Biology subjects

Afshar, Y.

Publications and source records attributed to Afshar, Y..

6 recordsLinked to original sources

bioRxiv2026

Predicting Pathway Dependency in Head and Neck Squamous Cell Carcinoma from Hallmark Transcriptomic Features

Despite frequent pathway activation, targeted molecular therapy remains limited in head and neck squamous cell carcinoma (HNSCC), highlighting the need to distinguish activation from dependence. Dependency is functional, context-specific, and coupled; mutations or expression alone cannot establish it. No validated framework identifies tumor pathway dependencies from baseline molecular profiles. We developed a transcriptome-based framework to infer pathway dependency in HNSCC. Nine Elastic Net models used 50 MSigDB Hallmark activity profiles from 953 GDSC cell lines and drug responses pooled across compounds annotated to each pathway. Cross-validated R2 ranged from 0.17 (IGF1R) to 0.48 (P53); leave-one-pathway-out validation retained rank agreement (Spearman {rho} = 0.19-0.56) for pathways with no drug response observed during training. We validated the models using pharmacological, genomic, and proteomic data, then applied them to TCGA-HNSC (n = 565) and GSE65858 (n = 256), examining HPV status, age, stage, tobacco history, and CD8+ infiltration. Seven of nine pathways were higher in HPV+ tumors and replicated directionally in GSE65858. Among TP53-wild-type tumors, HPV remained linked to greater P53 dependency ({beta} = +0.37, q = 0.010); HPV+ tumors also had higher p53 transcriptional activity, suggesting residual p53 function despite E6 expression. The codependency signature had a dominant global axis (PC1 = 62.3% variance; Cronbach's = 0.91), replicated across cohorts (Tucker congruence = 0.996), but largely reflected CD8+ T-cell infiltration ({rho} = 0.80). The framework uses RNA-sequenced bulk tumor cohorts to assess baseline transcriptome-based dependencies and match pathway-directed agents to likely responders before treatment. It is not prognostic.

bioinformatics↗

bioRxiv2026

Multi-factorial regulatory networks of placental antibody transfer by Fc receptors and maternal IgG Fc characteristics are modulated by clinical covariate profiles

Maternal immunoglobulin G (IgG) transferred across the placenta is crucial for newborn immunity. IgG transfer efficiency modulated by Fc characteristics including subclass and glycosylation gives rise to diverse transfer profiles across the population, yet the molecular mechanisms driving this variation are incompletely understood. To disentangle multimodal molecular relationships driving population heterogeneity in maternal-fetal antibody transfer, we characterized placental and serological antibody features in matched human tissues from two geographically distinct cohorts. Unsupervised clustering of maternal clinical covariates in both cohorts revealed a distinct patient profile with reduced plasma C-reactive protein and pregravid BMI and enhanced transfer efficiency of IgG subclasses. Quantification of IgG Fc glycan structures in matched maternal and cord plasma by liquid chromatography-mass spectrometry revealed subclass-specific IgG glycosylation patterns which impacted placental transfer efficiency and correlated with these key clinical features. We profiled expression and colocalization of key Fc {gamma} Receptors (Fc{gamma}Rs) by multiplex immunohistochemistry, revealing cell type-specific expression patterns. Variable Fc{gamma}R expression across gestation was consistent in both cohorts, implicating Fc{gamma}Rs as key drivers of temporal antibody transfer dynamics. While Fc{gamma}Rs were not strongly variable across the clinical profiles, partial correlation analysis of matched samples controlling for gestational age and demographic covariates revealed correlations between Fc{gamma}R expression frequencies and glycan- and subclass-specific transfer efficiency. These data systematically define multi-factorial regulatory networks of antibody transfer by placental Fc receptors and maternal IgG Fc characteristics, which are further modulated by clinical covariates. This study provides a basis for the rational design of prenatal vaccination strategies, administration schedules, and potential lifestyle interventions to improve maternal-fetal immunity.

immunology↗

bioRxiv2025

Transcriptomic comparison of early onset preeclampsia and placenta accreta identifies inverse trophoblast and decidua functions at the maternal-fetal interface

Early onset preeclampsia is a placental disorder characterized by shallow implantation, whereas placenta accreta spectrum is a placental disorder of deep placental attachment. This study compares the transcriptome of these two obstetric syndromes. By integrating available microarray and single-cell placenta/decidua transcriptomic datasets, we demonstrated that early onset preeclampsia genes are inversely expressed in placenta accreta, with the most marked differences noted in cell types of decidua, endothelial, and extravillous trophoblasts. Our findings highlight the key functions of trophoblast cell migration and invasion, decidua cell signaling, hypoxia pathways, and global growth factor and collagen contributions to these pregnancy disorders. This research provides new insights into the mechanisms of placentation and unifies these clinical siloes of disease by focusing on the fundamental biology of placental development at the maternal-fetal interface.

molecular biology↗

bioRxiv2022

Transcriptional drifts associated with environmental changes in endothelial cells

O_LIEnvironmental cues, such as physical forces and heterotypic cell interactions play a critical role in cell function, yet their collective contributions to transcriptional changes are unclear. Focusing on human endothelial cells, we performed broad individual sample analysis to identify transcriptional drifts associated with environmental changes that were independent of genetic background. Global gene expression profiling by RNA-seq and protein expression by LC-MS directed proteomics distinguished endothelial cells in vivo from genetically matched culture (in vitro) samples. Over 43% of the transcriptome was significantly changed by the in vitro environment. Subjecting cultured cells to long-term shear stress significantly rescued the expression of approximately 17% of genes. Inclusion of heterotypic interations by co-culture of endothelial cells with smooth muscle cells normalized approximately 9% of the original in vivo signature. We identify novel flow depedent genes, as well as, genes that necessitate heterotypic cell interactions to mimic the in vivo transcriptome. Our findings highlight specific genes and pathways that rely on contextual information and physical forces. C_LI

cell biology↗

bioRxiv2021

Sex differences in microRNA expression in first and third trimester human placenta

Maternal and fetal pregnancy outcomes related to placental function vary based on fetal sex, which may be the result of sexually dimorphic epigenetic regulation of RNA expression. We identified sexually dimorphic miRNA expression throughout gestation in human placentae. Next-generation sequencing was used to identify miRNA expression profiles in first and third trimester uncomplicated pregnancies using tissue obtained at chorionic villous sampling (n=113) and parturition (n=47). Sequencing and differential expression (DE) analysis identified 432 mature miRNAs expressed in the first trimester female, 425 in the first trimester male, 400 in the third trimester female, and 508 in the third trimester male placenta (baseMean >10). Of these, 11 sexually dimorphic (FDR<0.05, baseMean >10) miRNAs were identified in the first and 4 miRNAs were identified in the third trimester, including miR-361-5p, significant in both trimesters, all upregulated in females. Across gestation, 207 miRNAs were DE across gestation, common to both females and males, miR-4483, the most DE across gestation. There were twice as many female-specific differences across gestation as male-specific (44 miRNAs vs 21 miRNAs), indicating that miRNA abundance across human gestation is sexually dimorphic. Pathway enrichment analysis identified significant pathways that were differentially regulated in first and third trimester as well as across gestation. This work provides the normative sex dimorphic miRNA atlas in first and third trimester, as well as the sex independent and sex specific placenta miRNA atlas across gestation which may be used to identify biomarkers of placental function and direct functional studies investigating placental sex differences. Summary SentenceSex dimorphism in miRNA expression is more pronounced in first compared to third trimester placenta, and there are twice as many female-specific gestational differences, indicating miRNA abundance across human gestation is also sexually dimorphic.

developmental biology↗

bioRxiv2021

High-throughput miRNA-sequencing of the human placenta: expression throughout gestation

BackgroundAltered placenta miRNA abundance may impact the maternal-fetal interface and pregnancy outcomes. Understanding miRNA changes across gestation is essential before miRNAs can be used as biomarkers or prognostic indicators during pregnancy. Materials & MethodsUsing next-generation sequencing, we characterize the normative human placenta miRNA transcriptome in first (N=113) and third trimester (N=47). ResultsThere are 801 miRNAs expressed in both first and third trimester, including 182 with similar expression across gestation (P[≥]0.05) and 182 significantly different (FDR<0.05). Of placenta-specific miRNA clusters, C14MC is more upregulated in first trimester and C19MC is more highly expressed overall. ConclusionThis work provides a rich atlas of healthy pregnancies to direct functional studies investigating the epigenetic differences in first and third trimester placentae. Lay AbstractThe human body produces microRNAs which affect the expression of genes and proteins. This study uses next generation sequencing to identify the microRNA profile of first and third trimester human placentae using a large cohort (N=113 first, N=47 third trimester). All pregnancies resulted in healthy babies. We identify microRNAs with significantly different expression between first and third trimester, as well as stably expressed microRNAs. This work provides a baseline for future studies which may use microRNAs to monitor maternal-fetal health throughout pregnancy.

developmental biology↗