tbuckley/cabot-search huggingface dataset:
A comprehensive clinically informed map of dependencies in cancer cells and framework for target prioritization
Authors: Clare Pacini, Emma Duncan, Emanuel Gonçalves, James Gilbert, Shriram Bhosle, Stuart Horswell, Emre Karakoc, Howard Lightfoot, Ed Curry, Francesc Muyas, Monsif Bouaboula, Chandra Sekhar Pedamallu, Isidro Cortes-Ciriano, Fiona M. Behan, Lykourgos-Panagiotis Zalmas, Andrew Barthorpe, Hayley Francies, Steve Rowley, Jack Pollard, Pedro Beltrao, Leopold Parts, Francesco Iorio, Mathew J. Garnett
Journal: Cancer Cell (2024)

Genetic screens in cancer cell lines inform gene function and drug discovery. More comprehensive screen datasets with multi-omics data are needed to enhance opportunities to functionally map genetic vulnerabilities. Here, we construct a second-generation map of cancer dependencies by annotating 930 cancer cell lines with multi-omic data and analyze relationships between molecular markers and cancer dependencies derived from CRISPR-Cas9 screens. We identify dependency-associated gene expression markers beyond driver genes, and observe many gene addiction relationships driven by gain of function rather than synthetic lethal effects. By combining clinically informed dependency-marker associations with protein-protein interaction networks, we identify 370 anti-cancer priority targets for 27 cancer types, many of which have network-based evidence of a functional link with a marker in a cancer type. Mapping these targets to sequenced tumor cohorts identifies tractable targets in different cancer types. This target prioritization map enhances understanding of gene dependencies and identifies candidate anti-cancer targets for drug development.
Abstract A023: High glucose increases DNA damage and elevates the expression of multiple DDR genes
Authors: Mai A. Rahmoon, Reem A. Elghaish, Aya A. Ibrahim, Zina Alaswad, Mohamed Z. Gad, Sherif F. El-Khamisy, Menattallah Elserafy
Journal: Cancer Research (2024)

Abstract The DNA Damage Response (DDR) pathways sense DNA damage and coordinate robust DNA repair and bypass mechanisms. A series of repair proteins are recruited depending on the type of breaks and lesions to ensure overall survival. An increase in glucose levels was shown to induce genome instability, yet the links between DDR and glucose are still not well investigated. In this study, we aimed to identify dysregulation in the transcriptome of normal and cancerous breast cell lines upon changing glucose levels. We first performed bioinformatics analysis using a microarray dataset containing the triple-negative breast cancer (TNBC) MDA-MB-231 and the normal human mammary epithelium MCF10A cell lines grown in high glucose (HG) or in the presence of the glycolysis inhibitor 2-deoxyglucose (2DG). Interestingly, multiple DDR genes were significantly upregulated in both cell lines grown in HG. In the wet lab, we remarkably found that HG results in severe DNA damage to TNBC cells as observed using the comet assay. In addition, several DDR genes were confirmed to be upregulated using qPCR analysis in the same cell line. Our results propose a strong need for DDR pathways in the presence of HG to oppose the severe DNA damage induced in cells. Citation Format: Mai A. Rahmoon, Reem A. Elghaish, Aya A. Ibrahim, Zina Alaswad, Mohamed Z. Gad, Sherif F. El-Khamisy, Menattallah Elserafy. High glucose increases DNA damage and elevates the expression of multiple DDR genes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A023.
EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis: 2023 update
Authors: Tuva Moseng, Theodora P M Vliet Vlieland, Simone Battista, David Beckwée, Vladimira Boyadzhieva, Philip G Conaghan, Daniela Costa, Michael Doherty, Andrew G Finney, Tsvetoslav Georgiev, Milena Gobbo, Norelee Kennedy, Ingvild Kjeken, Féline P B Kroon, L Stefan Lohmander, Hans Lund, Christian D Mallen, Karel Pavelka, Irene A Pitsillidou, Margaret P Rayman, Anne Therese Tveter, Johanna E Vriezekolk, Dieter Wiek, Gustavo Zanoli, Nina Østerås
Journal: Annals of the Rheumatic Diseases (2024)

Hip and knee osteoarthritis (OA) are increasingly common with a significant impact on individuals and society. Non-pharmacological treatments are considered essential to reduce pain and improve function and quality of life. EULAR recommendations for the non-pharmacological core management of hip and knee OA were published in 2013. Given the large number of subsequent studies, an update is needed.
Response to Bruton’s tyrosine kinase inhibitors in aggressive lymphomas linked to chronic selective autophagy
Authors: James D. Phelan, Sebastian Scheich, Jaewoo Choi, George W. Wright, Björn Häupl, Ryan M. Young, Sara A. Rieke, Martine Pape, Yanlong Ji, Henning Urlaub, Arnold Bolomsky, Carmen Doebele, Alena Zindel, Tanja Wotapek, Monica Kasbekar, Brett Collinge, Da Wei Huang, Zana A. Coulibaly, Vivian M. Morris, Xiaoxuan Zhuang, Julius C. Enssle, Xin Yu, Weihong Xu, Yandan Yang, Hong Zhao, Zhuo Wang, Andy D. Tran, Christopher J. Shoemaker, Galina Shevchenko, Daniel J. Hodson, Arthur L. Shaffer, Louis M. Staudt, Thomas Oellerich
Journal: Cancer Cell (2024)
National and Provincial-Level Prevalence and Risk Factors of Carotid Atherosclerosis in Chinese Adults
Authors: Jingzhu Fu, Yuhan Deng, Yuan Ma, Sailimai Man, Xiaochen Yang, Canqing Yu, Jun Lv, Bo Wang, Liming Li
Journal: JAMA Network Open (2024)

Importance Epidemiologic studies on carotid atherosclerosis (CAS) based on nationwide ultrasonography measurements can contribute to understanding the future risk of cardiovascular diseases and identifying high-risk populations, thereby proposing more targeted prevention and treatment measures. Objectives To estimate the prevalence of CAS within the general population of China and to investigate its distribution among populations with potential risk factors and variation across diverse geographic regions. Design, Setting, and Participants This multicenter, population-based cross-sectional study used China’s largest health check-up chain database to study 10 733 975 individuals aged 20 years or older from all 31 provinces in China who underwent check-ups from January 1, 2017, to June 30, 2022. Main Outcomes and Measures Carotid atherosclerosis was assessed and graded using ultrasonography as increased carotid intima-media thickness (cIMT), carotid plaque (CP), and carotid stenosis (CS). The overall and stratified prevalences were estimated among the general population and various subpopulations based on demographic characteristics, geographic regions, and cardiovascular disease risk factors. Mixed-effects regression models were used to analyze the risk factors for CAS. Results Among 10 733 975 Chinese participants (mean [SD] age, 47.7 [13.4] years; 5 861 566 [54.6%] male), the estimated prevalences were 26.2% (95% CI, 25.0%-27.4%) for increased cIMT, 21.0% (95% CI, 19.8%-22.2%) for CP, and 0.56% (95% CI, 0.36%-0.76%) for CS. The prevalence of all CAS grades was higher among older adults (eg, increased cIMT: aged ≥80 years, 92.7%; 95% CI, 92.2%-93.3%), male participants (29.6%; 95% CI, 28.4%-30.7%), those residing in northern China (31.0%; 95% CI, 29.1%-32.9%), and those who had comorbid conditions, such as hypertension (50.8%; 95% CI, 49.7%-51.9%), diabetes (59.0%; 95% CI, 57.8%-60.1%), dyslipidemia (32.1%; 95% CI, 30.8%-33.3%), and metabolic syndrome (31.0%; 95% CI, 29.1%-32.9%). Most cardiovascular disease risk factors were independent risk factors for all CAS stages (eg, hypertension: 1.60 [95% CI, 1.60-1.61] for increased cIMT, 1.62 [95% CI, 1.62-1.63] for CP, and 1.48 [95% CI, 1.45-1.51] for CS). Moreover, the magnitude of the association between several cardiovascular disease risk factors and increased cIMT and CP differed between the sexes and geographic regions. Conclusions and Relevance These findings suggest that nearly one-quarter of Chinese adults have increased cIMT or CP. The burden of this disease is unevenly distributed across geographic regions and subpopulations and may require different levels of local planning, support, and management. Addressing these disparities is crucial for effectively preventing and managing cardiovascular and cerebrovascular diseases in China.
­­­­­­Topical Antifungal Prescribing for Medicare Part D Beneficiaries — United States, 2021
Authors: Kaitlin Benedict, Dallas J. Smith, Tom Chiller, Shari R. Lipner, Jeremy A. W. Gold
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Incorrect use of topical antifungals and antifungal-corticosteroid combinations is likely contributing to the global emergence and spread of severe antimicrobial-resistant superficial fungal infections, which have recently been detected in the United States.Understanding prescribing patterns is an initial step in establishing and promoting recommended use of these medications.Using 2021 Medicare Part D data, CDC examined prescription volumes, rates, and costs for topical antifungals (including topical combination antifungalcorticosteroid medications).Total prescription volumes were compared between higher-volume prescribers (top 10% of topical antifungal prescribers by volume) and lower-volume prescribers.During 2021, approximately 6.5 million topical antifungal prescriptions were filled (134 prescriptions per 1,000 beneficiaries), at a total cost of $231 million.Among 1,017,417 unique prescribers, 130,637 (12.8%) prescribed topical antifungals.Primary care physicians wrote the highest percentage of prescriptions (40.0%), followed by nurse practitioners or physician assistants (21.4%), dermatologists (17.6%), and podiatrists (14.1%).Higher-volume prescribers wrote 44.2% (2.9 million) of all prescriptions.This study found that enough topical antifungal prescriptions were written for approximately one of every eight Medicare Part D beneficiaries in 2021, and 10% of antifungal prescribers prescribed nearly one half of these medications.In the setting of emerging antimicrobial resistance, these findings highlight the importance of expanding efforts to understand current prescribing practices while encouraging judicious prescribing by clinicians and providing patient education about proper use.
Travel-acquired paediatric tuberculosis in the Greater Toronto Area, Canada, 2002–2018
Authors: Mohsin Ali, Melanie El Hafid, Daniel S. Farrar, Haifa Kourdi, Elizabeth Rea, Valerie Waters, Ray Lam, Shaun K. Morris, Ian Kitai
Journal: European Respiratory Journal (2024)

<h3>Tweetable abstract</h3> <b>Up to one in five children with tuberculosis (TB) managed by the Toronto regional paediatric TB programme, including one in three without a Canadian source-case, probably acquired TB by visiting friends and relatives in TB-endemic countries</b> https://bit.ly/48PD4ul
High-resolution quantification of stress perfusion defects by cardiac magnetic resonance
Authors: Cian M Scannell, Richard Crawley, Ebraham Alskaf, Marcel Breeuwer, Sven Plein, Amedeo Chiribiri
Journal:  (2024)

Quantitative stress perfusion cardiac magnetic resonance (CMR) is becoming more widely available, but it is still unclear how to integrate this information into clinical decision-making. Typically, pixel-wise perfusion maps are generated, but diagnostic and prognostic studies have summarized perfusion as just one value per patient or in 16 myocardial segments. In this study, the reporting of quantitative perfusion maps is extended from the standard 16 segments to a high-resolution bullseye. Cut-off thresholds are established for the high-resolution bullseye, and the identified perfusion defects are compared with visual assessment.
Loss in life expectancy in patients with stage II-III cutaneous melanoma in Sweden: A population-based cohort study
Authors: Sofi Vikström, Elisavet Syriopoulou, Therese M.-L. Andersson, Hanna Eriksson
Journal: Journal of the American Academy of Dermatology (2024)

Survival in cutaneous melanoma (CM) is heterogeneous. Loss in life expectancy (LLE) measures impact of CM on remaining lifespan compared to general population.
Single-cell transcriptomic analysis of human pleura reveals stromal heterogeneity and informs<i>in vitro</i>models of mesothelioma
Authors: Joanna Obacz, Jose Antonio Valer, Reshma Nibhani, Taylor S. Adams, Jonas C. Schupp, Niki Veale, Amanah Lewis-Wade, Jasper Flint, John Hogan, Giuseppe Aresu, Aman S. Coonar, Adam Peryt, Giulia Biffi, Naftali Kaminski, Hayley Francies, Doris M. Rassl, Mathew J. Garnett, Robert C. Rintoul, Stefan J. Marciniak
Journal: European Respiratory Journal (2024)

The pleural lining of the thorax regulates local immunity, inflammation and repair. A variety of conditions, both benign and malignant, including pleural mesothelioma, can affect this tissue. A lack of knowledge concerning the mesothelial and stromal cells comprising the pleura has hampered the development of targeted therapies. Here, we present the first comprehensive single-cell transcriptomic atlas of the human parietal pleura and demonstrate its utility in elucidating pleural biology. We confirm the presence of known universal fibroblasts and describe novel, potentially pleural-specific, fibroblast subtypes. We also present transcriptomic characterisation of multiple in vitro models of benign and malignant mesothelial cells, and characterise these through comparison with in vivo transcriptomic data. While bulk pleural transcriptomes have been reported previously, this is the first study to provide resolution at the single-cell level. We expect our pleural cell atlas will prove invaluable to those studying pleural biology and disease. It has already enabled us to shed light on the transdifferentiation of mesothelial cells, allowing us to develop a simple method for prolonging mesothelial cell differentiation in vitro .
Abstract IA024: Mechanistic insights into how RADX regulates RAD51 nucleoprotein filaments to maintain genome stability and control replication stress responses
Authors: Madison Adolph, Swati Balakrishnan, Walter Chazin, David Cortez
Journal: Cancer Research (2024)

Abstract RAD51 nucleoprotein filaments are central to maintaining genome stability, governing crucial processes like homology-directed double-strand break repair, replication fork reversal, and shielding replication forks from nucleases. The precise regulation of RAD51 filament formation and stability is critical for these functions, which suppress tumorigenesis and determine cellular responses to common cancer therapies. RADX is a pivotal regulator of RAD51 in the context of DNA replication, impacting replication fork reversal and fork stabilization. After identifying RADX as an RPA-related RAD51 regulator, we have worked to understand how it acts, thereby elucidating its role in genome stability and its influence on cancer cell responses to PARP inhibitors and chemotherapies. Genetically, RADX exhibits a dual role, capable of either inhibiting or promoting replication fork reversal based on the levels of replication stress. Biochemical studies show that RADX has inhibitory effects on RAD51 strand exchange and D-loop formation activities, achieved through direct binding to single-strand DNA and RAD51, along with the stimulation of RAD51 ATP hydrolysis. These activities collectively destabilize RAD51 nucleofilaments, opposing the stabilizing effects of BRCA2. Cells lacking RADX regulatory functions exhibit replication defects, DNA damage accumulation, reduced growth, and heightened sensitivity to DNA damage and replication stress. Structural analyses, including cryo-electron microscopy and mass photometry, revealed how RADX binds ssDNA and show it exists in multiple oligomeric states with a preference for trimers when bound to single-stranded DNA. Negative stain electron microscopy imaging supports a model wherein RADX functions by capping and restricting the growing ends of RAD51 filaments. In summary, our findings provide a comprehensive understanding of the regulatory mechanisms governing RAD51 nucleofilament dynamics by RADX, emphasizing its crucial role in coordinating replication fork stability and genome integrity. This knowledge not only contributes to the fundamental understanding of cellular processes but also offers insights into potential therapeutic interventions targeting RAD51-controlled pathways. Citation Format: Madison Adolph, Swati Balakrishnan, Walter Chazin, David Cortez. Mechanistic insights into how RADX regulates RAD51 nucleoprotein filaments to maintain genome stability and control replication stress responses [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA024.
The BMJ Appeal 2023-24: ActionAid offers immediate and long term help
Authors: Mun-Keat Looi
Journal: BMJ (2024)

The devastation pictured was caused by Cyclone Freddy in Blantyre, Malawi, last March.The flooding, which also affected Mozambique and Zimbabwe, displaced more than 500 000 people.ActionAid, the beneficiary of this year's BMJ appeal, assisted immediately.The charity continues to work with people across the three countries, and it has called on governments to make loss and damage funding available to those communities dealing with, and paying for, the consequences of climate change.This year's BMJ appeal has already raised more than £10 000 and remains open until the end of January, helping women in communities from Mozambique to Gaza.Please give generously.The BMJ's 2023-24 annual appeal supports ActionAid's work with women and girls in over 45 countries to help achieve social justice and gender equality and to eradicate poverty.Shifting the power and working directly with women and girls, including in humanitarian emergencies, means that women's specific health needs are less likely to be overlooked, putting them in a better position to build the future they deserve.Please donate to help women and girls live full, safe, and healthy lives, regardless of where they're born.
Social Risk and Dialysis Facility Performance in the First Year of the ESRD Treatment Choices Model
Authors: Kalli G. Koukounas, Rebecca Thorsness, Rachel E. Patzer, Adam S. Wilk, Kelsey M. Drewry, Rajnish Mehrotra, Maricruz Rivera-Hernandez, David J. Meyers, Daeho Kim, Amal N. Trivedi
Journal: JAMA (2024)

The End-Stage Renal Disease Treatment Choices (ETC) model randomly selected 30% of US dialysis facilities to receive financial incentives based on their use of home dialysis, kidney transplant waitlisting, or transplant receipt. Facilities that disproportionately serve populations with high social risk have a lower use of home dialysis and kidney transplant raising concerns that these sites may fare poorly in the payment model. To examine first-year ETC model performance scores and financial penalties across dialysis facilities, stratified by their incident patients' social risk. A cross-sectional study of 2191 US dialysis facilities that participated in the ETC model from January 1 through December 31, 2021. Composition of incident patient population, characterized by the proportion of patients who were non-Hispanic Black, Hispanic, living in a highly disadvantaged neighborhood, uninsured, or covered by Medicaid at dialysis initiation. A facility-level composite social risk score assessed whether each facility was in the highest quintile of having 0, 1, or at least 2 of these characteristics. Use of home dialysis, waitlisting, or transplant; model performance score; and financial penalization. Using data from 125 984 incident patients (median age, 65 years [IQR, 54-74]; 41.8% female; 28.6% Black; 11.7% Hispanic), 1071 dialysis facilities (48.9%) had no social risk features, and 491 (22.4%) had 2 or more. In the first year of the ETC model, compared with those with no social risk features, dialysis facilities with 2 or more had lower mean performance scores (3.4 vs 3.6, P = .002) and lower use of home dialysis (14.1% vs 16.0%, P < .001). These facilities had higher receipt of financial penalties (18.5% vs 11.5%, P < .001), more frequently had the highest payment cut of 5% (2.4% vs 0.7%; P = .003), and were less likely to achieve the highest bonus of 4% (0% vs 2.7%; P < .001). Compared with all other facilities, those in the highest quintile of treating uninsured patients or those covered by Medicaid experienced more financial penalties (17.4% vs 12.9%, P = .01) as did those in the highest quintile in the proportion of patients who were Black (18.5% vs 12.6%, P = .001). In the first year of the Centers for Medicare & Medicaid Services' ETC model, dialysis facilities serving higher proportions of patients with social risk features had lower performance scores and experienced markedly higher receipt of financial penalties.
An Intelligent and Soluble Microneedle Composed of Bi/BiVO<sub>4</sub> Schottky Heterojunction for Tumor Ct Imaging and Starvation/Gas Therapy‐Promoted Synergistic Cancer Treatment
Authors: Tingting Hu, Lu Jia, Heng Li, Chunyu Yang, Yuening Yan, Huiming Lin, Feng Zhang, Fengyu Qu, Wei Guo
Journal: Advanced Healthcare Materials (2024)

Phototherapy and sonodynamic therapy (SDT) are widely used for the synergistic treatment of tumors and have received considerable attention. However, an inappropriate tumor microenvironment, including pH, H
Abstract B033: Direct and sensitive in-situ detection of DNA breaks by STRIDE and its potential as a new biomarker
Authors: Kamil Solarczyk, Brian Patterson
Journal: Cancer Research (2024)

Abstract DNA damage is usually detected using indirect methods which require active signaling and triggered DNA repair mechanisms. These methods, although relatively sensitive, are prone to false (positive or negative) results. Methods for direct DNA damage detection, on the other hand, suffer from low sensitivity or require DNA isolation, what can result in misleading artefactual readouts of the analysis. Here we present a method called STRIDE (SensiTive Recognition of Individual DNA Ends), which allows for specific, very sensitive in-situ detection of DNA breaks. This fluorescence-based method, in its two variants (dSTRIDE and sSTRIDE), allows selective labelling of double-or single-strand breaks, respectively. STRIDE enables highly sensitive and specific detection and quantification of single and double-strand DNA breaks in cultured cells and FFPE human tissues, both PBMCs as well as solid tumors. STRIDE is superior to classic methods used to measure DNA damage, as it combines a direct detection that is independent of DNA repair mechanisms with an unprecedented sensitivity. With its versatility it can be used in any type of biological material, including liquid biopsies as well as different types of tumors. STRIDE has the potential to become a very useful biomarker reporting about the efficiency of therapies based on DNA damage induction, such as DNA repair inhibitors or radiotherapy. Citation Format: Kamil Solarczyk, Brian Patterson. Direct and sensitive in-situ detection of DNA breaks by STRIDE and its potential as a new biomarker [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B033.