tbuckley/cabot-search huggingface dataset:
A Cluster of Evolutionarily Recent KRAB Zinc Finger Proteins Protects Cancer Cells from Replicative Stress–Induced Inflammation
Authors: Filipe Martins, Olga Rosspopoff, Joana Carlevaro-Fita, Romain Forey, Sandra Offner, Evarist Planet, Cyril Pulver, HuiSong Pak, Florian Huber, Justine Michaux, Michal Bassani-Sternberg, Priscilla Turelli, Didier Trono
Journal: Cancer Research (2024)

Abstract Heterochromatin loss and genetic instability enhance cancer progression by favoring clonal diversity, yet uncontrolled replicative stress leads to mitotic catastrophe and inflammatory responses that promote immune rejection. KRAB domain-containing zinc finger proteins (KZFP) contribute to heterochromatin maintenance at transposable elements (TE). Here, we identified an association of upregulation of a cluster of primate-specific KZFPs with poor prognosis, increased copy-number alterations, and changes in the tumor microenvironment in diffuse large B-cell lymphoma (DLBCL). Depleting two of these KZFPs targeting evolutionarily recent TEs, ZNF587 and ZNF417, impaired the proliferation of cells derived from DLBCL and several other tumor types. ZNF587 and ZNF417 depletion led to heterochromatin redistribution, replicative stress, and cGAS–STING-mediated induction of an interferon/inflammatory response, which enhanced susceptibility to macrophage-mediated phagocytosis and increased surface expression of HLA-I, together with presentation of a neoimmunopeptidome. Thus, cancer cells can exploit KZFPs to dampen TE-originating surveillance mechanisms, which likely facilitates clonal expansion, diversification, and immune evasion. Significance: Upregulation of a cluster of primate-specific KRAB zinc finger proteins in cancer cells prevents replicative stress and inflammation by regulating heterochromatin maintenance, which could facilitate the development of improved biomarkers and treatments.
Author Correction: GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway
Authors: Ann Y. Park, Michael Leney-Greene, Matthew Lynberg, Justin Q. Gabrielski, Xijin Xu, Benjamin Schwarz, Lixin Zheng, Arasu Balasubramaniyam, Hyoungjun Ham, Brittany Chao, Yu Zhang, Helen F. Matthews, Jing Cui, Yikun Yao, Satoshi Kubo, Jean Michel Chanchu, Aaron R. Morawski, Sarah A. Cook, Ping Jiang, Juan C. Ravell, Yan H. Cheng, Alex George, Aiman Faruqi, Alison M. Pagalilauan, Jenna R. E. Bergerson, Sundar Ganesan, Samuel D. Chauvin, Jahnavi Aluri, Joy Edwards-Hicks, Eric Bohrnsen, Caroline Tippett, Habib Omar, Leilei Xu, Geoffrey W. Butcher, John Pascall, Elif Karakoc-Aydiner, Ayca Kiykim, Holden Maecker, İlhan Tezcan, Saliha Esenboga, Raul Jimenez Heredia, Deniz Akata, Saban Tekin, Altan Kara, Zarife Kuloglu, Emel Unal, Tanıl Kendirli, Figen Dogu, Esra Karabiber, T. Prescott Atkinson, Claude Cochet, Odile Filhol, Catherine M. Bosio, Mark M. Davis, Richard P. Lifton, Erika L. Pearce, Oliver Daumke, Caner Aytekin, Gülseren Evirgen Şahin, Aysel Ünlüsoy Aksu, Gulbu Uzel, V. Koneti Rao, Sinan Sari, Buket Dalgıç, Kaan Boztug, Deniz Cagdas, Sule Haskologlu, Aydan Ikinciogullari, David Schwefel, Silvia Vilarinho, Safa Baris, Ahmet Ozen, Helen C. Su, Michael J. Lenardo
Journal: Nature Immunology (2024)
SSBlazer: a genome-wide nucleotide-resolution model for predicting single-strand break sites
Authors: Sheng Xu, Junkang Wei, Siqi Sun, Jizhou Zhang, Ting-Fung Chan, Yu Li
Journal: Genome biology (2024)

Abstract Single-strand breaks are the major DNA damage in the genome and serve a crucial role in various biological processes. To reveal the significance of single-strand breaks, multiple sequencing-based single-strand break detection methods have been developed, which are costly and unfeasible for large-scale analysis. Hence, we propose SSBlazer, an explainable and scalable deep learning framework for single-strand break site prediction at the nucleotide level. SSBlazer is a lightweight model with robust generalization capabilities across various species and is capable of numerous unexplored SSB-related applications.
Prurigo nodularis: new insights into pathogenesis and novel therapeutics
Authors: Viviane Liao, Hannah L Cornman, Emily Ma, Shawn G Kwatra
Journal: British Journal of Dermatology (2024)

Lay Summary Prurigo nodularis (PN) is a chronic skin condition featuring extremely itchy nodules on the skin of the legs, arms and trunk of the body. PN affects approximately 72 per 100 000 people and the severe itch associated with the condition can negatively impact a person’s sleep, work and social life. However, the cause of PN remains unclear. Current understanding of PN is based on imbalances in the immune system leading to widespread inflammation as well as dysregulation of the nerves in the skin. Immune molecules released from T cells [such as interleukin (IL)-4, -13, -31, -17, -22 and -31] increase systemic inflammation and are elevated in people with PN. Activated inflammatory cells (such as mast cells or eosinophils) may also release factors that promote inflammation, itch and neural changes within the skin. Neural dysregulation in PN features a lower density of itch-sensing nerve fibres in the epidermis (upper layer of the skin) and a higher density of itch-sensing nerve fibres in the dermis (lower layer of the skin). Because the pathogenesis of PN is not fully understood, the therapies available for PN have had limited success in reducing itch and nodules. The only drug currently approved for PN in the USA and Europe is dupilumab, an IL-4Rα inhibitor that blocks signalling through IL-4 and IL-13, which is undergoing post-marketing surveillance. Other new drugs are being assessed in various phases of clinical trials, including nemolizumab, vixarelimab, barzolvolimab, ruxolitinib, abrocitinib, povorcitinib and nalbuphine.
Reply
Authors: Shreya A. Shah, Linus Amarikwa, Connie M. Sears, Kevin D. Clauss, Raneem D. Rajjoub, Julia Y. Kang, Madhura A. Tamhankar, César A. Briceño, Andrew R. Harrison, Kimberly P. Cockerham, Sara T. Wester, Raymond S. Douglas, Chrysoula Dosiou, Andrea L. Kossler
Journal: Ophthalmology (2024)
Novel genetic markers for chronic kidney disease in a geographically isolated population of Indigenous Australians: Individual and multiple phenotype genome-wide association study
Authors: Vignesh Arunachalam, Rodney Lea, Wendy Hoy, Simon Lee, Susan Mott, Judith Savige, John D. Mathews, Brendan J. McMorran, Shivashankar H. Nagaraj
Journal: Genome Medicine (2024)

Abstract Background Chronic kidney disease (CKD) is highly prevalent among Indigenous Australians, especially those in remote regions. The Tiwi population has been isolated from mainland Australia for millennia and exhibits unique genetic characteristics that distinguish them from other Indigenous and non-Indigenous populations. Notably, the rate of end-stage renal disease is up to 20 times greater in this population compared to non-Indigenous populations. Despite the identification of numerous genetic loci associated with kidney disease through GWAS, the Indigenous population such as Tiwi remains severely underrepresented and the increased prevalence of CKD in this population may be due to unique disease-causing alleles/genes. Methods We used albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) to estimate the prevalence of kidney disease in the Tiwi population ( N = 492) in comparison to the UK Biobank (UKBB) ( N = 134,724) database. We then performed an exploratory factor analysis to identify correlations among 10 CKD-related phenotypes and identify new multi-phenotype factors. We subsequently conducted a genome-wide association study (GWAS) on all single and multiple phenotype factors using mixed linear regression models, adjusted for age, sex, population stratification, and genetic relatedness between individuals. Results Based on ACR, 20.3% of the population was at severely increased risk of CKD progression and showed elevated levels of ACR compared to the UKBB population independent of HbA1c. A GWAS of ACR revealed novel association loci in the genes MEG3 (chr14:100812018:T:A), RAB36 (rs11704318), and TIAM2 (rs9689640). Additionally, multiple phenotypes GWAS of ACR, eGFR, urine albumin, and serum creatinine identified a novel variant that mapped to the gene MEIS2 (chr15:37218869:A:G). Most of the identified variants were found to be either absent or rare in the UKBB population. Conclusions Our study highlights the Tiwi population’s predisposition towards elevated ACR, and the collection of novel genetic variants associated with kidney function. These associations may prove valuable in the early diagnosis and treatment of renal disease in this underrepresented population. Additionally, further research is needed to comprehensively validate the functions of the identified variants/genes.
An atlas of cell-type-specific interactome networks across 44 human tumor types
Authors: Zekun Li, Gerui Liu, Xiaoxiao Yang, Meng Shu, Wen Jin, Yang Tong, Xiaochuan Liu, Yuting Wang, Jiapei Yuan, Yang Yang
Journal: Genome Medicine (2024)

Biological processes are controlled by groups of genes acting in concert. Investigating gene-gene interactions within different cell types can help researchers understand the regulatory mechanisms behind human complex diseases, such as tumors. We collected extensive single-cell RNA-seq data from tumors, involving 563 patients with 44 different tumor types. Through our analysis, we identified various cell types in tumors and created an atlas of different immune cell subsets across different tumor types. Using the SCINET method, we reconstructed interactome networks specific to different cell types. Diverse functional data was then integrated to gain biological insights into the networks, including somatic mutation patterns and gene functional annotation. Additionally, genes with prognostic relevance within the networks were also identified. We also examined cell-cell communications to investigate how gene interactions modulate cell-cell interactions. We developed a data portal called CellNetdb for researchers to study cell-type-specific interactome networks. Our findings indicate that these networks can be used to identify genes with topological specificity in different cell types. We also found that prognostic genes can deconvolved into cell types through analyzing network connectivity. Additionally, we identified commonalities and differences in cell-type-specific networks across different tumor types. Our results suggest that these networks can be used to prioritize risk genes. This study presented CellNetdb, a comprehensive repository featuring an atlas of cell-type-specific interactome networks across 44 human tumor types. The findings underscore the utility of these networks in delineating the intricacies of tumor microenvironments and advancing the understanding of molecular mechanisms underpinning human tumors.
Citizen data sovereignty is key to wearables and wellness data reuse for the common good
Authors: Stephen Gilbert, Katie Baca-Motes, Giorgio Quer, Marc Wiedermann, Dirk Brockmann
Journal: npj Digital Medicine (2024)

Smartphones, smartwatches, linked wearables, and associated wellness apps have had rapid uptake. These tools become ever ‘smarter’ in sensing intimate aspects of our surroundings and physiology over time, including activity, metabolites, electrical signals, blood pressure and oxygenation. Proposed EU law stipulates the ‘involuntary donation’ of depersonalized health and wellness data. There has been pushback against the ever-increasing gathering and sharing of wellness data in this context, increasing with every app purchased or updated. Is the potential of this data now lost to research? Consent-led COVID-19 data donation projects signpost a participative, standardized, and scalable approach to data sharing.
The American Heart Association at 100: A Century of Scientific Progress and the Future of Cardiovascular Science: A Presidential Advisory From the American Heart Association
Authors: Mitchell S.V. Elkind, Donna K. Arnett, Ivor J. Benjamin, Robert H. Eckel, Augustus O. Grant, Steven R. Houser, Alice K. Jacobs, Daniel W. Jones, Rose Marie Robertson, Ralph L. Sacco, Sidney C. Smith, Myron L. Weisfeldt, Joseph C. Wu, Mariell Jessup
Journal: Circulation (2024)

In 1924, the founders of the American Heart Association (AHA) envisioned an international society focused on the heart and aimed at facilitating research, disseminating information, increasing public awareness, and developing public health policy related to heart disease. This presidential advisory provides a comprehensive review of the past century of cardiovascular and stroke science, with a focus on the AHA's contributions, as well as informed speculation about the future of cardiovascular science into the next century of the organization's history. The AHA is a leader in fundamental, translational, clinical, and population science, and it promotes the concept of the "learning health system," in which a continuous cycle of evidence-based practice leads to practice-based evidence, permitting an iterative refinement in clinical evidence and care. This advisory presents the AHA's journey over the past century from instituting professional membership to establishing extraordinary research funding programs; translating evidence to practice through clinical practice guidelines; affecting systems of care through quality programs, certification, and implementation; leading important advocacy efforts at the federal, state and local levels; and building global coalitions around cardiovascular and stroke science and public health. Recognizing an exciting potential future for science and medicine, the advisory offers a vision for even greater impact for the AHA's second century in its continued mission to be a relentless force for longer, healthier lives.
The Macrophage Landscape Across the Lifespan of a Human Cardiac Allograft
Authors: Xiao Li, Diwakar Turaga, Rich G. Li, Chang-Ru Tsai, Julianna N. Quinn, Yi Zhao, Ruby Wilson, Katherine Carlson, Jun Wang, Joseph A. Spinner, Edward J. Hickey, Iki Adachi, James F. Martin
Journal: Circulation (2024)

BACKGROUND: Much of our knowledge of organ rejection after transplantation is derived from rodent models. METHODS: We used single-nucleus RNA sequencing to investigate the inflammatory myocardial microenvironment in human pediatric cardiac allografts at different stages after transplantation. We distinguished donor- from recipient-derived cells using naturally occurring genetic variants embedded in single-nucleus RNA sequencing data. RESULTS: Donor-derived tissue resident macrophages, which accompany the allograft into the recipient, are lost over time after transplantation. In contrast, monocyte-derived macrophages from the recipient populate the heart within days after transplantation and form 2 macrophage populations: recipient MP1 and recipient MP2. Recipient MP2s have cell signatures similar to donor-derived resident macrophages; however, they lack signatures of pro-reparative phagocytic activity typical of donor-derived resident macrophages and instead express profibrotic genes. In contrast, recipient MP1s express genes consistent with hallmarks of cellular rejection. Our data suggest that recipient MP1s activate a subset of natural killer cells, turning them into a cytotoxic cell population through feed-forward signaling between recipient MP1s and natural killer cells. CONCLUSIONS: Our findings reveal an imbalance of donor-derived and recipient-derived macrophages in the pediatric cardiac allograft that contributes to allograft failure.
Coronary Angiography, Intravascular Ultrasound, and Optical Coherence Tomography for Guiding of Percutaneous Coronary Intervention: A Systematic Review and Network Meta-Analysis
Authors: Daniele Giacoppo, Claudio Laudani, Giovanni Occhipinti, Marco Spagnolo, Antonio Greco, Carla Rochira, Federica Agnello, Davide Landolina, Maria Sara Mauro, Simone Finocchiaro, Placido Maria Mazzone, Nicola Ammirabile, Antonino Imbesi, Carmelo Raffo, Sergio Buccheri, Davide Capodanno
Journal: Circulation (2024)

Results from multiple randomized clinical trials comparing outcomes after intravascular ultrasound (IVUS)- and optical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI) with invasive coronary angiography (ICA)-guided PCI as well as a pivotal trial comparing the 2 intravascular imaging (IVI) techniques have provided mixed results.
Machine Learning for Myocardial Infarction Compared With Guideline-Recommended Diagnostic Pathways
Authors: Jasper Boeddinghaus, Dimitrios Doudesis, Pedro Lopez-Ayala, Kuan Ken Lee, Luca Koechlin, Karin Wildi, Thomas Nestelberger, Raphael Borer, Òscar Miró, F. Javier Martin-Sanchez, Ivo Strebel, Maria Rubini Giménez, Dagmar I. Keller, Michael Christ, Anda Bularga, Ziwen Li, Amy V. Ferry, Chris Tuck, Atul Anand, Alasdair Gray, Nicholas L. Mills, Christian Mueller, A. Mark Richards, Chris Pemberton, Richard W. Troughton, Sally J. Aldous, Anthony F.T. Brown, Emily Dalton, Chris Hammett, Tracey Hawkins, Shanen O’Kane, Kate Parke, Kimberley Ryan, Jessica Schluter, Stephanie Barker, Jennifer Blades, Andrew R. Chapman, Takeshi Fujisawa, Dorien M. Kimenai, Michael McDermott, David E. Newby, Stacey D. Schulberg, Anoop S.V. Shah, Andrew Sorbie, Grace Soutar, Fiona E. Strachan, Caelan Taggart, Daniel Perez Vicencio, Yiqing Wang, Ryan Wereski, Kelly Williams, Christopher J. Weir, Colin Berry, Alan Reid, Donogh Maguire, Paul O. Collinson, Yader Sandoval, Stephen W. Smith, Desiree Wussler, Tamar Muench-Gerber, Jonas Glaeser, Carlos Spagnuolo, Gabrielle Huré, Juliane Gehrke, Christian Puelacher, Danielle M. Gualandro, Samyut Shrestha, Damian Kawecki, Beata Morawiec, Piotr Muzyk, Franz Buergler, Andreas Buser, Katharina Rentsch, Raphael Twerenbold, Beatriz López, Gemma Martinez-Nadal, Esther Rodriguez Adrada, Jiri Parenica, Arnold von Eckardstein
Journal: Circulation (2024)

Collaboration for the Diagnosis and Evaluation of Acute Coronary Syndrome (CoDE-ACS) is a validated clinical decision support tool that uses machine learning with or without serial cardiac troponin measurements at a flexible time point to calculate the probability of myocardial infarction (MI). How CoDE-ACS performs at different time points for serial measurement and compares with guideline-recommended diagnostic pathways that rely on fixed thresholds and time points is uncertain.
Clinical Characteristics and Outcomes of Polyarteritis Nodosa: An International Study
Authors: Omer Karadag, Ertugrul Cagri Bolek, Gizem Ayan, Aladdin J. Mohammad, Peter C. Grayson, Christian Pagnoux, Eduardo Martín‐Nares, Sara Monti, Yoshiyuki Abe, Federico Alberici, Fatma Alibaz‐Oner, David Cuthbertson, Lorenzo Dagna, Haner Direskeneli, Nader A. Khalidi, Curry Koening, Carol A. Langford, Carol A. McAlear, Paul A. Monach, Luca Moroni, Roberto Padoan, Phillip Seo, Kenneth J. Warrington, Alojzija Hocevar, Andrea Hinojosa‐Azaola, Shunsuke Furuta, Giacomo Emmi, Seza Ozen, David Jayne, Peter A. Merkel
Journal: Arthritis & Rheumatology (2024)

Objective We describe the demographics, clinical features, disease course, and survival of polyarteritis nodosa (PAN) through an international collaboration (GLOBAL‐PAN). Methods Patients with PAN were recruited between 1990 and 2020 from observational cohorts of nine countries across Europe, Japan, and North America. Eligibility was retrospectively defined using the European Medicines Agency classification algorithm. Patients with PAN related to hepatitis B virus (n = 12) and two monogenic diseases mimicking PAN, deficiency of adenosine deaminase 2 enzyme (n = 16) or familial Mediterranean fever (n = 11), were excluded. Data regarding organ involvement, relapse, disease‐related damage, and survival were analyzed. Results Three hundred fifty‐eight patients (female:male ratio 174:184), including those with systemic PAN (sPAN, n = 282) and cutaneous PAN (n = 76), were included. Twenty‐five were pediatric onset. Mean ± SD age at diagnosis was 44.3 ± 18.1 years. Constitutional symptoms (71.5%), cutaneous involvement (70.5%), musculoskeletal findings (69.1%), and neurologic features (48.0%) were common manifestations. Among patients with sPAN, gastrointestinal involvement and proteinuria over 400 mg/day were reported in 52.2% and 11.2%, respectively. During a median (interquartile range) 59.6 (99.5) months of follow‐up, relapse occurred in 48.5% of patients. One, 5‐ and 10‐year survival rates for sPAN were 97.1%, 94.0%, and 89.0%, respectively. Predictors of death for sPAN included age ≥65 years at diagnosis, serum creatinine at diagnosis &gt;140 μmol/L, gastrointestinal manifestations, and central nervous system (CNS) involvement. Conclusion The spectrum of PAN remains a complex, multifaceted disease. Relapse is common. Age ≥65 years and serum creatinine &gt;140 μmol/L at diagnosis, as well as gastrointestinal and CNS involvement, are independent predictors of death in sPAN. image
Efficacy, safety, and survival findings after <scp>long‐term</scp> follow‐up of <scp>ZGJAK002</scp>: A phase 2 study comparing jaktinib at 100 mg twice daily (<scp>BID</scp>) and 200 mg once daily (<scp>QD</scp>) in patients with myelofibrosis
Authors: Yi Zhang, Hu Zhou, Zhongxing Jiang, Dengshu Wu, Junling Zhuang, Wei Li, Qian Jiang, Xiuli Wang, Jinwen Huang, Huanling Zhu, Linhua Yang, Xin Du, Fei Li, Ruixiang Xia, Feng Zhang, Jianda Hu, Yan Li, Yu Hu, Jing Liu, Chenghao Jin, Kai Sun, Zeping Zhou, Liqing Wu, Hewen Yin, Shanshan Suo, Wenjuan Yu, Jie Jin
Journal: American Journal of Hematology (2024)

Jaktinib, a novel JAK and ACVR1 inhibitor, has exhibited promising results in treating patients with myelofibrosis (MF). ZGJAK002 is a Phase 2 trial aimed to assess the efficacy and safety of jaktinib 100 mg BID (N = 66) and 200 mg QD (N = 52) in JAK inhibitor-naive patients with intermediate- or high-risk MF. We herein present the long-term data with a median follow-up of 30.7 months. At data cutoff, 30.3% of patients in 100 mg BID and 28.8% in 200 mg QD were still continuing their treatment. The 100 mg BID group displayed a numerically higher best spleen response compared with the 200 mg QD group (69.7% vs. 46.2%), with 50.4% from the BID and 51.2% from the QD group maintaining spleen responses over 120 weeks. The 36-month survival rates were 78.2% in BID and 73.6% in QD group. The tolerability of jaktinib remained well, and common grade ≥3 adverse drug reactions included anemia (15.2% vs. 21.2%), thrombocytopenia (15.2% vs. 11.5%), and infectious pneumonia (10.6% vs. 1.9%) in BID and QD groups, respectively. By comparing the two groups, the incidence of adverse events (AEs) were similar, except for drug-related serious AEs (24.2% vs. 9.6%) and AEs leading to treatment discontinuation (15.2% vs. 7.7%), which were higher in BID group. The percentages of AEs resulting in death were comparable, with 6.1% in BID and 5.8% in QD group. These analyses further support the long-term durable efficacy and acceptable safety of jaktinib at 100 mg BID and 200 mg QD doses for treating MF.