Investigating the role of JARID2 in treatment resistance in glioblastoma

Glioblastoma (GBM) is the deadliest primary brain tumour in adults with a median survival of 14-20 months from initial diagnosis. Despite aggressive treatment involving maximal surgical debulking followed by radiation therapy and chemotherapy, GBM remains incurable owing to a high rate of fatal recurrence. Understanding why unresected tumour cells survive treatment is necessary to better treat this disease. GBM tumours recur due to the presence of treatment-resistant cells, and this resistance phenotype is posited to be mediated by several epigenetic mechanisms including DNA methylation, histone modifications and chromatin remodelling. Work within the Glioma Genomics group in Leeds has specifically highlighted a potential role for histones, so this study focuses on understanding the role of histone modifications in GBM treatment resistance. More specifically, this group has recently proposed, for the first time, that Jumonji and AT- Rich Interacting Domain 2 (JARID2) plays a role in tumour recurrence via chromatin remodelling in GBM. JARID2 is an accessory protein of Polycomb Repressive Complex 2 (PRC2) which is the sole complex responsible for trimethylation on lysine 27 of histone H3 (H3K27me3). JARID2 promotes PRC2 recruitment to chromatin and regulates its enzymatic activity. PRC2 and JARID2 have a fundamental role in neurodevelopment but the role in GBM treatment resistance needs to be investigated. This can be achieved by generating genome-wide profiles of histone modifications associated with JARID2, and the binding of JARID2 itself, in paired primary (untreated) and recurrent (posttreatment) samples. Despite the tremendous work in generating global genome-wide profiling of histone modifications in various types of cancers, few genome-wide maps for H3K27me3 are available for GBM, therefore, current interest is placed on generating and comparing genome-wide mapping of histone modifications to locate and identify key epigenetic changes that are associated with GBM development and progression. Another histone mark (H3K4me3, which is a transcriptional activator) is known to work in concert with H3K27me3 during cell lineage determination in the brain, so it was also deemed necessary to prolife this mark. Thus, this study aimed to establish a workflow for generating and comparing the global distribution patterns of two histone modifications, along with binding patterns of the catalytic component of PRC2 (Enhancer of zeste homolog 2: EZH2) and JARID2, in paired primary and recurrent GBM samples. My hypothesis is that histone remodeling is driving the changes in the gene expression observed in GBM through treatment. I established iv a workflow and then generated a genome- wide chromatin landscape for H3K27me3, H3K4me3 and EZH2 binding from matched fresh frozen pair primary and recurrent GBM samples of our in-house dataset. Then, I performed an integrative analysis on histone marks along with EZH2 by correlating their modifications with the changes in gene expression. The analysis was performed on a subset of genes that have been found to be dysregulated in GBM’s patient following standard treatment due to the epigenetic remodeling of their promoters. The findings revealed that these genes are significantly found in the bivalent state, but the balance of histone marks is altered by therapy. Also, it revealed that histone modifications are driving gene expression in those genes more than the others This leads to the hypothesis that this bivalency is what causes the tumours to be able to adapt to treatment. I concluded that JARID2 genes facilitate tumour recurrence through transcriptional reprogramming in patients following standard therapy. Additionally, it implies that bivalent areas promote GBM tumorigenicity and are linked to chemo-resistance

A Turning Point for Paediatric Developmental Services in Oman : Establishment of a national autism screening programme

N

Assessment of In-Vitro Synergy of Fosfomycin with Meropenem, Amikacin and Tigecycline in Whole Genome Sequenced Extended and Pan Drug Resistant <i>Klebsiella Pneumoniae</i>: Exploring A Colistin Sparing Protocol

Fosfomycin has emerged as a very useful antimicrobial in management of extremely drug resistant (XDR) and pan drug resistant (PDR) Klebsiella pneumoniae. In this study, we assessed in-vitro synergy of colistin sparing combinations of fosfomycin (FOS) with meropenem (MEM), tigecycline (TGC) and amikacin (AK) against XDR and PDR Klebsiella pneumoniae. Method: Non-replicate fully characterised 18 clinical isolates of K. pneumoniae (15 XDR and 3 PDR strains) were subjected to in-vitro synergy testing by checkerboard and time kill assay. Combinations tested were FOS-MEM, FOS-TGC and FOS-AK with glucose-6-phosphate being incorporated in all runs.WGS was carried out on the Illumina next-generation sequencing platform. Results: FOS-MEM and FOS-AK both demonstrated excellent synergy against all PDRs and all but one XDR. Synergy led to lowering of MICs to susceptible breakpoints. FOS-TGC demonstrated antagonism. MLST-231 K. pneumoniae predominated (14), followed by ST-395 (3) and ST147 (1). Majority harboured OXA-232 (n = 15), while n = 2 carried NDM-1 type and n = 1 co-carried NDM-5 + OXA-232. Mortality was high in both ST-231 (57.1%) and ST-395 (66.6%). Synergy was observed despite widespread presence of resistance markers against aminoglycosides [aph(3′)-Ic, aacA4, and rmtf], beta-lactams [blaSHV-11, blaTEM-1b, blaCTX-M-15, and blaOXA-232], fosfomycin [fosA6 and fosA5] and presence of porin proteins OmpK37, OmpA and K. pneumoniae antibiotic efflux pumps Kpn F, H, G, and E. Conclusion: FOS + MEM and FOS + AK are excellent colistin sparing combinations against ST 231, ST-395 and ST-147 XDR and PDR K. pneumoniae. FOS with fewer side effects than colistin, excellent tissue distribution and minimal side effects may be recommended in combination with meropenem

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

Objective: This study aimed at evaluating advanced parental age as a risk factor for Autism Spectrum Disorder (ASD) in an Omani cohort. Methods: Case-control study of 278 ASD cases compared with 722 sex-matched controls retrieved from the electronic records of the Developmental Paediatric Clinic, Sultan Qaboos University Hospital (SQUH) between January 2015 and June 2016. Results: ASD cases (76.6% male) were mostly diagnosed between 3-4 years of age, with more than 50% of them originating from Muscat and Batinah governorates. Compared to controls, mothers from the case group had significantly higher educational level (post-secondary education versus high school/no formal education (odds-ratio (OR)=1.62; 95% C.I. 1.20-2.19). In a multivariate logistic regression, the odds ratio of maternal age as a risk for ASD increased dramatically with advancing age category (using age&lt;25 as a reference, OR was 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&lt;30 as referent, OR was 2.20, 2.36, and 3.12 for age categories 30-34, 35-39 and 40-44 years); however, there was a drop in the effect with paternal age ≥ 45 years (OR=1.42; 95% C.I .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. Keywords: Autism; parental age; case-control stud

Fluctuation in the Levels of Immunoglobulin M and Immunoglobulin G Antibodies for Cardiolipin and β2-Glycoprotein among Healthy Pregnant Women

Objectives: Antiphospholipid antibodies fluctuate during a healthy normal pregnancy. This study aimed to investigate the levels of both immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies for cardiolipin and β2-glycoprotein (β2GP) among healthy pregnant women. Methods:This study was conducted between May 2010 and December 2012. A total of 75 healthy Omani pregnant women with no history of autoimmune disease were investigated during their pregnancy and 90 days after delivery at the Armed Forces Hospital in Muscat, Oman. A control group of 75 healthy Omani non-pregnant women were also investigated as a comparison. Levels of IgM and IgG antibodies for both anti-cardiolipin antibodies (ACAs) and β2GP were measured using a standard enzymelinked immunosorbent assay. Results: The ACA IgM levels were significantly higher in the control group compared to the pregnant women (P &lt;0.001). No significant differences were observed in the ACA IgM levels between the control group and the pregnant women after delivery. In contrast, ACA IgG levels were significantly higher during pregnancy and after delivery compared with those of the healthy control group (P = 0.007 and 0.002, respectively). The levels of β2GP IgG were significantly higher during pregnancy than after delivery and in the control group (P = 0.001 and &lt;0.001, respectively). Conclusion: In this study, ACA IgG levels increased during healthy pregnancies and after normal deliveries whereas β2GP IgG levels increased transiently during the pregnancies. Both phenomena were found to be significantly associated with a transient decline in the levels of IgM specific for these antigens. Therefore, the levels of these antibodies may be regulated during a healthy pregnancy

Intellectual Profiles of Children with Autism Spectrum Disorder: Identification of verbal and nonverbal subscales predicting intellectual 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. Keywords: Autism; Intelligence; Oman

Transmission dynamics, responses, and clinical features for the first 1100 COVID-19 cases in South Batinah, Oman: Major lessons from a provincial perspective

الملخص: أهداف البحث: هدفت هذه الدراسة إلى استكشاف وتحليل الملامح الوبائية ورصد واستجابة كوفيد-19، وديناميكيات انتقالها وتشكل المجموعات. طرق البحث: تحليل استرجاعي لبيانات الرصد، بما في ذلك تتبع الاتصال، وعوامل الخطر، والمعلومات السريرية. أجريت تحليلات الانحدار اللوجستية الثنائية لتقييم احتمالات القبول، وتشكل المجموعات، وكونه حالة رئيسية. تم توضيح المجموعات باستخدام أنظمة البيانات الجغرافية وتحليل الشبكات وبرامج التصور. النتائج: تم تشخيص ١١٠٠ حالة إصابة بفيروس كوفيد-١٩ في الفترة من ٢٠ مارس إلى ٧ يونيو ٢٠٢٠، وكانت ١٤٤ حالة منها (١٣,١٪) بدون أعراض. كانت المدة المتوسطة من بدء الأعراض حتى القبول في المستشفى ٧ أيام (٤,٥ - ١٠)، ومدة الأعراض نفسها كانت ٥ أيام (٣ - ٩). تم تحديد 89 مجموعة تحتوي على ٧٣٦ مريضا. وتم تمييز ثلاث مراحل توضح إجراءات الرصد والسيطرة. بدأت المجموعات في المرحلة الثانية وزادت وضوحا في المرحلة الثالثة. المرضى الذين تجاوزوا سن ٥٠ عاما وأولئك الذين يعانون من الحمى لديهم فرصة أكبر للقبول في المستشفى، بنسبة ١٢,٨٥ (٩٥٪ م.م. ٥,١٣ – ٣٢,١٩) و ٢,٥٣ (٩٥٪ م.م. ١,٢٤ – ٥,١٧) على التوالي. وقد لوحظ تشكل المجموعات بين الإناث والمرضى الذين لم يظهروا أعراضا وبين سكان ولاية عوابي، بنسب ٢,٣ (٩٥٪ م.م. ١,٧ – ٣,١) و ٦,٣٩ (٩٥٪ م.م. ٢,٣٣ – ١٧,٢) و ٣,٥٤ (٩٥٪ م.م. ٢,٠٦ – ٦,٠٧) على التوالي. وكان لدى المرضى العاملين في قطاعات الشرطة والدفاع فرصة أعلى لكونهم حالة رئيسية، بنسبة ٧,٨٨ (٩٥٪ م.م. ٣,٣٥ – ١٨,٥٢). الاستنتاجات: يجب دعم التدخلات القائمة على الحالات من خلال التدابير الموسعة على مستوى السكان - خاصة قيود الحركة. يعد إنشاء فرق الوقاية أو وحدات المنطقة، أو من خلال الرعاية الأولية أمرا حاسما للسيطرة على الأوبئة المستقبلية. يجب أن تكون الوقاية دائما أولوية للفئات السكانية الضعيفة. Abstract: Objectives: This study was aimed at exploring and analyzing the epidemiological profile, surveillance, and response to COVID-19, including transmission dynamics and cluster formation. Methodology: This was a retrospective analysis of surveillance data, including contact tracing, risk factors, and clinical information. Binary logistic regressions were used to assess the likelihood of admission, cluster formation, and of each individual being an index patient. Clusters were demonstrated through geographic data systems, network analysis, and visualization software. Results: A total of 1100 COVID-19 cases were diagnosed from 20 March to 7 June 2020, of which 144 (13.1%) were asymptomatic. The median time from symptom onset to admission was 7 days (IQR, 4.5–10), and the median symptom duration was 5 days (IQR, 3–9). Eighty-nine clusters containing 736 patients were identified. The surveillance and control actions were divided into three phases. Clusters began to form in phase 2 and became more pronounced in phase 3. Patients ≥50 years of age and patients presenting with fever had relatively higher odds of admission: OR = 12.85 (95% CI 5.13–32.19) and 2.53 (95% CI 1.24–5.17), respectively. Cluster formation was observed among females, asymptomatic patients, and people living in Awabi: OR = 2.3 (95% CI 1.7–3.1), 6.39 (95% CI 2.33–17.2), and 3.54 (95% CI 2.06–6.07), respectively. Patients working in the police and defense sectors had higher odds of being an index patient: OR = 7.88 (95% CI 3.35–18.52). Conclusion: Case-based interventions should be supported by population-wide measures, particularly movement restrictions. Establishing prevention teams or district units, or primary care will be crucial for the control of future pandemics. Prevention should always be prioritized for vulnerable populations

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.</p