Biology subjects

Iftehimul, M.

Publications and source records attributed to Iftehimul, M..

4 recordsLinked to original sources

bioRxiv2026

Integrative Transcriptomic and Machine Learning Analysis of ecDNA-Associated Features for Studying Chemotherapy Resistance in TNBC

Extrachromosomal DNA (ecDNA) has emerged as a critical mediator of oncogene amplification and transcriptional dynamics in aggressive cancers, yet its contribution to chemotherapy resistance in vivo remains incompletely understood. This study investigates the contribution of ecDNA-associated molecular features to predictive chemotherapy resistance in TNBC. We analyzed RNA-seq data from 4T1 TNBC cells and 4T1 bulk tumors at different growth stages (1-, 3-, and 6-week) to identify differentially expressed ecDNA alterations. We then utilized molecular docking tools to predict ecDNA protein-drug interactions and employed machine learning (ML) models to predict ecDNA-associated therapeutic resistance. Our results revealed changes in global gene expression, including expression of ecDNA-associated genes, that continued over time, with significant molecular remodeling observed at six weeks. Additionally, we found gradual accumulation of mutations in ecDNA genes, which may have contributed to reduced drug binding affinity, indicating potential resistance. ML models generated stable, high-confidence classifications of resistant phenotypes, consistently identifying ecDNA burden and prevalence as dominant predictive features of drug resistance. Drug specific predictions further highlighted elevated resistance probabilities for paclitaxel and doxorubicin, whereas hydroxyurea, which depletes ecDNA, showed reduced resistance probabilities, indicating potential roles of ecDNA in chemoresistance. This study provides new insights into temporal remodeling of ecDNA within TNBC tumors over time and their potential association with drug resistance.

cancer biology↗

bioRxiv2025

Molecular Plasticity of T Cells Informs Their Possible Adaptation in 4T1 Tumors

BackgroundThe triple-negative breast cancer (TNBC) microenvironment (TME) undergoes progressive reprogramming, transitioning from an early immune-active state to a late immune-suppressed state. While tumor cell plasticity has been extensively studied, the molecular plasticity of T cells in vivo remains poorly defined. ObjectivesTo characterize transcriptional changes in T cells during TNBC progression and identify stage-specific shifts in T cell function, polarization, and antigen-presenting cell (APC)-T cell interactions. ResultsTranscriptional analysis of T cells from BALB/c mice bearing 4T1 tumors at 1, 3, and 6 weeks revealed a decline in T cell-associated genes from 194 at 1 week to 156 at 6 weeks, with a significant late-stage loss of TCR diversity and contraction of natural killer T (NKT)- and {gamma}{delta} T cell-related transcripts. Cytokine and transcription factor dynamics reflected temporal T cell polarization: early (1 week) IL-12/{beta}-STAT4 signaling supports CD4+ type 1 T helper cell (Th1) and type 1 CD8+ cytotoxic T cell (Tc1) responses; intermediate (3 weeks) IL-21 and BCL6 expression suggest transient CD8+ cytotoxic follicular T cell (Tfc) skewing; and late (6 weeks) AhR and IL-1{beta} induction reflect interleukin 17/22 producing CD8+ T cell (Tc17/Tc22) transition. Pro-inflammatory cytokines and chemokines increased over time, while immunosuppressive mediators (e.g., IL-10) declined significantly. Antigen-presenting cell (APC)-T cell crosstalk deteriorated at 6 weeks, characterized by a reduction in the expression of co-stimulatory and APC genes. Despite an early dominance of M1-like macrophage signals (e.g., IL-12/{beta}), persistent expression of arginase 1 (ARG1) and other M2-associated genes indicated a stable tolerogenic niche. ConclusionsTNBC progression is characterized by progressive T cell functional decline, narrowing of TCR diversity, impaired APC-T cell interactions, and sustained macrophage-driven immunosuppression. These temporally coordinated immune shifts suggest tumor-driven adaptation toward immune evasion and identify potential windows for stage-specific immunotherapeutic intervention.

cancer biology↗

bioRxiv2025

Molecular Phenotypic Plasticity Informs Possible Adaptive Change of Triple-Negative Breast Cancer Cells In Vivo

Background and ObjectivesCancer evolves via interconnected mechanisms, including changes in extrachromosomal DNA (ecDNA), genetic instability, and interactions with the tumor microenvironment (TME). These mechanisms allow for some clones to evolve metastatic traits, evade the immune system, and resist chemotherapy. However, how cancer cells evolve in vivo remains poorly understood. This study investigates the in vivo changes in gene expression of triple-negative breast cancer (TNBC) cells implanted in BALB/c mice. MethodologyWe analyzed RNA-seq data from 4T1 TNBC cells and tumors at different growth stages (1-, 3-, and 6-week) to identify differentially expressed genes, protein-protein interactions, and ecDNA alterations. We also assessed how ecDNA and genomic instability proteins interact with anti-TNBC drugs ResultsOur results reveal early transcriptional shifts within one week of tumor implantation, showing rapid acclimation. Changes in gene expression continued over time, with significant molecular reprogramming observed at six weeks under in vivo environmental pressures, including ecDNA alterations and immune evasion. The shift from the earlier generation (1 week) to the later generation (6 weeks) suggests cumulative alterations in key oncogenic pathways related to tumor progression. Additionally, we found that mutations in ecDNA and genomic instability proteins influence drug binding affinity, suggesting that adaptive changes may impact chemotherapy response. Conclusions and ImplicationsThis study provides new insights into how TNBC tumors may evolve over time and novel ecDNA-related mechanisms of possible tumor adaptation, highlighting potential biomarkers for tumor aggression and immune evasion, which could help develop more effective therapeutic strategies against TNBC.

cancer biology↗

bioRxiv2025

In Silico Evaluation and Therapeutic Targeting of LVDD9B Protein for WSSV Inhibition: Molecular and Ecological Insights for Aquaculture Solutions

BackgroundThis study aimed to investigate structural dynamics, binding interactions, stability, pharmacokinetics, ecological risks, and bioactivity of shrimp receptor protein LVDD9B to identify potential therapeutic candidates against White Spot Syndrome Virus (WSSV). MethodsLVDD9B proteins 3D structure was predicted using SWISS-MODEL and validated with ProSA and Ramachandran plots. Protein-protein docking between LVDD9B and VP26 (WSSV protein) was performed using HADDOCK 2.4 server. Molecular docking, dynamics simulations, binding-free energy calculations, principal component analysis (PCA), electrostatic, and vibrational frequency analyses evaluated binding affinity, stability and polarity of complexes. Results128-amino-acids of LVDD9B protein was predicted as predominantly cytoplasmic with stable, and hydrophilic, with structural analysis identified key secondary structures and conserved chitin-binding site. Docking studies revealed strong interactions between LVDD9B and VP26, supported by hydrogen-bonds and salt bridges. Molecular dynamics simulations demonstrated stable complexes with fluctuating RMSD values, and MM/GBSA calculations indicated favorable binding free energies. Pharmacokinetic analysis highlighted promising bioavailability and drug-like properties for Luteolin and Quercetin from Cuscuta reflexa, while ecological assessment identified Cosmosiin as least hazardous, with Quercetin and Luteolin showing higher toxicity. PCA revealed stable protein-ligand complexes with flexibility in Apo form. Isorhoifolin exhibited the lowest internal energy (-2099.4722 Hartree) and highest dipole moment (8.1833 Debye). Frontier orbital analysis showed HOMO-LUMO gaps (4.05-4.34 eV) influencing reactivity, while MEP and vibrational frequency analyses supported compound stability and bioactivity. ConclusionsThis study explores LVDD9Bs structural and interaction dynamics for developing antiviral therapy against WSSV, highlighting therapeutic potential of Cosmosiin, Isorhoifolin, Quercetin and Luteolin based on their pharmacokinetic and ecological profiles.

bioinformatics↗