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.

The prognostic values of the IL-10 (G1082A) and TNF-α (G308A) polymorphisms in Egyptian patients with acute lymphoblastic leukemia: A single-center study.

Background: Interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-α) genes contribute to oncogenesis. We evaluated the influence of the IL-10 (G1082A) and TNF-α (G308A) polymorphisms on the prognosis and outcomes of Egyptian patients with acute lymphoblastic leukemia (ALL). Materials and Methods: We investigated 64 children and 76 adults with ALL, between 2016 and 2019, for the IL-10 (G1082A) and TNF-α (G308A) polymorphisms using allele-specific polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism. Survival analyses were performed using the Kaplan-Meier estimator and the log-rank test. Results: In children with ALL, the A allele of TNF-α and IL-10 polymorphisms was associated with older age (P = 0.04 and 0.03), more extramedullary disease (P = 0.02 and 0.001), positive breakpoint cluster region-Abelson (BCR-ABL) rearrangement (p190; P = 0.04 and 0.001), and more relapse (P = 0.002). The IL-10 GG genotype was associated with higher overall survival in children (P = 0.026). Adults carrying the TNF-α A allele showed more extramedullary disease (P = 0.009) and relapse (P = 0.003). We also found a higher frequency of IL-10 A allele in adults with older age (P = 0.03), lower hemoglobin level (P = 0.04), positive BCR-ABL rearrangement (P = 0.001), more extramedullary disease (P = 0.001), more relapse (P = 0.002), and a longer time for the first complete remission (P = 0.003). Conclusion: A possible association exists between the A allele of IL-10 and TNF-α polymorphisms and poor prognosis in Egyptian patients with ALL, while the IL-10 GG genotype may be associated with better survival in children with ALL.

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.

Influence of time factor and albuminuria on characteristics of patients with type 2 diabetes Mellitus before, during and 1 year after COVID-19 recovery.

BACKGROUND: The potential effects of time factor and albuminuria on the morbid alterations in patients with type 2 diabetes (T2D) and COVID-19 are still unclear. We aimed to address the morbid alterations and the potential effects of time factor and albuminuria on the patients' characteristics before, during, and 1 year after COVID-19 recovery. METHODS: 83 patients with T2D were included, at Mansoura University Hospital, Egypt (July 2021-December 2021). Data of detailed history, physical examination, laboratory tests were recruited from files of the patients. Diagnosis and resolution of COVID-19 were established by Real time polymerase chain reaction (RT-PCR) test of SARS-CoV2. Complete blood count (CBC), renal and hepatic function tests, multiple measures of morning spot urine albumin to creatinine ratio (urine ACR), glycosylated hemoglobin (HBA1c), lipid profile, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Ferritin, neutrophil to lymphocyte ratio (NLR), vitamin D3, intact parathyroid hormone (intact PTH), serum calcium were applied to all participants. RESULTS: Our participants had a mean age of 45 years, 60.2% male, 56.6% were hospitalized, and 25.3% were admitted to ICU for severe COVID-19. Albuminuria was prevalent in 71.1% before, 98.8% during, and 92.8% after COVID-19 recovery. Patients with albuminuria showed older age, longer duration of T2D, more frequent severe COVID-19 and hospitalization (p = 0.03, p < 0.001, p = 0.023& p = 0.025) respectively. Body mass index (BMI), mean arterial blood pressure, ESR, CRP, ferritin, NLR, HBA1c, triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio, vitamin D3, serum calcium, alkaline phosphatase (ALP), hepatic aminotransferases, and urine ACR showed significant alterations throughout the study (p < 0.001 for all). Although the interaction between time and albuminuria showed non-significant effect on all studied parameters, we noticed relevant main effects of time factor on Body mass index (BMI), HBA1c, glomerular filtration rate (eGFR), TG/HDL ratio, NLR, vitamin D3, (p < 0.001 for all). Moreover, albuminuria showed main effects on BMI, serum creatinine, and intact PTH (p = 0.019, 0.005 & <0.001), respectively. CONCLUSION: The characteristics of patients with T2D significantly altered throughout the study. Time factor and albuminuria exerted relevant main effects on the patients' characteristics without significant effect of their interaction.

Prognostic value of MTSS1 gene expression on acute leukemia patients outcome.

Background: This study aimed to evaluate the prognostic value of the MTSS1 gene expression in patients with acute leukemia. Patients & methods: MTSS1 gene expression was quantified in 120 newly diagnosed acute leukemia patients, by quantitative reverse transcription PCR at diagnosis and after induction chemotherapy therapy. Results: Baseline MTSS1 gene expression was significantly higher in acute leukemia patients compared to the control group (p < 0.001). Acute leukemia patients with low baseline MTSS1 gene expression at diagnosis have significantly shorter overall survival and disease-free survival compared with those with higher expression (p < 0.001 for both). Conclusion: Downregulation of MTSS1 gene expression at diagnosis was associated with poor outcome in either cytogenetic acute myeloid leukemia or B-cell acute lymphoblastic leukemia.

Influence of sodium-glucose Co-transporter 2 inhibitors on clinical and biochemical markers of dehydration during the Holy Ramadan.

BACKGROUND AND AIMS: Alteration of the hydration status with the use of sodium-glucose co-transporter- 2 inhibitors (SGLT2i) during the Holy Ramadan has not been studied in depth. Precisely, we aimed to detect the potential alteration of hydration status in adult Muslims with type 2 diabetes mellitus (T2D) who used SGLT2i during Ramadan. METHODS: An observational non-interventional study included 245 patients with type 2 diabetes mellitus of matched age and sex. The study included 3 groups: empagliflozin group; 87 patients, dapagliflozin group; 85 patients and control group; 73 patients without the use of SGLT2i. Participants in each group were well-settled on their medications for more than 3 months before the onset of Ramadan. Clinical and biochemical parameters of hydration status were evaluated during the last week of Ramadan. RESULTS: We noticed a higher prevalence of orthostatic dizziness and postural hypotension among SGLT2i users than non-SGLT2i users (p < 0.001). The mean arterial blood pressure was significantly lowered among users of empagliflozin and dapagliflozin than non-SGLT2i users; 93.7 ± 5.1 and 93.1 ± 6.9 versus 106.2 ± 4.3, p < 0.001, respectively. Moreover, patients who used empagliflozin or dapagliflozin exhibited significantly higher values of urine specific gravity; 1029.6 ± 1.5 and 1029.1 ± 1.6 versus 1016.9 ± 4.4, p < 0.001, serum osmolality; 300.7 ± 10.2 and 297.8 ± 8.9 versus 290.9 ± 6.7, p < 0.001, and BUN/creatinine ratio; 24.1 ± 4.1 and 23.2 ± 4.6 versus 16.3 ± 4.2, p < 0.001 than non-SGLT2i users. CONCLUSION: Significant clinical and biochemical markers of dehydration were noticed among users of SGLT2i during the Holy Ramadan.

Prognostic Value of TLE1 Gene Expression in Patients with T-cell Acute Lymphoblastic Leukemia.

BACKGROUND: Transducin-like enhancer of split 1 (TLE1( is a member of the TLE family of transcriptional co-repressors that control the transcription of a wide range of genes. The aim of this study was to evaluate the prognostic role of TLE1 gene expression in patients with T-cell acute lymphoblastic leukemia (T-ALL). METHOD: This study was conducted on 97 newly diagnosed T-ALL patients admitted to the Mansoura University oncology center (59 males and 38 females) with median age (33 years) in addition to 102 apparently healthy individuals served as a control group. TLE1 gene expression was measured in both patients and control groups by real time - PCR. The calculation of relative gene expression was done using the ΔΔCt method. RESULTS: TEL1 gene expression was significantly down regulated in T-ALL cases (median 2.83) as compared to controls (median 84.65) (p < 0.001). The low TEL1 gene expression was significantly associated with CNS infiltration, non-remission and higher relapse rate (p < 0.001, 0.001 and 0.023 respectively). Likewise, Low TEL1 gene expression was significantly associated with shorter OS and DFS (P= 0.012 and 0.011 respectively). Furthermore, Low TEL1 gene expression was considered as risk predictor of relapse with OR 3.636(CI.1.422-9.295) (P =0.007); and OR 0.803(CI. 0.609-0.96) (P=0.021) and independent predictor of T-ALL patient's outcome with OR 0.619 (CI. 0.44-0.872) (P=0.006). CONCLUSION: TLE1 gene expression was significantly down regulated in T-ALL cases as compared with controls. Low TLE1 expression is independent predictor of the T-ALL patient's outcome.
.

Predictive Value of Kozak Gene Polymorphism for Thrombosis in Patients with Philadelphia-Negative MPNs.

BACKGROUND: Philadelphia-negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis are clonal haematopoietic stem cell disorders characterized by dysregulated proliferation. The arterial and venous thromboses are the major causes of morbidity and mortality in MPNs. The platelet GP Ib-IX-V receptor complex plays an important role in thrombus formation as the Kozak sequence polymorphism of platelet GP Ibα is associated with increased receptor density. MATERIALS AND METHODS: This study was conducted on 286 diagnosed patients with Ph-negative MPNs (94 patients of PV, 102 of ET and 90 of MF). In addition, 107 apparently healthy individuals served as a control group. RESULTS: This study revealed that by taking rs2243093 TT as the reference genotype and T as the reference allele; TC, CC, TC+CC genotypes showed lower frequency in ET patients (p= 0.005, 0.007 and 0.001 respectively) and MF patients (p= 0.002, 0.047 and 0.001 respectively) when compared to control groups also, C allele in both groups compared to control (p ≤ 0.001 both). CC genotypes and C allele showed lower frequency in PV patients when compared to control groups (p= 0.032 and 0.026 respectively). CONCLUSION: From this study we could conclude that patients with Philadelphia-negative MPNs carried Kozak gene polymorphism significantly TT genotype in all patients PV, ET, MF patients and TC in ET and MF patients. The platelet glycoprotein Ibα (Kozak) gene could be incorporated into the routine workup to predict venous thrombosis in patients with Ph-negative MPNs specially ET patients.

Prognostic Value of CD200 Expression and Soluble CTLA-4 Concentrations in Intermediate and High-Risk Myelodysplastic Syndrome Patients.

OBJECTIVE: This study was designed in order to identify the prognostic relevance of CD200 expression and soluble Cytotoxic T-lymphocyte antigen-4 (CTLA-4) levels in myelodysplastic syndrome (MDS) patients. METHODS: The study included 57 MDS (37 intermediate and 20 high risk) patients and 10 controls. For all of included patients; CD200 expression was identified by flowcytometry on CD33 positive cells and soluble CTLA-4 (CD152) concentration was determined by ELISA. RESULTS: CD200 positive expression was detected in 32/57 (56.1%) of MDS cases, the mean serum CTLA-4 concentrations were significantly higher in MDS patients as compared to controls (P<0.01). Significant association between high CD200 positive expression; high CTLA-4   concentration levels and   MDS risk stages being higher in high risk MDS group as compared to intermediate risk one (P < 0.01).  After 36-month follow-up; the subgroup of MDS patients with high expression of CD200; and high serum CTLA-4 concentrations showed high death rate and high frequency of acute myeloid leukemia transformation. CONCLUSIONS: CD200 positive expression could be considered as a new prognostic marker for risk stratification of MDS patients. CD200 expression may exert its effect through upregulation of CTLA-4.
.

Prognostic value of some inflammatory markers in patients with lymphoma.

Background: Lymphoma is a group of blood cell tumors which develop from lymphocytes. The main forms of lymphoma are Hodgkin lymphoma (HL) and non-HL (NHL). Cytokines may contribute to lymphoma and they are related to risk NHL and HL. Aim: Assessment of the serum level of certain inflammatory markers as complementary indicators to confirm diagnosis of lymphoma patients that may be subjected to more invasive biopsy methods. Method: The serum levels of interleukin (IL)-1ß (IL-1ß), IL-6, IL-10, tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), granulocyte colony-stimulating factor (G-CSF), and eotaxin were assessed by Bio-Plex Pro assays in 81 lymphoma patients and 44 NHL and 37 HL patients before and after chemotherapy treatment as well as 20 healthy persons as a control group. Results: Lymphoma patients showed significantly raised marker levels before treatment and significantly reduced levels related to pre-treatment and controls of post-treatment for most of the markers. MCP-1 reported the highest diagnostic accuracy. G-CSF significantly raised pre-treatment and TNF-α. MCP-1 significantly increased in post treated HL compared with NHL. In order to distinguish HL from NHL, G-CSF reported the highest diagnostic accuracy. NHL patients reported complete remission (CR) and those who reported stable disease (SD) and progressive disease (PD) represented 25% and 38% respectively compared with 16% and 27% of HL patients, while partial remission (PR) of HL patients were 56% compared with 36% of NHL patients. Conclusion: Most of the markers were significantly increased in pre-treatment but significantly decreased post-treatment. However, it was not considerably enough to get better prognosis of the disease. Elevated serum levels of inflammatory markers correlate with disease severity and low benefit from treatment.