min Park, De-Chen Lin
Journal: Cancer Research (2025)

Abstract Head and neck squamous cell carcinoma (HNSCC) remains a significant health burden due to tumor heterogeneity and treatment resistance, emphasizing the need for improved biological understanding and tailored therapies. In this study, we enrolled 31 HNSCC patients for the establishment of patient-derived tumor organoids (PDOs), which faithfully maintained the genomic features and histopathological traits of the primary tumors. Long-term culture preserved key characteristics, affirming PDOs as robust representative models. PDOs demonstrated predictive capability for cisplatin treatment responses, with ex vivo drug sensitivity correlating with patient outcomes. Bulk and single-cell RNA sequencing unveiled molecular subtypes and intratumor heterogeneity (ITH) in PDOs, paralleling patient tumors. Notably, a hybrid epithelial-mesenchymal transition (hEMT)-like ITH program was associated with cisplatin resistance and poor patient survival. Functional analyses identified amphiregulin (AREG) as a potential regulator of the hybrid epithelial/mesenchymal state. Moreover, AREG contributed to cisplatin resistance via EGFR pathway activation, corroborated by clinical samples. In summary, HNSCC PDOs serve as reliable and versatile models, offer predictive insights into ITH programs and treatment responses, and uncover potential therapeutic targets for personalized medicine.
The PUrE randomised controlled trial 1: Clinical and cost effectiveness of flexible ureterorenoscopy and extracorporeal shockwave lithotripsy for lower pole stones of ≤10 mm
Authors: Oliver Wiseman, Daron Smith, Kathryn Starr, Lorna Aucott, Rodolfo Hernández, Ruth Thomas, Steven MacLennan, Charles Terry Clark, Graeme MacLennan, Dawn McRae, Victoria Bell, Seonaidh Cotton, Zara Gall, Ben Turney, Sam McClinton
Journal: European Urology (2025)
Bladder Preservation Strategies in Muscle-invasive Bladder Cancer: Recommendations from the International Bladder Cancer Group
Authors: Shilpa Gupta, Patrick J Hensley, Roger Li, Ananya Choudhury, Siamak Daneshmand, Bishoy M Faltas, Thomas W Flaig, G Daniel Grass, Petros Grivas, Donna E Hansel, Comron Hassanzadeh, Wassim Kassouf, Janet Kukreja, Arturo Mendoza-Valdés, Marco Moschini, Kent W Mouw, Neema Navai, Andrea Necchi, Jonathan E Rosenberg, Jeffrey S Ross, Arlene O Siefker-Radtke, John Taylor, Stephen B Willliams, Alexandre R Zlotta, Roger Buckley, Ashish M Kamat
Journal: European Urology (2025)
Prediction models for liver decompensation in compensated advanced chronic liver disease: a systematic review
Authors: Vincent Haghnejad, Laura Burke, Siham El Ouahabi, Richard Parker, Ian A. Rowe1
Journal: Hepatology (2025)

Background and Aims: Identifying individuals with compensated advanced chronic liver disease (cACLD) at risk of decompensation allows for personalized therapy. However, predicting decompensation is challenging, and multiple models have been developed. This study systematically appraises the performance and clinical applications of published multivariable models predicting first decompensation in patients with cACLD or compensated cirrhosis. Approach and Results: We searched MEDLINE for liver decompensation prediction models from inception to December 2023. The research was registered with PROSPERO (CRD42023488395). Model risk of bias and applicability were assessed using the PROBAST tool, with results summarized via narrative synthesis. Reporting followed PRISMA and CHARMS guidelines. Sixteen studies (retrospective and prospective) were included. Seven focused on a single aetiology. No study specifically predicted outcomes in persons with alcohol-related liver disease. Outcome definitions varied, with some models predicting hepatocellular carcinoma together with decompensation. In total, 27 predictors were included in the models. The most frequent predictors were albumin, platelets, age, liver stiffness, bilirubin, international normalized ratio, and the presence of portal-hypertension-related findings during upper gastrointestinal endoscopy. All studies reported discrimination measures but only 10/16 evaluated calibration. External validation was conducted in 9/16 studies. Thirteen studies were rated as having a high overall risk of bias. Conclusions: For clinical utility, a predictive model must accurately describe future risks. Models for predicting decompensation in cACLD are often poorly described, infrequently include patients with ArLD, and lack external validation. These factors are barriers to the clinical utility and uptake of predictive models for first decompensation in patients with cACLD.
AI-based phenotyping of hepatic fiber morphology to inform molecular alterations in metabolic dysfunction-associated steatotic liver disease
Authors: Naoto Fujiwara, Yuki Matsushita, Mina Tempaku, Yutaro Tachi, Genki Kimura, Kiyora Izuoka, Yuki Hayata, Satoshi Kawamura, Akiko Eguchi, Takuma Nakatsuka, Masaya Sato, Atsushi Ono, Eisuke Murakami, Masataka Tsuge, Shiro Oka, Akinobu Hayashi, Yoshifumi Hirokawa, Masatoshi Watanabe, Neehar D. Parikh, Amit G. Singal, Jorge A. Marrero, Yujin Hoshida, Shugo Mizuno, Ryosuke Tateishi, Kazuhiko Koike, Mitsuhiro Fujishiro, Hayato Nakagawa
Journal: Hepatology (2025)

Background &amp; Aims: Hepatic fiber morphology may significantly enhance our understanding of molecular alterations in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to comprehensively characterize hepatic fiber morphological phenotypes in MASLD and their associated molecular alterations using multi-layer omics analyses. Approach &amp; Results: To quantify the morphological phenotypes of hepatic fibers, the artificial intelligence-based FibroNest algorithm (PharmaNest) was applied to 94 MASLD-affected liver biopsies, among which 12 (13%) had concurrent hepatocellular carcinoma (HCC). FibroNest identified 327 fiber phenotypes that were summarized into eight major principal components, named FibroPC1–8. Next, molecular alterations captured by morphological fiber phenotypes were evaluated by comparison with genome-wide transcriptomics of paired liver samples. Pathway analyses revealed that FibroPCs more sensitively captured MASLD-related molecular alterations, such as upregulation of interleukin-6 and susceptibility to resmetirom, compared with the histological fibrosis stage. Among them, FibroPC4, which reflects reticular fibers, was associated with a gene signature predictive of incident HCC from MASLD. Furthermore, we used a spatial single-cell transcriptome, CosMx, to reveal the cell-cell interactions driving MASLD pathogenesis, as captured by FibroPC4. CosMx revealed that the FibroPC4-rich microenvironment contains HCC-promoting hepatic stellate cells (HSCs) located adjacent to periportal endothelial cells (ECs). Neighboring cell analyses suggested that the HCC-promoting phenotype of HSCs was acquired by insulin growth factor-binding protein 7 (IGFBP-7) secreted from senescent periportal ECs. Consistently, in vitro experiments showed that IGFBP-7 transformed HSCs into an HCC-promoting phenotype. Conclusions: Hepatic morphological fiber phenotyping can reveal the disease progression and underlying mechanisms of MASLD.
European Association of Urology Guidelines on the Diagnosis and Treatment of Urolithiasis
Authors: Andreas Skolarikos, Robert Geraghty, Bhaskar Somani, Thomas Tailly, Helene Jung, Andreas Neisius, Ales Petřík, Guido M Kamphuis, Niall Davis, Carla Bezuidenhout, Michael Lardas, Giovanni Gambaro, John A Sayer, Riccardo Lombardo, Lazaros Tzelves
Journal: European Urology (2025)
Long-term mortality and extrahepatic outcomes in 1,096 children with MASLD: A retrospective cohort study
Authors: Jeffrey B. Schwimmer, Nhat Quang N. Thai, Sheila L. Noon, Patricia Ugalde-Nicalo, Sabina R. Anderson, Lauren F. Chun, Rhys S. David, Nidhi P. Goyal, Kimberly P. Newton, Eleanor G. Hansen, Bonnie Lin, Warren L. Shapiro, Andrew Wang, Elizabeth L. Yu, Cynthia A. Behling
Journal: Hepatology (2025)

Background &amp; Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in children, but its long-term outcomes are poorly understood. This study aimed to quantify mortality rates, identify causes of death, and evaluate the incidence of cirrhosis and extrahepatic outcomes in children with pediatric-onset MASLD. Approach &amp; Results: The Longitudinal InVestigation Evaluating Results of Steatosis (LIVERS) study is a single-center, retrospective cohort study conducted at Rady Children’s Hospital San Diego. We included 1,096 children aged 2–18 years who were diagnosed with MASLD between 2000 and 2017 and followed for a mean of 8.5 years. Mortality was ascertained via the National Death Index, and comorbidities were assessed through follow-up research visits and medical records. Overall, 3.4% of children died, yielding a mortality rate of 398 per 100,000 person-years; nearly half of these deaths were liver-related. Male sex and lower high-density lipoprotein levels independently predicted increased mortality risk. The cumulative incidence of cirrhosis was 4.7%. High incidence rates of extrahepatic comorbidities were observed, including dyslipidemia (3,664 per 100,000 person-years), hypertension (1,901), obstructive sleep apnea (1,185), and type 2 diabetes (911). Conclusions: Pediatric MASLD is associated with significant premature mortality and a substantial burden of hepatic and extrahepatic comorbidities. These findings highlight the need for timely screening, early intervention, and long-term management strategies to improve outcomes for children with MASLD.
Gene signature-guided drug screening identified narciclasine as a potential therapeutic for interstitial fibrosis of the kidney
Authors: An Xiao, Xiaoer Chen, Jingyi Ma, Xiaomei Chen, Tantan Long, Yuanyuan Ma, Qingzhou Chen, Zhiyuan Su, Zheng Hu, Liling Xie, Lei Zhang, Fengxin Zhu, Jing Nie
Journal: Kidney International (2025)
Corrigendum to “Pulmonary delivery of size-transformable nanoparticles improves tumor accumulation and penetration for chemo-sonodynamic combination therapy” [Journal of Controlled Release 350 (2022) 132–145]
Authors: Siqi Ma, Zhaoqing Cong, Jiaxing Wei, Weiya Chen, Di Ge, Feifei Yang, Yonghong Liao
Journal: Journal of Controlled Release (2025)
Genetics and Current Research Models of Mendelian Tumor Predisposition Syndromes with Ocular Involvement
Authors: Lola P Lozano, Renato Jensen, Madeleine Jennisch, Narendra G Pandala, Farzad Jamshidi, H Culver Boldt, Budd A Tucker, Elaine M Binkley
Journal: Progress in Retinal and Eye Research (2025)

In this review, we aim to provide a survey of hereditable tumor predisposition syndromes with a mendelian inheritance pattern and ocular involvement. We focus our discussion on von Hippel-Lindau disease, neurofibromatosis type 1, NF2-related schwannomatosis, tuberous sclerosis complex, retinoblastoma, and the BAP1 Tumor Predisposition Syndrome. For each of the six diseases, we discuss the clinical presentation and the molecular pathophysiology. We emphasize the genetics, current research models, and therapeutic developments. After reading each disease section, readers should possess an understanding of the clinical presentation, genetic causes and inheritance patterns, and current state of research in disease modeling and treatment.
LSD1 inhibition attenuates targeted therapy-induced lineage plasticity in BRAF mutant colorectal cancer
Authors: Christopher A Ladaika, Averi Chakraborty, Ashiq Masood, Galen Hostetter, Joo Mi Yi, Heather M O'Hagan
Journal: Molecular Cancer (2025)

Abstract Background BRAF activating mutations occur in approximately 10% of metastatic colorectal cancer (CRCs) and are associated with worse prognosis in part due to an inferior response to standard chemotherapy. Standard of care for patients with refractory metastatic BRAF V600E CRC is treatment with BRAF and EGFR inhibitors and recent FDA approval was given to use these inhibitors in combination with chemotherapy for patients with treatment naïve metastatic BRAF V600E CRC. Lineage plasticity to neuroendocrine cancer is an emerging mechanism of targeted therapy resistance in several cancer types. Enteroendocrine cells (EECs), the neuroendocrine cell of the intestine, are uniquely present in BRAF mutant CRC as compared to BRAF wildtype CRC. Methods BRAF plus EGFR inhibitor treatment induced changes in cell composition were determined by gene expression, imaging and single cell approaches in multiple models of BRAF mutant CRC. Furthermore, multiple clinically relevant inhibitors of the lysine demethylase LSD1 were tested to determine which inhibitor blocked the changes in cell composition. Results Combined BRAF and EGFR inhibition enriched for EECs in all BRAF mutant CRC models tested. Additionally, EECs and other secretory cell types were enriched in a subset of BRAF V600E CRC patient samples following targeted therapy. Importantly, inhibition of LSD1 with a clinically relevant inhibitor attenuated targeted therapy-induced EEC enrichment through blocking the interaction of LSD1, CoREST2 and STAT3. Conclusions Our findings that BRAF plus EGFR inhibition induces lineage plasticity in BRAF V600E CRC represents a new paradigm for how resistance to BRAF plus EGFR inhibition occurs. Additionally, our finding that LSD1 inhibition blocks lineage plasticity has the potential to improve responses to BRAF plus EGFR inhibitor therapy in patients.