Category Archives: PhD Thesis

Breast cancer is the most common type of cancer among women; every year, millions of new cases are detected worldwide, and the cases increase dramatically. Despite the fact that most of the cases are caused by non-genetic factors, hereditary and familial breast cancer also contribute and are considered risk factors that are responsible for about 20% of the cases. The present study aimed to be the first study to investigate the frequency of hereditary breast cancer caused by the high penetrance genes BReast CAncer gene 1 (BRCA1) and BReast CAncer gene 2 (BRCA2) using net generation sequencing (NGS) among Iraqi Kurdish women in Erbil province. Also, investigate several important parameters that some of them have studied for the first time among Kurdish breast cancer patients in Erbil, Iraq.

The present study included 150 participants who were already diagnosed with breast cancer and registered at Nanakali Hospital for Blood Diseases and Cancer, Erbil, Iraq. For mutation analysis and variant detection, 70 participants were selected for NGS. Samples underwent DNA extraction, estimation of the extracted DNA, polymerase chain reaction (PCR) for amplification of all exomes of the BRCA1 and BRCA2 genes, and NGS for sequencing of all coding regions (exomes) through (Illumina Inc., San Diego, CA). Results of NGS obtained in different formats (BAM, BAI, VCF, and FASTA) files. Variant viewing and detection were carried out through the Integrative Genomic Viewer (IGV) and MutationTaster websites. Finally, for interpretation of the clinical significance of the variants, different databases were used, including mainly: NCBI/ClinVar, BRCAExchange, ENIGMA, gnomAD, and COSMIC.

Many variants were detected on these two genes, variants in intronic regions were neglected (except one on BRCA2 that was not benign). At the end, 42 variants were included in the present study, 20 (47.6%) on BRCA1 and 22 (52.4%) on BRCA2. Regarding the clinical significance of the variants, 9 (21.4%) of them were clinically significant. On BRCA1, 4 (9.5%) pathogenic variants were detected (c.3607C>T, c.3544C>T, c.224_227delAAAG, c.68_69del), while on BRCA2, 2 (4.76%) pathogenic variants (c.100G>T, c.1813delA), 2 (4.76%) conflict interpretations of pathogenicity (c.3318C>G, c.1909+12delT), and 1 (2.38%) variant of uncertain significance (c.6966G>T) were detected. Also, 29 (69%) other benign variants were detected on these two genes.

An important finding of the present study was the detection of four new variants, three on the BRCA1 gene (c.463dupC, c.3190A>C, c.981del) and one on the BRCA2 gene (c.3787A>G). Those exact variants were not reported in any databases or articles before. Those new variants were submitted to NCBI/ClinVar, and unique accession numbers were obtained for each of them (SCV005196609, SCV005199865, SCV005199845, SCV005196610), respectively. Detecting new variants on these two genes is popular, especially among low- and middle-income countries, where little or no studies have been done among those populations.

Besides the molecular part, several other important parameters were investigated in the present study, including 150 participants. The mean age at the time of diagnosis with breast cancer was 49.5 years of age, with highly significant differences between the age groups (P<0.0001). The level of awareness by assessing previous knowledge about breast cancer was very low; 120 (80%), had no previous information about breast cancer, and the rest had simple knowledge about different aspects of the disease (P<0.0001). Most of the participants, 131 (87.3%) didn’t undergo any pre-tests before being diagnosed, and the rest underwent a few attempts or just once during their lifetime (P<0.0001). About half of the cases 72 (48%) were detected at advanced stages (stages III and IV), followed by stage I, then stage II (P<0.0001).

Many participants 103 (68.7%) indicated that the cases were observed by the patients themselves (P<0.0001), either by feeling a tumor or pain under the armpit. Despite the fact that cancer is known to be a silent disease, especially in its early stages, more than half 89 (59.3%) of the cases stated that they experienced some signs before the disease was detected; the most popular signs were swelling of the breast, while a few cases felt some pain, vomiting, stiffness of the breast, a shortage in breathing, and finally abnormal stuns in the breath and discharges of liquids, seen rarely (P<0.0001). For family history, 49 (32.7%) of the patients had relatives with breast cancer (P<0.0001). Regarding breast removing surgery, 62 (41.3%) already underwent mastectomy (P<0.04); among the rest of them, 73 (82.9%) stated they would take the choice of mastectomy if needed and recommended in the future.

Regarding the results of the psychological impact, 118 (78.7%) stated that the disease had a bad impact on their lives (P<0.0000.); most of them suffered from depression, and the quality of their sleep lowered dramatically after being diagnosed with cancer. For receiving sufficient information about their status, more than one-third, 53 (35.3%) of the participants stated that they were either little informed or not informed by the physician (P<0.0001). Regarding family support, 140 (93.3%) of them stated that they received good family, relatives, and friends’ support (P<0.0001). The majority 148 (98.7%) were taking one or two types of medications; chemotherapy was the most popular 129 (86%), followed by mastectomy (P<0.0001).

The emerging Fifth-Generation (5G) technology towards Internet of Vehicles (IoV) provides numerous advantages, such as lower levels of latency, stable link connections, and support for high mobility. However, avoiding vehicle collisions in IoV is a challenging task due to disseminating Emergency Safety Messages (ESMs) without strict delay and reliability requirements. To address this issue, this study proposes a novel intelligent Software-Defined Networking-based Collision Avoidance (SDNCA) framework assisted 5G. The proposed SDNCA framework employs two system models, each comprising three proposed algorithms. In the first system model, primarily, SDNCA performs the Vehicular Federated Learning (VFL) algorithm that accurately estimates the risk severity for each vehicle via training the proposed Risk Severity-Artificial Neural Network (RS-ANN) model through the implementation of federated learning among vehicles. The SDNCA framework applies the SDN algorithm to achieve three main objectives. First, it calculates the Quality of Service (QoS) of the ESM. Second, it dynamically allocates both 5G network and computing resources for three Virtual Networks (VNs). Third, it selects the optimal 5G base station (gNB) for routing the ESM to the destination vehicle. To ensure effective forwarding for each ESM, SDNCA deploys the gNB algorithm at the selected gNB to schedule the ESMs considering their priorities and configures the 5G network resources and computing resources based on the OpenFlow control message received from the SDN.

The implementation of the second system model integrates the VFL, SDN, and gNB algorithms, focusing on the risk distance between the source and destination vehicles. The objective of the second system model is to ensure the successful transmission of ESMs in scenarios when considering the risk distances between vehicles.

The two system models have been implemented using three simulation tools: Network Simulator (NS3), Python programming language, and a Mininet network emulator. The real-time simulation results demonstrate the evaluation of the SDNCA framework into two sections, compared with the existing related research. The first section assesses the performance of the SDNCA framework by varying the density and speed of the vehicles. These results include 17% and 20% Network Overhead (NO), 17% and 20% Computational Complexity (CC), 0% Collision Rate (CR), 18 ms End-to-End (E2E) Delay, 89%–90% Packet (ESM) Transmission Reliability (TR), 99.5% and 99.4% Successful Routing Ratio (SRR), 0.0050 ms Routing Efficiency (RE), 0% Packet Drop Ratio (PDR), 0.25    and 0.5    Channel Utilization (CU), and 4.5 ms and 4 ms E2E Delay with different values of the allocated bandwidth. The second section evaluates the performance of the SDNCA framework at distances ranging up to 30 meters between the source and destination vehicles, taking into account different vehicle densities and speeds. These results include 97%–99.5% and 98.4%–99.8% SRR, 4 ms and 3.5 ms RE, 0% CR, and 4.5 ms E2E Delay.

Information has been an integral part of firm success. Asymmetric information has been the main concern in successfully meeting firm objectives. This concern has been related to the need for more intense corporate governance and International Financial Reporting Standards (IAS, IFRS) as emphasized by recent studies and policymakers in some developing countries. Hence, the present study examines the integrative impact of corporate governance and International Financial Reporting Standards (IAS, IFRS) on the asymmetric information of the opinions of a sample of accounting academics and external auditors in Erbil city. The study uses four dimensions of corporate governance to predict the asymmetric information namely board of directors, audit committee, market mechanism and external audit. It has also used the survey method to obtain the primary data from the respondents by using survey questionnaires The researcher also used the mail method to distribute the survey questionnaires to selected respondents comprising auditors and academics. The study also used the SPSS to check the data reliability, validity and association among variables. The outcomes revealed that the corporate governance dimensions (i.e., board of directors, audit committee, market mechanism, and external audit and International Standards for Accounting (IAS, IFRS) implementation) have reduced the asymmetric information in firms. This study guides the policymakers in making policies related to reducing the asymmetric information by proper implanting International Financial Reporting Standards (IAS, IFRS) and effective corporate governance.

Summary

A long-term autoimmune illness called celiac disease (CD) mainly affects the small intestine, which is where gluten intolerance occurs. Since multiple extra-digestive signs are often present with this disease. CD may begin with extraintestinal symptoms, and related disorders may present at the time of diagnosis as well as the disease progresses. Adopting a gluten-free diet (GFD) prevents the development of related disorders and enhances the overall clinical course. According to these facts, the present work investigated the influence of gluten on the level of the number of autoantibodies associated with CD-related autoimmune illnesses, including anti-pituitary IgG, anti-thyroid peroxidase IgG (anti-TPO IgG), anti-islet IgG, and anti-ganglioside IgG, and analyzed the correlation between anti-tissue transglutaminase IgA(tTG-IgA) and the mentioned autoantibodies. In addition to investigate the association of one type of human leukocyte antigen (HLA) class 1 through the study of its level in serum as a soluble protein named soluble HLAG (sHLAG) and detected the HLAs class 2 type of CD patients regarding DQ2 and DQ8 alleles to determine the disease association with genetic haplotype.

To apply these aims, a total of 200 blood samples were collected in this study during the period from July 2021 until October 2022 in Raparin Children’s Hospital and Rizgary Teaching Hospital in Erbil City – Kurdistan Region of Iraq (KRI), 75 of them were collected from newly diagnoses (ND) of CD patients after they were diagnosed clinically and serologically, their ages ranged from 2 to 56 years. DNA was extracted and sera were separated then kept at -80Cº and -20Cº until used, respectively. After 4 months of GFD treatment, 75 blood samples were gathered from the same patients in addition to the control group which contained 50 healthy donors.

Sera were used to measure the level of tTG-IgA, anti-pituitary IgG, TPO- IgG, anti-islet IgG, anti-ganglioside IgG, and sHLAG level by enzyme-linked immunosorbent assay (ELISA). DNA was extracted; the purity and concentration were determined using the nanodrop technique. Real-time polymerase chain reaction (RT-PCR) was utilized to detect DQ2 and DQ8 alleles of the ND group, following the collection of samples. Graph Pad Prism 8 was used to conduct all statistical analyses

The result of the present study is divided into the finding of autoantibodies, sHLAG, and genetic study to determine homozygosity and heterozygosity of DQ2 and DQ8 alleles. The level of anti-tTG IgA, anti-pituitary IgG , anti-TPO IgG , anti-islet IgG and anti-ganglioside IgG were evidently greater (P < 0.05) in ND group of CD patients than control. Moreover, serum anti-tTG IgA , anti-pituitary IgG , anti-TPO IgG , anti-islet IgG and anti-ganglioside IgG levels were considerably higher (P < 0.05) in the CD patients under GFD group as compared with control. A comparison between CD patients, pre and post-4 months’ treatment with GFD, was conducted concerning the concentrations of autoantibodies (anti-tTG IgA, anti-pituitary IgG, anti-TPO IgG, anti-Islet IgG, and anti-ganglioside IgG). The result exhibited that the mean levels of all tested autoantibodies in CD patients were significantly (p < 0.0001) decreased after 4 months of the GFD regime compared with ND CD patients before starting the regime.

In the ND group, anti-tTG level showed a significant positive correlation with anti-ganglioside (rs=0.238, p = 0.039), however, no significant correlation was observed with other studied autoantibodies. Meanwhile, in GFD, anti-tTG IgA confirmed the significant positive correlation with anti-ganglioside (rs=0. 231, p = 0.046) as well as with anti-pituitary (rs=0.340, p = 0.002). Both anti-TPO and anti-islet did not correlate with anti-tTG IgA levels in the GFD group.

Patients were divided into two age groups: 25 of them were 2–17 years old, and 50 patients were 18–65 years old. Only anti-tTG and anti-pituitary levels differed significantly when compared between children and adults in ND patients while in GFD, the concentrations of anti-tTG, anti-pituitary, and anti-TPO were significantly (P < 0.05) influenced between age groups.Neither ND nor GFD patients reflect any significant alteration according to sex.

The other part of the findings related to sHLAG level in study groups. The level of sHLA-G was significantly (P < 0.05) dropped after 4 months of GFD treatment as compared with the ND patients but remained higher than its level in healthy controls. A weak correlation was recorded between sHLAG and anti-pituitary IgG (rs =0.317, p=0.005) in the ND group. After 4 months of GFD, anti-pituitary IgG was still in a weak correlation with sHLAG (rs= 0.324, p=0.004) while a weak correlation was also recorded between sHLAG and anti-tTG IgA (rs= 0.279, p=0.015). Concerning age and gender, there were no statistically significant (P > 0.05) variations between male and female patients of ND as well as GFD group in sHLAG mean levels.

Eight patients coded for DQ2 and twelve for DQ8, out of the patients included in this investigation. However, fifty-five individuals coded for both DQ2 and DQ8. Regarding the allele polymorphism of the DQ2 gene, DQA1*05 and DQB1*02 were encoded in 100% and 65.097% of patients carried DQ2. DQA1*03 and DQB1*0302 alleles of DQ8 were coded in 100% and 71.641% of patients carrying DQ8, respectively. Patients were categorized into three groups: homozygote, heterozygote, and negative for each gene included in this study, according to the RT-PCR results for the DQ2 and DQ8 alleles. Levels of anti-pituitary in the ND group and its levels in the GFD group in addition to anti-islet level in ND patients and  in GFD patients were significantly increased (p < 0.0001) among the patients with heterozygous DQ2 polymorphism compared to homozygous or negative. Concerning DQ8 categorizations, anti-pituitary levels and anti-TPO levels decreased significantly (p < 0.0001) in the homozygote group compared to the heterozygote and negative in the ND group while anti-islet levels decreased significantly in homozygote and heterozygote compared with the negative group. The same results were recorded regarding the GFD group where anti-pituitary levels, anti-TPO levels and anti-islet levels.

Statistically non-significant (P >0.05) differences were recorded in sHLA-G level in the homozygote group when compared with heterozygote and negative groups of CD patients , whereas significant (P < 0.05) elevation was found in heterozygote group in comparison with negative groups, the same result was obtained after GFD treatment where sHLA-G mean concentration of DQ2 heterozygote group significantly (P < 0.05) elevated in comparison with a negative group in contrast with  sHLA-G level  of DQ2 homozygote group which did not record significant alteration with other groups. Whereas ND and GFD patients did not record significant alteration of sHLA-G level among groups divided based on DQ8 categorizations.

The present study concluded that gluten-free meals have a significant impact on many autoimmune disorders by affecting the disease severity depending on the reduction in the levels of autoantibodies specific for the diagnosis of each disease and emphasized that sHLA-G has an important role in determining the severity of CD, which pertinent to the characters of genes related to this disease. As well as the results revealed that sHLA-G reflects the sequels of this disease after consuming gluten-free meals. Patients coded heterozygosity of the DQ2 allele were more severe than other polymorphisms to develop some type of autoimmune disease.