tbuckley/cabot-search huggingface dataset:
Strategic targeting of Cas9 nickase expands tandem gene arrays
Authors: Hiroaki Takesue, Satoshi Okada, Goro Doi, Yuki Sugiyama, Emiko Kusumoto, Takashi Ito
Journal: Cell Genomics (2025)

Expanding tandem gene arrays facilitates adaptation through dosage effects and gene family formation via sequence diversification. However, experimental induction of such expansions remains challenging. Here, we introduce a method termed break-induced replication (BIR)-mediated tandem repeat expansion (BITREx) to address this challenge. BITREx places Cas9 nickase adjacent to a tandem gene array to break the replication fork that has just replicated the array, forming a single-ended double-strand break. This break is subsequently end-resected to become single stranded. Since there is no repeat unit downstream of the break, the single-stranded DNA often invades an upstream unit to initiate ectopic BIR, resulting in array expansion. BITREx has successfully expanded gene arrays in budding yeast, with the CUP1 array reaching ∼1 Mb. Furthermore, appropriate splint DNAs allow BITREx to generate tandem arrays de novo from single-copy genes. We have also demonstrated BITREx in mammalian cells. Therefore, BITREx will find various unique applications in genome engineering.
Effects of long-term oxygen therapy on acute exacerbation and hospital burden: the national DISCOVERY study
Authors: Yet Hong Khor, Andreas Palm, Alyson W Wong, Sabina A Guler, Filip Björklund, Zainab Ahmadi, Josefin Sundh, Christopher J Ryerson, Magnus Ekström
Journal: Thorax (2025)

Background Long-term oxygen therapy (LTOT) improves survival in patients with chronic severe resting hypoxaemia, but effects on hospitalisation are unknown. This study evaluated the potential impact of starting LTOT on acute exacerbation and hospital burden in patients with chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and pulmonary hypertension (PH). Methods Longitudinal analysis of consecutive patients in the population-based Swedish DISCOVERY cohort who started LTOT between 2000 and 2018 with a follow-up duration≥3 months. Total and hospitalised acute exacerbations of the underlying disease, all-cause hospitalisations, and all-cause outpatient visits were annualised and compared between the year before and after LTOT initiation for each disease cohort, and by hypercapnic status in patients with COPD. Results Patients with COPD (n=10 134) had significant reduction in annualised rates of total and hospitalised acute exacerbations, as well as all-cause hospitalisations, following LTOT initiation, with increment in those with ILD (n=2507) and PH (n=850). All-cause outpatient visits increased across all cohorts following LTOT initiation. Similar findings were observed in patients with hypercapnic and non-hypercapnic COPD. Sensitivity analyses of patients with 12 months of follow-up showed reduced acute exacerbations and all-cause hospitalisations in the ILD and PH cohorts. Conclusion LTOT is associated with reduced rates of both total and hospitalised acute exacerbations and all-cause hospitalisations in patients with COPD, as well as patients with ILD and PH with 12 months of follow-up. There is increased all-cause outpatient visits in all disease groups following LTOT initiation.
Binding domain mutations provide insight into CTCF’s relationship with chromatin and its contribution to gene regulation
Authors: Catherine Do, Guimei Jiang, Giulia Cova, Christos C Katsifis, Domenic N Narducci, Theodore Sakellaropoulos, Raphael Vidal, Priscillia Lhoumaud, Aristotelis Tsirigos, Faye Fara D Regis, Nata Kakabadze, Elphege P Nora, Marcus Noyes, Anders S Hansen, Jane A Skok
Journal: Cell Genomics (2025)

Here we used a series of CTCF mutations to explore CTCF's relationship with chromatin and its contribution to gene regulation. CTCF's impact depends on the genomic context of bound sites and the unique binding properties of WT and mutant CTCF proteins. Specifically, CTCF's signal strength is linked to changes in accessibility, and the ability to block cohesin is linked to its binding stability. Multivariate modeling reveals that both CTCF and accessibility contribute independently to cohesin binding and insulation, but CTCF signal strength has a stronger effect. CTCF and chromatin have a bidirectional relationship such that at CTCF sites, accessibility is reduced in a cohesin-dependent, mutant-specific fashion. In addition, each mutant alters TF binding and accessibility in an indirect manner, changes which impart the most influence on rewiring transcriptional networks and the cell's ability to differentiate. Collectively, the mutant perturbations provide a rich resource for determining CTCF's site-specific effects.
A CT-based deep learning-driven tool for automatic liver tumor detection and delineation in patients with cancer
Authors: Maria Balaguer-Montero, Adrià Marcos Morales, Marta Ligero, Christina Zatse, David Leiva, Luz M Atlagich, Nikolaos Staikoglou, Cristina Viaplana, Camilo Monreal, Joaquin Mateo, Jorge Hernando, Alejandro García-Álvarez, Francesc Salvà, Jaume Capdevila, Elena Elez, Rodrigo Dienstmann, Elena Garralda, Raquel Perez-Lopez
Journal: Cell Reports Medicine (2025)

Liver tumors, whether primary or metastatic, significantly impact the outcomes of patients with cancer. Accurate identification and quantification are crucial for effective patient management, including precise diagnosis, prognosis, and therapy evaluation. We present SALSA (system for automatic liver tumor segmentation and detection), a fully automated tool for liver tumor detection and delineation. Developed on 1,598 computed tomography (CT) scans and 4,908 liver tumors, SALSA demonstrates superior accuracy in tumor identification and volume quantification, outperforming state-of-the-art models and inter-reader agreement among expert radiologists. SALSA achieves a patient-wise detection precision of 99.65%, and 81.72% at lesion level, in the external validation cohorts. Additionally, it exhibits good overlap, achieving a dice similarity coefficient (DSC) of 0.760, outperforming both state-of-the-art and the inter-radiologist assessment. SALSA's automatic quantification of tumor volume proves to have prognostic value across various solid tumors (p = 0.028). SALSA's robust capabilities position it as a potential medical device for automatic cancer detection, staging, and response evaluation.
Cross-ancestry analyses of Chinese and European populations reveal insights into the genetic architecture and disease implication of metabolites
Authors: Chenhao Lin, Mingfeng Xia, Yuxiang Dai, Qingxia Huang, Zhonghan Sun, Guoqing Zhang, Ruijin Luo, Qianqian Peng, Jinxi Li, Xiaofeng Wang, Huandong Lin, Xin Gao, Huiru Tang, Xia Shen, Sijia Wang, Li Jin, Xingjie Hao, Yan Zheng
Journal: Cell Genomics (2025)

Differential susceptibilities to various diseases and corresponding metabolite variations have been documented across diverse ethnic populations, but the genetic determinants of these disparities remain unclear. Here, we performed large-scale genome-wide association studies of 171 directly quantifiable metabolites from a nuclear magnetic resonance-based metabolomics platform in 10,792 Han Chinese individuals. We identified 15 variant-metabolite associations, eight of which were successfully replicated in an independent Chinese population (n = 4,480). By cross-ancestry meta-analysis integrating 213,397 European individuals from the UK Biobank, we identified 228 additional variant-metabolite associations and improved fine-mapping precision. Moreover, two-sample Mendelian randomization analyses revealed evidence that genetically predicted levels of triglycerides in high-density lipoprotein were associated with a higher risk of coronary artery disease and that of glycine with a lower risk of heart failure in both ancestries. These findings enhance our understanding of the shared and specific genetic architecture of metabolites as well as their roles in complex diseases across populations.
Small-molecule RNA therapeutics to target prostate cancer
Authors: Duygu Kuzuoglu-Ozturk, Hao G Nguyen, Lingru Xue, Emma Figueredo, Vishvak Subramanyam, Isabelle Liu, Kenya Bonitto, Ashish Noronha, Adrianna Dabrowska, Janet E Cowan, Juan A Oses-Prieto, Alma L Burlingame, Stephen T Worland, Peter R Carroll, Davide Ruggero
Journal: Cancer Cell (2025)
Seasonal variations in circulating endocannabinoidome mediators and gut microbiota composition in humans
Authors: Sophie Castonguay-Paradis, Élisabeth Demers-Potvin, Gabrielle Rochefort, Sébastien Lacroix, Julie Perron, Cyril Martin, Nicolas Flamand, Frédéric Raymond, Vincenzo Di Marzo, Alain Veilleux
Journal: Gut Microbes (2025)

Background The human gut microbiome-endocannabinoidome axis is crucial for several homeostatic processes, including inflammation and energy metabolism, and is influenced by many endogenous and exogenous factors, such as dietary habits. Changes in the gut microbiome in response to seasonal variations were previously reported and tentatively attributed to shifts in dietary patterns. However, there is a need for longitudinal studies in industrialized populations to comprehensively explore seasonal variations independently of lifestyle confounding factors.
Diabetes Mellitus and APOL1 Genotype Increase the Risk for Chronic Kidney Disease Progression in Sickle Cell Disease
Authors: Ryan Sun, Anand Srivastava, Joseph L Zapater, Franklin Njoku, Jin Han, Zalaya K Ivy, Marwah W. Farooqui, Insia Rizvi, Brian T Layden, Robert Molokie, Victor R Gordeuk, Santosh L Saraf
Journal: Blood (2025)
Practice Patterns and Survival Outcomes of Immunotherapy for Metastatic Colorectal Cancer
Authors: Shahla Bari, Marco Matejcic, Richard D. Kim, Hao Xie, Ibrahim H. Sahin, Benjamin D. Powers, Jamie K. Teer, Timothy A. Chan, Seth I. Felder, Stephanie L. Schmit
Journal: JAMA Network Open (2025)

Importance Immune checkpoint inhibitors (ICIs) have been approved for treatment of microsatellite instable (MSI-H) metastatic colorectal cancer (mCRC), but factors associated with receipt and efficacy of ICIs in routine clinical practice remain largely unknown. Objective To identify factors associated with receipt of ICIs and associated survival outcomes among patients with mCRC in routine clinical practice. Design, Setting, and Participants This population-based cohort study used deidentified data from a nationwide electronic health record–derived database to include 18 932 patients diagnosed with mCRC between January 2013 and June 2019. Population-based patients were diagnosed with de novo mCRC and had at least 2 documented clinical visits on or after the date of diagnosis. The study analyses were performed between September 2020 and April 2021. Exposure Patients received ICI therapy and/or chemotherapy as part of a systemic treatment for mCRC. Main Outcomes and Measures The outcomes were receipt of ICI therapy, overall survival (OS), and time to treatment discontinuation (TTD). Results In this cohort study of 18 932 patients diagnosed with mCRC (10 537 [55.7%] male; 546 [2.9%] Asian, 2005 [10.6%] Black or African American, 1674 [8.8%] Hispanic, 12 338 [65.2%] White, 4043 [21.4%] unknown race or ethnicity; median [IQR] age at metastatic diagnosis, 64.6 [55.0-73.3] years), patients with MSI-H tumors had a significantly higher probability of receiving ICIs than those with microsatellite stable (MSS) tumors (odds ratio [OR], 22.66 [95% CI, 17.30-29.73]; P &amp;amp;lt; .001), whereas patients initially diagnosed with synchronous mCRC had significantly lower odds of receiving ICIs than patients with metachronous mCRC (OR, 0.57 [95% CI, 0.45-0.73]; P &amp;amp;lt; .001). Patients with MSI-H tumors who received ICIs as first line of therapy had significantly longer OS than those receiving chemotherapy only (HR, 0.37 [95% CI, 0.25-0.56]; P &amp;amp;lt; .001). Among patients with MSS tumors, ICI-based therapy was associated with significantly longer OS for patients with high albumin level (vs low: HR, 0.28 [95% CI, 0.18-0.45]; P &amp;amp;lt; .001) and antibiotic use (vs nonuse: HR, 0.43 [95% CI, 0.27-0.67]; P &amp;amp;lt; .001), but a significantly shorter OS for patients with synchronous mCRC (vs metachronous: HR, 1.90 [95% CI, 1.24-2.89]; P = .003). In addition, 29 out of 235 patients with MSS tumors (12.3%) experienced durable responses on ICI-based therapy. Similar patterns of associations with TTD were observed. Conclusions and Relevance In this cohort study of patients with mCRC, clinical characteristics were associated with different survival outcomes in patients treated with ICI-based therapy, with important clinical implications for patients with MSS tumors who are generally unresponsive to immunotherapy.
Generalizability of Treatment Outcome Prediction Across Antidepressant Treatment Trials in Depression
Authors: Peter Zhukovsky, Madhukar H. Trivedi, Myrna Weissman, Ramin Parsey, Sidney Kennedy, Diego A. Pizzagalli
Journal: JAMA Network Open (2025)

Importance Although several predictive models for response to antidepressant treatment have emerged on the basis of individual clinical trials, it is unclear whether such models generalize to different clinical and geographical contexts. Objective To assess whether neuroimaging and clinical features predict response to sertraline and escitalopram in patients with major depressive disorder (MDD) across 2 multisite studies using machine learning and to predict change in depression severity in 2 independent studies. Design, Setting, and Participants This prognostic study included structural and functional resting-state magnetic resonance imaging and clinical and demographic data from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) randomized clinical trial (RCT), which administered sertraline (in stage 1 and stage 2) and placebo, and the Canadian Biomarker Integration Network in Depression (CANBIND-1) RCT, which administered escitalopram. EMBARC recruited participants with MDD (aged 18-65 years) at 4 academic sites across the US between August 2011 and December 2015. CANBIND-1 recruited participants with MDD from 6 outpatient centers across Canada between August 2013 and December 2016. Data were analyzed from October 2023 to May 2024. Main Outcomes and Measures Prediction performance for treatment response was assessed using balanced classification accuracy and area under the curve (AUC). In secondary analyses, prediction performance was assessed using observed vs predicted correlations between change in depression severity. Results In 363 adult patients (225 from EMBARC and 138 from CANBIND-1; mean [SD] age, 36.6 [13.1] years; 235 women [64.7%]), the best-performing models using pretreatment clinical features and functional connectivity of the dorsal anterior cingulate had moderate cross-trial generalizability for antidepressant treatment (trained on CANBIND-1 and tested on EMBARC, AUC = 0.62 for stage 1 and AUC = 0.67 for stage 2; trained on EMBARC stage 1 and tested on CANBIND-1, AUC = 0.66). The addition of neuroimaging features improved the prediction performance of antidepressant response compared with clinical features only. The use of early-treatment (week 2) instead of pretreatment depression severity scores resulted in the best generalization performance, comparable to within-trial performance. Multivariate regressions showed substantial cross-trial generalizability in change in depression severity (predicted vs observed r ranging from 0.31 to 0.39). Conclusions and Relevance In this prognostic study of depression outcomes, models predicting response to antidepressants show substantial generalizability across different RCTs of adult MDD.
In situ forming AIEgen-alginate hydrogel for remodeling tumor microenvironment to boost FLASH immunoradiotherapy
Authors: Meng Lyu, Tianfu Zhang, Zhirong Bao, Pei Li, Mingzhu Chen, Hong Quan, Cunchuan Wang, Ligang Xia, Yang Li, Benzhong Tang
Journal: Biomaterials (2025)
Stromal Fibrin Shapes Immune Infiltration Landscape of Pancreatic Ductal Adenocarcinoma
Authors: Mazharul Karim, Md Mahedi Hasan, Seung Hyun Kim, Zulfikar Azam, Riajul Wahab, Tamanna Islam, Farzana Alam, Yun-Jae Kim, Dong-Jun Bae, Sourav Roy, Paul Grippo, Faraz Bishehsari, Jeong Uk Choi, Taslim A Al-Hilal
Journal: Biomaterials (2025)
Accelerated Aging in Survivors of Childhood Cancer—Early Onset and Excess Risk of Chronic Conditions
Authors: Jennifer M. Yeh, Zachary J. Ward, Kayla L. Stratton, Mercedes V. McMahon, Chelsea S. Taylor, Gregory T. Armstrong, Eric J. Chow, Melissa M. Hudson, Lindsay M. Morton, Kevin C. Oeffinger, Lisa R. Diller, Wendy M. Leisenring
Journal: JAMA Oncology (2025)

Importance The lifetime risk of aging-related diseases among survivors of childhood cancer, accelerated by cancer treatment exposures, is unknown. Understanding this risk can provide a more comprehensive assessment of long-term health across the lifespan of survivors and guide adult care. Objective To estimate the lifetime risks of 8 treatment-related cancers and cardiovascular conditions among childhood cancer survivors and compare them with the general population. Design, Setting, Participants Using data from the Childhood Cancer Survivor Study and national databases, this simulation modeling study projected long-term outcomes for 5-year survivors diagnosed between 1970 and 1999 based on treatment exposures and age-related risks. The general population comparator was simulated using age-, sex-, and calendar year–matched individuals who faced only age-related risks. Exposures Treatment era (1970s, 1980s, 1990s), original cancer diagnosis, radiation treatment for primary diagnosis (any, none). Main Outcomes and Measures Estimated lifetime risks of 8 health conditions (breast cancer, colorectal cancer, glial tumors, sarcomas, heart failure, coronary heart disease/myocardial infarction, stroke, and valvular disease). Risks were projected and compared with the general population, stratified by radiation exposure. Results In the general population, 20% developed at least 1 health condition by age 65.0 years; in 5-year survivors this threshold was reached at age 47.3 years, representing a 17.7-year (95% uncertainty interval [UI], 14.0-21.0) acceleration in disease onset. By age 65 years, 55% of survivors were projected to develop at least 1 condition, indicating a 2.7-fold (95% UI, 2.2-3.5) higher relative risk and 34.2% (95% UI, 28.3-42.5) absolute excess risk compared with the general population. Risks were higher among those treated with radiation therapy for childhood cancer (22.0 years earlier onset [95% UI, 18.0-25.0]; 37.3% excess risk [95% UI, 31.6%-44.7%]) but still elevated for those without radiation exposure (13.5 years earlier onset [95% UI, 10.0-16.0]; 31.0% excess risk [95% UI, 23.9%-40.3%]). Reaching middle age was still associated with increased health risks. Compared with the general population, survivors who reached age 40 years had a 6.2-fold higher risk (95% UI, 4.8-9.4) of developing a new condition within 10 years. Conclusions and Relevance This study found that survivors of childhood cancer experience accelerated onset of aging-related diseases, regardless of prior radiation exposure. These findings underscore the importance of prioritizing cancer and cardiovascular disease prevention among survivors decades earlier than for the general population.
Food and Water Insecurity and Functional Disability in Adults
Authors: Yankun Wang, Rodrigo X. Armijos, Sarah Commodore, Aurelian Bidulescu, M. Margaret Weigel
Journal: JAMA Network Open (2025)

Importance Evidence from diverse global populations suggests that household food insecurity (HFI) is associated with adult disability, but the association between household water insecurity (HWI) and disability remains understudied. Examinations of the joint association of dual HFI and HWI with disability are lacking. Objective To explore independent and joint associations of HFI and HWI with functional disability in Ecuadorian adults. Design, Setting, and Participants This cross-sectional study used data from the 2018 Ecuadorian National Health and Nutrition Survey, a nationally representative, population-based survey conducted in Ecuador. The study included adults (aged 18-99 years) with information on sociodemographic characteristics, household food and water security, and functional disability status. Data were collected in 2 waves of the survey, from November 2018 to January 2019 and June to July 2019. Statistical analysis was performed from May to December 2024. Exposures HFI, WFI, or both. Main outcomes and Measures The primary outcome was self-reported functional disability, assessed using the Washington Group Short Set on Functioning, a tool that uses a set of 6 questions to measure activity limitations. Results Among 42 071 participants (mean [SE] age, 48.0 [0.1] years; 31 683 male [75.3%]; 1840 African descendant [4.4%], 5184 Indigenous [12.3%], and 35 047 Mestizo ethnic majority group [83.3%]), most lived in urban areas (26 164 participants [62.2%]). Exposure to HFI only was associated with an increased risk for any functional disability (adjusted relative risk [aRR], 1.44; 95% CI, 1.37-1.52), as well as sensory (aRR, 1.43; 95% CI, 1.35-1.52), physical (aRR, 1.56, 95% CI, 1.42-1.72), and cognitive (aRR, 1.78; 95% CI, 1.61-1.98) disabilities. HWI exposure only was associated with increased risk for any functional disability (aRR, 1.12; 95% CI, 1.06-1.20), as well as sensory (aRR, 1.17; 95% CI, 1.09-1.25), physical (aRR, 1.15; 95% CI, 1.05-1.26), and cognitive (aRR, 1.17; 95% CI, 1.03-1.34) disabilities. Exposure to dual HFI and HWI was associated with a greater increase in risk than HFI or HWI alone of any functional disability (aRR, 1.61; 95% CI, 1.50-1.72), as well as sensory (aRR, 1.65; 95% CI, 1.52-1.79), physical (aRR, 1.72; 95% CI, 1.59-1.87), and cognitive (aRR, 2.01; 95% CI, 1.76-2.29) disabilities. Conclusion and Relevance In this study, dual exposure to HFI and HWI was associated with a greater increase in risk of any and specific functional disabilities compared with independent contributions of HFI and HWI alone. These findings highlight the importance of addressing HFI and HWI jointly rather than independently when conducting research on disability and other health outcomes and in designing policies and programs to protect at-risk adults and their households.