Risk Factor For Susceptibility Research Articles

In Prostate Cancer Cells Cytokines Are Early Responders to Gravitational Changes Occurring in Parabolic Flights

The high mortality in men with metastatic prostate cancer (PC) establishes the need for diagnostic optimization by new biomarkers. Mindful of the effect of real microgravity on metabolic pathways of carcinogenesis, we attended a parabolic flight (PF) mission to perform an experiment with the PC cell line PC-3, and submitted the resulting RNA to next generation sequencing (NGS) and quantitative real-time PCR (qPCR). After the first parabola, alterations of the F-actin cytoskeleton-like stress fibers and pseudopodia are visible. Moreover, numerous significant transcriptional changes are evident. We were able to identify a network of relevant PC cytokines and chemokines showing differential expression due to gravitational changes, particularly during the early flight phases. Together with differentially expressed regulatory lncRNAs and micro RNAs, we present a portfolio of 298 potential biomarkers. Via qPCR we identified IL6 and PIK3CB to be sensitive to vibration effects and hypergravity, respectively. Per NGS we detected five upregulated cytokines (CCL2, CXCL1, IL6, CXCL2, CCL20), one zink finger protein (TNFAIP3) and one glycoprotein (ICAM1) related to c-REL signaling and thus relevant for carcinogenesis as well as inflammatory aspects. We found regulated miR-221 and the co-localized lncRNA MIR222HG induced by PF maneuvers. miR-221 is related to the PC-3 growth rate and MIR222HG is a known risk factor for glioma susceptibility. These findings in real microgravity may further improve our understanding of PC and contribute to the development of new diagnostic tools.

Role of single nucleotide polymorphisms of the HSD3B1 gene (rs6203 and rs33937873) in the prediction of prostate cancer risk

3-β-hydroxysteroid dehydrogenase 1 (HSD3B1) is shown to affect dihydrotestosterone level in prostatic tissue which is a risk factor for prostate cancer (PC). The present study aimed to determine whether rs33937873 (G313A) and rs6203 (C338T) single nucleotide polymorphisms (SNP) in HSD3B1 gene was a potential risk factor for PC susceptibility and can predict the recurrence of PC in Egyptian patients. A total of 186 Egyptian patients were selected with incident primary PC and compared with 180 age healthy controls. The frequencies and the main effect of rs33937873 and rs6203 in HSD3B1 were compared and investigated between the patients and control using genotyping technique and statistical analysis. The mutant GA genotype of G313A in rs33937873 SNP was considered as an independent risk for PC in the multivariate regression analysis [odds ratio (OR)=2.7, 95% confidence intervals (CI): 1.2-5.5, P=0.01] together with positive history of hypertension (HTN) (OR=6.2, 95% CI: 3.2-12.1, P=0.0001) and begin prostatic hyperplasia (BPH; OR=8.9, 95% CI: 4.5-17.5, P=0.0001). Conversely, in rs6203 (C338T), C allele is considered as major risk allele in the development of PC (OR=1.8, 95% CI: 1.3-2.4, P=0.0003). The univariate logistic regression analyses indicated that CC genotype of rs6203 was a PC risk factor (OR=1.9, 95% CI: 1.3-2.9, P=0.002). In addition, the frequency of the A-C haplotype established by rs33937873-rs6203 was also significantly higher for PC (P=0.013). The predication of PC recurrence was associated only with positive family history (OR=7.7, 95% CI: 2.3-25.9, P=0.001) and not for The G313A and C338T SNPs. These results suggested that the two HSD3B1 polymorphisms rs33937873 and rs6203 may modify the risk of PC, particularly among patients with HTN and history of BPH, suggesting them as prominent future markers for prediction of PC risk.

Study of ABO System and Multiple Sclerosis disease in Iraq

Multiple sclerosis (MS) is one of an autoimmune condition with uncertain etiopathology. According to new data, ABO system had played a role in the development and understanding numerous diseases. Lower level of 25-hydroxy vitamin D3 (25-OHD3) is considered as a risk factor for MS. The aims of this study is to identify the role of blood group distribution on the levels of parathyroid hormone (PTH), 25-OHD3, total calcium, inorganic phosphorus and total magnesium on MS patients. Additionally, we assessed the relation between Expanded Disability Status Scale (EDSS) and study parameters in patients. The Study included 107 patients with MS were distributed in to four groups according to their blood group (A, B, AB, and O). Additionally, 124 apparently healthy individuals as control group. Tukey analysis was showed the level of 25-OHD3 in patients with B+ was significant decrease than O+ and A+ patients group (P≤0.05). Furthermore, EDSS was negatively correlated with 25-OHD3 (P≤0.05) in B+ and O+ patient groups. Through this study, ABO group may be consider as a risk factor for MS susceptibility as another interesting variable.

Abstract 2216: Impact of EXO1 (K589E) single nucleotide polymorphism on breast cancer risk in Bangladeshi women

Abstract Background and aim: Exonuclease 1 (EXO1) is an essential member of the RAD2 nuclease family which is involved in mismatch repair system and contributes to the maintenance of genomic stability, modulation of DNA recombination and cell cycle arrest mediation. Potential polymorphism in EXO1 may have the ability to control cancer risks by influencing the repair activity. K589E (rs1047840) is a potentially functional polymorphism in EXO1 gene and we hypothesized that it might be associated with risk of breast cancer in Bangladesh. Method: We designed a case-control study consisting of 184 subjects with breast cancer and 200 healthy controls to identify the effect of K589E polymorphism on breast cancer susceptibility and clinicopathological features in Bangladeshi women. Genotype determination was performed by PCR-RFLP method. Results: After the adjustment of age and weight, a significant association was found between EXO1 K589E alleles and genotypes and risk of breast cancer. The frequencies of the three genotypes G/G, G/A, and A/A were 49, 42, and 9% in cases whereas 69, 27.5, and 3.5% in controls, respectively. The heterozygote G/A genotype and combined G/A+A/A genotypes showed 2.12-fold (OR=2.12, 95% CI=1.3733 - 3.2822 p=0.0007) and 2.27-fold (OR=2.27, 95% CI=1.5001 - 3.4493, p=0.0001) increased risk of breast cancer, respectively when compared with homozygous G/G genotypes. The variant A allele also was associated with increased risk of breast cancer (OR= 3.46, 95% CI=1.3720 - 8.7571, p=0.0086). Analysis of clinicopathological characteristics and genotype distribution also showed a significant correlation. Conclusion: Our results revealed that EXO1 K589E polymorphism could be a potential predisposing risk factor in genetic susceptibility to breast cancer in Bangladesh. Citation Format: Md. Mustafizur Rahman, Md. Mahmudul Kabir, Md. Abdur Rahman, Amir Hossain, Md. Golam Hossain. Impact of EXO1 (K589E) single nucleotide polymorphism on breast cancer risk in Bangladeshi women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2216.

SARS-CoV-2 infection in patients with inborn errors of immunity due to DNA repair defects.

Clinical information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with inborn errors of immunity (IEI) during the current Coronavirus disease 2019 (COVID-19) pandemic is still limited. Proper DNA repair machinery is required for the development of the adaptive immune system, which provides specific and long-term protection against SARS-CoV-2. This review highlights the impact of SARS-CoV-2 infections on IEI patients with DNA repair disorders and summarizes susceptibility risk factors, pathogenic mechanisms, clinical manifestations and management strategies of COVID-19 in this special patient population.

Genetic variations in NLRP1 and Glutathione S-Transferase are associated with Generalized Vitiligo of Phlegmatic Clinical Phenotypes in Unani Medicine Philosophy of South Indian Population

Background: Generalized vitiligo is a common, multifaceted, polygenic condition in which autoimmune loss of melanocytes results in depigmented skin patches, overlying hair and mucous membranes. NLRP1 has been proposed to be implicated in the susceptibility of a broad variety of autoimmune disorders, including generalized vitiligo (GV). Genetic polymorphisms in the NLRP1 encoding gene (formerly known as NALP1) have previously been found to be linked with GV and there is uncertainty as to their role in the modulation of NLRP1 expression. Oxidative stress is a significant pathogenesis theory for vitiligo. Glutathione S-transferases (GSTs) are enzymes active in the defense of cells against chemical toxicity and stress.This study validates some of the Unani concepts of humors or temperaments (Phenotypes), with regard to Vitiligo, Where vitiligo is regarded as a phlegmatic disease. We selected Vitiligo subjects with Phlegmatic Clinical Phenotype for our study, with an aim to determine its association with the genetic biomarkers- NLRP1, GSTM1 and GSTT1 null genotypes and other biochemical parameters. Methods: The Unani clinicians randomly selected 100 vitiligo patients with a phlegmatic Clinical Phenotype who were attending NRIUMSD for treatment and 100 healthy volunteers belonging to Phlegmatic (Phlegmatic clinical Phenotype). Besides looking at temperaments/ humors as susceptibility factors – we included a genetic factor- NLRP1, GSTM1- and GSTT1-null genotypes to our investigation. We have genotyped the NLRP1, GSTM1- and GSTT1-null genotypes by PCR-RFLP and by Multiplex PCR, GST protein level estimation by ELISA method. Results: NLRP1 rs2670660 polymorphism was shown to be in significant association with GV, with the presence of minor alleles in active GV. We found that the frequencies of GSTM1 null genotype and GSTT1 null genotype in vitiligo patients were significantly high compared to the controls (OR= 1.47, 95% CI=0.765--2.861), (OR = 4.75, 95% CI = 2.131-10.63), respectively. In combination analysis with both genes, the results suggested significant association of vitiligo risk with both GSTM1\GSTT1 null genotypes (OR=4.83, 95% CI=1.523– 15.32).We observed a significant decrease (p<0.001) in GST protein levels. Conclusion: Our findings indicate that NLRP1 rs2670660 polymorphism may be genetic risk factor for susceptibility to GV and the null genotypes of GSTM1 and GSTT1 of both genes increase the risk of the disease. A significant decrease (p<0.001) in GST protein levels appeared to be a key feature in Vitiligo subjects, Therefore, detection of antioxidant enzyme levels can be effective biomarkers for early detection of the disease. We believed that GSTM1-and GSTT1-null genotype polymorphisms were associated with an increased risk of vitiligo. This is the first study of its kind along with Clinical Phenotype as per Unani Philosophy.

RORA polymorphisms are risk factors for allergic rhinitis susceptibility in the Shaanxi Han population

BackgroundAllergic rhinitis (AR) is the most common inflammatory disorder induced by complex interactions between genetic and environmental factors. Genetic predisposition is the most important factor in the progression of AR. Previous studies have indicated that RORA is involved in the occurrence of AR. The present study aimed to determine the roles of RORA polymorphisms in AR susceptibility. MethodsPeripheral blood samples were collected from 990 patients with AR and 1004 normal controls. Four single nucleotide polymorphisms (SNPs) in the RORA gene were detected by MassARRAY iPLEX platform. The associations of RORA polymorphisms with AR risk were determined according to logistic regression analysis. We further evaluated the impact of SNP-SNP interaction on AR risk using multifactor dimensionality reduction (MDR) method. ResultsOur results showed that rs10519067 (OR 0.38, p = 0.021), rs10519068 (OR 0.45, p = 0.030), and rs11071559 (OR 0.83, p = 0.032) were significantly related to a decreased susceptibility to AR. Stratified analyses found that rs10519067 (OR 0.71, p = 0.046) and rs10519068 (OR 0.63, p = 0.010) could decrease the risk of AR in males.Rs10519068 (OR 0.73, p = 0.022), rs11071559 (OR 0.77, p = 0.041), and rs9302216 (OR 0.38, p = 0.017) significantly reduced the susceptibility to AR in people aged > 43 years. Furthermore, it was found that rs10519067 (OR 0.29, p = 0.032), rs10519068 (OR 0.72, p = 0.013), and rs11071559 (OR 0.36, p = 0.015) had a protective effect on AR patients with BMI ≤ 24 kg/m2. MDR revealed that the combination of rs10519067, rs10519068, rs11071559, and rs9302216 was the best predictive model for AR. ConclusionOur study suggests that RORA polymorphisms may play a protective role in the development of AR.

The Common Haplotype GATGACA in Surfactant-Protein B Gene Is Protective for Respiratory Distress Syndrome in Preterm Neonates.

BackgroundRespiratory distress syndrome (RDS), a disorder of primary surfactant deficiency resulting in pulmonary insufficiency, remains a significant problem for preterm neonates. Associations between genetic variants of surfactant proteins and RDS have been reported, but haplotypes of the surfactant protein B gene (SFTPB) have not been studied. The aim of the study was to prove the hypothesis that certain haplotypes of SFTPB may be protective or risk factors for RDS.MethodsThe study was performed with 149 preterm infants, born <34 weeks of gestation, with 86 infants with mild RDS or without RDS (control group) and 63 infants with severe RDS (patient group). RDS was considered severe if multiple doses of exogenous surfactant and/or mechanical ventilation within the first 72 h of life were needed. The venous blood sample was used for the analysis of gene polymorphisms associated with RDS, genotyping, and haplotype estimation. Multivariate logistic regression analysis and the odds ratio were calculated to detect the contribution of the studied variables to the development of RDS.ResultsA new association of the common single nucleotide polymorphism (SNP) rs2304566 with RDS in premature infants was detected. Analysis of rs2304566 polymorphisms using a logistic regression model showed that there are two significant predictors inversely related to the occurrence of RDS (Apgar score of 5 min, CT and TT genotype in rs2304566 polymorphism). Gestational age, birth weight, and sex have border significance. Moreover, in the patient group, the frequency of the GATGACA haplotype in the SFTPB gene was lower (p = 0.037), and the GATGGCA haplotype was higher (p = 0.059) in comparison with the control group.ConclusionThe common haplotype GATGACA of the SFTPB gene can be protective against RDS in preterm infants. The trend of a higher frequency of GATGGCA in the SFTPB gene in infants with severe RDS suggests that this haplotype may be a risk factor for RDS susceptibility.

Telomere Length and COVID-19 Outcomes: A Two-Sample Bidirectional Mendelian Randomization Study.

Observational studies have found a relationship between directly measured short leukocyte telomere length (LTL) and severe coronavirus disease 19 (COVID-19). We investigated the causal association between genetically predicted LTL and COVID-19 susceptibility or severity. A previous genome-wide association study (GWAS) of 78,592 European-ancestry participants identified single nucleotidepolymorphisms (SNPs) that can be utilized to genetically predict LTL. Summary-level data for COVID-19 outcomes were analyzed from the COVID-19 Host Genetics Initiative. A two-sample bidirectional Mendelian randomization (MR) study was designed to evaluate these causal relationships. Using an inverse-weighted MR analysis and population-based controls, genetically predicted LTL did not reveal any significant association with COVID-19 susceptibility (odds ratio (OR): 0.94; 95% CI: 0.85–1.04; p = 0.202) or severity (OR: 0.85; 95% CI: 0.70–1.03; p = 0.099). Similar results were found for five other definitions of cases/controls and/or COVID-19 outcomes. Six additional MR methods and sensitivity analyses were conducted after removing variants with potential horizontal pleiotropy and including variants at a liberal significance level, which produced similar results. Using SNPs identified for the prediction of LTL from another GWAS study, we found a non-significant association for COVID-19 susceptibility or severity with narrower CIs toward the null hypothesis. No proof of genetically predicted COVID-19 phenotypes remained causally associated with genetically predicted LTL, and the null association was consistent with a lack of significant genetic correlation. Genetic evidence does not support shorter LTL as a causal risk factor for COVID-19 susceptibility or severity.

The Role of Vitamin D in Immune System and Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a nonspecific inflammatory disease that includes ulcerative colitis (UC) and Crohn’s disease (CD). The pathogenesis of IBD is not fully understood but is most reported associated with immune dysregulation, dysbacteriosis, genetic susceptibility, and environmental risk factors. Vitamin D is an essential nutrient for the human body, and it not only regulates bone metabolism but also the immune system, the intestinal microbiota and barrier. Vitamin D insufficiency is common in IBD patients, and the abnormal low levels of vitamin D are highly correlated with disease activity, treatment response, and risk of relapse of IBD. Accumulating evidence supports the protective role of vitamin D in IBD through regulating the adaptive and innate immunity, maintaining the intestinal barrier and balancing the gut microbiota. This report aims to provide a broad overview of the role vitamin D in the immune system, especially in the pathogenesis and treatment of IBD, and its possible role in predicting relapse.

Epidemiology, Drug Susceptibility, and Clinical Risk Factors in Patients With Invasive Aspergillosis.

BackgroundThis study aimed to investigate the Aspergillus species distribution, antifungal sensitivities, clinical characteristics, and risk factors of patients with invasive aspergillosis (IA) in a tertiary teaching hospital in Anhui Province.MethodsIn the present study, 156 Aspergillus isolates were collected from patients admitted to a 2,800-bed comprehensive hospital between January 2019 and April 2021. The epidemiology of Aspergillus species was well-examined, and its antifungal susceptibility was specifically measured by the microbroth dilution method. The risk factors of patients with IA were documented and analyzed intensively. In addition, gene sequencing was employed to determine gene mutations of cytochrome P450 14-α sterol demethylase-Aspergillus (cyp51A) associated with azole resistance among Aspergillus fumigatus.ResultsThe Aspergillus species distribution was dominated by A. fumigatus (56.41%), Aspergillus flavus (20.51%), and Aspergillus niger (15.38%) locally. In particular, all Aspergillus species showed very low minimum inhibitory concentrations (MICs, ≤ 0.5 μg/ml) for azoles and echinocandins, slightly high MICs (1.66–2.91 μg/ml) for amphotericin B, and exceptionally high MICs (>64 μg/ml) for flucytosine. Azole-resistant rate of Aspergillus species in this local region reached up to 5.79%. Correlation analyses of multiple antifungals indicate a significant MIC relevance between isavuconazole and voriconazole (Pearson correlation coefficient was 0.81, P < 0.0001). The clinical risk factors for patients with IA were found primarily to be pulmonary diseases (P = 0.007) and patients' age (P < 0.001). Notably, three mutant loci (TR46/Y121F/T289A) of the cyp51A gene were identified in azole-resistant A. fumigatus.ConclusionsThe Aspergillus species emerged increasingly, of which A. fumigatus and A. flavus remained the main pathogens for invasive Aspergillus infections in the local region. The vast majority of Aspergillus species exhibited good susceptibility to all the antifungals, except flucytosine. The local occurrence of azole-resistant Aspergillus species grew gradually and needed monitoring in time. Pulmonary diseases and age were likely considered as highly associated risk factors for IA. To our knowledge, the clinically isolated azole-resistant A. fumigatus with TR46/Y121F/T289A mutations identified here were rarely reported in the area of China.

198P Association between BTLA polymorphisms and NSCLC risk

Importance of immune checkpoints molecules in NSCLC was proven by the introduction of blockade of these receptors in routine treatment. B and T lymphocyte attenuator (BTLA) is another immune checkpoint molecule that regulates immune response. Our previous studies showed a significant association between BTLA gene variants and susceptibility to renal cell carcinoma and chronic lymphoblastic leukemia. The aim of this study was to verify the hypothesis that BTLA polymorphic variants are associated with susceptibility to NSCLC. Genomic DNA was isolated from the venous blood of 384 patients diagnosed with NSCLC and 475 controls. Using TaqMan probes we genotyped seven BTLA SNPs: rs1982809, rs1844089, rs9288952, rs9288953, rs2705511, rs2633582, and rs11921669 on ViiA 7 Real-Time PCR System. Statistical analysis of genotypes and alleles distributions for all investigated BTLA SNPs showed that SNP rs1982809 may be associated with susceptibility to NSCLC. In particular presence of G allele at rs1982809 (AG+GG genotypes) was more frequent in NSCLC group compared to controls (38.8% vs 45.3%, p=0.056). Allele distribution showed that the presence of allele G in rs1982809 significantly increases NSCLC risk (OR=1.25, p=0.046). For other studied SNPs in the overall analysis, we did not observe differences between NSCLC patients and controls. However, in the subgroup analysis we found that in patients with adenocarcinoma (AD) genotypes distribution of rs1982809 was significantly different between AD patients and controls (p=0.048). Moreover, we noticed the trend for overrepresentation of rs2705511[C] allele (AC+CC genotypes) in patients with AD compared to controls (43.4% vs 53%, p=0.079). After stratification by gender, we observed an association between the presence of rs9288953[T] and NSCLC susceptibility (p=0.004) in females. The global distributions of the haplotypes did not differ significantly between the cases and controls. However, we noticed that the global distribution of the haplotypes differs significantly between the never-smokers and smokers (p=0.0003). Results of our study show that rs1982809 in BTLA gene might be considered a low penetrating risk factor for NSCLC susceptibility in the Polish population.

Celiac Disease and the Susceptibility of COVID-19 and the Risk of Severe COVID-19: A Mendelian Randomization Study.

INTRODUCTION:Previous observational studies have found that the susceptibility of coronavirus disease 2019 (COVID-19) and the risk of severe COVID-19 are not increased in patients with celiac disease (CeD). However, the findings of observational studies are prone to bias due to reverse causation and confounding factors, especially in the case of a newly emerged disease. In this study, we aimed to further clarify the underlying relationship by both observational and Mendelian randomization (MR) analysis.METHODS:This observational study was conducted in the UK Biobank cohort. Univariate and multivariate logistic regression analyses were performed to identify the risk factors of COVID-19 susceptibility and severe COVID-19. To understand the causality between CeD and COVID-19 susceptibility and severe COVID-19, we performed a 2-sample MR analysis.RESULTS:Our observational study showed that patients with CeD had a lower susceptibility of COVID-19 (odds ratio [OR] = 0.699, P = 0.006) while CeD was not significantly associated with severe COVID-19 (P > 0.05). The findings from our MR study further demonstrated that both the susceptibility to COVID-19 (OR = 0.963, P = 0.006) and severe COVID-19 (OR = 0.919, P = 0.049) were lower in patients with CeD, although the former seemed to be specific to the UK Biobank cohort.DISCUSSION:Our results suggested that it may be unnecessary to take extra COVID-19 precaution in patients with CeD.

Low serum levels of zinc and 25-hydroxyvitmain D as potential risk factors for COVID-19 susceptibility: a pilot case-control study.

Background and aimsThis study aimed to evaluate serum 25-hydroxyvitmain D and zinc levels in coronavirus disease 2019 (COVID-19) patients in comparison to healthy subjects.MethodsThis was a single-center case-control study performed from March 20, 2020, to January 20, 2021, in Tehran, Iran. All patients diagnosed with COVID-19 based on a positive nasopharyngeal swab polymerase chain reaction (PCR) test were included in the case group. Controls were selected from patients referred for routine checkups who had a negative COVID-19 PCR test. Age, sex, marital and educational status, comorbidities, and serum 25-hydroxyvitmain D and zinc levels of patients were recorded.ResultsNinety patients in the case group and 95 subjects in the control group who were sex and age-matched were studied. 25-hydroxyvitmain D levels higher than 20 ng/ml were observed in 58 (64%) cases and 72 (76%) controls (P = 0.09). The median 25-hydroxyvitmain D level in the case group was significantly lower than controls (26 (interquartile range [IQR] = 24) ng/ml vs. 38 (IQR = 22) ng/ml, respectively, P < 0.01). The median zinc level in the case group was 56 (IQR = 23) mcg/dL, while it was 110 (IQR = 27) mcg/dL among the controls (P < 0.01). There was no significant difference in the level of 25-hydroxyvitmain D and zinc between cases with and without comorbidities (P > 0.05). Susceptibility to SARS-CoV-2 infection could be predicted by serum 25-hydroxyvitmain D levels below 25.2 ng/ml (81% sensitivity; 48% specificity) or zinc levels below 86.3 mcg/dL (93% sensitivity; 92% specificity).ConclusionsLow serum zinc and 25-hydroxyvitmain D levels appear to be risk factors for COVID-19 affliction; thus, the treatment of individuals with such deficiencies is recommended.

Lnc-HNF1A-AS1 and its target gene ATG5 is dysregulated in HLA-DRB1*15:01-negative female patients with multiple sclerosis

Human investigations and animal model studies have confirmed that autophagy process plays crucial roles in multiple sclerosis (MS) predisposition. In addition, the essential role of long noncoding RNAs (lncRNAs) in MS development has been recently reported. Current study aimed to investigate the expression level of lnc-HNF1A-AS1 as a new lncRNA and its target gene ATG5 in patients with MS. A total of 50 female patients with MS and 50 female healthy subjects were included in this observational case-control study. HLA-DRB1*15:01 allele, as a main risk factor for MS susceptibility, was ruled out in all included patients. The peripheral blood samples were obtained from all patients and total RNA was extracted and cDNA synthesis was performed. The gene expression level of lnc-HNF1A-AS1 and ATG5 was evaluated by Real-time quantitative PCR. Our results have shown that expression level of lnc-HNF1A-AS1 and ATG5 was significantly higher in total MS patients compared with controls (P-value = 0.0278 and P-value = 0.0064, respectively). In addition, there was statistically significant correlation between lnc-HNF1A-AS1 expression level with age of onset (r = 0.2937, P-value <0.05). Current study indicated abnormal up-regulation of two autophagy-related genes in the peripheral blood of HLA-DRB1*15:01-negative MS female patients compared with healthy controls. Therefore, autophagy-related mechanisms might be implicated in the pathobiology of MS in this subpopulation.

Dysfunction of EAAT3 Aggravates LPS-Induced Post-Operative Cognitive Dysfunction.

Numerous results have revealed an association between inhibited function of excitatory amino acid transporter 3 (EAAT3) and several neurodegenerative diseases. This was also corroborated by our previous studies which showed that the EAAT3 function was intimately linked to learning and memory. With this premise, we examined the role of EAAT3 in post-operative cognitive dysfunction (POCD) and explored the potential benefit of riluzole in countering POCD in the present study. We first established a recombinant adeno-associated-viral (rAAV)-mediated shRNA to knockdown SLC1A1/EAAT3 expression in the hippocampus of adult male mice. The mice then received an intracerebroventricular microinjection of 2 μg lipopolysaccharide (LPS) to construct the POCD model. In addition, for old male mice, 4 mg/kg of riluzole was intraperitoneally injected for three consecutive days, with the last injection administered 2 h before the LPS microinjection. Cognitive function was assessed using the Morris water maze 24 h following the LPS microinjection. Animal behavioral tests, as well as pathological and biochemical assays, were performed to clarify the role of EAAT3 function in POCD and evaluate the effect of activating the EAAT3 function by riluzole. In the present study, we established a mouse model with hippocampal SLC1A1/EAAT3 knockdown and found that hippocampal SLC1A1/EAAT3 knockdown aggravated LPS-induced learning and memory deficits in adult male mice. Meanwhile, LPS significantly inhibited the expression of EAAT3 membrane protein and the phosphorylation level of GluA1 protein in the hippocampus of adult male mice. Moreover, riluzole pretreatment significantly increased the expression of hippocampal EAAT3 membrane protein and also ameliorated LPS-induced cognitive impairment in elderly male mice. Taken together, our results demonstrated that the dysfunction of EAAT3 is an important risk factor for POCD susceptibility and therefore, it may become a promising target for POCD treatment.

Association of FTO gene variants rs9939609 and rs1421085 with polycystic ovary syndrome

BackgroundPolycystic ovary syndrome (PCOS) is among the most common complex genetic endocrinopathy, and its etiology and pathophysiology remain controversial. FTO is a large highly polymorphic gene and was coined as the first locus associated with adiposity. The association of the intronic variant FTO rs9939609 or FTO rs1421085 with PCOS has been controversial and unclear, mainly due to ethnic differences among populations. The present study aims to investigate the association of FTO rs9939609 or FTO rs1421085 polymorphisms with PCOS in Saudi Arabian women.ResultsA total of 98 PCOS patients and 99 healthy females were included in this study. PCR and genotyping (TaqMan®SNP Genotyping Assay) were employed. For FTO rs9939609, the genotype TA and the recessive model (TA + AA) in PCOS patients were significantly different compared with control subjects (p = 0.008 and p = 0.007, respectively). The allele frequency of the FTO rs9939609 gene variant was associated significantly (p = 0.027) with PCOS, suggesting that the A allele is a risk factor for PCOS susceptibility. However, for the FTO rs1421085 variant, the genotype and allele distributions did not differ significantly between PCOS patients and controls (p > 0.05).ConclusionsThis is the first report to study the association of FTO rs9939609 and FTO rs1421085 with PCOS in Saudi women. Results suggest that the FTO rs9939609 gene variant could be a genetic predisposing factor for PCOS Saudi women.

Antimicrobial Susceptibility Characteristics and Risk Factors Associated with Adult Sepsis in Wenzhou, China.

PurposeTo clarify the distribution of pathogenic bacteria by analyzing the bacterial susceptibility characteristics and risk factors for adult sepsis in The Wenzhou city, Zhejiang province, China, and to aid early diagnosis, monitoring, and prognosis prediction in cases of bacterial sepsis.Patients and MethodsWe retrospectively analyzed 329 patients with sepsis admitted to the Second Affiliated Hospital of Wenzhou Medical University between January 2018 and March 2021. Laboratory data were collected before and after treatment; moreover, the bacterial susceptibility characteristics and risk factors for sepsis were comprehensively analyzed using the Sequential Organ Failure Assessment (SOFA) score.ResultsThe SOFA score was negatively correlated with the prognosis (P < 0.05). We isolated 47 pathogenic strains from blood culture samples, including 29 gram-positive strains, 18 gram-negative strains. The most common gram-negative pathogens in blood cultures are Klebsiella pneumoniae and Escherichia coli, while the most common gram-positive pathogens are Staphylococcus aureus and Staphylococcus hominis. Gram-negative pathogens had resistance rates of 77% and 62.5% to ciprofloxacin and ceftriaxone, respectively. Gram-positive bacteria had a high resistance to penicillin at 100%. Prognostic factors for sepsis included patients’ consciousness, SOFA score, prothrombin time, international normalized ratio, fibrinogen, D-dimer, and aspartate aminotransferase (P < 0.05). Of these, the D-dimer level could predict the outcome of patients with sepsis (AUC = 0.661, P < 0.05).ConclusionThe pathogens detected in adult sepsis in Wenzhou are mainly Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, and Staphylococcus hominis. The pathogens exhibited differences in drug susceptibility. The optimal antibiotics should be chosen based on the principles of rational use and drug susceptibility. Combined with D-dimer levels, these parameters can be used to determine the optimal strategy for preventing and treating pathogenic bacteria.

Association of TP53 P72R and MDM2 SNP309 variants with susceptibil-ity to chronic myeloid leukaemia development in Algerian population: TP53 P72R C allele is a strong risk marker and MDM2 SNP309 G allele has a protective effect

Chronic myeloid leukaemia is a monoclonal myeloproliferative syndrome, whose development is related to disturbance of growth, survival, and apop-totic pathways, such as MDM2-p53 pathway, mainly due to the abnormal kinase activity of BCR-ABL. A lot of work has to be done to understand chron-ic myeloid leukaemia genetic predisposition. This is a pilot study that search-es for association between TP53 P72R variant (rs1042522); and MDM2 T309G variant (rs2279744), and the risk of chronic myeloid leukaemia occur-rence in the Algerian population. It is a case-control study using DNA sam-ples of 74 Algerian chronic myeloid leukaemia patients and 104 healthy con-trol individuals. Our results attested that TP53 P72R C allele (Pro) was strong-ly associated with increased risk of chronic myeloid leukaemia, and that TP53 P72R homozygous CC genotype should be a genetic susceptibility factor in the pathogenesis of chronic myeloid leukaemia independently of age and of gender. Furthermore, MDM2 SNP309 TT genotype was moderately associat-ed with a risk of chronic myeloid leukaemia occurrence. In conclusion, our data suggest that, in Algerian population, TP53 P72R C allele (Pro) could be a possible biomarker of chronic myeloid leukaemia susceptibility, and that MDM2 SNP309 TT genotype seems to be a low penetrance risk factor of chronic myeloid leukaemia susceptibility.

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Pandemic: Are Africa's Prevalence and Mortality Rates Relatively Low?

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of coronavirus disease 19 (COVID-19), has been rapidly spreading since December 2019, and within a few months, it turned out to be a global pandemic. The disease affects primarily the lungs, but its pathogenesis spreads to other organs as well. However, its mortality rates vary, and in the majority of infected people, there are no serious consequences. Many factors including advanced age, preexisting health conditions, and genetic predispositions are believed to exacerbate outcomes of COVID-19. The virus contains several structural proteins including the spike (S) protein with subunits for binding, fusion, and internalization into host cells following interaction with host cell receptors and proteases (ACE2 and TMPRSS2, respectively) to cause the subsequent pathology. Although the pandemic has spread into all countries, most of Africa is thought of as having relatively less prevalence and mortality. Several hypotheses have been forwarded as reasons for this and include warmer weather conditions, vaccination with BCG (i.e., trained immunity), and previous malaria infection. From genetics or metabolic points of view, it has been proposed that most African populations could be protected to some degree because they lack some genetic susceptibility risk factors or have low-level expression of allelic variants, such as ACE2 and TMPRSS2 that are thought to be involved in increased infection risk or disease severity. The frequency of occurrence of α-1 antitrypsin (an inhibitor of a tissue-degrading protease, thereby protecting target host tissues including the lung) deficiency is also reported to be low in most African populations. More recently, infections in Africa appear to be on the rise. In general, there are few studies on the epidemiology and pathogenesis of the disease in African contexts, and the overall costs and human life losses due to the pandemic in Africa will be determined by all factors and conditions interacting in complex ways.