Fadhel Lafta

Introduction Genomic level data has significantly increased the depth of our understanding of genetic and epigenetic changes in cancer. However, using this complex data to improve patient management is challenging. Synthetic lethal (SL) genes (which are only required for growth/survival of cancer cells and not normal cells), represent ideal targets for the development of more targeted, less toxic and more effective cancer treatments. Here we report a novel bioinformatics approach that exploits the complexity of DNA methylation/expression changes to identify cancer subtype specific SL genes. Materials and Method Publicly available genome wide DNA methylation and expression data was obtained for ALL (n=517), medulloblastoma (n=763) and neuroblastoma (n=213). For neuroblastoma, which lacks established subgroups, novel subgroups were defined based on differential methylation (using the t-SNE/dbSCAN method) SL gene candidates were derived from genomic methylation/expression data using our in-house developed bioinformatic pipeline. Functional validation of identified candidate SL genes was performed using siRNA-mediated knockdown, coupled with analysis of cell proliferation (MTT assay) and apoptosis (annexin-V staining/caspase activity). Results 22 candidate SL genes were identified across six ALL genetic subgroups, ranging from nine in the TCF3-PBX1 to one in the iAMP21 subgroup. The identified genes lack any apparent genetic/epigenetic alterations, and thus most of the candidates have not previously been implicated in cancer. siRNA-mediated partial knockdown of ETV6/RUNX1 and TCF3-PBX1-specific candidate SL genes TUSC3 and FAT1 respectively resulted in a 40-60% reduction in cell proliferation (p <0.01) and induction of apoptosis (p <0.01), which was specific to the subtype in which the genes were predicted to be synthetically lethal. In medulloblastoma, seven candidate SL genes each were identified in the well-defined WNT and SHH subgroups, while identification of SL genes was limited in group 3 (0) and group 4 (1) tumours, which lack known group-defining molecular defects. However, using the recently defined further subtyping of Group3/Group4 tumours, nine additional candidates were identified across three of the novel subtypes. siRNA mediated knockdown of 5 candidate genes tested to date in the SHH subtype led to significant inhibition of cell growth (p<0.001) and induction of apoptosis (p<0.001). In neuroblastoma, we identified five novel methylation-dependent subgroups, which correlate with known molecular and clinical data. Six candidate SL genes were identified in methylation cluster 3, which consists almost exclusively of high-risk MYCN amplified cases. Conclusion We have demonstrated that SL genes, specific for defined molecular subtypes of cancer, can be identified utilising a novel approach combining methylation/expression data in multiple cancer types. Citation Format: Lalchung Nunga, Ed Schwalbe, Fadhel Lafta, Deborah Tweddle, John Maris, Timothy Barrow, Gordon Strathdee. Identification of cancer-specific synthetic lethal genes as novel therapeutic targets [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1275.

Pre-marital clinical tests are essential part of every national health system. They provide proper medical care early to prevent unnecessary stress and burden during marriage. This study was set to investigate the clinical findings as well as knowledge and attitude toward these tests among intending couples (n=244 couples, age mean 25.7 years ranged from 15 to 75 years) in Al-Yarmuok Hospital, Baghdad-Iraq, during September 2016-December 2017. The results showed that the Rh incompatibility ratio was relatively high when 17.5% (37/244) of the couples have different Rh blood groups (Rh-/Rh+). A significant number (9.43%) of Rh-females who were intending to marry from Rh+ blood-types partners was identified in the present study. The result of HIV, HBV, HCV and VDRL viral screening showed a significant number of the intending couples (13.73%(67/488)) have serious viral infections. The awareness levels of the importance of premarital screening tests were 67% and 64.4% in males and females respectively. In terms of knowing the complications of blood group incompatibility during/after pregnancy, a similar positive attitude was shown by males and females toward this concept (64.92% and 65.87% respectively). While the vast majority (67.82%), of the investigated individuals, from both genders, do not know what precaution should be taken if a mother's blood is Rh negative. 70.3% of the marriages were between non-consanguineous couples.

Ionizing radiation is one of the toxic and carcinogenic factors that potentially have direct and indirect long-term effects that are depending on the amount of doses and periods of exposure to radiation. These risks can appear in the form of changes in gene expression due to the influence of epigenetic mechanisms, especially DNA methylation. Exposure of DNA methylation to ionizing radiation for long periods of time can lead to genetic instability, which can be passed down through generations. In this review will. The aim of this study is to shine new light on these debates through an examination of.

Type 2 diabetes mellitus (T2DM) is an epidemic metabolic disorder that has life threatening health complications if left undetected and untreated. Understanding its molecular landscape alterations, especially DNA methylation that regulates the genome transcription activity, would aid with the prevention and management of this disease. This study was set to investigate the global DNA methylations (assessed by measuring 5mC level), along with other disease-related clinical features, including body mass index (BMI) and serum vitamin B12, in T2DM patients in comparison to healthy controls. One hundred subjects (70 T2DM patients and 30  healthy controls) who attended Baghdad Teaching  Hospital/ Department of Consulting Clinic - Endocrinology and Diabetes Consultant and the National Diabetes Center, Al-Mustansiriyah University, Baghdad, Iraq. Global DNA methylation levels were assessed using Methyl flash ™ Global DNA methylation (5-mC) ELISA Easy Kits. The results showed significant incre...

The present study was set to investigate the potential association between the level of Interleukin-6 (IL-6), as a key component of the pro-inflammatory response, with different thalassemia’s biological and clinical features. For this purpose, one hundred fifty blood samples were collected from 100 beta-thalassemia patients, who attended the Genetic Hematology Centre at Ibn Al- Baladi Hospital in Baghdad, Iraq, and 50 healthy subjects who were employed as a control group. IL-6 levels were estimated using an ELISA Kit, whereas other thalassemia-related clinical features (such as HbA, HbF, ferritin, blood transfusions, splenectomy status, and the history of frequent infection) were additionally assessed. The results of the present study showed a significant elevation (P≤0.01) in the levels of IL-6 in thalassemia patients as compared to healthy controls (57.7763± 8.94837 vs.  6.3059± 1.90364 pg/ml, respectively). Furthermore, IL-6 plasma levels seem to be influenced by the number of mu...

Breast cancer is the commonest cancer and the leading cause of malignancies-related mortality in women worldwide. Understanding the underlying biology of the disease could improve patients’ stratification and may offer novel therapeutic targets and strategies. This study was set to investigate the association between BRCA1 gene expression and some of the clinical features of breast cancer patients in Baghdad-Iraq. Eighty peripheral blood samples were collected from sixty patients diagnosed with breast cancer and twenty healthy age-matched controls for BRCA1 qPCR gene expression analysis.      The results showed a significant reduction in BRCA1 gene expression in all of the breast cancer patients with the vast majority of them (75%) having BRCA1expression below 25%. The down regulation of BRCA1 expression also showed consistency in breast cancer patients of both sporadic (n=45) and family history (n=15) cases,with expression averages of 18% and 20.19%, respectively. Moreover, the red...

Male infertility is a complex medical condition, in which epigenetic factors play an important role. Epigenetics has recently gained significant scientific attention since it has added a new dimension to genomic and proteomic research. As a mechanism for maintaining genomic integrity and controlling gene expression, epigenetic modifications hold a great promise in capturing the subtle, yet very important, regulatory elements that might drive normal and abnormal sperm functions. The sperm’s epigenome is known to be marked by constant changing over spermatogenesis, which is highly susceptible to be influenced by a wide spectrum of environmental stimuli. Recently, epigenetic aberrations have been recognized as one of the causes of idiopathic male infertility. Recent advances in technology have enabled humans to study epigenetics role in male infertility.

The identification of cancer-specific vulnerability genes is one of the most promising approaches for developing more effective and less toxic cancer treatments. Cancer genomes exhibit thousands of changes in DNA methylation and gene expression, with the vast majority likely to be passenger changes. We hypothesised that, through integration of genome-wide DNA methylation/expression data, we could exploit this inherent variability to identify cancer subtype-specific vulnerability genes that would represent novel therapeutic targets that could allow cancer-specific cell killing. We developed a bioinformatics pipeline integrating genome-wide DNA methylation/gene expression data to identify candidate subtype-specific vulnerability partner genes for the genetic drivers of individual genetic/molecular subtypes. Using acute lymphoblastic leukaemia as an initial model, 21 candidate subtype-specific vulnerability genes were identified across the five common genetic subtypes, with at least on...

Consanguineous marriages are the marriages contracted between blood relatives . many studies have suggested a strong association between consanguinity and the incidence of abnormal reproductive health parameters. The aims of this research was to determine the prevalence and type of consanguineous marriages and the associated factors for sample from families in Baghdad , Iraq. The research was conducted in urban areas of Baghdad .A total sample of 302 married women were interviewed at their home or work places. Information on the sociodemographic and fertility characteristics of the women were gathered using a written questionnaire .Data analysis was done by SSPS program. The overall prevalence of consanguinity was 44.04 % , with a mean of inbreeding coefficient of 0.01851 . The principal type of consanguineous marriages was first – cousins marriages , which accounted for 56.4 % of all consanguineous unions .There was a significant association) between consanguinity and sociodemograp...

Epigenetic landscape correlates with genetic subtype but does not predict outcome in childhood acute lymphoblastic leukemia. Epigenetics, 10 (8 Northumbria University has developed Northumbria Research Link (NRL) to enable users to access the University's research output. Copyright © and moral rights for items on NRL are retained by the individual author(s) and/or other copyright owners. Single copies of full items can be reproduced, displayed or performed, and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided the authors, title and full bibliographic details are given, as well as a hyperlink and/or URL to the original metadata page. The content must not be changed in any way. Full items must not be sold commercially in any format or medium without formal permission of the copyright holder. The full policy is available online: http://nrl.northumbria.ac.uk/policies.h...

The present study was carried out to evaluate the hematological and cytogenetic effects of waterpipe smoke (WPS) in albino male mice. The investigated parameters were total count ofleukocytes (TCL), mitotic index (MI), micronucleus (MN) formation and chromosomalaberrations. The results of our study showed that, mice were exposed to WPS using a specialinhalation glass chamber (whole body exposure). Mice exposed daily to 100 puffs of WPS on thebases of (1h exposure per day). The exposure experiment continued daily for the periods of 3, 5, 7weeks consequently. The results revealed that the TCL significantly decreased in the second andthird treatment (5930, 4120 cell/ cu. mm. blood) respectively, in comparison to control (6200 cell/cu. mm. blood), while the MI decreased in all 3 treatment after 3, 5, 7 weeks. Nevertheless, boththe MN cells and chromosomal aberration remain the same percentage as the control in the firsttreatment and then began to be higher than the control in the second...

Breast cancer is the commonest cancer and the leading cause of malignancies-related mortality in women worldwide. Understanding the underlying biology of the disease could improve patients’ stratification and may offer novel therapeutic targets and strategies. This study was set to investigate the association between BRCA1 gene expression and some of the clinical features of breast cancer patients in Baghdad-Iraq. Eighty peripheral blood samples were collected from sixty patients diagnosed with breast cancer and twenty healthy age-matched controls for BRCA1 qPCR gene expression analysis.      The results showed a significant reduction in BRCA1 gene expression in all of the breast cancer patients with the vast majority of them (75%) having BRCA1expression below 25%. The down regulation of BRCA1 expression also showed consistency in breast cancer patients of both sporadic (n=45) and family history (n=15) cases,with expression averages of 18% and 20.19%, respectively. Moreover, the red...

Background Chronic lymphocytic leukaemia (CLL) patients display a highly variable clinical course, with progressive acquisition of drug resistance. We sought to identify aberrant epigenetic traits that are enriched following exposure to treatment that could impact patient response to therapy. Methods Epigenome-wide analysis of DNA methylation was performed for 20 patients at two timepoints during treatment. The prognostic significance of differentially methylated regions (DMRs) was assessed in independent cohorts of 139 and 163 patients. Their functional role in drug sensitivity was assessed in vitro. Results We identified 490 DMRs following exposure to therapy, of which 31 were CLL-specific and independent of changes occurring in normal B-cell development. Seventeen DMR-associated genes were identified as differentially expressed following treatment in an independent cohort. Methylation of the HOXA4, MAFB and SLCO3A1 DMRs was associated with post-treatment patient survival, with HO...

Tobacco smoking is affecting fundamental aspects of human health. This preliminary study was set to investigate the effect of tobacco smoking on the salivary pH. The saliva is an essential part of healthy oral cavity, it is mostly made of water and also contains other substances that your body needs to digest food and keep your teeth strong. Smoking is expected to have an effect on salivary pH. The salivary pH levels were measured using digital pH meter in 100 voluntary participants in Baghdad- Iraq. The participants were divided into two groups of 50 subjects in each group: smokers and non-smokers. Along with that, the reasons behind tobacco smoking also were investigated in a separate group of 82 smokers using a prepared questioner for this purpose. The results showed decrease salivary pH average levels in the tobacco smokers compare to the non-smoker group (7.058 and 7.168 respectively), however, these differences did not reach the significant level. Regarding the investigation of the reasons behind tobacco smoking habit, seeking for fun, overcome psychiatric problem, anger, friendship, relieves stress and anxiety and work problems (((29 (35.4%), (28(34.1%), 27(32.9%), 22(26.8%), 22(26.8%), 21(25.6%) respectively, were on the top of the listed reasons for smoking tobacco cigarettes stated by the questioned participants. Participants who think that cigarettes could help to relieve boredom (age average 35.3 yrs (17-55 yrs) smoke the largest number of cigarettes (30(20-60) compare to those who smoke for other reasons.

Abstract Background The role of exercise in oxidative stress and genomic damage was evaluated as the main target population of ASS and protein supplement in usually physical active individuals. Therefore, the purposes of this study were to determine the effects of exercise and abuse of synthetic anabolic steroids and food supplements on micronuclei frequency in buccal cells and 8-hydroxy-2-deoxyguanosine (8-OHdG) as markers for DNA damage. Methods The study included one hundred males aged 17–44 years, distributed into five distinct groups including Group I: 20 bodybuilder individuals with AAS consumption, Group II: 20 bodybuilder individuals with diet supplement (proteins) consumption. Group III: 20 bodybuilders without AAS and diet supplement (proteins) consumption, Group IV: 20 football players without AAS and proteins consumption, and Group V 20 non-athletes without diet supplement or AAS consumption. Results The mean age + standard deviation (SD) of groups I, II, III, IV and V were (27.00 ± 5.53, 27.85 ± 5.60, 29.70 ± 8.04, 22.35 ± 3.89 and 26.05 ± 6.42, respectively. The mean of BMI values was significantly different among groups (p  Conclusion Our results outlined that exceeded usage of AAS or food supplement (proteins) exerted no increasing effects of oxidative DNA and/or chromosomal aberration accounting for serum 8-OHdG and micronuclei in buccal cells. These are possibly due to the adaptive responses such as up regulation of DNA repair systems and enhancement of the anti-oxidant capacity in highly-trained individuals.

Although children with acute lymphoblastic leukemia (ALL) generally have a good outcome, some patients do relapse and survival following relapse is poor. Altered DNA methylation is highly prevalent in ALL and raises the possibility that DNA methylation-based biomarkers could predict patient outcome. In this study, genome-wide methylation analysis, using the Illumina Infinium HumanMethylation450 BeadChip platform, was carried out on 52 diagnostic patient samples from 4 genetic subtypes [ETV6-RUNX1, high hyperdiploidy (HeH), TCF3-PBX1 and dic(9;20)(p11-13;q11)] in a 1:1 case-control design with patients who went on to relapse (as cases) and patients achieving long-term remission (as controls). Pyrosequencing assays for selected loci were used to confirm the array-generated data. Non-negative matrix factorization consensus clustering readily clustered samples according to genetic subgroups and gene enrichment pathway analysis suggested that this is in part driven by epigenetic disrupti...

Pre-marital clinical tests are essential part of every national health system. They provide proper medical care early to prevent unnecessary stress and burden during marriage. This study was set to investigate the clinical findings as well as knowledge and attitude toward these tests among intending couples (n=244 couples, age mean 25.7 years ranged from 15 to 75 years) in Al-Yarmuok Hospital, Baghdad-Iraq, during September 2016-December 2017. The results showed that the Rh incompatibility ratio was relatively high when 17.5% (37/244) of the couples have different Rh blood groups (Rh-/Rh+). A significant number (9.43%) of Rh-females who were intending to marry from Rh+ blood-types partners was identified in the present study. The result of HIV, HBV, HCV and VDRL viral screening showed a significant number of the intending couples (13.73%(67/488)) have serious viral infections. The awareness levels of the importance of premarital screening tests were 67% and 64.4% in males and females respectively. In terms of knowing the complications of blood group incompatibility during/after pregnancy, a similar positive attitude was shown by males and females toward this concept (64.92% and 65.87% respectively). While the vast majority (67.82%), of the investigated individuals, from both genders, do not know what precaution should be taken if a mother's blood is Rh negative. 70.3% of the marriages were between non-consanguineous couples.