tbuckley/cabot-search huggingface dataset:
Pan-tumor analysis to investigate the obesity paradox in immune checkpoint blockade
Authors: Stephanie L Alden, Soren Charmsaz, Howard L Li, Hua-Ling Tsai, Ludmila Danilova, Kabeer Munjal, Madelena Brancati, Aanika Warner, Kathryn Howe, Ervin Griffin, Mari Nakazawa, Chris Thoburn, Jennifer Gizzi, Alexei Hernandez, Nicole E Gross, Erin M Coyne, Elsa Hallab, Sarah S Shin, Jennifer Durham, Evan J Lipson, Yasser Ged, Marina Baretti, Jean Hoffman-Censits, Tanguy Y Seiwert, Aditi Guha, Sanjay Bansal, Laura Tang, G Scott Chandler, Rajat Mohindra, Rachel Garonce-Hediger, Elizabeth M Jaffee, Won Jin Ho, Chester Kao, Mark Yarchoan
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Obesity is a risk factor for developing cancer but is also associated with improved outcomes after treatment with immune checkpoint inhibitors (ICIs), a phenomenon called the obesity paradox. To interrogate mechanisms of divergent immune responses in obese and non-obese patients, we examined the relationship among obesity status, clinical responses, and immune profiles from a diverse, pan-tumor cohort of patients treated with ICI-based therapy. Methods From June 2021 to March 2023, we prospectively collected serial peripheral blood samples from patients with advanced or metastatic solid tumors who received ICI as standard of care at Johns Hopkins. Patients were stratified by obesity status at treatment initiation, with obesity defined as body mass index (BMI)≥30 at treatment initiation and BMI≥18.5 and &lt;30 considered non-obese; underweight patients (BMI&lt;18.5) were excluded. We evaluated the concentration of 37 cytokines and used cytometry by time of flight to characterize immune cell clusters and cell-surface expression markers at baseline and on-treatment. Results We enrolled 94 patients, of whom 30 (32%) were obese and 64 (68%) were non-obese. Compared with non-obese patients, obese patients had superior progression-free survival (HR: 0.44 (95% CI: 0.24 to 0.81), p=0.01) and overall survival (OS) (HR: 0.24 (95% CI: 0.07 to 0.80), p=0.02). Obese patients had lower serum IL-15 levels at treatment baseline and lower on-treatment levels of IL-6, IL-8, and IL-15. Low on-treatment IL-6 was associated with improved OS (HR: 0.27 (95% CI: 0.08 to 0.88), p=0.03), as was low on-treatment IL-8 (HR: 0.19 (95% CI: 0.05 to 0.70), p=0.01). Obese patients demonstrated lower levels of T effector cells with reduced expression of cytotoxicity markers and higher expression of exhaustion markers at baseline and on-treatment. Conclusions Obese and non-obese patients with cancer have divergent immunological responses to ICIs. Obesity is associated with reduced levels of certain inhibitory cytokines and higher expression of T-cell exhaustion markers. ICI-based therapy may more effectively reverse T-cell dysfunction in obese patients, potentially contributing to the paradoxically improved responses in this population.
Application of antisense oligonucleotide drugs in amyotrophic lateral sclerosis and Huntington’s disease
Authors: Kaili Ou, Qingqing Jia, Dandan Li, Shihua Li, Xiao-Jiang Li, Peng Yin
Journal: Translational Neurodegeneration (2025)

Abstract Amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) are diverse in clinical presentation and are caused by complex and multiple factors, including genetic mutations and environmental factors. Numerous therapeutic approaches have been developed based on the genetic causes and potential mechanisms of ALS and HD. Currently, available treatments for various neurodegenerative diseases can alleviate symptoms but do not provide a definitive cure. Gene therapy, which aims to modify or express specific proteins for neuroprotection or correction, is considered a powerful tool in managing neurodegenerative conditions. To date, antisense oligonucleotide (ASO) drugs targeting the pathological genes associated with ALS and HD have shown promising results in numerous animal studies and several clinical trials. This review provides a comprehensive overview of the development, mechanisms of action, limitations, and clinical applications of ASO drugs in neurodegenerative diseases, with a specific focus on ALS and HD therapeutic strategies.
The Gender Euphoria Scale (GES): development of a tool to measure gender euphoria
Authors: Charlotte A. Blacklock, Michelle A. Tollit, Carmen C. Pace, Bradley Elphinstone, Sav Zwickl, Ada S. Cheung, Kyra Citron, Samuel Marsan, Nancy Zucker, Simone Buzwell, Ken C. Pang
Journal: International Journal of Transgender Health (2025)

Background Gender euphoria is a concept that arose from within the trans and gender diverse (hereafter trans) community to describe positive feelings associated with gender identity, expression, and affirmation. Despite its importance within the trans population, there is currently no consistent, valid or reliable way of measuring gender euphoria. Accordingly, this article describes the development and validation of a tool to measure gender euphoria in trans individuals.
Positive selection on mammalian immune genes—effects of gene function and selective constraint
Authors: Mridula Nandakumar, Max Lundberg, Fredric Carlsson, Lars Råberg
Journal: Molecular Biology and Evolution (2025)

Abstract Genome-wide analyses of various taxa have repeatedly shown that immune genes are important targets of positive selection. However, little is known about what factors determine which immune genes are under positive selection. To address this question, we here focus on the mammalian immune system and investigate the importance of gene function and other factors like gene expression, protein-protein interactions, and overall selective constraint as determinants of positive selection. We compiled a list of &amp;gt;1100 immune genes that were divided into six functional categories and analysed using data from rodents. Genes encoding proteins that are in direct interactions with pathogens, such as pattern recognition receptors (PRRs), are often expected to be the most important targets of positive selection. We found that categories containing cytokines, cytokine receptors, and other cell surface proteins involved in for example cell–cell interactions were at least as important targets as PRRs, with three times higher rate of positive selection than non-immune genes. The higher rate of positive selection on cytokines and cell surface proteins was partly an effect of these categories having lower selective constraint. Nonetheless, cytokines had a higher rate of positive selection than non-immune genes even at a given level of selective constraint, indicating that gene function per se can also be a determinant of positive selection. These results have broad implications for understanding the causes of positive selection on immune genes, specifically the relative importance of host-pathogen coevolution versus other processes.
Non-invasive pressure volume loops provide incremental value to age, sex, and infarct size for predicting adverse cardiac remodeling after ST-elevation myocardial infarction
Authors: Theodor Lav, Thomas Engstrøm, Kasper Kyhl, David Nordlund, Jacob Lønborg, Henrik Engblom, David Erlinge, Håkan Arheden
Journal:  (2025)

Abstract Aims This study aimed to assess the predictive value of non-invasive pressure–volume (PV) loop variables by cardiovascular magnetic resonance (CMR) for determining development of adverse remodelling 3 months after primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). Methods and results In total, 181 STEMI patients examined with CMR during the index admission (baseline) after primary PCI and at 3-month follow-up in The Third DANish Study of Optimal Acute Treatment of Patients with STEMI (DANAMI-3) study were retrospectively analysed. A time-varying elastance model for generating PV loops from CMR volumetry and brachial blood pressure was used to calculate contractility, arterial elastance, stroke work, potential energy, efficiency, external power, ventriculoarterial coupling, and energy per ejected volume. Adverse remodelling was seen in 28 patients (15%), defined as a concomitant increase in end-diastolic and end-systolic volume of ≥12% from baseline to follow-up. PV loop variables measured at baseline showed predictive value for adverse remodelling, independent of age, sex, and infarct size (IS) by a logistic regression analysis: contractility [odds ratio (OR) 4.6, 95% confidence interval (CI) 1.8–12.4] and efficiency (OR 1.05, 95% CI 1.00–1.11). Furthermore, females showed a higher increase in contractility between the timepoints (ΔContractility = 0.4 ± 0.4 mmHg/mL vs. 0.1 ± 0.4 mmHg/mL, P &amp;lt; 0.0001). A higher energy expenditure was seen at baseline in left arterial descending artery infarctions compared to left circumflex artery and right coronary artery infarctions. Conclusion Non-invasive PV loop variables by CMR have incremental predictive value to age, sex, and IS for determining development of adverse cardiac remodelling in STEMI patients treated with primary PCI. Furthermore, the PV loop variables show significant differences in post-infarct cardiovascular adaptation between sexes and culprit vessels.
Comprehensive single-cell atlas of colorectal neuroendocrine tumors with liver metastases: unraveling tumor microenvironment heterogeneity between primary lesions and metastases
Authors: Yiqiao Deng, Qichen Chen, Chengyao Guo, Jinghua Chen, Xin Li, Zhiyu Li, Yefan Zhang, Jianjun Zhao, Jianguo Zhou, Jianqiang Cai, Tao Yan, Xiaobing Wang, Xinyu Bi, Zhen Huang, Hong Zhao
Journal: Molecular Cancer (2025)

Colorectal neuroendocrine tumors with liver metastases (CRNELM) are associated with a poorer prognosis compared to their nonmetastatic counterparts. A comprehensive understanding of the tumor microenvironment (TME) heterogeneity between primary lesions (PL) and liver metastases (LM) could provide crucial insights for enhancing clinical management strategies for these patients. We utilized single-cell RNA sequencing to analyze fresh tissue samples from CRNELM patients, aiming to elucidate the variations in TME between PL and LM. Complementary multidimensional validation was achieved through spatial transcriptomics, bulk RNA sequencing, and multiplex immunohistochemistry/immunofluorescence. Our single-cell RNA sequencing analysis revealed that LM harboured a higher proportion of CD8 + T cells, CD4 + T cells, NK cells, NKT cells, and B cells exhibiting a stress-like phenotype compared to PL. RGS5 + pericytes may play a role in the stress-like phenotype observed in immune cells within LM. MCs in PL (PL_MCs) and LM (LM_MCs) exhibit distinct activation of tumor-associated signaling pathways. Notably, COLEC11 + matrix cancer-associated fibroblasts (COLEC11_mCAFs) were found to be significantly associated with LM_MCs. Cell communication analysis unveiled potential targetable receptor-ligand interactions between COLEC11_mCAFs and LM_MCs. Multidimensional validation confirmed the prominence of the characteristic stress-like phenotypes, including HSPA6_CD8_Tstr, HSPA6_NK, and COLEC11_mCAFs in LM. Moreover, a higher abundance of COLEC11_mCAFs correlated with poorer survival rates in the neuroendocrine tumor patient cohort. Overall, our study provides the first single-cell analysis of the cellular and molecular differences between PL and LM in CRNELM patients. We identified distinct cell subsets and receptor-ligand interactions that may drive TME discrepancies and support metastatic tumor growth. These insights highlight potential therapeutic targets and inform strategies for better managing CRNELM patients.
Effects of maternal vitamin D supplementation on childhood health
Authors: Nanna S Svensson, Tabia Volqvartz, Anna Louise Vestergaard, Esben T Vestergaard, Agnete Larsen, Pinar Bor
Journal: Endocrine Reviews (2025)

Abstract Vitamin D deficiency during pregnancy is associated with an increased risk of health issues in the offspring. Accordingly, recent Endocrine Society guidelines strongly support supplementation in pregnancy, also underlining that without consensus on optimal maternal vitamin D levels, routine screening is currently irrelevant. Knowledge of organ-specific effects of vitamin D and its association with maternal vitamin D status may aid to optimize vitamin D supplementation. This systematic review outlines the proposed next-generation effects of vitamin D supplementation ≥ 400 IU/d, and explores whether such effects are attributed to a specific maternal vitamin D level obtained during pregnancy. A systematic literature search was conducted in PubMed and Embase according to the PRISMA guidelines, focusing on health outcomes from ten days post-partum and beyond. Of the 2,383 screened articles, 39 were included. In 11 of 16 studies, vitamin D supplementation reduced respiratory tract infections in the first years of life. Growth or bone development benefits were observed in six of 12 studies. Positive effects on neurodevelopment and reduced autoimmune risk (diabetes-related antibodies) were noted, although further research is needed to determine the role of vitamin D. Very few studies have measured vitamin D concentrations, but even 1,600 IU/d supplementation was associated with high frequency of infant vitamin D insufficiency. Current recommendations may not ensure sufficient vitamin D levels at birth, among others, increasing the risk of early-life infections. Further studies linking maternal and infant vitamin D levels to specific outcomes would aid in personalized nutritional advice during pregnancy and improve next-generation health.
Circulating growth differentiation factor‐15 levels are associated with early echocardiographic signs of diastolic function impairment in the <scp>STANISLAS</scp> cohort: A 20‐year follow‐up study
Authors: Luca Monzo, Constance Xhaard, João Pedro Ferreira, Guillaume Baudry, Zohra Lamiral, Kevin Duarte, Erwan Bozec, Jean‐Marc Boivin, Olivier Huttin, Patrick Rossignol, Faiez Zannad, Nicolas Girerd
Journal: European Journal of Heart Failure (2025)
Dysbiosis of infant gut microbiota is related to the altered fatty acid composition of human milk from mothers with gestational diabetes mellitus: a prospective cohort study
Authors: Kelei Li, Jin Jin, Zhizuo Liu, Chuanjing Chen, Ludi Huang, Yongye Sun
Journal: Gut Microbes (2025)

Gestational diabetes mellitus (GDM) is known to be associated with dysbiosis of offspring gut microbiota, but the mechanism remains unclear. The present prospective study explored the role of human milk fatty acid composition in this association. Mothers with GDM and normal controls were recruited at 24–28 gestational weeks. Follow-up was conducted at 1–3 days postpartum and 1 month postpartum to collect human milk and infant feces. A total of 80 mother-infant pairs (40 in the GDM group and 40 in the normal group) were included in the study. The mothers received guidance on diet and exercise but not drug therapy. All infants were exclusively breastfed. We observed significant differences in 8 phyla and 13 genera in the infant between GDM and normal groups at 1–3 days postpartum or 1 month postpartum. Among these bacteria, significant time × group interaction was observed for 7 phyla (such as Acidobacteriota, Gemmatimonadota, and Myxococcota) and 9 genera (such as Sphingomonas, Allorhizobium Neorhizobium Pararhizobium Rhizobium, and TM7a), after adjusting for confounding factors. Changes in these differential infant bacteria were negatively correlated with changes in C18:3n-3 and total n-3 PUFA levels of breast milk. The increases in C18:3n-3 and total n-3 PUFA levels in human milk over time were much greater in the normal group compared to the GDM group. Our findings indicate that altered human milk fatty acid composition is one important reason for GDM-related dysbiosis of offspring gut microbiota.
Unleashing the Power of Covalent Drugs for Protein Degradation
Authors: Meng‐Jie Fu, Hang Jin, Shao‐Peng Wang, Liang Shen, Hong‐Min Liu, Ying Liu, Yi‐Chao Zheng, Xing‐Jie Dai
Journal: Medicinal Research Reviews (2025)

ABSTRACT Targeted protein degradation (TPD) has emerged as a significant therapeutic approach for a variety of diseases, including cancer. Advances in TPD techniques, such as molecular glue (MG) and lysosome‐dependent strategies, have shown substantial progress since the inception of the first PROTAC in 2001. The PROTAC methodology represents the forefront of TPD technology, with ongoing evaluation in more than 20 clinical trials for the treatment of diverse medical conditions. Two prominent PROTACs, ARV‐471 and ARV‐110, are currently undergoing phase III and II clinical trials, respectively. Traditional PROTACs are encountering obstacles such as limited binding affinity and a restricted range of E3 ligase ligands for facilitating the protein of interest (POI) degradation. Covalent medicines offer the potential to enhance PROTAC efficacy by enabling the targeting of previously considered “undruggable” shallow binding sites. Strategic alterations allow PROTAC to establish covalent connections with particular target proteins, including Kirsten rat sarcoma viral oncogene homolog (KRAS), Bruton's tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), as well as E3 ligases such as DDB1 and CUL4 associated factor 16 (DCAF16) and Kelch‐like ECH‐associated protein 1 (Keap1). The concept of covalent degradation has also been utilized in various new forms of degraders, including covalent molecule glue (MG), in‐cell click‐formed proteolysis targeting chimera (CLIPTAC), HaloPROTAC, lysosome‐targeting chimera (LYTAC) and GlueTAC. This review focuses on recent advancements in covalent degraders beyond covalent PROTACs and examines obstacles and future directions pertinent to this field.
Therapeutic potential of cannabidiol polypharmacology in neuropsychiatric disorders
Authors: Olivier J Manzoni, Antonia Manduca, Viviana Trezza
Journal: Trends in Pharmacological Sciences (2025)

Cannabidiol (CBD), the primary non-intoxicating compound in cannabis, is currently approved for treating rare, treatment-resistant seizures. Recent preclinical research suggests that CBD's multifaceted mechanisms of action in the brain, which involve multiple molecular targets, underlie its neuroprotective, anti-inflammatory, anxiolytic, and antipsychotic effects. Clinical trials are also exploring CBD's therapeutic potential beyond its current uses. This review focuses on CBD's polypharmacological profile and discusses the latest preclinical and clinical findings regarding its efficacy in neuropsychiatric disorders. Existing evidence suggests that CBD's ability to modulate multiple signaling pathways may benefit neuropsychiatric disorders, and we propose further research areas to clarify its mechanisms, address data gaps, and refine its therapeutic indications.
Inhibition of PDT-induced PGE2 Surge for Enhanced Photo-immunotherapy
Authors: Xu Liu, Jiaxin Huang, Huanli Zhou, Sijie Wang, Xuemeng Guo, Jiapeng Mao, Xiang Li, Yichao Lu, Yongzhong Du, Fuchun Yang, Lihua Luo, Jian You
Journal: Biomaterials (2025)
Mapping the cellular etiology of schizophrenia and complex brain phenotypes
Authors: Laramie E. Duncan, Tayden Li, Madeleine Salem, Will Li, Leili Mortazavi, Hazal Senturk, Naghmeh Shahverdizadeh, Sam Vesuna, Hanyang Shen, Jong Yoon, Gordon Wang, Jacob Ballon, Longzhi Tan, Brandon Scott Pruett, Brian Knutson, Karl Deisseroth, William J. Giardino
Journal: Nature Neuroscience (2025)

Abstract Psychiatric disorders are multifactorial and effective treatments are lacking. Probable contributing factors to the challenges in therapeutic development include the complexity of the human brain and the high polygenicity of psychiatric disorders. Combining well-powered genome-wide and brain-wide genetics and transcriptomics analyses can deepen our understanding of the etiology of psychiatric disorders. Here, we leverage two landmark resources to infer the cell types involved in the etiology of schizophrenia, other psychiatric disorders and informative comparison of brain phenotypes. We found both cortical and subcortical neuronal associations for schizophrenia, bipolar disorder and depression. These cell types included somatostatin interneurons, excitatory neurons from the retrosplenial cortex and eccentric medium spiny-like neurons from the amygdala. In contrast we found T cell and B cell associations with multiple sclerosis and microglial associations with Alzheimer’s disease. We provide a framework for a cell-type-based classification system that can lead to drug repurposing or development opportunities and personalized treatments. This work formalizes a data-driven, cellular and molecular model of complex brain disorders.
Variants and vaccines impact nasal immunity over three waves of SARS-CoV-2
Authors: Jaclyn M. L. Walsh, Vincent N. Miao, Anna H. Owings, Ying Tang, Joshua D. Bromley, Samuel W. Kazer, Kyle Kimler, Chelsea Asare, Carly G. K. Ziegler, Samira Ibrahim, Tasneem Jivanjee, Micayla George, Andrew W. Navia, Riley S. Drake, Adam Parker, Benjamin C. Billingsley, Paul Dotherow, Spurthi Tarugu, Sai K. Kota, Hannah Laird, T. Grant Wichman, Yesenia T. Davis, Neha S. Dhaliwal, Yilianys Pride, Yanglin Guo, Michal Senitko, Jessie Harvey, John T. Bates, Gill Diamond, Michael R. Garrett, D. Ashley Robinson, I. J. Frame, Jonathan J. Lyons, Tanya O. Robinson, Alex K. Shalek, Bruce H. Horwitz, Sarah C. Glover, Jose Ordovas-Montanes
Journal: Nature Immunology (2025)
Dedicator of Cytokinesis 2 regulates cytoskeletal actin dynamics and is essential for platelet biogenesis and functions
Authors: Jiani Ji, Xulin Xu, Lili Zhang, Shuang Liu, Jiayi Chen, Huihui Gao, Limin Xiang, Yaofeng Li, Hui Xu, Yaobing Chen, Huiqin Xiang, Shuai Chen, Yunyun Han, Zhaoming Tang, Xuanbin Wang, Xiaofeng Shi, Jianhua Mao, Xiaodong Xi, Jinyu Wang, Chao Fang
Journal: Cardiovascular Research (2025)

Abstract Aims Dedicator of Cytokinesis 2 (DOCK2), a member of the DOCK family of Guanine nucleotide exchange factors that specifically act on the Rho GTPases including Rac and Cdc42, plays pivotal roles in the regulation of leukocyte homeostasis. However, its functions in platelets remain unknown. Methods and Results Using mice with genetic deficiency of DOCK2 (Dock2-/-), we showed that Dock2-/-mice exhibited a macrothrombocytopenic phenotype characterized as decreased platelet count and enlarged platelet size by transmission electron microscopy. Dock2-/- megakaryocytes had reduced polyploidization determined by propidium iodide staining and defective proplatelet formation by confocal microscopy. DOCK2 deficiency led to enriched F-actin level in resting platelets but defective F-actin assembly in activated platelets by phalloidin staining, and mechanistically, attenuated activity of Rac1, unchanged Cdc42 but enhanced RhoA measured by immunoprecipitation of GTP-bound proteins. Immunoblotting analysis showed that Dock2-/- platelets had reduced Immunoreceptor Tyrosine-based Activation Motif signaling downstream of impaired clustering of GPVI receptors determined by stochastic optical reconstruction microscopy. Further, DOCK2 deficiency resulted in reduced density and branches of fibrin fibers in the clots in vitro and diminished platelet aggregation in a microfluidic chamber ex vivo. Dock2-/- platelets exhibited impaired incorporation into a growing thrombus in cremaster arterioles following allogeneic transfusion into a WT recipient, and defective heterotypic interactions with neutrophils in cremaster venules as reflected by decreased platelet-neutrophil aggregate formation in vitro under stirring condition. In addition, myeloid deficiency of DOCK2 caused prolonged tail bleeding times. Finally, pharmacological inhibition of DOCK2 using a small-molecular inhibitor CPYPP suppressed actin dynamics leading to impaired responses to GPVI activation, and defects in platelet spreading, clot retraction, and thrombus formation. Conclusions DOCK2 plays critical roles in the regulation of platelet biogenesis and functions by controlling Rac1 activity and cytoskeletal actin dynamics, and may be a novel target for the treatment of thrombotic and thrombo-inflammatory diseases.