The role of polymorphic cytochrome P450 gene (CYP2B6) in B-chronic lymphocytic leukemia (B-CLL) incidence and outcome among Egyptian patients.

Cytochromes P450 (CYPs) play a prominent role in catalyzing phase I xenobiotic biotransformation and account for about 75% of the total metabolism of commercially available drugs, including chemotherapeutics. The gene expression and enzyme activity of CYPs are variable between individuals, which subsequently leads to different patterns of susceptibility to carcinogenesis by genotoxic xenobiotics, as well as differences in the efficacy and toxicity of clinically used drugs. This research aimed to examine the presence of the CYP2B6*9 polymorphism and its possible association with the incidence of B-CLL in Egyptian patients, as well as the clinical outcome after receiving cyclophosphamide chemotherapy. DNA was isolated from whole blood samples of 100 de novo B-CLL cases and also from 100 sex- and age-matched healthy individuals. The presence of the CYP2B6*9 (G516T) polymorphism was examined by PCR-based allele specific amplification (ASA). Patients were further indicated for receiving chemotherapy, and then they were followed up. The CYP2B6*9 variant indicated a statistically significant higher risk of B-CLL under different genetic models, comprising allelic (T-allele vs. G-allele, OR = 4.8, p < 0.001) and dominant (GT + TT vs. GG, OR = 5.4, p < 0.001) models. Following cyclophosphamide chemotherapy, we found that the patients with variant genotypes (GT + TT) were less likely to achieve remission compared to those with the wild-type genotype (GG), with a response percentage of (37.5% vs. 83%, respectively). In conclusion, our findings showed that the CYP2B6*9 (G516T) polymorphism is associated with B-CLL susceptibility among Egyptian patients. This variant greatly affected the clinical outcome and can serve as a good therapeutic marker in predicting response to cyclophosphamide treatment.

Impact of IL-6 and IL-1ß Gene Variants on Non-small-cell Lung Cancer Risk in Egyptian Patients.

Lung cancer is a serious health and life issue, with the fastest-growing incidence and fatality rates worldwide. It is now clear that inflammation is a key factor involved in all aspects of carcinogenesis, notably lung cancer development. Genetic changes, including polymorphisms in inflammatory genes, are supposed to be a significant cause of increased lung cancer risk. The main idea of this research was to disclose the linkage between both IL-6 rs1800795 and IL-1ß rs16944 variants and susceptibility to non-small-cell lung cancer (NSCLC) in Egyptians. This case-control design was composed of 127 cases and 138 controls, which were genotyped using the ARMS-PCR technique. To examine the NSCLC susceptibility under various genetic models, the odds ratio (OR) and 95% confidence intervals (CIs) were determined by logistic regression. Rs1800795 of the IL-6 gene was linked to higher odds of NSCLC under the allele model (adjusted, OR 2.28; 95% CI 1.2-4.33; p = 0.011). In the genetic models, IL-6 rs1800795 elevated the odds of NSCLC, while IL-1ß rs16944 decreased the odds of NSCLC. Stratification analysis showed that IL-6 rs1800795 greatly increased the NSCLC risk in females and adenocarcinoma subtypes, whereas IL-1ß rs16944 largely decreased the NSCLC risk for males, patients aged < 55, and nonsmokers. Regarding clinical data, the IL-6 variant was remarkably correlated with tumor size. This work primarily established that IL-6 and IL-1ß variants have a great impact on NSCLC development in the Egyptian population; thus, it may be a supportive guide for earlier NSCLC prevention.

Detection of EGFR gene polymorphisms in non-small cell lung cancer Egyptian patients: a case-control study.

BACKGROUND: Non-Small Cell Lung Cancer displays several genetic mutations including epidermal growth factor receptor. This study's objective was to determine if the EGFR exon19 rs121913438 and exon21 rs121434568 variations play a role in NSCLC susceptibility. METHODS: Case-control research was done at the Mansoura university oncology center including 124 NSCLC patients, and 124 healthy volunteers. blood was used to obtain genomic DNA. ARMS-PCR was used to genotype single-nucleotide polymorphisms. RESULTS: Molecular study for EGFR exon 19 del. showed NSCLC cases were significantly associated with a higher proportion of heterozygous WD, WD + DD dominant genotypes, and mutant D allele, (p < 0.05 for each), with a risk to develop NSCLC. also, NSCLC cases were significantly associated with a higher proportion of heterozygous TG, TG + GG dominant genotype, G mutant allele, (p < 0.05 for each), with a risk to develop LC (OR > 1 for each). regarding the two EGFR mutations, TTF1 staining was significantly associated with WD + DD genotypes for EGFR exon 19 del But not EGFR exon 21. No substantial differences were found among all studied cases with CK7 or napsin A Tumor cytochemistry. CONCLUSIONS: The WD heterozygous genotype and D allele in exon 19 del. mutation as well as the TG heterozygous and G allele in exon 21 substitution mutation in EGFR gene are strongly associated with the development of advanced-NSCLC in the Egyptians.

Association of A1AT genetic polymorphism and NSCLC: a case- control study in Egyptian population.

BACKGROUND: Lung cancer mortality is higher than other forms of cancer. Genetic tendencies in cancer patients have long been known. Given the link between A1ATD and numerous lung disorders, it is worth investigating if this genetic trait is linked to a higher risk of developing LC, as the lung is the most afflicted organ in individuals with severe A1ATD. This study is intended to investigate the possible association between AAT rs17580 and rs8004738 gene polymorphisms and susceptibility to non-small cell lung cancer for early prediction in Egyptians. METHODS: A case-control study was performed on 124 NSCLC cases and 124 healthy controls from 2021 to 2022 in the oncology center of Mansoura University. Peripheral blood was used to obtain genomic DNA. ARMS-PCR was used to genotype SNPs and other chemical parameters. Windows SPSS Statistics was used to review, encode, and tabulate the acquired data. RESULTS: A molecular study for A1AT rs17580 and rs8004738 genotypes showed that NSCLC cases were significantly associated with a higher proportion of mutant S (T) and mutant Z (A) alleles (p = 0.042, 0.041, respectively). Different A1AT genotypes (MS, MZ, SS, SZ, and ZZ) showed no significant association with NSCLC or NLR. CONCLUSION: S and Z alleles might have significant impacts on NSCLC risk and can be useful for detecting and protecting individuals who may be vulnerable to carcinogens. Further research with larger sample sizes is needed to confirm the current findings.

Association of CYP1A1 T3801C (rs4646903) variant with the susceptibility and progression of B-chronic lymphocytic Leukemia (B-CLL) in the Egyptian population.

BACKGROUND: The frequency of hematological malignancies is increasing universally, and over the last few decades, a significant increase in the incidence of B-chronic lymphocytic leukemia (B-CLL) has been observed. Many studies have revealed the involvement of genetic predisposition along with environmental exposure to genotoxic xenobiotics in the leukemogenesis process of B-CLL. CYP1A1 is a vital member of the cytochromes P450 (CYPs) superfamily, which is involved in pro-carcinogens activation into reactive intermediates during phase I xenobiotic biotransformation. AIM: This study aimed to determine the possible role of the CYP1A1*2A (T3801C, rs4646903) single nucleotide polymorphism (SNP) as a risk factor for developing B-CLL, as well as the impact of this SNP on the disease progression and the clinical outcome. PATIENTS AND METHODS: The study was conducted on 100 patients newly diagnosed with B-CLL, and 100 healthy individuals with matched ages and sex, served as the control group. CYP1A1 (T3801C) genotyping of all patient and control samples was performed using the PCR-based Restriction Fragment Length Polymorphism (RFLP-PCR) method. In addition, serum levels of both IL-6 and TNF-α were estimated by the ELISA technique. RESULTS: Higher frequencies of the heterozygous carrier (TC) and homozygous variant (CC) genotypes of the CYP1A1 (T3801C) variant were observed in B-CLL patients compared to the controls (P < 0.001 for both). The frequencies of the CYP1A1 (T3801C) variant indicated a significant elevated risk of B-CLL under various genetic models, including allelic (OR = 8.8, P < 0.001) and dominant (OR = 9.3, P < 0.001) models. In addition, the median IL-6 level was significantly higher in patients with (TC) and (CC) genotypes than in patients with (TT) genotype (P = 0.001 and P < 0.001, respectively). Also, the median TNF-α level was significantly higher in patients with (TC) and (CC) genotypes than in patients with (TT) genotype (P < 0.001 for both). CONCLUSION: Our results showed that the CYP1A1*2A (T3801C, rs4646903) SNP increases the susceptibility to B-CLL incidence and is associated with poor disease progression.

Prognostic significance of the genetic variant of lymphotoxin alpha (p.Thr60Asn) in egyptian patients with advanced hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide in terms of mortality, and susceptibility is attributed to genetic, lifestyle, and environmental factors. Lymphotoxin alpha (LTA) has a crucial role in communicating the lymphocytes with stromal cells and provoking cytotoxic effects on the cancer cells. There are no reports on the contribution of the LTA (c.179 C>A; p.Thr60Asn; rs1041981) gene polymorphism to HCC susceptibility. The main aim of this study is to investigate the association of LTA (c.179 C>A; p.Thr60Asn; rs1041981) variant with the HCC risk in the Egyptian population. METHODS: This case-control study included 317 participants (111 HCC patients, and 206 healthy controls). The LTA (c.179 C>A; p.Thr60Asn; rs1041981) polymorphism was assessed by tetra-primer amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR) technique. RESULTS: The frequencies of the dominant and recessive models (CA + AA; AA) of the LTA (c.179 C>A; p.Thr60Asn; rs1041981) variant were statistically significant among HCC patients in comparison to controls (p = 0.01; p = 0.007; respectively). The A-allele of LTA (c.179 C>A; p.Thr60Asn; rs1041981) variant was statistically significant in HCC patients in comparison to controls (p ˂ 0.001). CONCLUSION: The LTA (c.179 C>A; p.Thr60Asn; rs1041981) polymorphism was independently associated with an increased risk for hepatocellular carcinoma in the Egyptian population.

Involvement of INF-γ functional single nucleotide polymorphism +874 T/A (rs2430561) in breast cancer risk.

According Global Cancer Statistics 2020 GLOBOCAN estimates female breast cancer was found as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), and the fourth leading cause (6.9%) of cancer death among women worldwide. Identification of new diagnostic marker sharply characterize the tumor feature is intensive need. The present work was performed to investigate the involvement of the INF-γ + 874 T/A gene polymorphism in different breast cancer prognostic factors. Polymorphism detection analysis was performed on 163 subjects from breast cancer patients, 79 with inflamed cells of breast patients and 144 controls. The gene polymorphism was detected using the amplification refractory mutation system- polymerase chain reaction method (ARMS-PCR). The distribution of INF-γ T + 874A gene polymorphism shows strong significant association between INF-γ + 874 T/A genotypes TT in BC patients (ORTT: 6.41 [95% CI = 2.72-15.1] P < 0.0001) as well as strong significant association regarding T allele (ORT: 1.99 [95% CI = 1.43-2.76] P < 0.0001) when compared to the healthy control. In ICB group the strong association was noted with INF-γ + 874 T/A genotypes AT genotype (ORAT: 2.28 [95% CI = 1.22-4.29] P = 0.007). From the different histological BC hormonal markers the human epidermal growth factor receptor 2 (HER2) was showing significant association in INF-γ + 874 T/A genotypes TT (P = 0.03) and recessive model (TT versus AA + AT P = 0.03). Concerning different BC prognostic models, the poor prognostic one of luminal B, (ER+ve PR+ve Her2+ve) show significant association in the host INF-γ + 874 T/A genotype (TT, P = 0.03) and recessive model (TT versus AA + AT P = 0.02) when compared to the good prognostic hormonal status luminal A model, (ER+ve PR+ve Her2-ve). It seems that this is the first study that interested in correlate the INF-γ + 874 T/A gene polymorphisms in Egyptian BC patients. T allele, TT genotype and recessive model of the INF-γ + 874 T/A gene variants were documented as risk factors for BC pathogenesis. It may be used as practical biomarker to guide the BC carcinogenesis and risk process.

Prognostic significance of transforming growth factor ß receptor II in clinical stage III breast cancer patients - a pilot study.

BACKGROUND: Transforming growth factor-ß (TGFß) has a dual function in breast cancer, having a tumor suppressor activity in early carcinomas while enhancing tumor metastasis in advanced breast carcinoma. Consequently, the prognostic role of TGFß and its signaling cascade in breast cancer remain unclear. OBJECTIVE: To investigate the relationship between TßRII expression, clinic-pathological characteristics, and prognostic significance of TßRII expression in clinical stage III breast cancer. METHODS: Biopsy from the primary tumor was obtained from 30 newly diagnosed clinical stage III breast cancer patients before receiving any therapy. Expression of TßRII, ER, PR, Her2 and Ki-67 was assessed by immunohistochemistry. RESULTS: TßRII expression was positive in 66.7% of cases and was significantly associated with advanced nodal stage and distant metastases. After a median follow up of 42.3 months, TßRII was associated with poor disease-free survival and it was an independent factor for predicting the poor outcome for breast cancer patients, especially in node positive tumors, ER/PR positive and Her2-negative tumors. CONCLUSIONS: These findings suggest the usage of therapeutic drugs that target TGFß in advanced breast cancer patients may be effective. Nevertheless, blockage of the tumor promoting and sparing of the tumor suppressor effect of TGFß pathway should be taken into consideration. We suggest that these therapies might have more benefit in ER and PR positive tumors.

Efficacy of Quercetin-Sensitized Cisplatin against N-Nitroso-NMethylurea Induced Testicular Carcinogenesis in Wistar Rats.

BACKGROUND: Testicular cancer is a public health problem. The goal of this study was to demonstrate the efficacy of quercetin treatment on N-nitroso-N-methyl-urea (MNU)-induced testicular carcinogenesis alone or in combination with cisplatin-treatment. METHODS: In total 70 adult male albino rats were categorized into six groups, control, quercetin-treatment (10 mg/kg body weight), cisplatin-treatment (2 mg/kg. body weight), cisplatin and quercetin-treatment, MNU-treatment, MNU plus quercetin-treatment and MNU plus quercetin and cisplatin-treatment. Treatment with quercetin and/or cisplatin was performed after 2 months of MNU induced testicular carcinogenesis. The studied groups were euthanized and sacrificed and their testes were examined for gene expression, biochemical, histological and immunohistochemically analysis, inflammation and apoptosis of germ cells. RESULTS: The fertility of the rats subjected to MNU carcinogenesis was impaired following cisplatin and/or quercetin-treatment. Cisplatin-treatment reduced the fertility rate and improved after quercetin-treatment. Quercetin-treatment decreased the sharp increase in RNA expression of BAX and MPO in both cisplatin-toxicated testes and after MNU carcinogenesis induction. In addition, the testicular levels of testosterone and SOD increased in parallel with depletion of MDA, IL-6, AFP and caspase-3 levels in MNU and/or cisplatin-treatment after -quercetin-treatment. The testicular structure of the cisplatin-treated group recovered their dividing germ and sperm differentiation after-quercetin-treatment. While, there was a great appearance of flourishing germ cell of MNU carcinogenesis post quercetin therapy, there was still a lack of sperm differentiation.  Conclusion: Quercetin-treatment showed increased cisplatin activity and decreased testicular carcinogenesis due to anti-neoplastic and antioxidant activities.

Imaging spectrum of CNS vasculitis.

Cerebral vasculitis is characterized by inflammation of the walls of blood vessels and may affect vessels of any size. The pathogenesis of vasculitis remains poorly understood. Vasculitis may affect large vessels (Takayasu arteritis, giant cell arteritis), medium-sized vessels (Kawasaki disease, polyarteritis nodosa), small vessels (immunoglobulin A vasculitis, microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis), or variable-sized vessels (Behçet disease, Cogan syndrome). Primary angiitis of the central nervous system (CNS) is an idiopathic disorder with no evidence of generalized inflammation that may simulate reversible cerebral vasoconstriction syndromes. Vasculitis may be secondary to systemic disease, infection, malignancy, drug use, or radiation therapy. Imaging findings vary from small ischemic changes to frank infarction, hemorrhage, and white matter edema and may show contrast material enhancement. The cerebral arteries may demonstrate a beaded appearance with variable degrees of stenosis, occlusion, and contrast enhancement of the vessel wall. Correlation of imaging findings with clinical presentation and laboratory test results helps establish the diagnosis of CNS vasculitis.