tbuckley/cabot-search huggingface dataset:
Trans-ancestral rare variant association study with machine learning-based phenotyping for metabolic dysfunction-associated steatotic liver disease
Authors: Robert Chen, Ben Omega Petrazzini, Áine Duffy, Ghislain Rocheleau, Daniel Jordan, Meena Bansal, Ron Do
Journal: Genome biology (2025)

Abstract Background Genome-wide association studies (GWAS) have identified common variants associated with metabolic dysfunction-associated steatotic liver disease (MASLD). However, rare coding variant studies have been limited by phenotyping challenges and small sample sizes. We test associations of rare and ultra-rare coding variants with proton density fat fraction (PDFF) and MASLD case–control status in 736,010 participants of diverse ancestries from the UK Biobank, All of Us, and BioMe and performed a trans-ancestral meta-analysis. We then developed models to accurately predict PDFF and MASLD status in the UK Biobank and tested associations with these predicted phenotypes to increase statistical power. Results The trans-ancestral meta-analysis with PDFF and MASLD case–control status identifies two single variants and two gene-level associations in APOB , CDH5 , MYCBP2 , and XAB2 . Association testing with predicted phenotypes, which replicates more known genetic variants from GWAS than true phenotypes, identifies 16 single variants and 11 gene-level associations implicating 23 additional genes. Two variants were polymorphic only among African ancestry participants and several associations showed significant heterogeneity in ancestry and sex-stratified analyses. In total, we identified 27 genes, of which 3 are monogenic causes of steatosis ( APOB , G6PC1 , PPARG ), 4 were previously associated with MASLD ( APOB , APOC3 , INSR , PPARG ), and 23 had supporting clinical, experimental, and/or genetic evidence. Conclusions Our results suggest that trans-ancestral association analyses can identify ancestry-specific rare and ultra-rare coding variants in MASLD pathogenesis. Furthermore, we demonstrate the utility of machine learning in genetic investigations of difficult-to-phenotype diseases in trans-ancestral biobanks.
Author Correction: The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer
Authors: Jiacheng He, Xiaolei Chai, Qiansen Zhang, Yang Wang, Yijie Wang, Xinyu Yang, Jingbo Wu, Bo Feng, Jing Sun, Weiwei Rui, Shuyin Ze, Yuanyuan Fu, Yumiao Zhao, Ying Zhang, Yao Zhang, Meizhen Liu, Chuang Liu, Meifu She, Xiangfei Hu, Xueyun Ma, Huaiyu Yang, Dawei Li, Senlin Zhao, Guichao Li, Zhen Zhang, Zhonghui Tian, Yanlin Ma, Lingyan Cao, Bo Yi, Dali Li, Ruth Nussinov, Charis Eng, Timothy A. Chan, Eytan Ruppin, J. Silvio Gutkind, Feixiong Cheng, Mingyao Liu, Weiqiang Lu
Journal: Nature Immunology (2025)
Precise engineering of gene expression by editing plasticity
Authors: Yang Qiu, Lifen Liu, Jiali Yan, Xianglei Xiang, Shouzhe Wang, Yun Luo, Kaixuan Deng, Jieting Xu, Minliang Jin, Xiaoyu Wu, None Liwei Cheng, Ying Zhou, Weibo Xie, Hai-Jun Liu, Alisdair R. Fernie, Xuehai Hu, Jianbing Yan
Journal: Genome biology (2025)

Identifying transcriptional cis-regulatory elements (CREs) and understanding their role in gene expression are essential for the precise manipulation of gene expression and associated phenotypes. This knowledge is fundamental for advancing genetic engineering and improving crop traits. We here demonstrate that CREs can be accurately predicted and utilized to precisely regulate gene expression beyond the range of natural variation. We firstly build two sequence-to-expression deep learning models to respectively identify distal and proximal CREs by combining them with interpretability methods in multiple crops. A large number of distal CREs are verified for enhancer activity in vitro using UMI-STARR-seq on 12,000 synthesized sequences. These comprehensively characterized CREs and their precisely predicted effects further contribute to the design of in silico editing schemes for precise engineering of gene expression. We introduce a novel concept of "editingplasticity" to evaluate the potential of promoter editing to alter expression of each gene. As a proof of concept, both exhaustive prediction and random knockout mutants are analyzed within the promoter region of ZmVTE4, a key gene affecting α-tocopherol content in maize. A high degree of agreement between predicted and observed expression is observed, extending the range of natural variation and thereby allowing the creation of an optimal phenotype. Our study provides a robust computational framework that advances knowledge-guided gene editing for precise regulation of gene expression and crop improvement. By reliably predicting and validating CREs, we offer a tool for targeted genetic modifications, enhancing desirable traits in crops.
The Landscape of m6A RNA Methylation in Skin Diseases
Authors: Qi Zhang, Guozhen Liu, Li Jing, Sis Aghayants, Fangjing Xu, Yucheng Fan
Journal: British Journal of Dermatology (2025)

Abstract Skin diseases encompass a diverse range of conditions with significant psychological and physiological impacts. N6-methyladenosine (m6A) RNA methylation is a key epitranscriptomic modification that regulates gene expression by influencing RNA stability, splicing, translation, export, and degradation. Recent studies have highlighted the crucial role of m6A modification in the pathogenesis and progression of various skin diseases. M6A modification affects critical biological processes of the skin, such as inflammation, immune response, and cellular aging. This review systematically explores the landscape of m6A modification in non-tumor skin diseases, elucidating its regulatory roles and therapeutic implications, including wound healing, scar and keloid, skin aging, psoriasis, systemic lupus erythematosus, acne vulgaris, rosacea, chronic actinic dermatitis, and scleroderma. The intricate mechanisms of m6A modification can lead to the development of novel diagnostic biomarkers and therapeutic strategies, ultimately improving patient outcomes.
Radiotherapy results in decreased time to second cancer in children with Li Fraumeni syndrome
Authors: Emma R Woodward, John-Paul Kilday, Stephanie Ng, Anna Kelsey, D Gareth R Evans
Journal: JNCI Journal of the National Cancer Institute (2025)

Abstract Li Fraumeni Syndrome (LFS) arising from germline TP53 mutation results in defective DNA repair and increased risk of multiple primary cancers beginning in childhood. Curative intent radiotherapy is often used to treat childhood cancer but its impact in children in LFS has not been reviewed. We undertook a retrospective case-series review of 4 children with a solid cancer diagnosed ≤16years to assess time and survival following second cancer diagnosis. Following radiotherapy for the first cancer diagnosis, median time to second primary cancer diagnosis was 13.3 years and median survival 9.7 years. Where no radiotherapy was received median time to second primary cancer diagnosis was 25.1 years [Chi2=14.8, P &amp;lt; .0001; HR = 7.9 (95% CI:2.8-22.6)], and median survival of 29.2 years [Chi2=12.5, P = .004, HR = 3.2 (95% CI : 1.5-6.6)]. Radiotherapy for first cancer in children with LFS is associated with adverse outcomes and ought be considered only in the absence of other potentially curative options. Where unavoidable, second cancer risks must be minimised.
Myocardial extracellular volume fraction by computed tomography vs. cardiovascular magnetic resonance imaging in patients with stable chest pain
Authors: Bunny Saberwal, Kush Patel, Ernst Klotz, Anna Herrey, Andreas Seraphim, Sebastian Vandermolen, George D Thornton, Mohammed Y Khanji, Thomas A Treibel, Francesca Pugliese
Journal:  (2025)

Abstract Aims Computed tomography (CT) is increasingly being recognized as a diagnostic modality across a range of cardiovascular conditions. Myocardial late enhancement imaging has shown value as an imaging biomarker for the identification and prognostication of disease. The objective of this study was to compare extracellular volume fraction by CT (ECVCT) against cardiovascular magnetic resonance (ECVCMR), the latter considered as reference standard for this study. Methods and results Consecutive patients with an index history of cardiac chest pain referred for invasive angiography were prospectively recruited. In addition to late gadolinium enhancement (LGE) imaging, patients underwent 1.5 T CMR with T1-mapping [by MOdified Look-Locker Inversion (MOLLI) recovery]. Pre- and post-contrast CT was performed for whole-heart ECVCT quantification. Averaged and segmental ECVCT was compared in patients with and without LGE, as well as between mid-ventricular averaged ECVCT and ECVCMR. Bland–Altman analysis was used to determine limits of agreement and identify differences between ECVCT and ECVCMR. A total of 88 participants (74% male, mean age 59.8 ± 9.1 years) underwent ECVCT and LGE; 49 of these also underwent mid-ventricular ECVCMR. For these, the CMR and CTECV fractions were 27.6 ± 2.4 and 26.8 ± 2.2, respectively. Patients with LGE findings on CMR (n = 24) had a significantly higher ECVCT than those without (n = 64): 27.2 [25.8, 28.7] vs. 26.1 [25.0, 27.7] (P = 0.02). Segments with LGE demonstrated a consistently higher ECV: 30.8 [25.7, 35.9] (P = 0.008) (endocardial LGE) and 30.9 [27.9, 33.1] (P = 0.0001) (transmural LGE) vs. 26.1 [25.0, 27.4]. Conclusion ECVCT obtained from 5 min post-contrast CT protocols shows good agreement with CMR in a stable chest pain cohort. Such a protocol could be seamlessly introduced into a CT workflow for the identification of significant secondary pathologies.
Anti-SARS-CoV-2 prodrug ATV006 has broad-spectrum antiviral activity against human and animal coronaviruses
Authors: Tiefeng Xu, Kun Li, Siyao Huang, Konstantin I. Ivanov, Sidi Yang, Yanxi Ji, Hanwei Zhang, Wenbin Wu, Ye He, Qiang Zeng, Feng Cong, Yingjun Li, Jian Pan, Jinchun Zhao, Chunmei Li, Xumu Zhang, Liu Cao, Deyin Guo
Journal: Acta Pharmaceutica Sinica B (2025)
Oncologic outcomes of retroperitoneal lymph node dissection following first-line chemotherapy for metastatic non-seminomatous germ cell tumors
Authors: R S Matulewicz, F Baky, N Liso, B M Williams, S Porwal, M Assel, B S Carver, D F Bajorin, R J Motzer, G J Bosl, D J McHugh, V E Reuter, S K Tickoo, H Al-Ahmadie, A J Vickers, S A Funt, D R Feldman, J Sheinfeld
Journal: Annals of Oncology (2025)
Targeted Therapies in Myelofibrosis: Present Landscape, Ongoing Studies, and Future Perspectives
Authors: Giuseppe G. Loscocco, Paola Guglielmelli
Journal: American Journal of Hematology (2025)

ABSTRACT Myelofibrosis (MF) is a myeloproliferative neoplasm that is accompanied by driver JAK2 , CALR , or MPL mutations in more than 90% of cases, leading to constitutive activation of the JAK–STAT pathway. MF is a multifaceted disease characterized by trilineage myeloid proliferation with prominent megakaryocyte atypia and bone marrow fibrosis, as well as splenomegaly, constitutional symptoms, ineffective erythropoiesis, extramedullary hematopoiesis, and a risk of leukemic progression and shortened survival. Therapy can range from observation alone in lower‐risk and asymptomatic patients to allogeneic hematopoietic stem cell transplantation, which is the only potentially curative treatment capable of prolonging survival, although burdened by significant morbidity and mortality. The discovery of the JAK2 V617F mutation prompted the development of JAK inhibitors (JAKi) including the first‐in‐class JAK1/JAK2 inhibitor ruxolitinib and subsequent approval of fedratinib, pacritinib, and momelotinib. The latter has shown erythropoietic benefits by suppressing hepcidin expression via activin A receptor type 1 (ACVR1) inhibition, as well as reducing splenomegaly and symptoms. However, the current JAKi behave as anti‐inflammatory drugs without a major impact on survival or disease progression. A better understanding of the genetics, mechanisms of fibrosis, cytopenia, and the role of inflammatory cytokines has led to the development of numerous therapeutic agents that target epigenetic regulation, signaling, telomerase, cell cycle, and apoptosis, nuclear export, and pro‐fibrotic cytokines. Selective JAK2 V617F inhibitors and targeting of mutant CALR by immunotherapy are the most intriguing and promising approaches. This review focuses on approved and experimental treatments for MF, highlighting their biological background.
Comparative Evaluation of an Allergen Exposure Chamber and Nasal Allergen Challenge Versus In‐Field Symptom Assessment in Patients With Allergic Rhinitis Triggered by Timothy Grass Pollen
Authors: Magdalena Zemelka‐Wiacek, Anna Kosowska, Oliver Pfaar, Ioana Agache, Krzysztof Kujawa, Marek Jutel
Journal: Allergy (2025)

An allergen exposure chamber (AEC) is a specialized medical facility designed to expose individuals to allergens at precise and consistent concentrations within a controlled environment. This study aimed to correlate the assessment of clinical endpoints in patients with allergic rhinitis sensitized to timothy grass pollen (Phleum pratense) by comparing three different methods: AEC, nasal allergen challenge (NAC), and symptoms during natural exposure during the grass pollen season. Fifteen allergic subjects and twelve healthy controls were evaluated in the ALLEC AEC; allergic symptoms were measured by subjective and objective methods, including total nasal symptom score (TNSS), acoustic rhinometry (AcR), peak nasal inspiratory flow (PNIF), and nasal discharge amount. For the in-field evaluation, a combined symptom medication score (EAACI-CSMS), as proposed by the European Academy of Allergy and Clinical Immunology (EAACI), was used, which was assessed for 14 days during the peak of the pollen season. The AcR, PNIF, and TNSS were used for the NAC assessment. Both in the AEC and NAC, all allergic individuals developed symptoms at the optimal pollen/allergen concentration across all the measured endpoints. Using Spearman's rank correlation coefficient (p < 0.05), the analysis revealed significant correlations between symptoms assessed in AEC at 120 min of the challenge, as well as in NAC after 15 min with the EAACI-CSMS in-field. The correlations between in-field assessment and AEC were stronger than those with NAC, which showed weaker or no significant correlations. This indicates that the AEC challenge correlates better with in-field assessments than NAC. Clinical endpoints assessed to allergen exposure in the AEC and NAC significantly correspond to the efficacy analysis in-field (EAACI-CSMS during the peak of pollen exposure). The effect of NAC was not significant for all outcomes measured. Both methods might be considered to be an alternative to traditional assessment during natural exposure.
A Sophisticated Ratiometric Nuclear Medicine Imaging Strategy for Biological Microenvironment Abnormal Factor Detection
Authors: Jianxian Ge, Haodi Qi, Lishu Zhao, Xiaoyi Cao, Can Chen, Ruru Zhang, Mohammad Javad Afshari, Yun Gao, Chaoping Sun, Lei Chen, Jianfeng Zeng, Mingyuan Gao
Journal: Advanced Healthcare Materials (2025)

Biological microenvironment detection is crucial for deciphering the mechanisms underlying malignant progression and predicting the treatment efficacy of diseases. Nevertheless, only very limited progress has been made toward non-invasive and quantitative detection of microenvironment abnormal factors, let alone with clinically compatible imaging modalities. Herein, a smart nuclear medicine probe is proposed, innovatively designed for quantitative visualization of glutathione (GSH) in vivo. This probe contains a disulfide bond that links two molecular segments labeled with 125I and 177Lu, respectively. Upon systemic delivery, the probe preferentially accumulates in the liver, where GSH cleaves it into two fragments with completely different metabolic fates: one retained at the response site and the other rapidly excreted. This unique feature provides an opportunity to use the 177Lu/125I signal ratio to non-invasively characterize the GSH concentration in vivo, enabling highly sensitive quantification of GSH that is strongly associated with many hepatic diseases. Moreover, the strategy also provides a reliable method for the quantitative visualization of GSH levels in tumors. It is thus believed the current study provides a groundbreaking method for non-invasively and quantitatively revealing disease-related microenvironment factors, not limited to GSH, in vivo.
Age‐ and gender‐specific molecular characteristics of diffuse large B‐cell lymphoma: Results from clinical trials of the DSHNHL/GLA
Authors: Katrin S. Kurz, Sophia Steinlein, Markus Kreuz, Marita Ziepert, Annette M. Staiger, Thomas F. E. Barth, Peter Möller, Heinz‐Wolfram Bernd, Alfred C. Feller, Julia Richter, Wolfram Klapper, Harald Stein, Sylvia Hartmann, Martin‐Leo Hansmann, Lorenz Trümper, Markus Loeffler, Norbert Schmitz, Andreas Rosenwald, German Ott, Heike Horn
Journal: HemaSphere (2025)

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. Despite a high cure rate, too many patients show refractory (ref) or relapsed (rel) disease. This study examines the frequency of recurring gene mutations and their interplay with well-known biomarkers in female and male patients between 18 and 80 years with ref/rel DLBCL compared to patients with complete remission (CR) to identify biological risk factors associated with treatment response, using cohorts of R-CHOP-like treated DLBCL enrolled in clinical trials of the DSHNHL. The biomarker profile of patients differed between younger and elderly patients with ref/rel DLBCL, with a higher frequency of BCL2 translocations in younger patients, and higher numbers of ABC subtypes and MYC protein expression in the elderly. Amplicon sequencing revealed generally higher mutation frequencies in the younger cohort. Mutations in CREBBP and TNFRSF14 were associated with shorter overall survival (OS) only in younger patients. A higher proportion of GNA13 mutations was detected in female patients of the elderly DLBCL patient cohort, clearly emphasizing the striking differences in biomarker distribution between younger and elderly as well as female and male patients.
Prevascularized Hydrogel Enhancing Innervation and Repair of Full‐Thickness Volumetric Muscle Loss in Abdominal Wall Defects
Authors: Chia‐Chang Hsieh, Jun‐Zhi Dai, Chun‐Chuan Ni, Shih‐Yen Wei, Min‐Chun Tsai, Po‐Yu Chen, Ling Fang, Ren‐Hao Xie, Guan‐Yu Chen, Gung‐Chian Yin, Ying‐Chieh Chen
Journal: Advanced Healthcare Materials (2025)

Current materials for repairing abdominal peritoneal defects face rapid degradation, infection risk, insufficient vascular ingrowth, slow muscle regeneration, and suboptimal postoperative integration, often causing fibrotic healing and hindering volumetric muscle loss (VML) repair exceeding 30%. To address these issues, photo-cross-linkable gelatin hydrogels are combined with blood vessel-forming cells to reconstruct vascular networks, providing temporary nutrient and gas channels that support cell repair. By developing a polymer-chain propagation time technique, hydrogel properties are optimized, avoiding limitations of conventional light exposure. These gels guide blood-vessel formation in vitro and promote robust microvessel and neural development in vivo. Precise control of light exposure and propagation times balances cross-linking and degradation, fostering blood vessel growth and host motor neuron ingrowth. In 55% VML, these hydrogels enable full-thickness abdominal muscle regeneration, restoring up to 70% of lost muscle while mimicking healthy tissue's strength and structure. Achieving higher degradation rates and a vascular density exceeding 50 vessels/mm-2 is essential for functional muscle repair. These strategies effectively bridge current clinical gaps, advancing regenerative medicine. The ability to fine-tune degradation and stiffness underscores gelatin hydrogels' potential as cell carriers, allowing the reconstruction of temporary vascular and neural channels at injury sites and significantly enhancing muscle tissue regeneration.
The emerging role of neutrophil extracellular traps in autoimmune and autoinflammatory diseases
Authors: Liuting Zeng, Wang Xiang, Wei Xiao, Yang Wu, Lingyun Sun
Journal: MedComm (2025)

Neutrophil extracellular traps (NETs) are unique fibrous structures released by neutrophils in response to various pathogens, exhibiting both anti-inflammatory and proinflammatory effects. In autoimmune conditions, NETs serve as crucial self-antigens triggering inflammatory cascades by activating the inflammasome and complement systems, disrupting self-tolerance mechanisms and accelerating autoimmune responses. Furthermore, NETs play a pivotal role in modulating immune cell activation, affecting adaptive immune responses. This review outlines the intricate relationship between NETs and various diseases, including inflammatory arthritis, systemic autoimmune diseases, Behçet's disease, systemic lupus erythematosus, autoimmune kidney diseases, autoimmune skin conditions, systemic sclerosis, systemic vasculitis, and gouty arthritis. It highlights the potential of targeting NETs as a therapeutic strategy in autoimmune diseases. By examining the dynamic balance between NET formation and clearance in autoimmune conditions, this review offers critical insights and a theoretical foundation for future research on NET-related mechanisms. Advances in systems biology, flow cytometry, and single-cell multiomics sequencing have provided valuable tools for exploring the molecular mechanisms of neutrophils and NETs. These advancements have renewed focus on the role of neutrophils and NETs in autoimmune diseases, offering promising avenues for further investigation into their clinical implications.
PD‐1/PD‐L1 Inhibitors Plus Chemotherapy Versus Chemotherapy Alone as First‐Line Therapy for Patients With Unfavorable Cancer of Unknown Primary: A Multicenter, Retrospective Cohort Study
Authors: Riqing Huang, Haifeng Li, Shuo Li, Ditian Shu, Rishang Chen, Zhousan Zheng, Tinghua Gao, Meiting Chen, Anqi Hu, Yunjie Huang, Qiufan Zheng, Xin An, Cong Xue, Yuchen Cai, Yanxia Shi
Journal: MedComm (2025)

This multicenter study aimed to investigate the efficacy and safety of PD-1/PD-L1 inhibitors plus chemotherapy (ICI-Chemo group) versus chemotherapy alone (Chemo group) for patients with cancer of unknown primary (CUP) in the first-line setting. We included patients with unfavorable CUP across four medical centers in China. Between January 2014 and December 2023, 117 patients were enrolled: 46 patients in the ICI-Chemo group and 71 patients in the Chemo group. After a median follow-up of 28.1 months, the ICI-Chemo group exhibited a significant improvement over the Chemo group in median PFS (9.10 months vs. 6.37 months; hazard ratio [HR] 0.46; 95% CI: 0.30-0.71; p < 0.001) and OS (35.67 months vs. 10.2 months; HR 0.37; 95% CI: 0.22-0.64; p < 0.001). Similarly, among patients who received TP (taxane plus platinum)-based chemotherapies, OS and PFS benefits were observed in the ICI-Chemo group. The objective response rate was higher in the ICI-Chemo group than in the Chemo group (54.35% vs. 22.53%, p < 0.001). Grade 3 or higher drug-related adverse events occurred in 11 patients (23.91%) in the ICI-Chemo group and 28 patients (39.44%) in the Chemo group. Thus, PD-1/PD-L1 inhibitors plus chemotherapy could be the preferred first-line treatment for patients with unfavorable CUP, providing improved efficacy and manageable toxicity.