Impacts of DROSHA (rs10719) and DICER (rs3742330) Variants on Breast Cancer Risk and Their Distribution in Blood and Tissue Samples of Egyptian Patients.

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression and play critical roles in tumorigenesis. Genetic variants in miRNA processing genes, DROSHA and DICER, have been implicated in cancer susceptibility and progression in various populations. However, their role in Egyptian patients with breast cancer (BC) remains unexplored. This study aims to investigate the association of DROSHA rs10719 and DICER rs3742330 polymorphisms with BC risk and clinical outcomes. This case-control study included 209 BC patients and 106 healthy controls. Genotyping was performed using TaqMan assays in blood, tumor tissue, and adjacent non-cancerous tissue samples. Associations were analyzed using logistic regression and Fisher's exact test. The DROSHA rs10719 AA genotype was associated with a 3.2-fold increased risk (95%CI = 1.23-9.36, p < 0.001), and the DICER rs3742330 GG genotype was associated with a 3.51-fold increased risk (95%CI = 1.5-8.25, p = 0.001) of BC. Minor allele frequencies were 0.42 for rs10719 A and 0.37 for rs3742330 G alleles. The risk alleles were significantly more prevalent in tumor tissue than adjacent normal tissue (rs10719 A: 40.8% vs. 0%; rs3742330 G: 42.7% vs. 0%; p < 0.001). However, no significant associations were observed with clinicopathological features or survival outcomes over a median follow-up of 17 months. In conclusion, DROSHA rs10719 and DICER rs3742330 polymorphisms are associated with increased BC risk and more prevalent in tumor tissue among our cohort, suggesting a potential role in miRNA dysregulation during breast tumorigenesis. These findings highlight the importance of miRNA processing gene variants in BC susceptibility and warrant further validation in larger cohorts and different ethnic populations.

Hesperetin protects against rotenone-induced motor disability and neurotoxicity via the regulation of SIRT1/NLRP3 signaling.

Rotenone is a pesticide that causes complex I inhibition and is widely known to induce motor disability and experimental Parkinson's disease (PD) in rodents. Evidence suggests a crucial role for sirtuin/nuclear factor-kappaB/nod-like receptor family, pyrin domain-containing 3 (SIRT1/NFκB/NLRP3) signaling and inflammation in PD and rotenone neurotoxicity. Hesperetin (C16H14O6) is a citrus flavonoid with documented anti-inflammatory activity. We investigated the value of hesperetin in delaying rotenone-induced PD in mice and the possible modulation of inflammatory burden. PD was induced in mice via rotenone injections. Groups were assigned as a vehicle, PD, or PD + hesperetin (50 or 100 mg/kg) and compared for the motor function, protein level (by ELISA), and gene expression (by real-time PCR) of the target proteins, histopathology, and immunohistochemistry for tyrosine hydroxylase enzyme. Hesperetin (50 or 100 mg/kg) alleviated the motor disability and the striatal dopamine level and decreased the expression of NLRP3 and NF-κB but increased SIRT1 expression (p < 0.05). Further, it enhanced the neural viability and significantly decreased neural degeneration in the substantia nigra, hippocampus, and cerebral cortex (p < 0.05). Taken together, we propose that hesperetin mediates its neuroprotective function via alleviating modulation of the SIRT1/NFκB/NLRP3 pathway. Therefore, hesperetin might delay the PD progression.

The HCV-Melanoma Paradox: First Multi-Cohort and Molecular Net-Work Analysis Reveals Lower Incidence but Worse Outcomes-Integrating Clinical, Real-World, and In Silico Data.

Background and Objectives: The relationship between hepatitis C virus (HCV) infection and melanoma remains poorly understood. This study aimed to investigate the association between HCV and melanoma, assess outcomes in patients with both conditions, and explore potential molecular mechanisms connecting the two diseases. Materials and Methods: We conducted a retrospective cohort study of 142 melanoma patients, including 29 with HCV-related cirrhosis, and analyzed their clinical outcomes. For external validation, we used the TriNetX Global Collaborative Network database, comprising 219,960 propensity-matched patients per group. An in silico analysis was performed to identify the molecular pathways linking HCV and melanoma. Results: In the retrospective cohort, HCV-positive melanoma patients showed an increased risk of early relapse (41.4% vs. 18.6%, p = 0.014), recurrence (65.5% vs. 39.8%, p = 0.020), and mortality (65.5% vs. 23.0%, p < 0.001) compared to HCV-negative patients. TriNetX data analysis revealed that HCV-positive patients had a 53% lower risk of developing melanoma (RR = 0.470, 95% CI: 0.443-0.498, p < 0.001). However, HCV-positive melanoma patients had higher all-cause mortality (HR = 1.360, 95% CI: 1.189-1.556, p < 0.001). An in silico analysis identified key molecular players, including IL-6 and CTLA4, in the HCV-melanoma network. Conclusions: While HCV infection may be associated with a lower risk of melanoma development, HCV-positive patients who develop melanoma have poorer outcomes. The identified molecular pathways provide potential targets for future research and therapeutic interventions.

Circulating Soluble Urokinase Plasminogen Activator Receptor as a Predictive Indicator for COVID-19-Associated Acute Kidney Injury and Mortality: Clinical and Bioinformatics Analysis.

Urokinase receptors regulate the interplay between inflammation, immunity, and blood clotting. The soluble urokinase plasminogen activator system is an immunologic regulator affecting endothelial function and its related receptor; the soluble urokinase plasminogen activator receptor (suPAR) has been reported to impact kidney injury. This work aims to measure serum levels of suPAR in COVID-19 patients and correlate the measurements with variable clinicolaboratory parameters and patient outcomes. In this prospective cohort study, 150 COVID-19 patients and 50 controls were included. The circulating suPAR levels were quantified by Enzyme-linked immunosorbent assay (ELISA). Routine COVID-19 laboratory assessments, including CBC, CRP, LDH, serum creatinine, and estimated glomerular filtration rates, were performed. The need for oxygen therapy, CO-RAD score, and survival rates was assessed. Bioinformatic analysis and molecular docking were run to explore the urokinase receptor structure/function and to characterize molecules as potential anti-suPAR therapeutic targets, respectively. We found higher circulating suPAR levels in COVID-19 patients vs. controls (p < 0.001). Circulating suPAR levels positively correlated with COVID-19 severity, the need for O2 therapy, the total leukocytes count, and the neutrophils to lymphocyte ratio, while they were negatively correlated with the O2 saturation level, albumin, blood calcium, lymphocytic count, and GFR. In addition, the suPAR levels were associated with poor prognostic outcomes such as a high incidence of acute kidney injury (AKI) and mortality rate. Kaplan-Meier curves showed a lower survival rate with higher suPAR levels. The logistic regression analysis confirmed the significant association of suPAR levels with the occurrence of AKI related to COVID-19 and with increased mortality probability within three months of COVID-19 follow-up. Some compounds that can act similarly to uPAR were discovered and tested by molecular docking to identify the possible ligand-protein interactions. In conclusion, higher circulating suPAR levels were associated with COVID-19 severity and could be considered a putative predictor of AKI development and mortality.

Asthma and COVID-19; different entities, same outcome: a meta-analysis of 107,983 patients.

OBJECTIVE: There are varying reports of the prevalence and effect of comorbid asthma in coronavirus disease-2019 (COVID-19) patients. We sought to conduct a meta-analysis comparing asthmatic and non-asthmatic patients to determine the clinical significance of preexisting asthma in COVID-19 patients. DATA SOURCES: Online databases PubMed, ScienceDirect, Web of Science, and Scopus, were searched up to July 15, 2020, for papers comparing asthma versus non-asthma COVID-19 patients. STUDY SELECTION: According to prespecified inclusion criteria, this analysis included eleven retrospective studies with 107,983 COVID-19 patients. Subgroup analysis was performed based on age groups. RESULTS: The mean age of the patients was 59.9 years (95%CI = 51.9-67.9). Across studies, the prevalence of asthma was 11.2% (95%CI: 9.1%-13.3%) among COVID-19 patients who attended the hospitals. Asthma patients were more likely to be younger (SMD = -0.36, 95%CI = -0.61 to -0.10, p = 0.005), and obese (OR = 1.98, 95%CI = 1.54-2.55, p < 0.001), there was no differential risk of hospitalization rate, ICU admission, or development of acute respiratory distress syndrome (ARDS) between asthmatic and non-asthmatic cohorts. However, asthmatic patients had increased risk of endotracheal intubation (RR = 1.27, 95%CI = 1.02-1.58, p = 0.030) especially patients aged <50 years (RR = 6.68, 95%CI = 1.76-11.13, p = 0.009). Despite this result, asthmatic patients had better recovery with a higher liability of being discharged and were less likely to die (RR = 0.80, 95%CI = 0.65-0.97, p = 0.026). CONCLUSION: To our knowledge, our meta-analysis is the largest to shed light on preexisting asthma as a predictor of intubation in COVID-19, especially in young and obese patients. Identifying high-risk groups is crucial for designing more effective intervention plans and optimization of efficient resource allocation.

Excess of cesarean births in pregnant women with COVID-19: A meta-analysis.

BACKGROUND: Studies have suggested that cesarean birth in pregnant women with COVID-19 may decrease maternal adverse events and perinatal transmission. This systematic review aimed to evaluate variations in clinical presentation, laboratory findings, and maternal/neonatal outcomes in COVID-19 patients who delivered vaginally versus via cesarean. METHODS: A comprehensive search following PRISMA guidelines was performed for studies published up to May 23, 2020, using PubMed, Web of Science, Scopus, Embase, Cochrane, Science Direct, and clinicaltrials.gov. Original retrospective and prospective studies, case reports, or case series with sufficient data for estimating the association of COVID-19 with different pregnancy outcomes with no language restriction and published in peer-reviewed journals were included. Pooled mean and arcsine transformation proportions were applied. Next, a two-arm meta-analysis was performed comparing the perinatal outcomes between the study groups. RESULTS: Forty-two studies with a total of 602 pregnant women with COVID-19 were included. The mean age was 31.8 years. Subgroup analysis showed that Americans had the lowest gestational age (mean = 32.7, 95%CI = 27.0-38.4, P < 0.001) and the highest incidence of maternal ICU admission (95%CI = 0.45%-2.20, P < 0.001) of all nationalities in the study. There was no significant difference in perinatal complications, premature rupture of membrane, placenta previa/accreta, or gestational hypertension/pre-eclampsia between women who delivered vaginally versus by cesarean. Importantly, there were also no significant differences in maternal or neonatal outcomes. CONCLUSION: Vaginal delivery was not associated with worse maternal or neonatal outcomes when compared with cesarean. The decision to pursue a cesarean birth should be based on standard indications, not COVID-19 status.

Association of B-cell lymphoma 2/microRNA-497 gene expression ratio score with metastasis in patients with colorectal cancer: A propensity-matched cohort analysis.

BACKGROUND: Deregulated microRNAs (miRs) significantly impact cancer development and progression. Our in silico analysis revealed that miR-497 and its target gene B-cell lymphoma-2 (BCL2) could be related to poor cancer outcomes. PURPOSE: To investigate the BCL2/miRNA-497 expression ratio in colorectal cancer (CRC) and explore its association with the clinicopathological characteristics and CRC prognosis. METHODS: Archived samples from 106 CRC patients were enrolled. MiR-497 and BCL2 gene expressions were detected by Taq-Man Real-Time quantitative polymerase chain reaction in propensity-matched metastatic and nonmetastatic cohorts after elimination of confounder bias. RESULTS: B-cell lymphoma-2 gene was upregulated in metastatic samples (median = 1.16, 95%CI = 1.09-1.60) compared to nonmetastatic (median = 1.02, 95%CI = 0.89-1.25, p < 0.001). In contrast, lower levels of miR-495 were detected in specimens with distant metastasis (median = 0.05, 95%CI = 0.04-0.20) than nonmetastatic samples (median = 0.54, 95%CI = 0.47-0.58, p < 0.001). Estimated BCL2/miR-497 ratio yielded a significant differential expression between the two cohort groups. Higher scores were observed in metastasis group (median = 1.39, 95%CI = 0.9-1.51) than nonmetastatic patients (median = 0.29, 95%CI = 0.19-0.39, p < 0.001). Receiver operating characteristic curve analysis showed BCL2/miR-497 ratio score to have the highest predictive accuracy for metastasis at presentation. The area under the curve was 0.90 (95%CI = 0.839-0.964, p < 0.001) at cut-off of >0.525, with high sensitivity 81.1% (95%CI = 68.6%-89.4%) and specificity 92.5% (95%CI = 82.1%-97.0%). Also, the ratio score was negatively correlated with disease-free survival (r = -0.676, p < 0.001) and overall survival times (r = -0.650, p < 0.001). Kaplan-Meier curves showed lower survival rates in cohorts with high-score compared to low-score patients. CONCLUSION: The BCL2/miR497 expression ratio is associated with poor CRC prognosis in terms of metastasis and short survival.

Analysis of anti-apoptotic PVT1 oncogene and apoptosis-related proteins (p53, Bcl2, PD-1, and PD-L1) expression in thyroid carcinoma.

BACKGROUND: An aberrant expression of long non-coding RNA PVT1 has been associated with apoptosis in various cancer types. We aimed to explore the PVT1 and four apoptosis-related proteins (p53, Bcl2, and PD-1/PD-L1) signature in thyroid cancer (TC). METHODS: The PVT1 expression level was measured in 64 FFPE TC paired samples by real-time quantitative PCR. Overall and stratified analyses by different clinicopathological features were done. The apoptotic proteins were evaluated by immunohistochemistry staining. RESULTS: Overall analysis showed significant PVT1upregulation in TC tissues (p < 0.001). Similarly, subgroup analysis by BRAFV600E mutation showed consistent results. Lower expression of p53 was associated with mortality (p = 0.001). Bcl2 overexpression was associated with greater tumor size (p = 0.005). At the same time, HCV-positive cases were associated with repressed Bcl2 expression levels (54.3% in HCV-negative vs. 6.9% in HCV-positive cases, p = 0.011). PD-1 expression was associated with lymph node metastasis (p = 0.004). Enhanced PD-L1 expression in the tumor was associated with a higher tumor stage, lymphovascular invasion, and mortality risk. Kaplan-Meier curves for overall survival showed that low p53 and high PD-L1 expressions were associated with lower survival time. The p53-positive staining is associated with a 90% decreased mortality risk (HR = 0.10, 95%CI = 0.02-0.47, p = 0.001), while patients with high PD-L1 were five times more likely to die (HR = 4.74, 95%CI = 1.2-18.7, p = 0.027). CONCLUSION: Our results confirm the upregulation of PVT1 in TC. The apoptosis-related proteins (p53, Bcl2, and PD-1/PD-L1) showed different prognostic utility in TC patients; in particular, low p53 and high PD-L1 expressions associated with low survival times. Further large-scale and mechanistic studies are warranted.

Trampoline Injuries in Children and Adolescents: A Jumping Threat.

OBJECTIVE: As trampoline use grows more popular in the United States, the frequency of injuries continues to climb. We hypothesized that toddlers would be at the highest risk for trampoline injuries requiring hospitalization. METHODS: The National Electronic Injury Surveillance System database was examined for trampoline injuries from 2009 to 2018. Patients were categorized into 3 main age groups: toddlers (<2 years), children (2-12 years), and adolescents (13-18 years). Regression models were used to identify patients at high risk for injury or hospitalization. RESULTS: There was a total of 800,969 meeting inclusion criteria, with 433,827 (54.2%) occurring at their own homes and 86,372 (18.1%) at the sporting venue. Of the total, 36,789 (4.6%) were admitted to a hospital. Fractures (N = 270,884, 34%), strain/sprain injuries (N = 264,990, 33%), followed by skin contusions/abrasions (N = 115,708, 14%) were the most common diagnoses. The most frequent injury sites were lower and upper extremities accounting for 329,219 (41.1%) and 244,032 (30.5%), whereas 175,645 (21.9%) had head and neck injuries. Musculoskeletal injuries (74%) and concussions (2.6%) were more frequent in adolescents than children (67.6% and 1.6%) and toddlers (56.3% and 1.3%). Internal organ and soft tissue injuries were frequent in toddlers. There were no fatalities reported in the injured patients. Multivariate analysis showed adolescents, female sex, extremity injuries, and musculoskeletal injuries were associated with hospitalization. Injury at a sporting venue was not associated with hospitalization. CONCLUSIONS: Adolescents and girls are at increased risk of trampoline injury, warranting hospitalization. Safety standards may help prevent extremity and musculoskeletal injuries in the pediatric population. Finally, use of trampolines at sporting venues does not appear to be particularly dangerous.

Time-varying Reproductive Rates for SARS-CoV-2 and its Implications as a Means of Disease Surveillance on Lockdown Restrictions.

OBJECTIVE: To quantify the time-varying reproductive rates for SARS-CoV-2 and its implication in Louisiana. SUMMARY OF BACKGROUND DATA: Basic reproductive number (R0) and effective reproductive number (Re or Rt) are 2 measures of the ability of an infectious agent to spread in the environment. They differ in that R0 assumes zero immunity in the population, while Re or Rt accounts for change over time. Reproductive number modeling is influenced by several factors, including serial interval, the time between the onset of symptoms in an infector, and a secondary case. Quantification of the ability of a pathogen to spread is essential in guiding policy. METHODS: Here, we construct epidemic curves and calculate daily Rt values for the state of Louisiana and each of its 9 regions. RESULTS: Our results demonstrated variation over both time and geography in calculated R0 and Rt values. Generally, as time has progressed, predicted R0 and Rt values have decreased. In Louisiana, mean Rt was calculated at 3.07 in March and 0.82 by May. A reproductive number less than one is important as it indicates infectious spread will decline with time. The most recent finding of mean Rt = 0.82 is important. It stands in stark contrast to the situation in April when New Orleans, Louisiana, had the highest per capita coronavirus mortality rate in the United States - twice that of New York City and 4 times the rate in Seattle. CONCLUSION: As locations around the world begin to lift restrictions, monitoring of infectious spread will be essential.

Vitamin D insufficiency as a potential culprit in critical COVID-19 patients.

BACKGROUND: As an immune modulator, vitamin D has been implicated in the coronavirus disease-2019 (COVID-19) outcome. We aim to systematically explore the association of vitamin D serum levels with COVID-19 severity and prognosis. METHODS: The standardized mean difference (SMD) or odds ratio and 95% confidence interval (CI) were applied to estimate pooled results from six studies. The prognostic performance of vitamin D serum levels for predicting adverse outcomes with detection of the best cutoff threshold was determined by receiver operating characteristic curve analysis. Decision tree analysis by combining vitamin D levels and clinical features was applied to predict severity in COVID-19 patients. RESULTS: Mean vitamin D serum level of 376 patients, was 21.9 nmol/L (95% CI = 15.36-28.45). Significant heterogeneity was found (I2 = 99.1%, p < .001). Patients with poor prognosis (N = 150) had significantly lower serum levels of vitamin D compared with those with good prognosis (N = 161), representing an adjusted standardized mean difference of -0.58 (95% Cl = -0.83 to -0.34, p < .001). CONCLUSION: Serum vitamin D levels could be implicated in the COVID-19 prognosis. Diagnosis of vitamin D deficiency could be a helpful adjunct in assessing patients' potential of developing severe COVID-19. Appropriate preventative and/or therapeutic intervention may improve COVID-19 outcomes.

Gastroenterology manifestations and COVID-19 outcomes: A meta-analysis of 25,252 cohorts among the first and second waves.

A meta-analysis was performed to identify patients with coronavirus disease 2019 (COVID-19) presenting with gastrointestinal (GI) symptoms during the first and second pandemic waves and investigate their association with the disease outcomes. A systematic search in PubMed, Scopus, Web of Science, ScienceDirect, and EMBASE was performed up to July 25, 2020. The pooled prevalence of the GI presentations was estimated using the random-effects model. Pairwise comparison for the outcomes was performed according to the GI manifestations' presentation and the pandemic wave of infection. Data were reported as relative risk (RR), or odds ratio and 95% confidence interval. Of 125 articles with 25,252 patients, 20.3% presented with GI manifestations. Anorexia (19.9%), dysgeusia/ageusia (15.4%), diarrhea (13.2%), nausea (10.3%), and hematemesis (9.1%) were the most common. About 26.7% had confirmed positive fecal RNA, with persistent viral shedding for an average time of 19.2 days before being negative. Patients presenting with GI symptoms on admission showed a higher risk of complications, including acute respiratory distress syndrome (RR = 8.16), acute cardiac injury (RR = 5.36), and acute kidney injury (RR = 5.52), intensive care unit (ICU) admission (RR = 2.56), and mortality (RR = 2.01). Although not reach significant levels, subgroup-analysis revealed that affected cohorts in the first wave had a higher risk of being hospitalized, ventilated, ICU admitted, and expired. This meta-analysis suggests an association between GI symptoms in COVID-19 patients and unfavorable outcomes. The analysis also showed improved overall outcomes for COVID-19 patients during the second wave compared to the first wave of the outbreak.

Association of cyclin-dependent kinase inhibitor 2B antisense RNA 1 gene expression and rs2383207 variant with breast cancer risk and survival.

BACKGROUND: The expression signature of deregulated long non-coding RNAs (lncRNAs) and related genetic variants is implicated in every stage of tumorigenesis, progression, and recurrence. This study aimed to explore the association of lncRNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) gene expression and the rs2383207A>G intronic variant with breast cancer (BC) risk and prognosis and to verify the molecular role and networks of this lncRNA in BC by bioinformatics gene analysis. METHODS: Serum CDKN2B-AS1 relative expression and rs2383207 genotypes were determined in 214 unrelated women (104 primary BC and 110 controls) using real-time PCR. Sixteen BC studies from The Cancer Genome Atlas (TCGA) including 8925 patients were also retrieved for validation of results. RESULTS: CDKN2B-AS1 serum levels were upregulated in the BC patients relative to controls. A/A genotype carriers were three times more likely to develop BC under homozygous (OR = 3.27, 95% CI 1.20-8.88, P = 0.044) and recessive (OR = 3.17, 95% CI 1.20-8.34, P = 0.013) models. G/G homozygous patients had a higher expression level [median and quartile values were 3.14 (1.52-4.25)] than A/G [1.42 (0.93-2.35)] and A/A [1.62 (1.33-2.51)] cohorts (P = 0.006). The Kaplan-Meier curve also revealed a higher mean survival duration of G/G cohorts (20.6 months) compared to their counterparts (A/A: 15.8 and A/G: 17.2 months) (P < 0.001). Consistently, BC data sets revealed better survival in cohorts with high expression levels (P = 0.003). Principal component analysis (PCA) showed a deviation of patients who had shorter survival towards A/A and A/G genotypes, multiple lesions, advanced stage, lymphovascular invasion, and HER2+ receptor staining. Ingenuity Pathway Analysis (IPA) showed key genes highly enriched in BC with CDKN2B-AS1. CONCLUSIONS: The findings support the putative role of CDKN2B-AS1 as an epigenetic marker in BC and open a new avenue for its potential use as a therapeutic molecular target in this type of cancer.

Annual flu shot: Does it help patients with COVID-19?

AIM OF THE STUDY: The impact of annual flu vaccination on the patients' clinical course with COVID-19 and the outcome were tested. METHODS: A total of 149 patients with COVID-19-positive admitted from March 20 to May 10, 2020, were retrospectively enrolled. RESULTS: Ninety-eight (65.8%) patients received at least a single annual flu shot in the last year, and fifty-one (34.2%) were never vaccinated. On presentation, vaccinated patients were more likely to present with gastrointestinal symptoms (P < .05). There were no significant differences between study groups in laboratory findings or clinical outcomes. In multivariate analysis, receiving the annual shot did not influence risk of intensive care unit admission (OR = 1.17, 95%CI = 0.50-2.72, P = .72), intubation (OR = 1.40, 95%CI = 0.60-3.23, P = .43), complications (OR = 1.08, 95%CI = 0.52-2.26, P = .83) or mortality (OR = 1.29, 95%CI = 0.31-5.29, P = .73). CONCLUSION: Although the benefits of the influenza vaccine for preventing disease and reducing morbidity in influenza patients are well established, no differences in outcomes for hospitalised patients with COVID-19 who received their annual influenza vaccination versus the non-vaccinated cohort were evident. There is a need for future meta-analyses, including randomised controlled studies in which the number of cases is increased to validate these findings.

Impact of cytotoxic T-lymphocyte-associated protein 4 codon 17 variant and expression on vitiligo risk.

BACKGROUND: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is one of the essential brakes expressed on T cells that prevent T-cell hyperactivation-associated autoimmune disorders. Several CTLA4 polymorphisms were implicated in the regulation of gene expression. We aimed to explore the association of CTLA4 expression and rs231775 (c.49A>G) variant with vitiligo risk and severity of the disease in a sample of the Middle Eastern population. METHODS: The CTLA4 gene expression and genotyping for rs231775 (A/G) variant were assessed in 161 vitiligo patients and 165 controls using a real-time polymerase chain reaction. Vitiligo Area Severity Index (VASI) and Vitiligo Disease Activity score (VIDA) were evaluated. RESULTS: A higher frequency of rs231775 G allele was observed in vitiligo cases than controls (45% vs. 33%, p = 0.002). After adjustment of age, sex, family history of vitiligo, and CTLA expression level, using multivariate analysis, G/G carriers were associated with a higher risk of vitiligo under recessive (OR = 2.94, 95% CI = 1.61-5.35, p < 0.001), dominant (OR = 1.87, 95% CI = 1.14-3.06, p = 0.013), and homozygote comparison (OR = 3.34, 95% CI = 1.73-6.42, p = 0.001) models. Although the CTLA4 relative expression levels were comparable to that of controls, G/G carriers exhibited a significantly lower expression profile (median = 0.63, IQR = 0.34-1.75) than A/A (median = 1.43, IQR = 0.39-4.25, p = 0.018) and A/G carriers (median = 1.68, IQR = 0.49-3.92, p = 0.007). No significant associations of CTLA4 variant/expression with disease severity and/or activity were observed. CONCLUSION: The CTLA4 rs231775 variant was associated with vitiligo susceptibility and gene expression; the risky genotype (GG) was associated with lower CTLA4 relative expression levels than the other genotypes. Further large-scale studies in different populations are warranted.

Prognostic value of BRAF/MIR-17 signature and B-Raf protein expression in patients with colorectal cancer: A pilot study.

BACKGROUND: Despite the recent improvement in colorectal cancer (CRC) treatment, it still has a poor prognosis with a low survival rate. Genetic and epigenetic mechanisms have proved to play a substantial role in CRC tumorigenesis and progression. According to Gene Ontology and TargetScan analyses, the B-Raf proto-oncogene (BRAF) gene is one of the microRNA-17 (miR-17) targets. We aimed to explore the prognostic value of B-Raf protein and BRAF/microRNA-17 (MIR-17) gene expression signature in CRC archived samples. METHODS: B-Raf protein expression was identified by immunohistochemistry, while gene expression studies were quantified by real-time qPCR in 53 paired archived CRC specimens. RESULTS: The BRAF showed higher expressions in CRC specimens relative to non-cancer tissues (p = 0.006). MIR17 expression was inversely and significantly correlated with both B-Raf protein (r = -0.79, p < 0.001) and gene expression (r = -0.35, p = 0.010) and showed a significant direct correlation with a high rate of relapse (p = 0.020). BRAF/miR-17 expression in CRC was associated inversely with tumor size, high grade of colonic carcinoma, lymph node metastasis, and carcinoma subtype. Spearman correlation and Kaplan-Meier survival curve analyses revealed that disease-free survival and overall survival were inversely and significantly correlated with positive B-Raf protein expression (r = -0.31 and -0.35, p = 0.023 and 0.011, respectively) and directly correlated with log BRAF/MIR17 ratio (r = 0.50 and 0.41, p < 0.001 and = 0.003, respectively). Cox hazard regression analysis revealed the BRAF/MIR17 ratio could predict both types of patients' survival, among other variables. CONCLUSION: BRAF/MIR17 ratio could have prognostic utility in patients with CRC. Further larger-scale studies are warranted to confirm this utility.

Association of VEGF Gene Family Variants with Central Macular Thickness and Visual Acuity after Aflibercept Short-Term Treatment in Diabetic Patients: A Pilot Study.

INTRODUCTION: Diabetic retinopathy (DR) is one of the major vision-threatening causes worldwide. Searching for an individualized therapeutic strategy to prevent its progress is challenging. OBJECTIVE: This work aimed to investigate the association of angiogenesis-inducer vascular endothelial growth factor (VEGF) gene family and related receptor variants (rs833069, rs12366035, rs7664413, rs7993418, and rs2305948) with susceptibility of DR and the response to 1 dose of aflibercept treatment in type 2 diabetes mellitus (T2DM). METHODS: Consecutive eligible patients with T2DM (n = 125) and 110 unrelated controls were enrolled in this preliminary prospective case-controlled study. Genotyping was identified using TaqMan real-time PCR. Adjusted odds ratio (OR) with 95% confidence interval (CI) was applied to assess the strength of the association with the clinical/ophthalmological characteristics and early response to intravitreal aflibercept treatment in terms of improved visual acuity (BCVA) and central macular thickness (CMT). RESULTS: We found that both VEGFB rs12366035 and VEGFC rs7664413 conferred higher risk for DR progression under allelic (OR [95% CI]: 1.71 [1.07-2.74]), homozygote comparison (3.55 [1.32-9.57]), and recessive (3.77 [1.43-9.93]) models for the former and under allelic (2.09 [1.25-3.490, homozygote comparison (2.76 [1.02-7.45]), and recessive (2.62 [0.98-6.98] models for the latter. In contrast, VEGFR1 rs7993418 conferred protection against DR under heterozygote comparison and dominant models. The rs12366035*T/T genotype showed the worst pretreatment BCVA score (0.35 ± 0.24) compared to other corresponding genotypes (0.66 ± 0.26 in C/T and 0.54 ± 0.25 in C/C carriers) (p = 0.008). Meanwhile, patients with rs7993418*G/G of VEGFR1 exhibited a significant reduction in CMT after aflibercept injection (12.26 ± 35.43 µ in G/G vs. 3.57 ± 8.74 µ in A/A) (p = 0.037). CONCLUSIONS: Polymorphisms of the studied VEGF/receptors could be considered as genetic risk factors of DM/DR development and could play an important role in aflibercept early response for DR patients in the study population.

Association of cardiac biomarkers and comorbidities with increased mortality, severity, and cardiac injury in COVID-19 patients: A meta-regression and decision tree analysis.

BACKGROUND: Coronavirus disease-2019 (COVID-19) has a deleterious effect on several systems, including the cardiovascular system. We aim to systematically explore the association of COVID-19 severity and mortality rate with the history of cardiovascular diseases and/or other comorbidities and cardiac injury laboratory markers. METHODS: The standardized mean difference (SMD) or odds ratio (OR) and 95% confidence intervals (CIs) were applied to estimate pooled results from the 56 studies. The prognostic performance of cardiac markers for predicting adverse outcomes and to select the best cutoff threshold was estimated by receiver operating characteristic curve analysis. Decision tree analysis by combining cardiac markers with demographic and clinical features was applied to predict mortality and severity in patients with COVID-19. RESULTS: A meta-analysis of 17 794 patients showed patients with high cardiac troponin I (OR = 5.22, 95% CI = 3.73-7.31, P < .001) and aspartate aminotransferase (AST) levels (OR = 3.64, 95% CI = 2.84-4.66, P < .001) were more likely to develop adverse outcomes. High troponin I more than 13.75 ng/L combined with either advanced age more than 60 years or elevated AST level more than 27.72 U/L was the best model to predict poor outcomes. CONCLUSIONS: COVID-19 severity and mortality are complicated by myocardial injury. Assessment of cardiac injury biomarkers may improve the identification of those patients at the highest risk and potentially lead to improved therapeutic approaches.

Association of Autoimmune Regulator Gene Rs2075876 Variant, but Not Gene Expression with Alopecia Areata in Males: A Case-control Study.

Alopecia areata (AA) is a non-scarring hair loss of autoimmune etiology. The autoimmune regulator (AIRE) gene is believed to be an important driver in AA pathogenesis. Genetic variants can alter mRNA expression levels which may provoke an autoimmune response. A total of 337 males (97 AA patients and 240 controls) were enrolled in the current case-control study. On screening of the most frequent variants in the gene, rs2075876 (A/G) polymorphism in intron 5 was selected and genotyped using Real-Time PCR (polymerase chain reaction) technology. Additionally, circulatory AIRE expression levels were quantified by quantitative reverse-transcription PCR (qRT-PCR). Allelic discrimination analysis revealed GG genotype to be more frequent in patients (90.7% in AA compared to 32.5% in controls, p < .001). G variant conferred increased risk to alopecia under homozygote comparison (GG versus AA: OR = 16.1, 95%CI = 5.57-46.3), dominant model (GG+AG versus AA: OR = 7.24, 95%CI = 2.5-20.5), recessive model (GG versus AG+AA: OR = 20.3, 95%CI = 9.7-42.4), and allelic model (G versus A: OR = 11.6, 95%CI = 6.47-21.1). The expression levels of AIRE gene did not differ significantly between patients and controls and were not related to rs2075876 variant. In conclusion, the intronic variant (rs2075876) is suggested to be a potent susceptibility variant for AA development in the studied population.Abbreviations: AA: Alopecia areata; AIRE: Autoimmune Regulator; APECED: Autoimmune, Polyendocrinopathy Candidiasis Ectodermal Dystrophy; DLQI: Dermatology life quality index questionnaire; MIQE: Minimum information for publication of quantitative real-time PCR experiments; mTEC: Medullary thymic epithelial cells; PHD: Plant homeodomain; qRT-PCR: Quantitative reversetranscription-polymerase chain reaction; RA: Rheumatoid arthritis.

Analysis of the autoimmune regulator (AIRE) gene variant rs2075876 (G/A) association with breast cancer susceptibility.

BACKGROUND: Recently, unexpected autoimmune regulator (AIRE) implication in the scenario of several cancers, including breast cancer (BC), has emerged. This study aims to explore for the first time the possible association between AIRE gene rs2075876 G>A variant and BC risk in a sample of the Middle East population. METHOD: In this case-control study, we genotyped AIRE rs2075876 G>A variant in 200 unrelated patients with BC and 340 cancer-free controls using a real-time allelic discrimination polymerase chain reaction. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to estimate the strength of association under several genetic models. In silico analysis of AIRE was also executed. RESULTS: The minor allele (A) frequency of the specified variant accounted for 0.28 in the controls. G/G homozygote was significantly more frequent among patients (94%) compared to controls (66%) (P < .001). After adjusting confounding variables, individuals with A allele conferred protection against developing BC under allelic model (OR = 0.33, 95% CI = 0.20-0.55), recessive model (OR = 0.25, 95% CI = 0.10-0.60), dominant model (OR = 0.12, 95% CI = 0.05-0.29), and homozygote comparison (OR = 0.20, 95% CI = 0.08-0.50). In silico analysis revealed AIRE enrichment in several cancer-related pathways. Kaplan-Meier plotter for the cancer databases showed association of AIRE expression with prognosis in triple-negative BC (HR = 2.44, 95% CI = 1.44-4.15, log-rank P-value < .001). CONCLUSION: The AIRE rs2075876 G>A variant showed association with BC risk in the study population. Further large-scale replication studies in different ethnicity are warranted to confirm the findings.