Biology subjects

Sayed, S.

Publications and source records attributed to Sayed, S..

6 recordsLinked to original sources

bioRxiv2026

Spatial epigenomics reveals ancestry-associated regulatory states linked to aggressive prostate cancer biology

Prostate cancer (PCa) exhibits substantial biological heterogeneity, including population associated differences in tumor aggressiveness and clinical outcomes. Although socioeconomic and environmental factors contribute to these disparities, intrinsic tumor regulatory programs may also influence disease behavior. Here, we investigated whether differences in chromatin regulation contribute to distinct tumor states in Black and White men with localized PCa. We performed spatial chromatin accessibility profiling (ATAC-seq) of prostatectomy specimens from Black and White patients receiving equal healthcare access at the Center for Prostate Disease Research (USUHS) and Walter Reed National Military Medical Center. Tumors showed distinct chromatin accessibility landscapes between the two populations, with tumors from Black patients exhibiting reduced accessibility of motifs associated with the chromatin architectural regulator CTCF and enrichment of motifs linked to epithelial-mesenchymal transition and inflammatory programs. Reduced CTCF expression was independently validated by immunohistochemistry in 99 prostatectomy specimens. These findings identify population-associated differences in chromatin regulation in localized PCa and suggest that altered CTCF-associated regulation, inflammatory signaling, and epithelial plasticity may contribute to the biological heterogeneity underlying ancestry-dependent PCa disparities.

cancer biology↗

bioRxiv2025

Single-cell-guided identification of logic-gated antigen combinations for designing effective and safe CAR therapy

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematological malignancies. However, its application in solid tumors remains limited because single targets are unlikely to suffice due to tumor antigen heterogeneity and off-tumor toxicities. To overcome these obstacles, we developed LogiCAR designer, a computational approach that utilizes single-cell transcriptomics data from patient tumors to systematically identify the cancer-specific antigen circuits with logic gates ("AND," "OR," and "NOT") that target the majority of cancer cells in a tumor while sparing normal cells and tissues as much as possible. LogiCAR designer efficiently scales to higher-order antigen combinations involving up to five genes. Applied to a large-scale dataset encompassing approximately 2 million cells (including > 620k tumor cells) from 342 clinical patient samples across all major breast cancer subtypes, LogiCAR designer identified antigen circuits with enhanced tumor-targeting efficacy and improved safety profiles compared to both previously reported circuits and single-target therapies in clinical trials. However, even these optimized shared circuits still proved insufficient for some patients. We hence systematically studied LogiCAR designers ability to identify highly effective CAR circuits that are individualized to each patient. Remarkably, such personalized CAR circuits provide estimated tumor-targeting efficacy tantamount to complete response in 76% of patients and partial response for all patients. Taken together, this analysis is the first systematic quantification of the efficacy and safety of all possible CAR circuits, showing that: (a) the quality of existing solutions leaves much to be desired; (b) the ability of shared circuits optimized across many patients is moderate, and finally, (c) individually tailored circuits offer significantly higher tumor-targeting efficacies for patients. LogiCAR designer offers a rigorous, data-driven way to facilitate the rational design of safe and effective CAR-based immunotherapies for cancer. Statement of Significance Development of a computational approach that efficiently identifies logic-gated CAR target combinations, called circuits, from single-cell transcriptomics, addressing a critical unmet clinical need. Application to the largest ensemble of breast cancer datasets to date, comprising [~]2 million cells (> 620k tumor cells) from 17 clinical cohorts, to identify CAR circuits predicted to be effective. Comprehensive safety profiling of candidate circuits spanning major tissues at both RNA and protein levels. Logic-gated CAR circuits generated by our pipeline address tumor heterogeneity and achieve efficacy and safety scores that surpass clinical trial and previously computationally identified circuits. Individualized rational CAR design offers a transformative approach to deliver precision-engineered CAR therapies with unprecedented efficacy.

bioinformatics↗

bioRxiv2024

Altered Purinergic Signaling and CD8+ T Cell Dysregulation in STAT3 GOF Syndrome

Signal transduction downstream of activating stimuli controls CD8+ T cell biology, however these external inputs can become uncoupled from transcriptional regulation in Primary Immune Regulatory Disorders (PIRD). Gain-of-function (GOF) variants in STAT3 amplify cytokine signaling and cause a severe PIRD characterized by early onset autoimmunity, lymphoproliferation, recurrent infections, and immune dysregulation. In both primary human and mouse models of STAT3 GOF, CD8+ T cells have been implicated as pathogenic drivers of autoimmunity. The molecular mechanisms by which STAT3 GOF variants drive this pathology remain unclear. We found that naive CD8+ T cells have an increased capacity for IFN-{gamma} and TNF- secretion. Given this dysregulation of CD8+ T cell function, we evaluated changes in immunoregulatory pathways and found evidence of dysregulated purinergic signaling via high dimensional immune profiling, single-cell RNA sequencing, and functional assessment. Specifically, while expression of CD39, which transforms ATP to AMP, was increased on CD8+ T cells from patients with STAT3 GOF, downstream purinergic family members, CD73 and the adenosine receptor, A2AR, were downregulated, impairing the potential to produce or sense inhibitory adenosine. Patients with STAT3 GOF can be clinically treated with JAK inhibitors and this partially normalized naive CD8+ T cell dysregulation, including aberrant cytokine production. The extent of normalization of cytokine secretion scaled with normalization of CD73 and A2AR. This suggests that a dysregulated purinergic signaling axis plays an important role in CD8+ T cell dysregulation in STAT3 GOF, which may have implications for other inflammatory disorders with amplified STAT signaling. One Sentence SummaryAmplified STAT3 signaling in CD8+ T cells from STAT3 GOF patients alters purinergic signaling and dysregulates CD8+ T cell function.

immunology↗

bioRxiv2024

The Association between the JAK-STAT Pathway and Hypertension among Kenyan Women Diagnosed with Breast Cancer

BackgroundBreast cancer is the most common malignant tumor in women worldwide, and disproportionately affects Sub-Saharan Africa compared to high income countries. The global disease burden is growing, with Sub-Saharan Africa reporting majority of the cases. In Kenya, breast cancer is the most commonly diagnosed cancer, with an annual incidence of 7,243 new cases in 2022, representing 25.5% of all reported cancers in women. Evidence suggests that women receiving breast cancer treatment are at a greater risk of developing hypertension than women without breast cancer. Hypertension prevalence has been on the rise in SSA, with poor detection, treatment and control. The JAK-STAT signaling is activated in hormone receptor-positive breast tumors, leading to inflammation, cell proliferation, and treatment resistance in cancer cells. We sought to understand the association between the expression of JAK-STAT Pathway genes and hypertension among Kenyan women diagnosed with breast cancer. MethodsBreast tumor and non-tumor tissues were acquired from patients with a pathologic diagnosis of invasive breast carcinoma. RNA was extracted from fresh frozen tumor and adjacent normal tissue samples of 23 participants who had at least 50% tumor after pathological examination, as well as their corresponding adjacent normal samples. Differentially expressed JAK-STAT genes between tumor and normal breast tissues were assessed using the DESEq2 R package. Pearson correlation was used to assess the correlation between differentially expressed JAK-STAT genes and participants blood pressure, heart rate, and body mass index (BMI). Results11,868 genes were differentially expressed between breast tumor and non-tumor tissues. Eight JAK-STAT genes were significantly dysregulated (Log2FC [≥] 1.0 and an Padj [≤] 0.05), with two genes (CISH and SCNN1A) being upregulated. Six genes (TGFBR2, STAT5A, STAT5B, TGFRB3, SMAD9, and SOCS2) were downregulated. We identified STAT5A and SOCS2 genes to be significantly correlated with elevated systolic pressure and heart rate, respectively. ConclusionsOur study provides insights underlying the molecular mechanisms of hypertension among Kenyan women diagnosed with breast cancer. Understanding these mechanisms may help develop targeted treatments that may improve health outcomes of Kenyan women diagnosed with breast cancer. Longitudinal studies with larger cohorts will be needed to validate our results.

cancer biology↗

bioRxiv2019

CDK4 as a phytochemical based anticancer drug target

Success story of plant-based medicine had been overlooked during the advent of modern pharmaceutical industry. Despite the negligence of the multimillion-dollar drug industry, people entirely rely on medicinal plants in some part of the world. In this study, we have emphasized on going back to those traditional medicinal practices to figure out their underlying mechanism to move forward on phytochemical based drug development. We screened Medicinal Plant Database Bangladesh 1.0 (MPDB1.0) and on-going extension, MPDB2.0, of that database to find traditionally used medicinal plants and their active compounds. Here, Mangiferin, extracted from Mangifera indica, have been demonstrated to interact with cell cycle regulator Cyclin-dependent Kinase 4 (CDK4). CDK4 is differentially expressed during Glioblastoma multiforme (GBM), Brain Lower Grade Glioma (LGG), and Sarcoma (SARC). Expression of CDK4 is interlinked to the patients survival rate and its consistent expression throughout different stages have provided the advantage to use it as diagnostic tool and drug target. Altogether, this study demonstrated that simple mango tree extracted active compounds, mangiferin, can work as potential anticancer drug and leveraging the recent advancement of sequencing and gene expression data can accelerate the phytochemical based drug discovery process.

cancer biology↗

bioRxiv2017

Loss Of lrrk2 Impairs Cell Proliferation And Neuronal Regeneration In The Zebrafish Brain

LRRK2 mutations are a major cause of Parkinsons disease. Pathogenicity of LRRK2 loss-of-function is controversial, as knockout in rodents reportedly induces no brain-specific effects and knockdown studies in zebrafish are conflicting. Here we show that CRISPR/Cas9-engineered deletion of the ~60-kbp-long zebrafish lrrk2 locus elicits a pleomorphic, albeit transient brain phenotype in maternal-zygotic mutants (mzLrrk2). Intriguingly, 11-month-old mzLrrk2 adults display increased dopamine and serotonin catabolism. Additionally, we find decreased mitosis in the larval brain and reduced stab injury-induced neuronal regeneration in the adult telencephalon. Finally, hypokinesia associates with loss of lrrk2 in larvae. Our results demonstrate that lrrk2 knockout has an early neurodevelopmental effect, and leads to perturbed dopamine and serotonin catabolism in a LRRK2 knockout. We propose mzLrrk2 zebrafish as a valuable tool to study LRRK2 loss-of-function in vivo, and provide a link between LRRK2 and the control of basal cell proliferation in the brain that may become potentially critical upon challenges like brain injury.

neuroscience↗