Alaa Salah Jumaah Alam

Abstract Background: The true role of thymic function in children with congenital heart defects is largely unknown. Aim: To study the possible role of thymic CD3 (T-lymphocyte marker) and CD20 (B-lymphocyte marker) expression and thymic histopathological changes in complications after surgery for congenital heart defects. Methods: Between January and July 2014, thymic tissue samples were obtained from 13 (69% male, 31% female, mean age 10.9 2 years) of 25 Iraqi patients who underwent open heart surgery with partial thymectomy for correction of congenital heart defects. The samples were evaluated for thymic expression of CD markers (CD3 and CD20) and histopathological changes. For up to 6 months after surgery, data on complications were collected from each patient, including wound infection, cardiac arrhythmias, heart failure, rehospitalization, chest infection, and death. Results: The prevalence of thymic hypoplasia was 15% and it occurred more frequently in patients with absent thymic CD3 expression (p ¼ 0.005). Only wound infection (n ¼ 2) and atrial fibrillation (n ¼ 1) comprised the postoperative complications in our patients. Absence of thymic CD20 expression correlated significantly with postoperative complications and obstructive cardiac defects (p ¼ 0.04), whereas no significant correlations were found between thymic hypoplasia with CD3 expression and postoperative complications (p > 0.05). Conclusion: Patients with absent thymic CD20 expression had significantly more postoperative complications and cardiac obstructive defects than those with positive CD20 expression.

Background :Urinary bladder carcinoma is a common malignant tumor of the urogenital system worldwide. In United State; there is 74,000 new cases and 16,000 deaths and it is the fourth most common cancer in men in 2015, and in Iraq, it is one of the ten most common cancers in 2011. Forkhead box M1 (FOXM1) is a transcription factor plays crucial roles in regulating the proliferation, differentiation, and transformation of cells. Objective: The main objective of the current study is to analyze FOXM1 gene expression levels in bladder cancer specimens FOXM1 gene as genetic factors that contribute to development and prognosis of bladder cancer. Results: Analysis of the data of FOXM1gene expression revealed that the expression of FOXM1 gene were found to be 18.187 folds in malignant bladder tumors in relation to non-tumorous bladder tissue. FOXM1 genes were observed to be expressed excessively in high grade and advanced stage tumors. results of our study were conclude that FOXM1 may represent a novel bladder tumor marker with prognostic significance that could be introduced in plans of bladder cancer management.

Abstract Background: Amongst the extensive literature on immunohistochemical profile of breast cancer, very little is found on populations exposed to a potential risk factor such as depleted uranium. This study looked at the immunohistochemical expression of HER-2/neu (c-erbB2) and p53 in different histological types of breast cancer found in the middle Euphrates region of Iraq, where the population has been exposed to high levels of depleted uranium. Findings: The present investigation was performed over a period starting from September 2008 to April 2009. Formalin-fixed, paraffin-embedded blocks from 70 patients with breast cancer (62 ductal and 8 lobular carcinoma) were included in this study. A group of 25 patients with fibroadenoma was included as a comparative group, and 20 samples of normal breast tissue sections were used as controls. Labeled streptavidin-biotin (LSAB+) complex method was employed for immunohistochemical detection of HER-2/neu and p53. The detection rate of HER-2/neu and p53 immunohistochemical expression were 47.14% and 35.71% respectively in malignant tumors; expression was negative in the comparative and control groups (p < 0.05). HER-2/neu immunostaining was significantly associated with histological type, tumor size, nodal involvement, and recurrence of breast carcinoma (p < 0.05), p53 immunostaining was significantly associated with tumor size, nodal involvement and recurrence of breast cancer (p < 0.05). There was greater immunoexpression of HER-2/neu in breast cancer in this population, compared with findings in other populations. Both biomarkers were positively correlated with each other. Furthermore, all the cases that co-expressed both HER- 2/neu and p53 showed the most unfavorable biopathological profile. Conclusion: P53 and HER-2/neu over-expression play an important role in pathogenesis of breast carcinoma. The findings indicate that in regions exposed to high levels of depleted uranium, although p53 and HER-2/neu overexpression are both high, correlation of their expression with age, grade, tumor size, recurrence and lymph node involvement is similar to studies that have been conducted on populations not exposed to depleted uranium. HER-2/neu expression in breast cancer was higher in this population, compared with results on nonexposed populations.

Abstract Background Endometrial carcinoma (EC) is classified into four distinct molecular subgroups. Patients with polymerase epsilon exonuclease domain mutated (POLE-EDM) tumors have the best prognosis of all. This meta-analysis consolidated the clinicopathology variations reported in the POLE-mutant subtype and survival parameters in patients with EC. Methods The following internet data bases were searched: PubMed, Web of science, Embase and Scimage directory. Data was extracted from eligible studies including sample size, number of positive POLE-mutant cases, EDM sequencing information, clinicopathologic, and survival data. Meta-analysis and a random-effects model produced pooled estimates of POLE prognostic parameters using 95% confidence intervals (CI), hazard ratios (HR), and odds ratios (OR). Results The meta-analysis included 11 cohort studies comprising 5508 EC patients (442 POLE EDM tumors). Patients with POLE mutant EC were associated with improved disease specific survival (HR = 0.408, 95% CI: 0.306 to 0.543) and progression-free survival (HR = 0.231, 95% CI: 0.117 to 0.456). POLE-mutated tumors were mostly endometrioid histology (84.480%; 95% CI: 77.237 to 90.548), although not significantly more than wild type tumors (OR = 1.386; p = 0.073). The POLE mutant tumors significantly present (p<0.001) at Federation of International of Gynecologists and Obstetricians (FIGO) lower stages I-II (OR = 2.955, p<0.001) and highest grade III (OR = 1.717, P = 0.003). The tumors are significantly associated with invasion less than half (<50%) of the myometrium (OR = 1.765, p = 0.001), but not deeply invasive EC (MI>50%, OR = 0.83, p = 0.34). POLE mutations significantly protected against lymph node metastases (OR = 0.202, p = 0.001), and have no clear association with lymph-vascular space invasion (OR = 0.967, 95% 0.713–1.310, p = 0.826). The tumors are predominantly of low ESMO risk stratification distribution (40.356%; 95% CI: 27.577 to 53.838). Conclusions POLE mutations serve as an important biomarker of favorable prognosis in EC. The tumors are characteristically high grade, early stage, and remain localized in the endometrium with reduced likelihood of lymph node metastasis for improved survival prospects and the lowest risk classification. These findings have implications for medical management of EC.

Background: Endometrial carcinoma (EC) is classified into four distinct molecular subgroups including ultramutated DNA polymerase epsilon (POLE). POLE-mutated tumors have the best prognosis and are a promising target for immunotherapy. This meta-analysis consolidated the reported variation of POLE-mutant frequency and assessed prognostic value in EC. Methods: Internet searches explored scientific data bases: EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials databases. Data was extracted from eligible studies including: sample size, number of positive POLE-mutant cases, sequencing information, clinicopathologic data, and survival data. Meta-analysis and a random-effects model produced pooled estimates of POLE frequency and prognostic parameters using 95% confidence intervals (CI), hazard ratios (HR), and odd ratios (OR). Results: Six thousand three hundred and forty-six EC patient cases were pooled from 25 studies. The pooled proportion of POLE gene mutation in EC was 8.59% (95% CI, 7.01 to 10.32), of which 8.22% (95% CI, 6.27 to 10.42) were type I and 0.93% (95% CI, 0.34 to 1.81) type 2. Clinicopathologic data showed that POLE-mutated tumors are mostly endometrioid. They present at higher levels in earlier stages (I–II) of EC (89.51%; 95% CI, 81.11 to 95.66) at the highest grade III (51.53%; 95% CI, 36.08 to 66.84) with reduced myometrial invasion (OR, 1.48, 95% CI, 0.99 to 2.20). Survival analysis indicated favorable overall survival (HR, 0.90), disease-specific survival (HR, 0.41), and progression-free survival (HR, 0.23) for POLE mutant EC. Conclusions: Almost one-tenth of EC patients have POLE-mutated tumors. Given their improved prognostic potential, identifying the POLE mutation status is key for the management of EC patients. Key Words: Endometrial carcinoma; POLE gene

Background: Loss of mismatch repair (MMR) occurs frequently in endometrial carcinoma (EC) and is an important prognostic marker. However, the frequency of MMR deficiency (D-MMR) in EC remains inconclusive. This systematic review and meta-analysis addressed this inconsistency and evaluated related clinicopathology. Methods: Electronic databases were searched for articles: PubMed, Science Direct, Web of Science, EMBASE, and the Wiley Online Library. Data were extracted from 25 EC studies of D-MMR to generate a clinical dataset of 7,459 patients. A random-effects model produced pooled estimates of D-MMR EC frequency with 95% confidence interval (CI) for meta-analysis. Results: The overall pooled proportion of D-MMR was 24.477% (95% CI, 21.022 to 28.106) in EC. The Lynch syndrome subgroup had 22.907% pooled D-MMR (95% CI, 14.852 to 32.116). D-MMR was highest in type I EC (25.810) (95% CI, 22.503 to 29.261) compared to type II (13.736) (95% CI, 8.392 to 20.144). Pooled D-MMR was highest at EC stage and grades I–II (79.430% and 65.718%, respectively) and lowest in stages III–IV and grade III (20.168% and 21.529%). The pooled odd ratios comparing D-MMR to proficient MMR favored low-stage EC disease (1.565; 0.894 to 2.740), lymphovascular invasion (1.765; 1.293 to 2.409), and myometrial invasion >50% (1.271; 0.871 to 1.853). Conclusions: Almost one-quarter of EC patients present with D-MMR tumors. The majority has less aggressive endometrioid histology. D-MMR presents at lower tumor stages compared to MMR-proficient cases in EC. However other metastatic parameters are comparatively higher in the D-MMR disease setting. Key Words: Microsatellite instability; MMR-D; Endometrial carcinoma

Background Impairment of social functioning skills is a key hallmark of autism. The neuropeptide oxytocin (OXT) is a blood-based biomarker of social functioning, and a candidate for individualized treatment of ASD. The effects of OXT on the social brain are mediated by the OXT receptor (OXTR). This study assessed the clinical utility of blood OXT serum levels and the OXT receptor (OXTR) genotype as biomarkers of autism and its severity in a pediatric population in Iraq. Methods Blood samples were collected from patients with a clinical diagnosis of ASD (n = 60) and corresponding age and gender matched healthy controls (n = 60). All clinical samples were processed at the Department of Pathology and Forensic Medicine, Faculty of Medicine, University of Kufa in Iraq. Blood serum was assayed for OXT by sandwich ELISA. Receiver operator analysis (ROC) determined area under the curve (AUC), cutoff values, and sensitivity and specificity of OXT values for accuracy of diagnosis of ASD. Isolated genomic DNA was genotyped for the OXTR gene rs2268491(C/T) SNP using allele-specific PCR. The significance of genotype (CC, CT, and TT) and allele (C and T) distributions in different patient groups was assessed using odd ratios (OR) with 95% confidence intervals (CI) and the Chisquare test. All statistical analysis was performed used SPSS software. Results Study characteristics in the ASD population revealed a high level of consanguinity (36.66%), and ASD recurrence rate (11.66%) and family history (28.33%). OXT levels in patients with ASD (157.58±28.81 pg/ml) were significantly higher (p = 0.003) compared to controls (75.03±6.38 pg/ml). Within stratified ASD severity groups—OXT levels were significantly different (P = 0.032). ROC analysis determined similar AUC values for overall ASD (0.807), and stratified mild (0.793), moderate (0.889), and severe categories (0.795). The best cutoff for diagnosis of ASD was 83.8 pg/ml OXT with a sensitivity and specificity of 80% and 72.1% respectively. OXTR gene rs2268491(C/T) genotyping found that ASD patients have significantly lower (p = 0.021) genotype CC frequency and a significantly higher (p = 0.04) occurrence of the heterozygous CT genotype relative to controls. ASD subjects produced highest OXT levels with the TT genotype. T allele distribution was higher in ASD males. ASD males had significantly lower distribution of the CC genotype (48.89%) compared to females (80%) (Chi-square test: χ2 = 4.43, df = 1, p = 0.035). Whereas distribution of the CT genotype was significantly higher in autistic males (44.45%) compared to females (13.33%) (Chi-square test: χ2 = 4.68, df = 1, p = 0.03). Conclusion Peripheral OXT levels and OXTR genetic alterations are potential biomarkers of social functioning in the ASD patient setting. The stratification of patients with ASD into severity categories shows significant differences both in OXT levels and OXTR (rs2268491, C/T) genotype and allele distributions, that can be sex dependent. OXT based therapies will require personalized medicine tactics to correctly identify patients with ASD who require neuropeptide boosting in social settings

Abstract Introduction Autism spectrum disorder (ASD) is an increasing concern among the Iraqi Arab population. The genetic alterations that cause ASD are likely to converge at the synapse. This study investigated polymorphisms in the GABAA receptor subunit (GABRG3) and the RELN gene as putative biomarkers of ASD in a pediatric population in Iraq. Methods The case control study included 60 patients with a clinical diagnosis of ASD (mild, moderate, or severe) according to DSM-IV criteria and matched healthy controls (n = 60). Blood samples were collected for DNA genotyping of SNPs rs736707 and rs208129 for RELN and GABRG3 using allele specific PCR. Assessment of genotype and allele distributions in patient groups used odd ratios (OR) with 95% confidence intervals and the Chi-square test. All statistical analysis was performed used SPSS software. Result The patient cohort was highly consanguineous, with increased ratio (p> 0.05) of males to females (3:1) in both ASD (mean age, 6.66 ± 3.05) and controls (mean age, 5.76 ± 2.3). Both GABRG3 rs208129 genotypes TT (OR 4.33, p = 0.0015) and TA (OR 0.259, P = 0.008), and the T and A alleles were significantly associated with ASD. The RELN rs736707 TC genotype (OR 2.626, P = 0.034) was the only significant association with ASD. Conclusion GABRG3 SNP rs208129 is a leading biomarker to predict genetic vulnerability to ASD in Iraqi Arabs. Expanded SNP panels and increased sample sizes are required for future GABRG3 studies, and to reach a consensus on RELN utility. Future ASD screening programs in Iraq should include genetic metrics in addition to clinical phenotype assessments. Keywords Pediatric ASD · SNP-biomarkers · RELN · GABRG3

Abstract Background and Aims: Coronavirus disease 2019 (COVID‐19) is a major public health problem that requires preventative vaccines. However, there is vaccine hesitancy among women of reproductive age in Iraq. This study aimed to investigate SARS‐CoV‐2 vaccination effects on intracytoplasmic sperm injection (ICSI) and related fertility parameters. Methods: The study population comprised 54 infertile patients undergoing the ICSI procedure at a fertility clinic: vaccinated (n = 17) and non‐vaccinated (n = 37). SARS‐ CoV‐2‐IgG/mL was assayed in follicular fluid from patients. Fertility parameters were assessed using oocyte and embryo quality and pregnancy outcomes between study groups, with respect to the time interval from vaccination to ova pick up. Results: There were no significant differences between non‐vaccinated and vaccinated groups in respect of oocytes quality with regard to the mean number of picked up oocytes (p = 0.564), abnormal oocyte (p = 0.827), oocytes metaphase I and II (p = 0.306; p = 0.165), germinal vesicles (p = 0.076), grade I, II, and III fertilized oocytes (p > 0.05), and for maturation rate (p = 0.13). There were also no significant differences (p > 0.05) in embryo quality parameters with the mean number of grade I, II, and III fertilized oocytes and the fertilization rate, the number of transferred embryo (0.086). There were no significant differences between vaccinated and unvaccinated groups with respect to follicular fluid SARS‐CoV‐2‐IgG (p = 0.854), and pregnancy outcomes (p = 0.550). Conclusions: The COVID‐19 mRNA vaccine has no effect on ICSI, fertility parameters, and pregnancy outcome. K E Y W O R D S fertilization rate, ICSI, mRNA vaccination, oocyte quality, SARS‐CoV‐2