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Multimodal integration of blood RNA and ctDNA reflects response to immunotherapy in metastatic urothelial cancer.
JCI Insight
January 2025
Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Background: Previously, we demonstrated that changes in circulating tumor DNA (ctDNA) are promising biomarkers for early response prediction (ERP) to immune checkpoint inhibitors (ICI) in metastatic urothelial cancer (mUC). In this study, we investigated the value of whole blood immunotranscriptomics for ERP-ICI and integrated both biomarkers into a multimodal model to boost accuracy.
Methods: Blood samples of 93 patients were collected at baseline and after 2-6 weeks of ICI for ctDNA (N=88) and immunotranscriptome (N=79) analyses.
HoxBlinc lncRNA reprograms CTCF-independent TADs to drive leukemic transcription and HSC dysregulation in NUP98-rearranged leukemia.
J Clin Invest
January 2025
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, United States of America.
Although nucleoporin 98 (NUP98) fusion oncogenes often drive aggressive pediatric leukemia by altering chromatin structure and expression of HOX genes, underlying mechanisms remain elusive. Here, we report that a Hoxb-associated lncRNA HoxBlinc was aberrantly activated in NUP98-PHF23 fusion-driven leukemias. HoxBlinc chromatin occupancies led to elevated MLL1 recruitment and aberrant homeotic topologically associated domains (TADs) that enhanced chromatin accessibilities and activated homeotic/hematopoietic oncogenes.
View Article and Find Full Text PDFSystematic bias in malaria parasite relatedness estimation.
G3 (Bethesda)
January 2025
Infectious Disease Epidemiology and Analytics G5 Unit, Institut Pasteur, Université Paris Cité, Paris 75015, France.
Genetic studies of Plasmodium parasites increasingly feature relatedness estimates. However, various aspects of malaria parasite relatedness estimation are not fully understood. For example, relatedness estimates based on whole-genome-sequence (WGS) data often exceed those based on sparser data types.
View Article and Find Full Text PDFInferring demographic and selective histories from population genomic data using a two-step approach in species with coding-sparse genomes: an application to human data.
G3 (Bethesda)
January 2025
School of Life Sciences, Center for Evolution & Medicine, Arizona State University, Tempe, AZ 85281, USA.
The demographic history of a population, and the distribution of fitness effects (DFE) of newly arising mutations in functional genomic regions, are fundamental factors dictating both genetic variation and evolutionary trajectories. Although both demographic and DFE inference has been performed extensively in humans, these approaches have generally either been limited to simple demographic models involving a single population, or, where a complex population history has been inferred, without accounting for the potentially confounding effects of selection at linked sites. Taking advantage of the coding-sparse nature of the genome, we propose a 2-step approach in which coalescent simulations are first used to infer a complex multi-population demographic model, utilizing large non-functional regions that are likely free from the effects of background selection.
View Article and Find Full Text PDFElevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma.
J Clin Invest
January 2025
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Metabolic reprogramming shapes tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. "Immune cold" PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of pro-tumor macrophages, and reduced cytotoxic T cell in the TME.
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