TUSC3, p53 and p21 genetic association with development of oral submucous fibrosis and oral squamous cell carcinoma among addictive tobacco chewers of Pakistan.

BACKGROUND: This study delves into the intricate landscape of oral cancer, a global concern with a high incidence in Asian countries. We focus on oral squamous cell carcinoma (OSCC), primarily driven by the consumption of betel nut and its derivatives. OSCC often arises from premalignant lesions like oral submucous fibrosis (OSF). In Pakistan, OSCC is prevalent among men due to various addictive substances, including smokeless tobacco and chewing materials. Mutations in tumor suppressor genes, such as TP53 and p21, play crucial roles in this malignancy's development. We also explore the involvement of TUSC3 gene deletion in OSCC and OSF. METHODS: In this study we investigated demographics, TUSC3 gene expression, deletion analysis, and TP53 and p21 genetic alterations in OSCC and OSF patients (blood and tissue of 50 samples in each condition) who had tobacco derivates usage history. The association analysis was carried out mainly through PCR based genotyping. RESULTS: The study's patient cohort (OSCC and OSF) displayed a wide age range from 13 to 65 years (Mean = 32.96 years). Both conditions were more prevalent in males, with a male-female ratio of approximately 2.5:1. Chewing habits analysis revealed high frequencies of gutka use in both OSF and OSCC patients. TUSC3 expression analysis in OSCC cell lines indicated significant downregulation. Genotyping showed no TUSC3 deletion in OSF cases, but a deletion rate of over 22% in OSCC tissue samples. Analysis supported a significant association of TUSC3 deletion with OSCC development but not with OSF. Polymorphism in p53 exon 4 and p21 (rs1801270) were significantly associated with both OSCC and OSF, adding to their pathogenesis. Our findings further revealed a strong correlation between TUSC3 deletion and the excessive use of tobacco and related products, shedding light on the genetic underpinnings of OSCC development. CONCLUSIONS: Notably, our study provides a crucial insight into genetic aspects underlying OSCC and OSF in response of addictive consumption of areca nut, betel quid, and tobacco derivatives. A significant association between TUSC3 deletion and OSCC development, along with polymorphisms in TP53 and p21, underscores the importance of further research into the molecular mechanisms driving oral cancer progression for improved diagnosis and treatment outcomes.

Understanding the intricacies of cellular senescence in atherosclerosis: Mechanisms and therapeutic implications.

Cardiovascular disease is currently the largest cause of mortality and disability globally, surpassing communicable diseases, and atherosclerosis is the main contributor to this epidemic. Aging is intimately linked to atherosclerosis development and progression, however, the mechanism of aging in atherosclerosis is not well known. To emphasize the significant research on the involvement of senescent cells in atherosclerosis, we begin by outlining compelling evidence that indicates various types of senescent cells and SASP factors linked to atherosclerotic phenotypes. We subsequently provide a comprehensive summary of the existing knowledge, shedding light on the intricate mechanisms through which cellular senescence contributes to the pathogenesis of atherosclerosis. Further, we cover that senescence can be identified by both structural changes and several senescence-associated biomarkers. Finally, we discuss that preventing accelerated cellular senescence represents an important therapeutic potential, as permanent changes may occur in advanced atherosclerosis. Together, the review summarizes the relationship between cellular senescence and atherosclerosis, and inspects the molecular knowledge, and potential clinical significance of senescent cells in developing senescent-based therapy, thus providing crucial insights into their biology and potential therapeutic exploration.

Integrative Analysis of Machine Learning and Molecule Docking Simulations for Ischemic Stroke Diagnosis and Therapy.

Due to the narrow therapeutic window and high mortality of ischemic stroke, it is of great significance to investigate its diagnosis and therapy. We employed weighted gene coexpression network analysis (WGCNA) to ascertain gene modules related to stroke and used the maSigPro R package to seek the time-dependent genes in the progression of stroke. Three machine learning algorithms were further employed to identify the feature genes of stroke. A nomogram model was built and applied to evaluate the stroke patients. We analyzed single-cell RNA sequencing (scRNA-seq) data to discern microglia subclusters in ischemic stroke. The RNA velocity, pseudo time, and gene set enrichment analysis (GSEA) were performed to investigate the relationship of microglia subclusters. Connectivity map (CMap) analysis and molecule docking were used to screen a therapeutic agent for stroke. A nomogram model based on the feature genes showed a clinical net benefit and enabled an accurate evaluation of stroke patients. The RNA velocity and pseudo time analysis showed that microglia subcluster 0 would develop toward subcluster 2 within 24 h from stroke onset. The GSEA showed that the function of microglia subcluster 0 was opposite to that of subcluster 2. AZ_628, which screened from CMap analysis, was found to have lower binding energy with Mmp12, Lgals3, Fam20c, Capg, Pkm2, Sdc4, and Itga5 in microglia subcluster 2 and maybe a therapeutic agent for the poor development of microglia subcluster 2 after stroke. Our study presents a nomogram model for stroke diagnosis and provides a potential molecule agent for stroke therapy.

Immunotherapy: Constructive Approach for Breast Cancer Treatment.

A novel and rapid therapeutic approach is the treatment of human breast cancer by enhancing the host's immune system. In initial findings, program death one (PD-1) and program cell death ligand one (PD-L1) showed positive results towards solid tumors, but tumor relapse and drug resistance are the major concerns. Breast cancer therapy has been transformed by the advent of immune checkpoint blockades (ICBs). Triple-negative breast cancers (TNBCs) have exhibited enduring responses to clinical usage of immune checkpoint inhibitors (ICBs) like atezolizumab and pembrolizumab. Nonetheless, a notable proportion of individuals with TNBC do not experience advantages from these treatments, and there is limited comprehension of the resistance mechanisms. Another approach to overcome resistance is cancer stem cells (CSCs), as these cells are crucial for the initiation and growth of tumors in the body. Various cancer vaccines are created using stem cells (dendritic, whole cell, bacterial) and focus primarily on targeting tumor-related antigens. The ultimate objective of cancer vaccines is to immunize the patients by active artificial immunity against cancer, though. In this review, we primarily focused on existing immunotherapeutic options, immune checkpoint blockers, the latest progress in understanding the molecular mechanisms underlying resistance to immune checkpoint inhibitors (ICBs), advanced strategies to overcome resistance to ICBs, cancer stem cell antigens and molecular markers, ongoing clinical trials for BCs and cancer vaccines for breast cancer.

Increasing Frequency of New Delhi Metallo-beta-Lactamase and Klebsiella pneumoniae Carbapenemase Resistant Genes in a Set of Population of Karachi.

OBJECTIVE: To determine the frequency of Klebsiella pneumoniae Carbapenemase (blaKPC) and New Delhi Metallo-Beta-Lactamase (blaNDM) resistant genes among clinical isolates of Enterobacterales in a set of Karachi population. STUDY DESIGN: An observational study. PLACE AND DURATION OF STUDY: Department of Microbiology, Dr. Ziauddin University Hospital, Karachi, Pakistan, from January 2019 to December 2020. METHODOLOGY: A total of 2100 clinical isolates of Enterobacterales were collected. All isolates of Carbapenem-Resistant Enterobacterales (CRE) (Escherichia coli, Enterobacter and Klebsiella species) on the basis of Meropenem screening test positivity were included in the study. DNA was extracted and PCR was performed for resistant genes detection. Frequencies and percentages were computed for categorical variables and mean values and standard deviation for quantitative variables. RESULTS: Among 2100 isolates of Enterobacterales, the majority were E. coli 1260 (60%), followed by Klebsiella species 462 (22%), and Enterobacter species 210 (10%). The sources of CRE isolates included 34 (25%) from respiratory (tracheal aspirate, pleural fluid, and gastric lavage); 33 (24.26%) urine, 32 (25.53%) pus, 15 (11.03%) blood, and 20 (14.7%) others (ascitic fluid, stents, and tissue). All isolates of CRE were sensitive (100%) to Colistin, Tigecycline and Fosfomycin. Biochemically confirmed CRE 136 (6.5%) isolates, (79 (58%) males and 57 (42%) females), were selected for detecting resistant genes. The PCR showed 32 (23.52%) positive for both NDM and KPC resistant genes, 28 (20.58%) for NDM and 19 (13.97%) for KPC alone. Out of 79 followed up patients, 58 (73.4%) expired while 21 (26.6%) were discharged. CONCLUSION: The frequency of blaNDM and blaKPC resistant genes in CRE isolates depicted increasing trend. Colistin, Fosfomycin, and Tigecycline showed high antimicrobial sensitivities in vitro. Further measures need to be applied for CRE with comprehensive resistant genes detection to curtail antimicrobial resistance. KEY WORDS:  Frequency, KPC, NDM, Klebsiella species, Carbapenemases, Enterobacterales E.coli.