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Protein Arginine Methyltransferase 5 (PRMT5) is an enzyme that regulates gene expression and protein function through arginine methylation. Its association with isocitrate dehydrogenase (IDH) mutation in Grade-4 astrocytoma was rarely investigated. Our aim was to aim to explore the association between IDH mutation and PRMT5 and its effect on tumor recurrence. A retrospective cohort of 34 patients with Grade 4 astrocytoma has been tested for PRMT5 expression using protein and gene expression arrays. The impact of IDH-mutation and PRMT5 expression on tumor recurrence was explored. IDH-wildtype was detected in 13 tumors. PRMT5 protein was highly expressed in 30 tumors and the expression was low in four tumors. PRMT5 gene expression was upregulated in 33 tumors and downregulated in a single tumor case. Tumors with different PRMT5 gene expressions and IDH mutation were found to have a significant statistical difference in recurrence-free interval (RFI) (p-value<0.001). IDH-wildtype glioblastoma with upregulated PRMT5 gene or protein expression showed earlier tumor recurrence compared to IDH-mutant Grade 4 astrocytoma with upregulated PRMT5 expression. The association between IDH mutation and PRMT5 in IDH-mutant Grade 4 astrocytoma or IDH-wildtype glioblastoma is indirectly bidirectional. PRMT5 upregulation in glioblastoma can lead to increased cell proliferation and tumor regrowth. [ABSTRACT FROM AUTHOR]

Nuclear factor erythroid-2-related factor 2 (NRF2), a transcriptional gene factor related to nuclear factor erythroid 2, plays a role in the development of gliomas with isocitrate dehydrogenase (IDH) mutation. Its impact on tumour recurrence has seldom been investigated. A group of 34 patients diagnosed with Grade 4 astrocytoma was included in a retrospective cohort. NRF2 protein and gene expressions were assessed using different profiling assays. The association between IDH mutation, NRF2 expression, and tumor recurrence was investigated. The mean patients' age in this study was 50 years. Out of the total number of tumors analyzed, 21 of them had IDH mutation. NRF2 protein expression was found to be overexpressed in 27 tumors and reduced in 7 tumors. Additionally, NRF2 gene was upregulated in 24 tumors and downregulated in 10 tumors. Insignificant statistical difference was observed in recurrence-free interval (RFI) between patients with upregulated or downregulated NRF2 gene or protein expressions (p-value>0.05). However, this relationship is distinctive when NRF2 expression was compared to IDH mutation. Tumors with different levels of NRF2 expressions and IDH mutations showed significant statistical variation in RFI (p-value=0.001). There was insignificant impact on RFI among patients receiving different chemotherapies (TMZ or TMZ plus) who had abnormal NRF2 gene activities (p-value=0.97). WHO-Grade 4 astrocytoma with IDH mutation and altered NRF2 expression showed a delayed tumor recurrence compared to IDH-wildtype glioblastoma. [ABSTRACT FROM AUTHOR]

Introduction: CD8+ T-cells and MHC-I have been detected in brain gliomas with a significant outcome. The effect of chemotherapies on the crosstalk interaction between CD8+ T-cells and MHC-I has never been explored. Material and methods: The protein expression profiling of CD8 cytotoxic T-cells and the gene expression assay of MHC-I in 35 patients diagnosed with WHO grade 4 astrocytoma were performed. The impact of these two factors on tumor recurrence was analyzed. Results: IDH was wildtype in 13 tumors. MHC-I protein expression was absent or low in 34 tumors and dense in a single case. MHC-I gene expression was upregulated in 10 tumors and 25 tumors showed MHC-I gene downregulation. Temozolomide (TMZ) was given to 24 patients and 11 patients received TMZ plus other chemotherapies. No statistically signifi- cant association was observed between IDH mutation and CD8+ T-cells (p = 0.383). However, this association was significant in recurrence-free interval (RFI) (p = 0.012). IDH-wildtype tumors with highly infiltrated CD8+ T-cells or IDH-mutant tumors with low CD8+ T-cells showed late tumor recurrence. There was a statistically significant difference in RFI between tumors with different MHC-I expression and CD8+ T-cell counts after treatment with TMZ or TMZ plus (p = 0.026). Conclusions: No association between IDH mutation and CD8+ cytotoxic T-cell was found. IDH is directly linked to tumor recurrence regardless of CD8+ T-cells infiltration. TMZ plus other adjuvants is proved to be more effective in improving patient survival and delaying tumor recurrence, as compared to using TMZ alone. Nonetheless, none-TMZ adjuvants may increase tumor sensitization to cytotoxic T-cells more than TMZ. [ABSTRACT FROM AUTHOR]

Background: Corticosteroid is commonly used before surgery to control cerebral oedema in brain tumours and is frequently continued throughout treatment. Its long-term effect of on the recurrence of WHO-Grade 4 astrocytoma remains controversial. The interaction between corticosteroid, SRC-1 gene and cytotoxic T-cells has never been investigated. Methods: A retrospective cohort of 36 patients with WHO-Grade 4 astrocytoma were examined for CD8 + T-cell and SRC-1 gene expressions through IHC and qRT-PCR. The impact of corticosteroid on CD8+T-cells infiltration, SRC-1 expression, and tumour recurrence was analyzed. Results: The mean patients age was 47-years, with a male to female ratio 1.2. About 78% [n = 28] of the cases showed reduced or no CD8+T-cell expression while 22% [n = 8] of cases have showed medium to high CD8+T-cell expression. SRC-1 gene was upregulated in 5 cases [14%] and 31 cases [86%] showed SRC-1 downregulation. The average of total days and doses of administered corticosteroid from the preoperative period to the postoperative period was at range of 14–106 days and 41–5028 mg, respectively. There was no significant statistical difference in RFI among tumours expressing high or low CD8+T-cells when corticosteroid was administered in recommended or exceeded doses [p-value = 0.640]. There was a significant statistical difference in RFI between CD8+T-Cell expression and SRC-1 gene dysregulation [p-value = 002]. Tumours with high CD8+T T-cell expression and SRC-1 gene downregulation had late recurrence. Conclusions: Corticosteroid treatment can directly affect the SRC-1 gene regulation but does not directly influence cytotoxic T-cells infiltration or tumor progression. However, SRC-1 gene downregulation can facilitate late tumor recurrence. [ABSTRACT FROM AUTHOR]

aimi,7,8 Ghadeer Alrefaei,9 Nouf Alsubhi,10 Aziza Alrafiah,7 Safiah Alhazmi1,31Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; 2Department of Biology, King Khalid University, Abha, Saudi Arabia; 3Princess Dr. Najla Bint Saud Al-Saud Center for Excellence Research in Biotechnology, King Abdulaziz University, Jeddah, Saudi Arabia; 4Department of Internal Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 5Medical Reference Clinics, Jeddah, Saudi Arabia; 6Hematology Research Unit (HRU), King Fahad Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; 7Department of Medical Laboratory Science, King Abdulaziz University, Jeddah, Saudi Arabia; 8Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia; 9Department of Biology, University of Jeddah, Jeddah, Saudi Arabia; 10Biological Sciences Department, College of Science & Arts, King Abdulaziz University, Rabigh, Saudi Arabia*These authors contributed equally to this workCorrespondence: Aziza Alrafiah, Tel +966‐126401000 (ext. 23495), Fax +966‐126401000 (Ext. 21686), Email [email protected] Background: Breast cancer is one of the most common malignancies among women. Recent studies revealed that differentially methylated regions (DMRs) are implicated in regulating gene expression. The goal of this research was to determine which genes and pathways are dysregulated in breast cancer when their promoters are methylated in an abnormal way, leading to differential expression. Whole-genome bisulfite sequencing was applied to analyze DMRs for eight peripheral blood samples collected from five Saudi females diagnosed with stages I and II of breast cancer aligned with three normal females. Three of those patients and three normal samples were used to determine differentially expressed genes (DEG) using Illumina platform NovaSeq PE150.Results: Based on ontology (GO) and KEGG pathways, the analysis indicated that DMGs and DEG are closely related to associated processes, such as ubiquitin-protein transferase activity, ubiquitin-mediated proteolysis, and oxidative phosphorylation. The findings indicated a potentially significant association between global hypomethylation and breast cancer in Saudi patients. Our results revealed 81 differentially promoter-methylated and expressed genes. The most significant differentially methylated and expressed genes found in gene ontology (GO) are pumilio RNA binding family member 1 (PUM1) and zinc finger AN1-type containing 2B (ZFAND2B) also known as (AIRAPL).Conclusion: The essential outcomes of this study suggested that aberrant hypermethylation at crucial genes that have significant parts in the molecular pathways of breast cancer could be used as a potential prognostic biomarker for breast cancer. [ABSTRACT FROM AUTHOR]

Introduction: Fenofibrate is an agonist of peroxisome proliferator activated receptor alpha (PPAR-α), that possesses anti-inflammatory, antioxidant, and anti-thrombotic properties. Fenofibrate is effective against a variety of viral infections and different inflammatory disorders. Therefore, the aim of critical review was to overview the potential role of fenofibrate in the pathogenesis of SARS-CoV-2 and related complications. Results: By destabilizing SARS-CoV-2 spike protein and preventing it from binding angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV-2 entry, fenofibrate can reduce SARS-CoV-2 entry in human cells Fenofibrate also suppresses inflammatory signaling pathways, which decreases SARS-CoV-2 infection-related inflammatory alterations. In conclusion, fenofibrate anti-inflammatory, antioxidant, and antithrombotic capabilities may help to minimize the inflammatory and thrombotic consequences associated with SARSCoV-2 infection. Through attenuating the interaction between SARS-CoV-2 and ACE2, fenofibrate can directly reduce the risk of SARS-CoV-2 infection. Conclusions: As a result, fenofibrate could be a potential treatment approach for COVID-19 control. [ABSTRACT FROM AUTHOR]

Objective: To assess the recurrence interval and predictive significance of TP53 expression and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastomas treated with radiotherapy and combined chemotherapies, including temozolomide, lomustine, procarbazine and bevacizumab. Method: We reviewed the clinical outcomes of 52 totally resected glioblastoma patients, who received conventional radiotherapy and temozolomide with other chemotherapeutic agents. Correlation of TP53 expression and MGMT promotor methylation with recurrence interval was analyzed using Kaplan Meier estimates. Results: No significant association was found between MGMT promotor methylation and TP53 expression in glioblastomas (P-value = 0.158). Patients with non-methylated MGMT who received temozolomide chemotherapy with other chemotherapeutic agents showed significantly later recurrence (P-value = 0.007) compared with patients with non-methylated MGMT who received temozolomide alone. No significant difference was found in recurrence interval among glioblastoma patients with methylated MGMT who received temozolomide alone or with other chemotherapies (P-value = 0.667). Moreover, patients with non-TP53-expressing tumors who received temozolomide with other chemotherapies had significantly later recurrence (P-value = 0.04) compared with patients who received temozolomide alone. Conclusion: Totally resected glioblastoma patients, with non-methylated MGMT or non-TP53-expressing tumors treated with radiotherapy and combined chemotherapies had a reduced chance of tumor recurrence and a more favorable outcome. Furthermore, both MGMT and TP53 are independent prognostic factors for glioblastoma. [ABSTRACT FROM AUTHOR]

Multidrug resistance member 1 (MDR1) is located on chromosome 7 and encodes P-glycoprotein, which is universally accepted as a drug resistance biomarker. MDR1 polymorphisms can alter protein expression or function, which has been previously reported to associate with various types of malignancies, such as colorectal cancer (CRC). Therefore, the present study aimed to determine the effects of MDR1 polymorphisms on drug responses of Saudi patients with CRC. DNA samples were obtained from 62 patients with CRC and 100 healthy controls. Genotypes and allele frequencies of MDR1 single nucleotide polymorphisms (SNPs) G2677T and T1236C were determined using the PCR-restriction fragment length polymorphism procedure. The results showed no significant differences in the genotype distribution and allele frequency of T1236C between patients with CRC and controls. However, G2677T was found to serve a highly significant role in protecting against the progression of CRC. In addition, none of the genotypes in SNPs T1236C and G2677T was found to affect chemoresistance to XELIRI and XELOX. In conclusion, although T1236C in the MDR1 gene is not associated with CRC risk, G2677T protects against the development of CRC. Neither of the MDR1 SNPs tested were associated with the risk of chemoresistance. Therefore, these two SNPs cannot be used as molecular markers for predicting drug response in patients with CRC. [ABSTRACT FROM AUTHOR]

Aim: Do not resuscitate (DNR) is an order in medical practice for the patients who are suffering from a grave medical condition, and their life is in danger to end. DNR decision-making varies from one hospital to another. This study is aimed to assess the knowledge of the patients' relatives about DNR concept and their opinion about the DNR decision-making. Materials and Methods: This was a nonintervention cross-sectional study conducted, during 2016, among 420 patients' relatives in the Emergency Department at King Abdul-Aziz University Hospital in KSA. Data were collected by interviewing the participants. Data were further analyzed using SPSS software. The Chi-square test was used to determine the associations. Results: Variation in responses related to the DNR concept was observed. Around 44% of participants thought that DNR involved maximum intervention in the hospital, including intensive care. Further, the majority (55.2%) of the participants were assured about the quality of the services the patient would receive. Furthermore, 51% of the participants believed that ultimately, it should always be the doctor who decides on a DNR decision. Meanwhile, 36.4% of the relatives opined that the family members should be involved in the discussion regarding the DNR order. Conclusion: We observed a gap in the understanding of the concept and decision-making of DNR-order among the participants. Health-care providers should provide a greater explanation about DNR orders to the families of the patients to avoid any misunderstandings, and also support them psychologically to avoid any stress they might encounter in such situations. [ABSTRACT FROM AUTHOR]

This study aims to assess the association of two single nucleotide polymorphisms (SNPs), G34A and C376T, in the ABCG2 gene with the risk of developing CRC. To the best of our knowledge, this is the first study that determined the role of genetic variations in the ABCG2 gene with the risk of CRC in Saudi Arabia. The gDNA was extracted from the blood of 58 CRC patients and 48 healthy subjects. The DNA sequencing was used to determine the distribution of genotypes. The results showed that CRC patients carried a heterozygous (GA) genotype for SNP G34A had a low risk of developing CRC (odds ratio=0.015, 95% CI [0.00-0.12]; risk ratio=0.35, 95% CI [0.25-0.12], P <0.0001). On the other hand, patients that carried a heterozygous (CT) genotype for SNP C376T had a high risk of developing CRC (odds ratio=13.83, 95% CI [4.31-44.38]; risk ratio=4.88, 95% CI [1.95-12.24], P <0.0001). In conclusion, the results indicated that a heterozygous (GA) genotype in SNP G34A may decrease the risk of CRC development, whereas, the heterozygous (CT) genotype in SNP C376T may increase the risk of CRC. The results may suggest a protective role of ABCG2 SNP G34A against CRC and a deleterious effect of ABCG2 SNP C376T for increasing the risk of CRC. [ABSTRACT FROM AUTHOR]

This cross-sectional study is aimed at assessing the quality of life in a cohort of breast cancer patients at the Oncology Department, King Abdulaziz University Hospital (KAUH), King Abdulaziz University (KAU), Jeddah, Saudi Arabia (SA), and to differentiate QoL among different groups. Mean time since diagnosis was 3.97±1.90 years. European Organization for Research and Treatment of Cancer Quality of Life Questionnaires—Core30 and BR23 (EORTC QLQ-C30 & BR23) were used to assess QoL in breast cancer survivors. ANOVA and independent t-test (parametric tests) were used for the categorical variables and Kruskal-Wallis and Mann-Whitney tests used for non-parametric tests. Linear regression analysis was done to measure predictors’ significance and to calculate the coefficient of determination. Two hundred and eighty-four patients completed the survey. Global health status and functional scales, in most of the domains, were high, while symptom scales were moderate-to-low for most items, showing better QoL. Insomnia and fatigue were the most disturbing symptoms. Patients exhibited higher scores for body image and future perspective, while the least score is for sexual functioning. Global health, physical functioning, and role functioning were better in the age group ≤50 years (p<0.05). Premenopausal and perimenopausal patients showed a better level of functioning as compared to postmenopausal patients (p = 0.001). Premenopausal patients scored higher for sexual enjoyment, as compared to peri- and post-menopausal patients (p = 0.04). Systemic therapy side effects were more evident in the breast conservative surgery group. Predictors explained 8% of the variation in Physical functioning (R-squared = 0.08). A predictor that had a remarkable influence on physical functioning, as compared to the other predictors in the model, was menopausal status (P = 0.02). So, it was concluded that the breast cancer patients visiting our institute had a better quality of life regarding overall global health status as well as functional and symptom scales. Some issues, for instance, fatigue, insomnia, hair loss, and others, warrant good supportive therapy. [ABSTRACT FROM AUTHOR]

Copyright of Journal of King Abdulaziz University: Medical Sciences is the property of King Abdulaziz University, Scientific Publishing Centre and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Invasive ductal carcinoma of the breast is the most common cancer affecting women worldwide. The marked heterogeneity of breast cancer is matched only with the heterogeneity in its associated or causative factors. Breast cancer in Saudi Arabia is apparently an early onset with many of the affected females diagnosed before they reach the age of 50 years. One possible rationale underlying this observation is that consanguinity, which is widely spread in the Saudi community, is causing the accumulation of yet undetermined cancer susceptibility mutations. Another factor could be the accumulation of epigenetic aberrations caused by the shift toward a Western-like lifestyle in the past two decades. In order to shed some light into the molecular mechanisms underlying breast cancer in the Saudi community, we identified KLOTHO (KL) as a tumor-specific methylated gene using genome-wide methylation analysis of primary breast tumors utilizing the MBD-seq approach. KL methylation was frequent as it was detected in 55.3 % of breast cancer cases from Saudi Arabia ( n = 179) using MethyLight assay. Furthermore, KL is downregulated in breast tumors with its expression induced following treatment with 5-azacytidine. The involvement of KL in breast cancer led us to investigate its relationship in the context of breast cancer, with one of the protagonists of its function, fibroblast growth factor receptor 4 (FGFR4). Overexpression of FGFR4 in breast cancer is frequent in our cohort and this overexpression is associated with poor overall survival. Interestingly, FGFR4 expression is higher in the absence of KL methylation and lower when KL is methylated and presumably silenced, which is suggestive of an intricate relationship between the two factors. In conclusion, our findings further implicate 'metabolic' genes or pathways in breast cancer that are disrupted by epigenetic mechanisms and could provide new avenues for understanding this disease in a new context. [ABSTRACT FROM AUTHOR]

Copyright of Journal of King Abdulaziz University: Medical Sciences is the property of King Abdulaziz University, Scientific Publishing Centre and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Identifying and distinguishing cancer driver genes among thousands of candidate mutations remains a major challenge. Accurate identification of driver genes and driver mutations is critical for advancing cancer research and personalizing treatment based on accurate stratification of patients. Due to inter-tumor genetic heterogeneity many driver mutations within a gene occur at low frequencies, which make it challenging to distinguish them from non-driver mutations. We have developed a novel method for identifying cancer driver genes. Our approach utilizes multiple complementary types of information, specifically cellular phenotypes, cellular locations, functions, and whole body physiological phenotypes as features. We demonstrate that our method can accurately identify known cancer driver genes and distinguish between their role in different types of cancer. In addition to confirming known driver genes, we identify several novel candidate driver genes. We demonstrate the utility of our method by validating its predictions in nasopharyngeal cancer and colorectal cancer using whole exome and whole genome sequencing. [ABSTRACT FROM AUTHOR]