Biology subjects

Chambwe, N.

Publications and source records attributed to Chambwe, N..

7 recordsLinked to original sources

bioRxiv2026

Comprehensive Molecular Characterization of High-Grade Endometrial Cancer in an Ancestrally-Diverse Cohort

Endometrial cancer (EC) exhibits one of the most striking racial disparities in oncology with black women disproportionately affected by aggressive high-grade subtypes that have poorer outcomes. While social and environmental factors undoubtedly contribute, the molecular underpinnings of these disparities remain critically understudied. To bridge this knowledge gap, we performed matched tumor-normal whole-genome sequencing and tumor transcriptome sequencing on 71 predominantly high-grade EC patient samples from an ancestrally diverse cohort of women recruited at a large hospital system in the New York metropolitan area. Our analysis characterized the germline and somatic mutation landscape, identifying ancestry-associated molecular differences. Notably, focal amplification of the EVI1 transcription factor (encoded at the MECOM locus) was significantly more frequent in African ancestry patients and associated with poorer clinical outcomes in an external validation cohort. Additionally transcriptome analysis revealed decreased CD8+ T cell infiltration with increasing African ancestry, suggesting tumor immune microenvironment differences with potential therapeutic implications. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/721962v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@12125b9org.highwire.dtl.DTLVardef@133c787org.highwire.dtl.DTLVardef@707af0org.highwire.dtl.DTLVardef@97615c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThis study represents the most ancestrally diverse whole-genome sequencing characterization of high-grade endometrial cancer, with 62% of patients of African ancestry. C_LIO_LIMECOM focal amplification preferentially targets the oncogenic short isoform (EVI1) and is more frequent in patients of African ancestry. C_LIO_LIAfrican ancestry is associated with reduced CD8+ T cell infiltration and differential activation of immune and metabolic pathways in copy-number high endometrial tumors. C_LI

cancer biology↗

bioRxiv2025

Uncovering Functional Sequence Gaps in Human Reference Genomes using African Pan Genome Contig Sequences

Human reference genomes underpin biomedical discovery but remain incomplete and biased toward European populations, constraining interpretation of genetic variation in underrepresented populations. Here we characterize African Pan Genome (APG) contigs totaling 296.5 Mb to define the sequence and functional landscape of genomic regions absent from current references. Most contigs align to the telomere-to-telomere (T2T-CHM13) genome and across 47 haplotype-resolved Human Pangenome Reference Consortium (HPRC) assemblies, with T2T-CHM13 placements enriched in centromeric and satellite repeats and overlapping 373 genes, including disease-associated loci. Mapping across HPRC assemblies revealed ancestry-associated contig enrichment, particularly in African genomes. Notably, 742 contigs remained unmapped under both stringent and relaxed criteria. These sequences are largely nonrepetitive and exhibit strong functional potential, including predicted protein-coding genes, CpG islands and transcriptional activity. Together, these results demonstrate that functionally relevant, ancestry-enriched genomic sequences remain absent from current references, with important implications for disease variant interpretation and precision medicine.

genomics↗

bioRxiv2025

Cellular heterogeneity and therapeutic response profiling of human IDH+ glioma stem cell cultures

Summary/AbstractGlioblastoma stem cell (GSC) cultures are initiated from glioblastoma (GBM) surgical resection tissue. They can capture and propagate key GBM primary tumor molecular and cellular features. We have deeply characterized four isocitrate dehydrogenase (IDH)-expressing (or IDH+) GSC cultures from unrelated adults to serve as cellular models for the majority of adult primary GBM. We demonstrate that GSC cultures can be continuously propagated in defined, serum-free media and 5% oxygen without requiring specialized growth substrates; have well-defined genomic and mtDNA variants and gene/protein expression profiles; and highly reproducible dose-survival curves when treated with the GBM standard-of-care therapies of ionizing radiation (IR) and temozolomide (TMZ). We also illustrate how expressed lentiviral barcodes, mtDNA variants and single cell gene expression profiling can be used to define and track cellular heterogeneity over 40 days after IR treatment. These well-characterized IDH+ GSC cultures can support many high throughput in vitro assay formats, including xenograft, organoid and other GBM disease modeling protocols. They should prove a useful resource to better understand GBM biology, and to identify new and more effective GBM therapies and treatment regimens. HighlightsO_LIGlioblastoma (GBM)-derived IDH-expressing Glioma Stem Cell (GSC) cultures can capture and propagate GBM genomic variants, gene and protein expression programs. C_LIO_LIMitochondrial DNA (mtDNA) variants identified by high accuracy Duplex DNA sequencing are abundant and sub-clonally organized in GSC cultures. C_LIO_LIGSC cultures have highly reproducible dose-survival curves for ionizing radiation and temozolomide, the GBM standard-of-care therapies. C_LIO_LIGSC culture cellular heterogeneity can be captured, characterized and tracked by using expressed lentiviral barcodes, mtDNA variants and scRNA sequencing. C_LI eTOC blurbIDH-expressing glioma stem cell cultures (GSCs) are experimentally tractable and versatile glioblastoma (GBM) cellular disease models. Deeply characterized GSC cultures can enable new work to understand GBM biology, and help identify new and more effective GBM therapies and treatment regimens. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/667532v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@82aceeorg.highwire.dtl.DTLVardef@1277c18org.highwire.dtl.DTLVardef@144188eorg.highwire.dtl.DTLVardef@1a84bb3_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Active learnings impact on student course performance in STEM varies by type and intensity

We updated a recent meta-analysis of active learnings impact on student achievement in undergraduate STEM courses by following the same protocol to evaluate studies published from 2010-2017. We screened 1659 papers, coded 1294, and found 210 that met five pre-established inclusion criteria and six pre-established criteria for methodological quality. After further dropping 76 studies with no exam scores data, 134 of these studies contained data on student performance on identical or equivalent exams. We found that on average, active learnings effect size on exam scores was 0.519 {+/-} 0.049, meaning that when students are in active learning classes, they perform roughly half a standard deviation higher on an identical exam. Funnel plots and sensitivity analyses indicated that these results were not due to sampling bias. Active learning had a positive impact on student outcomes regardless of class size, course level, or STEM discipline, though there was heterogeneity in the effects. All of these results are very similar when compared to earlier meta-analyses, however increased resolution in the studies analyzed here revealed two novel results. First, student performance was significantly better in courses that employed high-intensity active learning, defined as students being on task at least two-thirds of class time, versus lower-intensities. Additionally, there was significant heterogeneity in efficacy across different types of active learning employed. These results suggest that most, if not all types of active learning are effective, and that when innovating in their classes, instructors should continually work to increase active learning intensity. We urge caution in interpreting the results on active learning types, however, and propose a preliminary framework for making more-sophisticated and reliable analyses of variation in course design. Finally, the evidence presented here for active learnings impact on student outcomes creates a strong foundation for faculty professional development and administration.

scientific communication and education↗

bioRxiv2024

Genetic ancestry-specific meQTLs control immune function regulation in a breast cancer cohort of African and European patients

We explored the impact of genetic ancestry on DNA methylation (DNAm) in African and European ancestry breast cancer patients. Analyzing data from 578 subjects in The Cancer Genome Atlas (TCGA) cohort, we identified 757 differentially methylated sites associated with genetic ancestry (aDMS). Methylation quantitative trait loci (meQTL) mapping showed that the majority of aDMS are regulated by multiple SNPs differentially prevalent by ancestry. Notably, expression quantitative methylation (eQTM) mapping linked 95% of aDMS to local gene expression, indicating potential impact on gene regulation. Furthermore, 72% of ancestry eQTMs were regulated by meQTLs, underscoring the genetic regulation of DNAm variation affecting the transcriptome. Immune response regulation, particularly involving HLA genes, was the most enriched process among ancestry eQTMs. Additionally, 31% of differentially expressed genes between groups defined by genetic ancestry were under ancestry eQTM control. These findings highlight the gene regulatory potential of ancestry-associated DNAm and its importance in population-specific analyses.

cancer biology↗

bioRxiv2021

SL-Cloud: A Computational Resource to Support Synthetic Lethal Interaction Discovery

Synthetic lethal interactions (SLIs), genetic interactions in which the simultaneous inactivation of two genes leads to a lethal phenotype, are promising targets for therapeutic intervention in cancer, as exemplified by the recent success of PARP inhibitors in treating BRCA1/2-deficient tumors. We present SL-Cloud, an integrated resource and framework to facilitate the prediction of context-specific SLIs by using cloud-based technologies. This resource addresses two main challenges related to SLI inference: the need to wrangle and preprocess large multi-omic datasets and the multiple comparable prediction approaches available. We demonstrate the utility of this resource by using a set of DNA damage repair genes as the basis for predicting potential SLI partners, using multiple computational strategies. Context-specific synthetic lethality potential can also be compared using the framework. We demonstrate various use cases for our cloud-based computational resource and the utility of this approach for customizable and extensible computational inference of SLIs.

bioinformatics↗

bioRxiv2018

An RNAi screen in human cell lines reveals conserved DNA damage repair pathways that mitigate formaldehyde sensitivity

Formaldehyde is a ubiquitous DNA damaging agent, with human exposures occuring from both exogenous and endogenous sources. Formaldehyde can also form DNA-protein crosslinks and is representative of other such DNA damaging agents including ionizing radiation, metals, aldehydes, chemotherapeutics, and cigarette smoke. In order to identify genetic determinants of cell proliferation in response to continuous formaldehyde exposure, we quantified cell proliferation after siRNA-depletion of a comprehensive array of over 300 genes representing all of the major DNA damage response pathways. Three unrelated human cell lines (SW480, U-2 OS and GM00639) were used to identify common or cell line-specific mechanisms. Four cellular pathways were determined to mitigate formaldehyde toxicity in all three cell lines: homologous recombination, double-strand break repair, ionizing radiation response, and DNA replication. Differences between cell lines were further investigated by using exome sequencing and Cancer Cell Line Encyclopedia genomic data. Our results reveal major genetic determinants of formaldehyde toxicity in human cells and provide evidence for the conservation of these formaldehyde responses between human and budding yeast.

cell biology↗