Extracellular vesicle-mediated drug delivery in breast cancer theranostics.

Breast cancer (BC) continues to be a significant global challenge due to drug resistance and severe side effects. The increasing prevalence is alarming, requiring new therapeutic approaches to address these challenges. At this point, Extracellular vesicles (EVs), specifically small endosome-released nanometer-sized EVs (SEVs) or exosomes, have been explored by literature as potential theranostics. Therefore, this review aims to highlight the therapeutic potential of exosomes in BC, focusing on their advantages in drug delivery and their ability to mitigate metastasis. Following the review, we identified exosomes' potential in combination therapies, serving as miRNA carriers and contributing to improved anti-tumor effects. This is evident in clinical trials investigating exosomes in BC, which have shown their ability to boost chemotherapy efficacy by delivering drugs like paclitaxel (PTX) and doxorubicin (DOX). However, the translation of EVs into BC therapy is hindered by various challenges. These challenges include the heterogeneity of EVs, the selection of the appropriate parent cell, the loading procedures, and determining the optimal administration routes. Despite the promising therapeutic potential of EVs, these obstacles must be addressed to realize their benefits in BC treatment.

Vulnerability, Preparedness, and Previous Experience of Disasters Among the Population of a High Hazard Region-Rural Southern Sindh, Pakistan.

A cross-sectional, mixed-method study was conducted in Badin, a rural area in southern Sindh, which is considered a high-risk disaster zone, to assess the vulnerability, preparedness, and disaster experiences of the coastal population. A multistage sampling technique was employed to select the villages, study area, and 3 distinct populations (I, II, and III). Family heads of households were recruited for population I, village heads for population II, and community support group leaders from selected clusters for population III. The survey was conducted through face-to-face interviews. The results revealed that the population of rural southern Sindh, Pakistan, is highly vulnerable to disasters and exhibits lower levels of preparedness. The statistics about the vulnerable population may prove helpful in designing policies targeting specific groups to mitigate hazards in the future.

Association of methylenetetrahydrofolate reductase gene variant C677T and folate levels in non-syndromic cleft lip/palate among Sindhi, Pakistani population.

The object ives of this study were to determine the association of methylenetetrahydrofolate reduc tase (MTHFR) gene variant C67 7 T with non -syndromic cl eft lip/palate (NSCLP) in Pakistani population and compare the m aternal serum foli c acid levels in NSCLP-affected and healthy group. A c om parative cross sec ti onal study was conducted between 2017 and 2019 at Liaquat U niversity of Medi cal and Health Science s, Jamshoro. Sixty motherinfant dy ads were recruited (n=120), inc luding NSCLP-affected and healthy infants alo ng with t heir mother s. The MTHFR C677T vari ant exhibited si gnificant association with NSCLP in dominant and over-domi nant models. No differences in maternal serum folic acid levels were obse rved between both th e groups; however, the folic acid intake during pre-conception period was associated w ith decreased risk for NSC LP. Our stu dy suggested that MTHFR 677 CT genotype was related with decreased risk for NSCLP in Sindhi, Pakistani, population. Pre -conception folic acid may decrease the ri sk for ora l clefts.

Serum and salivary Cu/Zn ratio as a diagnostic biomarker for oral submucosal fibrosis: an analysis of trace metals and LOX gene variants.

This study aimed to analyze the serum and salivary levels of copper (Cu), zinc (Zn), iron (Fe), chromium (Cr), manganese (Mn) and the Cu/Zn ratio and investigate the association between LOX gene variants (rs18800449 and rs2288393) and oral submucosal fibrosis (OSMF). A total of 250 subjects were included in the study: OSMF patients (n = 50), areca nut chewers without OSMF (n = 100) and controls (n = 100). Trace metals were measured using an atomic absorption spectrophotometer, while LOX gene variants were genotyped using the tetra primer amplification refractory mutation system (tetra ARMS) polymerase chain reaction (PCR) method. The results showed significant variations in serum and salivary Cu, Zn, Fe and Cr levels and serum Mn concentrations among the three groups (p < 0.0001). Serum Cu levels were significantly higher in OSMF patients, while serum Zn levels were significantly lower. Both serum and salivary Cu/Zn ratios demonstrated a statistically significant difference (p < 0.0001) and diagnostic potential to differentiate OSMF from chewers and controls. However, LOX gene variants did not show an association between OSMF and chewers, except for rs1800449 genotypes, which showed a significant and increased risk with the AA genotype in OSMF patients compared to controls (OR = 7.58; 95%CI 2.30-24.97). The study suggests that trace elements and genetic variants may impact the etiology of OSMF. The findings may aid in early diagnosis, suitable treatment, and as a prognostic indicator for disease progression.

Impact of ACE2 gene variations on COVID-19 pathogenicity in Pakistani patients.

Background: COVID-19, caused by the SARS-CoV-2 virus, swiftly disseminated and was declared a pandemic. Variations in the ACE2 gene can impact the virus's ability to bind to ACE2 receptor, potentially influencing an individual's susceptibility and its association with COVID-19 severity across various populations. Methods: In total, 200 individuals were sequenced for the ACE2 gene and potential impact of the found variants on the ACE2 protein was assessed using in-silico tools. Results: Eight variations in the ACE2 gene were identified in 27 COVID-19 patients, of which four were missense and four were intronic variants. Three variants had a MAF of < 0.01 (c.251C > T, p.Pro86Leu; 15C > G, p.S5S; and c. 91 A > G, p.Lys31Glu). A missense variant, p.Pro86Leu, C > T, TT genotype, was found in 9 out of 200 individuals with an allele frequency of 0.045 and showed a significant association with COVID-19 (P = 0.003). The heterozygous allele of 15C > G, p.S5S, was found with a frequency of 0.02 (8/400) in eight patients, and its CG genotype showed a significant association with COVID-19 (P = 0.0068). The remaining identified variants were not associated with COVID-19 susceptibility. Conclusion: The ACE2 gene sequence in Pakistani individuals exhibited a low frequency of identified variants in COVID-19 patients. Overall, only two variants were associated with susceptibility to the disease, possibly contributing to Pakistan's lower COVID-19 mortality and infection rates. However, individuals carrying the mutant variant experienced more severe symptoms.

Association of MSX1 Gene Variants with Nonsyndromic Cleft Lip and/or Palate in the Pakistani Population.

OBJECTIVES: This study investigated the association of MSX1 gene variants rs3821949 and rs12532 with nonsyndromic cleft lip and/or palate (NSCL/P) in the Pakistani population. DESIGN: Comparative cross-sectional study.Setting: Multicenter of CL/P malformation.Patients/Participants: Unrelated Non-Syndromic cleft Lip/Palate patients and healthy controls were enrolled. METHODS: One hundred (n = 100) subjects with NSCL/P and n = 50 unrelated healthy controls were enrolled in a multicenter comparative cross-sectional study. A tetra amplification refractory mutation system (ARMS) polymerase chain reaction (PCR) was performed to analyze MSXI gene single nucleotide variants (SNVs). RESULTS: Among 100 NSCL/P subjects, the majority were males (56%; male: female = 1.27: 1). Most of the cases (74%) had cleft lip and palate (CLP) compared to isolated clefts. Genotyping of MSX1 gene variant rs3821949 showed an increased risk for NSCL/P in various genetic models (P < 0.0001), and the A allele exhibited a more than 4-fold increased risk among cases (OR = 4.22: 95% CI = 2.16-8.22; P < 0.0001). Our investigation found no significant difference between the rs12532 variation and NSCL/P. CONCLUSION: Our study findings suggest that MSX1 gene variants may increase predisposition to NSCL/P in the Pakistani population. Further studies comprising large samples are required to identify the genetic aetiology of NSCL/P among our people.

Role of Confocal Laser Endomicroscopy in Early Detection of Upper Gastrointestinal Malignancy in High Risk Patients.

BACKGROUND: Upper gastrointestinal malignancies are a major global health burden. Early diagnosis of upper gastrointestinal premalignant and malignant lesions is crucial for improving prognosis and reducing morbidity and mortality. The purpose of this study was to investigate the diagnostic accuracy of confocal laser endomicroscopy (CLE) in detecting upper gastrointestinal premalignant and early malignant lesions in high-risk patients, as well as diagnosing patients with inconclusive white light endoscopy (WLE) and histopathology results. METHODS: It was a cross-sectional study that included ninety (n = 90) high-risk patients with inconclusive diagnoses of upper gastrointestinal lesions on WLE and WLE-based biopsy histopathology. These patients underwent CLE, and the definitive diagnosis was confirmed using CLE and CLE-target biopsy histopathology. Diagnostic accuracy was determined by comparing the sensitivity, specificity, predictive values, and accuracy between the procedures. RESULT: The mean patient age was 47.43 ± 11.18 years. CLE and target biopsy confirmed that 30 (33.3%) patients had normal histology, while 60 (66.7%) patients were diagnosed with gastritis, gastric intestinal metaplasia, high-grade dysplasia, adenocarcinoma, Barrett's esophagus, and squamous cell carcinoma of the esophagus. The results of CLE were superior to those of WLE in terms of diagnostic parameters. Additionally, CLE demonstrated nearly similar results in sensitivity (98.33%), specificity (100%), positive predictive value (100%), negative predictive value (96.77%), and accuracy (98.89%) when compared to CLE-target biopsy. CONCLUSION: CLE showed higher diagnostic accuracy in differentiating normal, premalignant and malignant lesions. It effectively diagnosed patients who initially had inconclusive WLE and/or biopsy results. Furthermore, early detection of upper gastrointestinal premalignant or malignant lesions may improve prognosis and reduce morbidity and mortality.

Frequency of abnormal Pap smear in patients presenting with postcoital bleeding in Tertiary Care Hospital, Karachi, Pakistan.

Postcoital bleeding increases the chance of detecting cervical dysplasia and cancer; and the Pap smear is the recommended screening test in these patients. We conducted a cross-sectional study that included 110 women to find out the frequency of abnormal Pap smear in such patients. Their age range was 15-65 years with a mean age of 31.2 ± 11.2 years. Abnormal Pap smear was found in 54 (49%) women. Atypical squamous cells of unknown significance (ASCUS) were found in 13.6%, low-grade squamous intraepithelial lesion (LSIL) in 20.9%, high-grade squamous intraepithelial lesion (HSIL) in 11.8% and carcinoma in 2.7% of those. Because of the high frequency of abnormal Pap smear associated with postcoital bleeding in our population, cervical screening and strict monitoring are suggested as the important screening indications.

Physical Activity, Dietary Habits and Factors Associated with Depression Among Medical Students of Sindh, Pakistan, During the COVID-19 Pandemic.

Objective: To find out the association of physical activity, dietary habits and factors associated with depression among medical students of Sindh, Pakistan, during the coronavirus disease 2019 (COVID-19) pandemic. Methods: An online cross-sectional study was conducted between June and August, 2020, on medical students from three medical institutions of Sindh, Pakistan. The study comprised three structured questionnaires related to demographic details, physical activity, dietary and sleep habits, COVID-19 pandemic-associated factors and patient health questionnaire, PHQ-9. A total of 864 students completed the questionnaires and participated in the study. The data was analysed on SPSS version 23. Results: Our study showed that 244 (28.2%) medical students had mild depression, 192 (22.2%) had moderate depression, 80 (9.3%) had moderately severe depression and 80 (9.3%) had severe depression during the COVID-19 pandemic. Out of 864 students, 268 (31%) had no depression. Socioeconomic status, body mass index (BMI), chronic disease/comorbidity, addiction and non-medical prescription drug use were found to be statistically significant predictors of depression among medical students. On multilogistic regression analysis, physical activity, social media/app use and sleeping habits during COVID-19 were associated with depression (p-value < 0.05). Conclusion: The COVID-19 pandemic adversely affected physical activity and sleeping habits in association with depression among medical students. Promoting healthy eating habits, adequate physical activity, and a healthy lifestyle, particularly among students during lockdowns, is a critical component of coping with mental stress and depression. The findings of this study will aid in future research and campaign design in preparation for future pandemics and lockdowns.

An Investigation of Selected Socio-Demographic Factors with Aplastic Anemia in Pakistan: A Case-Control Study.

INTRODUCTION: In Pakistan, the incidence rate of aplastic anemia is 3.5 cases/million. The associated risk factors are exposure to pesticides, chemicals, and some drugs. The link between aplastic anemia and socio-demographic factors is debatable. PURPOSE: We conducted this study to investigate the role of socio-economic and -demographic factors with aplastic anemia. METHODOLOGY: A total of 191 lab-confirmed incident cases of aplastic anemia were identified from the tertiary hospital of Karachi-Pakistan in between 2015 and 2018. Age and gender-matched 694 controls were randomly selected from the same institute admitted or visited for other non-neoplastic conditions. Socio-demographic and exposure information was gathered using a data collection form. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were computed for selected socio-demographic factors. RESULTS: Among socio-demographic factors, significant associations of aplastic anemia risk emerged for illiteracy (aOR: 2.3; 1.5; 3.5) occupation (any type) (aOR: 2.1; 1.7; 2.5), living in rural environments (aOR: 2.9; 1.9; 4.2). The odds of aplastic anemia increased with the age group 31-50 years (aOR: 1.8; 1.7; 3.5) and >50 years (aOR: 2.5; 2.1; 4.2). We observed no association of income with the risk of aplastic anemia. CONCLUSION: This study highlights the importance of socio-demographic factors as a risk factor for the development of aplastic anemia in the population of Pakistan. In order to reduce disease incidence, health education program and use of personal protective equipment and organization of screening camps in high-risk population is warranted.

MTHFR and F5 genetic variations have association with preeclampsia in Pakistani patients: a case control study.

BACKGROUND: To study the role of single nucleotide variants (SNVs) of genes related to preeclampsia in Pakistani pregnant women. METHODS: After ethical approval and getting informed consent; 250 pregnant women were enrolled and equally divided into two groups (125 preeclamptic cases and 125 normotensive pregnant women). Demographic details and medical history were recorded, and 10 ml blood sample was obtained for DNA extraction. The tetra-primer amplification refractory mutation system (ARMS) assays were developed for assessing the variants of three preeclampsia related genes; F5, MTHFR and VEGFA. An association of six SNVs; F5:c.1601G > A (rs6025), F5:c.6665A > G (rs6027), MTHFR: c.665C > T (rs1801133), MTHFR: c.1286A > C (rs1801131), VEGFA: c.-2055A > C (rs699947) and VEGFA: c.*237C > T (rs3025039) with preeclampsia was determined by using different genetic models. RESULTS: Genotyping of the SNVs revealed that patients with MTHFR:c.665C > T, have increased susceptibility to preeclampsia (CT versus CC/TT: OR = 2.79, 95% CI = 1.18-6.59; P* = 0.046 and CT/TT vs CC: OR = 2.91, 95% CI = 1.29-6.57; P* = 0.0497, in overdominant and dominant models, respectively), whereas F5:c.6665A > G, (A/G vs AA/GG: OR = 0.42, 95% CI = 0.21-0.84; P* = 0.038 in overdominant model) and MTHFR:c.1286A > C, (CC versus AA: OR = 0.36, 95% CI = 0.18-0.72; P* = 0.0392 in codominant model) have significantly decreased risk for preeclampsia. F5:c.1601G > A, VEGFA: c.-2055A > C and VEGFA: c.*237C > T variants revealed no relationship with the disease. CONCLUSION: This is the first case control study describing the protective role of F5:c.6665A > G against preeclampsia in any world population. In addition, the present study confirmed the association and role of MTHFR gene variations in the development of preeclampsia in Pakistani patients. Further genetic studies may be required to better understand the complex genetic mechanism of SNVs in preeclampsia related genes in pregnant women.