Biology subjects

Olshen, A.

Publications and source records attributed to Olshen, A..

7 recordsLinked to original sources

bioRxiv2025

Consensus Co-Expression Analysis Identifies A Common Set Of Co-Expressed Genes Associated With Diabetic Peripheral Neuropathy And Chemotherapy-Induced Peripheral Neuropathy

BackgroundDiabetic peripheral neuropathy (DPN) and chemotherapy-induced peripheral neuropathy (CIPN) are major clinical challenges with limited therapeutic options. While these conditions arise from different causes, they may share common molecular mechanisms that could be targeted for intervention. MethodsWe performed consensus weighted gene co-expression network analysis (WGCNA) on two publicly available datasets: GSE185011 (DPN vs. healthy controls in peripheral blood mononuclear cells) and GSE173610 (paclitaxel-treated vs. control iPSC-derived sensory neurons). After filtering all but the most variable genes, consensus analysis was used to identify conserved co-expression modules across both conditions. ResultsConsensus analysis identified a 193-gene module (ME3/brown) significantly associated with both DPN (correlation=0.817, p=0.0040) and CIPN (correlation=0.971, p=0.0060). Functional enrichment analysis of this module revealed pathways related to Glycolysis, FoxO signaling, Apoptosis, and Autophagy. ConclusionsOur analysis reveals a convergent molecular signature underlying both DPN and CIPN, centered on metabolic reprogramming, transcriptional stress, and programmed cell death. These findings provide a systems-level framework for developing therapies targeting shared pathological mechanisms.

systems biology↗

bioRxiv2025

Alternative Splicing And Global Transcriptome Changes Associated With LPS Stimulation In Human Peripheral Blood Mononuclear Cells

IntroductionLipopolysaccharide (LPS), a major component of gram-negative bacterial cell walls, elicits strong innate immune activation and is a widely used model for studying inflammatory responses. While the transcriptional response to LPS stimulation has been characterized, the role of alternative splicing (AS) in modulating this response remains largely unexplored. MethodsUsing deep RNA sequencing of Peripheral Blood Mononuclear Cells from three healthy female donors, we evaluated transcriptome-wide differential gene expression and alternative splicing in response to LPS stimulation. ResultsOur global differential gene expression and pathway impact analyses identified 490 differentially expressed genes and 46 significantly perturbed KEGG pathways, recapitulating known LPS-induced inflammatory responses and identifying two novel signaling pathways, (e.g., SNARE interactions in vesicular transport and the mRNA surveillance pathways). Differential alternative splicing analysis revealed critical impacts on immune-related pathways, including Toll-like receptor signaling, PI3K/AKT signaling, and pro-inflammatory macrophage polarization. Notably, we identified alternative splicing events in genes such as MyD88 and TLR4, which play key roles in terminating inflammatory signaling, as well as splicing of long non-coding RNAs (e.g., MALAT1, PVT1) with potential regulatory functions in immune responses. DiscussionThis study is the first transcriptome-wide characterization of alternative splicing in response to LPS stimulation in PBMCs. Our findings suggest that alternative splicing is a fundamental regulatory mechanism in the inflammatory response and provides potential targets for therapeutic intervention in immune-related conditions.

immunology↗

bioRxiv2025

RAS pathway activation drives clonal selection and monocytic differentiation in FLT3 and BCL2 inhibitor resistance

Despite efficacy of FLT3 and BCL2 inhibition in acute myeloid leukemia (AML), relapse limits survival. Mutation status and AML monocytic differentiation are implicated in resistance. On-treatment tumor evolution may select for genetically distinct clones or shifts in differentiation not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of patients treated on a clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Git) to characterize immunophenotypic, transcriptional, and genetic clonal evolution on therapy. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, it selected for RAS mutations, RAS pathway activation and RAS-associated monocytic differentiation. In an in vitro model of monocytic differentiation associated with heightened RAS pathway activation, we demonstrated that MEK inhibition re-sensitized to Ven/Gilt. These data indicate RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to monocytic differentiation and can be overcome by RAS pathway inhibition. COIC.C.S. has provided educational talks for Astellas Pharma, served on advisory boards for Genentech/Abbvie and received research funding from Abbvie. B.C., Y.S. and J.H. are employees of Abbvie. M.S. and H.H. are or were previously employees of Genentech. FundingThis work was supported in part by Abbvie. C.C.S. is a Leukemia & Lymphoma Society Scholar in Clinical Research and a Damon Runyon-Richard Lumsden Foundation Clinical Investigator supported (in part) by the Damon Runyon Cancer Research Foundation (CI-99-18). Statement of SignificanceMutational and non-mutational RAS signaling activation drives clonal selection, monocytic differentiation and treatment resistance to FLT3 and BCL2 inhibition in AML. MEK inhibition can resensitize resistant AML cells, suggesting therapeutic potential for combined FLT3, BCL2 and RAS pathway inhibition in AML.

cancer biology↗

bioRxiv2024

Molecular effects of indoor tanning

BackgroundTanning bed users have a significantly increased risk of melanoma, but it remains unclear how indoor tanning drives melanomagenesis. Tanning bed radiation is often thought of as a substitute for natural UV radiation despite differences in the maximum doses, UV content, body sites exposed, and patterns of melanoma that arise. MethodsTo better understand the epidemiologic trends and etiology of melanoma associated with tanning bed use, we described the patterns of melanoma in patients with quantifiable tanning bed usage and performed exome sequencing of 182 melanocytes from normal skin of a subset of these patients. ResultsTanning bed users were more likely than non-users to have melanoma on body sites with low cumulative levels of sun damage and were more likely to have multiple melanomas. The melanocytes in normal appearing skin from tanning bed users had higher mutation burdens, a higher proportion of melanocytes with pathogenic mutations, and distinct mutational signatures. These differences were most prominent over body sites that experience comparatively less exposure to natural sunlight. ConclusionsWe conclude that tanning bed radiation induces melanoma by increasing the mutation burden of melanocytes and by mutagenizing a broader field of melanocytes than are typically exposed to natural sunlight. The unique signatures of mutations in skin cells of tanning users may be attributable to the distinct spectra of radiation emitted from solariums.

genomics↗

bioRxiv2024

Single Nucleotide Polymorphism (SNP) and Antibody-based Cell Sorting (SNACS): A tool for demultiplexing single-cell DNA sequencing data

MotivationRecently, single-cell DNA sequencing (scDNA-seq) and multi-modal profiling with the addition of cell-surface antibodies (scDAb-seq) have provided key insights into cancer heterogeneity. Scaling these technologies across large patient cohorts, however, is cost and time prohibitive. Multiplexing, in which cells from unique patients are pooled into a single experiment, offers a possible solution. While multiplexing methods exist for scRNAseq, accurate demultiplexing in scDNAseq remains an unmet need. ResultsHere, we introduce SNACS: Single-Nucleotide Polymorphism (SNP) and Antibody-based Cell Sorting. SNACS relies on a combination of patient-level cell-surface identifiers and natural variation in genetic polymorphisms to demultiplex scDNAseq data. We demonstrated the performance of SNACS on a dataset consisting of multi-sample experiments from patients with leukemia where we knew truth from single-sample experiments from the same patients. Using SNACS, accuracy ranged from 0.948 - 0.991 vs 0.552 - 0.934 using demultiplexing methods from the single-cell literature. Availability ImplementationSNACS is available at https://github.com/olshena/SNACS. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/579345v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1e52aaorg.highwire.dtl.DTLVardef@c51d1dorg.highwire.dtl.DTLVardef@fa68a6org.highwire.dtl.DTLVardef@1ec6bd1_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2023

Multiomic Single Cell Sequencing Identifies Stemlike Nature of Mixed Phenotype Acute Leukemia and Provides Novel Risk Stratification

Mixed phenotype acute leukemia (MPAL) is a leukemia whose biologic drivers are poorly understood, therapeutic strategy remains unclear, and prognosis is poor. We performed multiomic single cell (SC) profiling of 14 newly diagnosed adult MPAL patients to characterize the immunophenotypic, genetic, and transcriptional landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. However, progressive acquisition of mutations is associated with increased expression of immunophenotypic markers of immaturity. Using SC transcriptional profiling, we find that MPAL blasts express a stem cell-like transcriptional profile distinct from other acute leukemias and indicative of high differentiation potential. Further, patients with the highest differentiation potential demonstrated inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in this cohort, is applicable to bulk RNA sequencing data and was predictive of survival in an independent patient cohort, suggesting utility for clinical risk stratification.

cancer biology↗

bioRxiv2023

Torch-eCpG: A fast and scalable eQTM mapper for thousands of molecular phenotypes with graphical processing units

BackgroundGene expression may be regulated by the DNA methylation of regulatory elements in cis, distal, and trans regions. One method to evaluate the relationship between DNA methylation and gene expression is the mapping of expression quantitative trait methylation (eQTM) loci (also called expression associated CpG loci, eCpG). However, no open-source tools are available to provide eQTM mapping. In addition, eQTM mapping can involve a large number of comparisons which may prevent the analyses due to limitations of computational resources. Here, we describe Torch-eCpG, an open-source tool to perform eQTM mapping that includes an optimized implementation that can use the graphical processing unit (GPU) to reduce runtime. ResultsWe demonstrate the analyses using the tool are reproducible, up to 18x faster using the GPU, and scale linearly with increasing methylation loci. ConclusionsTorch-eCpG is a fast, reliable, and scalable tool to perform eQTM mapping. Source code for Torch-eCpG is available at https://github.com/kordk/torch-ecpg.

bioinformatics↗