IDHwt glioblastomas can be stratified by their transcriptional response to standard treatment, with implications for targeted therapy.

BACKGROUND: Glioblastoma (GBM) brain tumors lacking IDH1 mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumors almost always fatally recur. RESULTS: Using RNA sequencing data from 107 pairs of pre- and post-standard treatment locally recurrent IDHwt GBM tumors, we identify two responder subtypes based on longitudinal changes in gene expression. In two thirds of patients, a specific subset of genes is upregulated from primary to recurrence (Up responders), and in one third, the same genes are downregulated (Down responders), specifically in neoplastic cells. Characterization of the responder subtypes indicates subtype-specific adaptive treatment resistance mechanisms that are associated with distinct changes in the tumor microenvironment. In Up responders, recurrent tumors are enriched in quiescent proneural GBM stem cells and differentiated neoplastic cells, with increased interaction with the surrounding normal brain and neurotransmitter signaling, whereas Down responders commonly undergo mesenchymal transition. ChIP-sequencing data from longitudinal GBM tumors suggests that the observed transcriptional reprogramming could be driven by Polycomb-based chromatin remodeling rather than DNA methylation. CONCLUSIONS: We show that the responder subtype is cancer-cell intrinsic, recapitulated in in vitro GBM cell models, and influenced by the presence of the tumor microenvironment. Stratifying GBM tumors by responder subtype may lead to more effective treatment.

Immunohistochemical expression of BCL-2 in hydatidiform moles: a tissue microarray study.

Background: Hydatidiform moles (HM) are members of gestational trophoblastic diseases (GTD) and, in some cases, might progress to gestational trophoblastic neoplasia (GTN). HMs are either partial (PHM) or complete (CHM). Some HMs are challenging in arriving at a precise histopathological diagnosis. This study aims to investigate the expression of BCL-2 by immunohistochemistry (IHC) in HMs as well as in normal trophoblastic tissues "products of conception (POC) and placentas" using Tissue MicroArray (TMA) technique. Methods: TMAs were constructed using the archival material of 237 HMs (95 PHM and 142 CHM) and 202 control normal trophoblastic tissues; POC and unremarkable placentas. Sections were immunohistochemically stained using antibodies against BCL-2. The staining was assessed semi-quantatively (intensity and percentage of the positive cells) in different cellular components (trophoblasts and stromal cells). Results: BCL-2 showed cytoplasmic expression in more than 95% of trophoblasts of PHM, CHM and controls. The staining showed a significant reduction of the intensity from controls (73.7%), PHMs (76.3%) to CHM (26.9%). There was a statistically significant difference between PHM and CHM in the intensity (p-value 0.0005) and the overall scores (p-value 0.0005), but not the percentage score (p-value > 0.05). No significant difference was observed in the positivity of the villous stromal cells between the different groups. All cellular components were visible using the TMA model of two spots/case (3 mm diameter, each) in more than 90% of cases. Conclusions: Decreased BCL-2 expression in CHM compared to PHM and normal trophoblasts indicates increased apoptosis and uncontrolled trophoblastic proliferation. Construction of TMA in duplicates using cores of 3 mm diameter can overcome tissue heterogeneity of complex lesions.

Applying whole exome sequencing in a consanguineous population with autism spectrum disorder.

This study aimed to systematically assess the impact of clinical and demographic variables on the diagnostic yield of Whole Exome Sequencing (WES) when applied to children with Autism Spectrum Disorder (ASD) from a consanguineous population. Ninety-seven children were included in the analysis, 63% were male and 37% were females. 77.3% had a suspected syndromic aetiology of which 68% had co-existent central nervous system (CNS) clinical features, while 69% had other systems involved. The diagnostic yield of WES in our cohort with ASD was 34%. Children with seizures were more likely to have positive WES results (46% vs. 31%, p = 0.042). Probands with suspected syndromic ASD aetiology showed no significant differential impact on the diagnostic yield of WES.

Intellectual Profile of Children with Autism Spectrum Disorder: Identification of verbal and nonverbal subscales predicting intelligence quotient.

OBJECTIVES: This study aimed to explore the intelligence quotient (IQ) profile among children with autism spectrum disorder (ASD) and identify the most important subscales that predict the IQ. The analysis of an intellectual profile with age and gender differentials and the identification of a battery of subscales of intelligence are important for clinical management of ASD among children and for facilitating placement for remedial and educational services. METHODS: Data were collected through an exploratory study of 100 children aged between three and 13 years, who were referred to the department of child health and development in Sultan Qaboos University Hospital, a tertiary hospital, in Oman between June 2016 and June 2019. RESULTS: Among the 100 participants of this study, 79% were male, resulting in a male-female ratio of 4:1. The mean of full-scale IQ was found to be 68.6 ± 18.1. Furthermore, the mean of nonverbal IQ (73.5 ± 17.5) was significantly higher than that of verbal IQ (65.5 ± 17.6). Finally, more than half (61%) of the children were observed to have had mild to moderate impairment in their IQ levels. CONCLUSIONS: Age and gender showed no significant association with IQ level. The regression analysis identified nonverbal fluid reasoning, nonverbal visual-spatial processing, nonverbal working memory and verbal knowledge as the significant predictors of total IQ. The crucial dimensions of verbal and nonverbal IQ identified in this study can be used to evaluate complicated cases.

Parental Age and the Risk of Autism Spectrum Disorder in Oman: A case-control study.

OBJECTIVES: This study aimed at evaluating advanced parental age as a risk factor for autism spectrum disorder (ASD) in an Omani cohort. METHODS: This case-control study compared 278 ASD cases with 722 gender-matched controls, retrieved from the electronic records of the Developmental Paediatric Clinic, Sultan Qaboos University Hospital, Muscat, Oman, between January 2015 and June 2016. RESULTS: Most ASD cases were male (76.6%) and mostly diagnosed between 3-4 years of age, with more than 50% of the cases originating from Muscat and Batinah governorates. Compared to controls, mothers from the case group had significantly higher educational levels (post-secondary education versus high school/no formal education: odds ratio [OR] = 1.62, 95% confidence interval [CI]: 1.197-2.192). In a multivariate logistic regression, the OR of maternal age as a risk for ASD increased dramatically with advancing age category (using age <25 as reference, OR = 3.39, 6.12, 7.86 and 13.13 for age categories 25-29, 30-34, 35-39 and ≥40 years, respectively). The ORs of advancing paternal age as a risk for ASD were also statistically significant (using age <30 as reference, OR = 2.20, 2.36 and 3.12 for age categories 30-34, 35-39 and 40-44 years, respectively); however, there was a drop in the effect with paternal age ≥45 years (OR = 1.42; 95% CI: 0.64-3.15). CONCLUSION: Both maternal and paternal increased age were associated with a higher risk of ASD; however, the association was more pronounced and more consistent with advanced maternal age compared to paternal age.