Role of circ-FOXO3 and miR-23a in radiosensitivity of breast cancer

Identifying the radiosensitivity of cells before radiotherapy (RT) in breast cancer (BC) patients allows appropriate switching between routinely used treatment regimens and reduces adverse side effects in exposed patients. In this study, blood was collected from 60 women diagnosed with Invasive Ductal Carcinoma (IDC) BC and 20 healthy women. To predict cellular radiosensitivity, a standard G2-chromosomal assay was performed. From these 60 samples, 20 BC patients were found to be radiosensitive based on the G2 assay. Therefore, molecular studies were finally performed on two equal groups (20 samples each) of patients with and without cellular radiosensitivity. QPCR was performed to examine the expression levels of circ-FOXO3 and miR-23a in peripheral blood mononuclear cells (PBMCs) and RNA sensitivity and specificity were determined by plotting Receiver Operating Characteristic (ROC) curves. Binary logistic regression was performed to identify RNA involvement in BC and cellular radiosensitivity (CR) in BC patients. Meanwhile, qPCR was used to compare differential RNA expression in the radiosensitive MCF-7 and radioresistant MDA-MB-231 cell lines. An annexin -V FITC/PI binding assay was used to measure cell apoptosis 24 and 48 h after 2 Gy, 4 Gy, and 8 Gy gamma-irradiation. Results indicated that circ-FOXO3 was downregulated and miR-23a was upregulated in BC patients. RNA expression levels were directly associated with CR. Cell line results showed that circ-FOXO3 overexpression induced apoptosis in the MCF-7 cell line and miR-23a overexpression inhibited apoptosis in the MDA-MB-231 cell line. Evaluation of the ROC curves revealed that both RNAs had acceptable specificity and sensitivity in predicting CR in BC patients. Binary logistic regression showed that both RNAs were also successful in predicting breast cancer. Although only circ-FOXO3 has been shown to predict CR in BC patients, circ-FOXO3 may function as a tumor suppressor and miR-23a may function as oncomiR in BC. Circ-FOXO3 and miR-23a may be promising potential biomarkers for BC prediction. Furthermore, Circ-FOXO3 could be a potential biomarker for predicting CR in BC patients.</p

The Progress and Pitfalls of Pharmacogenetics-Based Precision Medicine in Schizophrenia Spectrum Disorders:A Systematic Review and Meta-Analysis

The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsychotic-induced weight/BMI gain, metabolic syndrome, antipsychotic-related prolactin levels, antipsychotic-induced tardive dyskinesia (TD), clozapine-induced agranulocytosis (CLA), and drug concentration level (pharmacokinetics) in SSD patients. Through an in-depth systematic search in 2010–2022, we identified 501 records. We included 29 meta-analyses constituting pooled data from 298 original studies over 69 PGx variants across 39 genes, 4 metabolizing phenotypes of CYP2D9, and 3 of CYP2C19. We observed weak unadjusted nominal significant (p &lt; 0.05) additive effects of PGx variants of DRD1, DRD2, DRD3, HTR1A, HTR2A, HTR3A, and COMT (10 variants) on antipsychotic response; DRD2, HTR2C, BDNF, ADRA2A, ADRB3, GNB3, INSIG2, LEP, MC4R, and SNAP25 (14 variants) on weight gain; HTR2C (one variant) on metabolic syndrome; DRD2 (one variant) on prolactin levels; COMT and BDNF (two variants) on TD; HLA-DRB1 (one variant) on CLA; CYP2D6 (four phenotypes) and CYP2C19 (two phenotypes) on antipsychotics plasma levels. In the future, well-designed longitudinal naturalistic multi-center PGx studies are needed to validate the effectiveness of PGx variants in antipsychotic outcomes before establishing any reproducible PGx passport in clinical practice.</p

Staple Food Fortification with Folic Acid and Iron and Gastrointestinal Cancers:Critical Appraisal of Long-Term National Fortification

The co-occurrence of wheat flour fortification with folic acid and iron and gastrointestinal cancer incidences were critically assessed in the East Azerbaijan province in Northwest of Iran. In an ecological design, overall gastrointestinal cancer rate ratios and their 95% confidence intervals (95% CI) were calculated as primary outcome before (2004-2006) and after (2007-2015) the introduction of fortification. No consistent changes were observed in esophageal and gastric cancer, but the rate ratios of colorectal cancer increased significantly after fortification in the 35-54 years age group (women: 2.07, 95% CI: 1.79-2.49; men: 1.59, 95% CI: 1.33-1.89) and the 55-74 years age group (women 1.50, 95% CI: 1.27-1.76; men: 2.51, 95% CI: 2.13-2.95). The increased incidence of colorectal cancer was contemporary with long-term fortification; further investigation is required to establish the associations

Identification of environmental risk factors associated with the development of Inflammatory Bowel Disease

BACKGROUND AND AIMS: Multiple genetic and environmental factors are involved in the etiology of inflammatory bowel disease (IBD), consisting of Crohn's disease (CD) and ulcerative colitis (UC) but data on these exposome factors are difficult to identify . Several exposome factors as smoking have been shown to be involved, as for other environmental factors, i.e. stress, results have been conflicting. METHODS: We performed a case-control study including 674 IBD patients of the 1000IBD cohort frequency-matched based on sex and age to 1,348 controls from population based Lifelines Cohort Study. Exposome data was obtained using the validated Groningen IBD Environmental Questionnaire (GIEQ), capturing exposome factors through different stages of life using 844 items, of which 454 applicable to study the role of 93 exposome factors in disease etiology. Logistic regression modeling with Bonferroni correction for multiple testing was applied to estimate the multivariable-adjusted effect of each exposome factor. RESULTS: For IBD, we identified four novel factors; stressful life-events (CD OR2.61/UC OR 2.92), high perceived stress (2.29/2.67), alcohol use (0.40/0.43), and bronchial hyperreactivity (3.04/2.36). Four novel factors were associated with only CD; prenatal smoke exposure (1.89), having a bedpartner (0.53), allergies (2.66) and cowmilk-hypersensitivity (5.87), two solely with UC; carpet flooring (0.57) and neuroticism (1.32). Nine factors were replicated. CONCLUSION: In this study we identified ten novel and replicated nine previous reported exposome factors associated with IBD. Identifying these factors is important for both understanding disease etiology and future prevention strategies to decrease the development of IBD in genetically susceptible persons

Polygenic risk score for schizophrenia was not associated with glycemic level (HbA1c) in patients with non-affective psychosis:Genetic Risk and Outcome of Psychosis (GROUP) cohort study

Introduction: Type 2 diabetes (T2D) is a common comorbidity in patients with schizophrenia (SCZ). The underlying pathophysiologic mechanisms are yet to be fully elucidated, although it can be argued that shared genes, environmental factors or their interaction effect are involved. This study investigated the association between polygenic risk score of SCZ (PRSSCZ) and glycated haemoglobin (HbA1c) while adjusting for polygenic risk score of T2D (PRST2D), and clinical and demographic covariables. Methods: Genotype, clinical and demographic data of 1129 patients with non-affective psychosis were extracted from Genetic Risk and Outcome of Psychosis (GROUP) cohort study. The glycated haemoglobin (HbA1c) was the outcome. PRS was calculated using standard methods. Univariable and multivariable linear regression analyses were applied to estimate associations. Additionally, sensitivity analysis based on multiple imputation was done. After correction for multiple testing, a two-sided p-value ≤.003 was considered to discover evidence for an association. Results: Of 1129 patients, 75.8% were male with median age of 29 years. The mean (standard deviation) HbA1c level was 35.1 (5.9) mmol/mol. There was no evidence for an association between high HbA1c level and increased PRSSCZ (adjusted regression coefficient (aβ) = 0.69, standard error (SE) = 0.77, p-value =.37). On the other hand, there was evidence for an association between high HbA1c level and increased PRST2D (aβ = 0.93, SE = 0.32, p-value =.004), body mass index (aβ = 0.20, SE = 0.08, p-value =.01), diastolic blood pressure (aβ = 0.08, SE = 0.04, p-value =.03), late age of first psychosis onset (aβ = 0.19, SE = 0.05, p-value =.0004) and male gender (aβ = 1.58, SE = 0.81, p-value =.05). After multiple testing correction, there was evidence for an association between high HbA1c level and late age of first psychosis onset. Evidence for interaction effect between PRSscz and antipsychotics was not observed. The multiple imputation-based sensitivity analysis provided consistent results with complete case analysis. Conclusions: Glycemic dysregulation in patients with SCZ was not associated with PRSSCZ. This suggests that the mechanisms of hyperglycemia or diabetes are at least partly independent from genetic predisposition to SCZ. Our findings show that the change in HbA1c level can be caused by at least in part due to PRST2D, late age of illness onset, male gender, and increased body mass index and diastolic blood pressure

Clinical response to antipsychotic drug treatment:Association study of polymorphisms in six candidate genes

AbstractPharmacogenetic studies have demonstrated significant associations between several candidate genes (DRD2, DRD3, 5HTR2A and 5HTR2C, COMT and MTHFR) and antipsychotic drug response. The present study investigates the effect of nine polymorphisms in these genes for an association with antipsychotic treatment response. 329 Caucasian patients with a non-affective psychotic disorder using antipsychotics were included. All patients participated in the longitudinal GROUP-study in The Netherlands. We genotyped 9 SNPs in 6 candidate genes (DRD2: TaqI_A, -141C; DRD3: Ser9Gly; HTR2A: 102-T/C, His452Tyr; HTR2C: Cys23Ser; COMT: Val158Met; MTHFR: 677-C/T) using standard protocols. Polymorphisms were based on previous studies showing associations with positive symptoms treatment response. The Clinical Global Impression - Improvement (CGI-I) scale was used to assess improvement in positive psychotic symptoms since the start of current antipsychotic treatment. Ordinal regression was used for association analyses. Ninety percent of the patients used second generation antipsychotics, with olanzapine (28%) and risperidone (29%) being the most prescribed drugs. Ser9Gly of the dopamine D3 receptor gene (P value 0.034) and 677-C/T of MTHFR (P value 0.019) were tested statistically significant. Gly-carriers and T-carriers, respectively, showed more clinical improvement on the CGI-I. The other polymorphisms did not show a statistically significant association (P values>0.10). In conclusion, we replicated two out of nine of the previously reported associations between polymorphisms and treatment response. The direction and magnitude of the associations presented here in DRD3 (Ser9Gly) and MTHFR (677-C/T) are in line with previous association studies in Caucasian patients. These polymorphisms may be of value for predicting clinical response

Tacrolimus and mycophenolate mofetil as second-line treatment in autoimmune hepatitis:Is the evidence of sufficient quality to develop recommendations?

BACKGROUND The standard management of autoimmune hepatitis (AIH) is based on corticosteroids, alone or in combination with azathioprine. Second-line treatments are needed for patients who have refractory disease. However, high-quality data on the alternative management of AIH are scarce. AIM To evaluate the efficacy and safety of tacrolimus and mycophenolate mofetil (MMF) and the quality of evidence by using the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE). METHODS A systematic review and meta-analysis of the available data were performed. We calculated pooled event rates for three outcome measures: Biochemical remission, adverse events, and mortality, with their corresponding 95% confidence intervals (CI). RESULTS The pooled biochemical remission rate was 68.9% (95%CI: 60.4-76.2) for tacrolimus, and 59.6% (95%CI: 54.8-64.2) for MMF, and rates of adverse events were 25.5% (95%CI: 12.4-45.3) for tacrolimus and 24.1% (95%CI: 15.4-35.7) for MMF. The pooled mortality rate was estimated at 11.5% (95%CI: 7.1-18.1) for tacrolimus and 9.01% (95%CI: 6.2-12.8) for MMF. Pooled biochemical remission rates for tacrolimus and MMF in patients with intolerance to standard therapy were 56.6% (CI: 43.4-56.6) vs 73.5% (CI: 58.1-84.7), and among non-responders were 59.1% (CI: 48.7-68.8) vs 40.8% (CI: 32.3-50.0), respectively. Moreover, the overall quality assessments using GRADE proved to be very low for all our outcomes in both treatment groups. CONCLUSION Tacrolimus and MMF are in practice considered effective for patients with AIH who are non-responders or intolerant to first-line treatment, but we found no high-quality evidence to support this statement

Folic Acid Supplement Intake and Risk of Colorectal Cancer in Women; A Case Control Study

Background: An ongoing controversy exists on the role of folic acid supplementation in colorectal cancer risk among epidemiological studies. Objective: To assess the association between maternal folic acid supplementation and colorectal cancer risk. Methods: A paired matched case control study of 405 subjects was performed, including women residing in 135 villages of East Azerbaijan, Iran. Per area, subjects were followed regularly in local healthcare centers, where health- and social-related information have been collected prospectively in face to face interviews by well-trained health workers. We extracted folic acid supplement intake, baseline characteristics, and confounders from healthcare records. The data for study participants were linked to national cancer registry repositories, from which we retrieved the data of 135 women diagnosed with colorectal cancer between 2005 to 2015. Two hundred seventy controls were individually matched with cases in terms of residing village, age, and gender. We applied multivariate conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Findings: There was no significant association between folic acid supplementation and colorectal cancer risk in those with history of folic acid intake compared to those with no history of intake (OR 0.95; 95% CI 0.59 to 1.53), in those with less than five years of folic acid (0.79; 0.45 to 1.39) or in those with ≥5 years intake (1.09; 0.52 to 2.26). This risk did not change after adjustment for covariates or further stratification. Conclusions: Maternal folic acid supplementation did not affect colorectal cancer risk in a population where supplemental folic acid is prescribed with regular intervals for women of child-bearing age

Vitamin C Supplementation in Healthy Individuals Leads to Shifts of Bacterial Populations in the Gut - A Pilot Study

Gut microbes are crucial to human health, but microbial composition is often disturbed in a number of human diseases. Accumulating evidence points to nutritional modulation of the gut microbiota as a potentially beneficial therapeutic strategy. Vitamin C (ascorbic acid) may be of particular interest as it has known antioxidant and anti-inflammatory properties. In this study, we investigated whether supplementation with high-dose vitamin C may favourably affect the composition of the gut microbiota. In this pilot study, healthy human participants received 1000 mg vitamin C supplementation daily for two weeks. Gut microbiota composition was analysed before and after intervention by performing faecal 16S rRNA gene sequencing. In total, 14 healthy participants were included. Daily supplementation of high-dose vitamin C led to an increase in the relative abundances of Lachnospiraceae (p < 0.05), whereas decreases were observed for Bacteroidetes (p < 0.01), Enterococci (p < 0.01) and Gemmiger formicilis (p < 0.05). In addition, trends for bacterial shifts were observed for Blautia (increase) and Streptococcus thermophilus (decrease). High-dose vitamin C supplementation for two weeks shows microbiota-modulating effects in healthy individuals, with several beneficial shifts of bacterial populations. This may be relevant as these bacteria have anti-inflammatory properties and strongly associate with gut health

Diet quality indices and gastrointestinal cancer risk:results from the Lifelines study

OBJECTIVE: To investigate the long-term association between four dietary quality indices and the risk of gastrointestinal (GI) cancer. METHODS: Baseline details of the dietary intake of participants, assessed by a single food frequency questionnaire from the prospective Lifelines population-based cohort were translated to diet quality scores using several dietary and dietary-lifestyle indices. Incident cases of GI cancer were then assessed by linkage to the Dutch nationwide histo-cytopathology registry. The association between GI cancer risk and diet quality (defined as higher quintiles on dietary indices compared to the first quintile) was assessed by multivariable Cox proportional hazard models. RESULTS: We included 72,695 participants aged 51.20 ± 8.71 years with a median follow-up to cancer diagnosis of 8 years (interquartile range 2 years). During follow-up, 434 colorectal cancers and 139 upper GI cancers were diagnosed. There was a significant reduction in colorectal cancer risk for high categories in the American Cancer Society (ACS) Index (hazard ratio 0.62; 95% CI 0.46–0.84). However, high dietary index scores were not associated with strong beneficial effects on upper GI cancer risk. CONCLUSION: High quintiles on the ACS Index were associated with a significantly reduced risk of colorectal cancer. This index may be of use in a colorectal cancer prevention program. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00394-021-02648-3