Manal A. Eid

BAALC and ERG expression in acute myeloid leukemia with normal karyotype: impact on prognosis.

Cytogenetic aberrations are important prognostic factors in acute myeloid leukemia (AML). About 45% of de novo AML lack cytogenetic abnormalities, so identification of predictive molecular markers might improve therapy. We studied the prognostic impact of brain and acute leukemia, cytoplasmic (BAALC) and ETS‐related gene (ERG) expression in AML with normal karyotype. Pretreatment bone marrow samples from 30 cytogenetically normal AML patients were analysed for BAALC and ERG expression using real time RT‐PCR. The patients were dichotomized at BAALC and ERG mean expression into low and high expression. BAALC showed high expression in 70% of patients and its expression did not correlate with the clinical parameters of patients. ERG was high in 33.3% of patients and its expression was associated with lower ages and higher white cell counts. With follow‐up for 2 years, patients with high BAALC and high ERG had low rates of clinical remission (P < 0.005) and inferior overall survival (OS) (P < 0.001 and <0.002 for BAALC and ERG respectively). No significant association was observed between the increase in BAALC and ERG expression (P = 0.398). Multivariable analysis confirmed high BAALC expression as an independent risk factor for OS. Overexpression of BAALC and ERG either separate or concomitant predict adverse clinical outcome and may define important risk factor in cytogenetically normal AML.

Evaluation of serum DNA integrity as a screening and prognostic tool in patients with hepatitis C virus-related hepatocellular carcinoma.

Background Hepatocellular carcinoma (HCC) is a common malignancy in Egypt due to the high frequency of hepatitis C virus (HCV) infection among the general population. Circulating free DNA is a potential molecular marker for the diagnosis and prognosis of malignant tumors. DNA released from apoptotic cells usually consists of short uniform fragments while DNA released from cancer cells is longer. The ratio of long DNA fragments to total DNA (DNA integrity) may be a potential marker for early detection of HCC and its progression in HCV patients. Methods Sera from 25 patients with HCV-related HCC, 25 patients with chronic HCV infection, and 15 healthy volunteers were examined for Alu repeats by quantitative real-time PCR (qPCR) using 2 sets of primers of 115 and 247 base pairs. DNA integrity was calculated as the ratio of 247-bp to 115-bp Alu fragments. Results Compared with healthy volunteers and HCV patients, significantly higher DNA integrity was found in HCC patients. DNA integrity was associated with tumor size, TNM stage, vascular invasion, lymph node involvement, and distant metastasis. DNA integrity had a higher sensitivity and specificity in discriminating HCC from HCV patients than total DNA. Patients with high DNA integrity had a significantly shorter overall survival and high DNA integrity was shown to be an independent prognostic factor for survival in HCV-related HCC. Conclusions DNA integrity is a promising molecular biomarker for detecting HCC in patients with chronic HCV infection; it reflects the progression and metastatic potential of the tumor, and high DNA integrity is associated with short overall survival in HCV-related HCC.

Doppler-derived indexes and B-type natriuretic peptide in prediction of paroxysmal atrial fibrillation in essential hypertension: a prospective study.

Background: Onset of atrial fibrillation in hypertensive patients is usually associated with a high occurrence of cardiovascular complications. Despite its leading importance as a highly prevalent and modifiable risk factor, only a few data are available regarding the predictors of paroxysmal atrial fibrillation (PAF) in hypertensive patients. Objectives: This study was undertaken to determine if PAF could be predicted in hypertensive patients while in sinus rhythm using Doppler‐derived indexes and the plasma B‐type natriuretic peptide (BNP) concentration. Methods: We prospectively evaluated 165 consecutive patients with hypertension and no known history of PAF or cardiovascular events who attended the cardiology outpatient clinic. Their mean age was 62 ± 12, 94 male, 71 female. The conventional echocardiographic parameters were measured including: left atrial (LA) volume, mitral regurgitation (MR), left ventricular (LV) function, LV mass. The ratio of transmitral peak E‐wave velocity to flow propagation velocity (E/Vp), ratio of E‐wave to mitral annular early diastolic velocity (E/Ea) obtained by Doppler tissue at the lateral and septal corners of the mitral annulus were calculated. The plasma BNP was measured at the study entry. Results: After a mean follow‐up of 15 ± 3 months, PAF (symptomatic attacks or documented on the ECG) occurred in 36 (21.8%) of 165 patients. The patients with PAF had significant higher BNP levels than those with sinus rhythm (160 ± 109.8 vs. 87.9 ± 57.7 pg/ml, P < 0.001) Also, E/Ea and E/Vp ratios were significantly higher in hypertensives with PAF (15.1 ± 2.8 vs. 8.39 ± 1.33, P < 0.001), and (1.65 ± 1.29 vs. 1.19 ± 1.06, P < 0.001) respectively. In univariate analysis, E/Vp, E/Ea, and BNP and LV hypertrophy were significant predictors of PAF. Barely E/Vp and E/Ea remained independently significant after adjustment of clinical and other echocardiographic variables by multivariate logistic regression analysis (odd ratio: 3.36, P < 0.001 and 4.93, P < 0.001 respectively). A cutoff value of ≥1.7 for E/Vp predicted PAF with 91% sensitivity and 88% specificity; E/Ea >12 has sensitivity 98%, specificity 89%, while BNP>170 pg/ml has 83% and 72% specificity, respectively, for prediction of PAF in hypertensive patients. Conclusion: Paroxysmal atrial fibrillation could be predicted in hypertensive patients while in sinus rhythm using Doppler‐derived indexes. Increased E/Vp, E/Ea ratios and elevated BNP appear to be useful parameters to identify patients at heightened risk. They may reflect early left ventricular dysfunction and atrial hypertension in this population.

The role of hepatic expression of STAT1, SOCS3 and PIAS1 in the response of chronic hepatitis C patients to therapy

BACKGROUND The underlying mechanisms of hepatitis C virus (HCV) resistance to treatment are unknown. Signal transducers and activators of transcription (STAT) proteins play a critical role in antiviral defense. OBJECTIVE To explore some of the mechanisms of HCV resistance to interferon, the expression of STAT1 and its negative regulators, protein inhibitor of activated STAT (PIAS1) and suppressor of cytokine signalling (SOCS3), in liver tissues of both inteferon responders and nonresponders in chronic HCV patients. METHODS Sixty patients were divided into the following groups: group 1a comprised 38 treatment-responder chronic HCV patients; group 1b consisted of 22 treatment-nonresponder chronic HCV patients; and group 2 consisted of six control subjects. Liver biopsies were examined for histological scoring; STAT1, SOCS3 and PIAS1 expression was analyzed using Western blotting methods. RESULTS STAT1 expression in the liver tissue of patients in group 1 was significantly increased compared with group 2 patients (P=0.001), while no significant difference in expression was observed between group 1a and group 1b patients (P=0.747). However, phosphorylated STAT1 protein was expressed at a significantly higher level in liver tissue of patients in group 1a compared with patients in group 1b (P=0.001). Western blot analysis of PIAS1 and SOCS3 protein expression in liver tissues from groups 1 and 2 revealed significantly increased expression in group 1 compared with group 2 (P=0.001). In addition, PIAS1 and SOCS3 protein expression was significantly higher in the liver tissues of patients in group 1b compared with patients in group 1a. CONCLUSION Levels of STAT1 and⁄or the protein expression of its negative regulators, PIAS1 and SOCS3, may be a good predictor of response to therapy. These could be used as biomarkers that are easily detected by Western blotting or immunostaining during standard histopathological liver biopsy analysis.

Prognostic relevance of 9q34 deletion and the suppressor of cytokine signalling‐1 in CML patients

Chronic myeloid leukemia (CML) is characterized by formation of the BCR/ABL fusion gene. The response to therapy may vary because of development of secondary cytogenetic changes or resistance. In addition, suppressor of cytokine signalling (SOCS) proteins is also hypothesized as a cause of resistance and poor prognosis when aberrantly overexpressed. This study aims to determine the incidence and prognostic value of the 9q34 deletion using fluorescence in situ hybridization and SOCS‐1 mRNA aberrant expression by PCR in 43 CML patients at different phases of the disease and in 10 normal controls and correlate the data to interferon response. All patients were Philadelphia‐positive, deletions of 9q34 were observed in 20.9% of all patients (13.3% chronic phase, 10% accelerated phase and 33.3% in blast crisis). SOCS expressions were positive in 53.4% of all patients (40% chronic phase, 50% AP and 66.67% in blast crisis). Analysing outcome based on 9q34 deletion and SOCS expression status showed a statistically significant difference in overall survival and progression‐free survival between those with deletions and those without (P < 0.001) and between those with abnormal SOCS expression and those without (P < 0.001). Deletion of 9q34 and aberrant expression of SOCS‐1 are associated with poor prognosis in CML patients with different phases of the disease under interferon therapy.

Association of the C242T polymorphism of the p22 phox gene with advanced carotid atherosclerosis in type 2 diabetes.

Reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase is an important source of superoxide (O2-) in human blood vessels. A critical component of this oxidase is the p22phox protein, which is encoded by the cytochrome b-245 α (CYBA) gene. Studies have suggested a possible association between polymorphisms of the CYBA gene and susceptibility to atherosclerosis in diabetes mellitus (DM). To address this hypothesis, we examined the relationship between the C242T polymorphism of the p22 phox gene and carotid intima/media thickness (IMT) as a factor of atherosclerosis in a group of type 2 DM patients. The study included 40 type 2 diabetic patients and 20 healthy individuals as controls. All patients and controls were matched in terms of age, gender, lipid profile, blood pressure and body mass index (BMI) The C242T p22 phox polymorphism was investigated by RFLP-PCR, and carotid IMT was measured by color duplex scanning. Diabetic subjects with the T242C and T242T genotypes displayed a significantly lower average of carotid IMT (mean 1.033±0.143 mm, range 0.85-1.25, P<0.0001) than did those with the C242C genotype (mean 1.36±0.177 mm, range 0.98-1.63) despite no differences in other risk factors. The average carotid IMT of both diabetic groups was significantly higher than that of the controls (mean 0.828±0.072 mm, range 0.72-0.86, P<0.0001). In non-diabetic subjects, the average carotid IMT of the TC+TT group did not differ from that of the CC group (0.81±0.08 vs. 0.84±0.069 mm, P>0.05). There was a significant positive correlation between carotid IMT and blood glucose level and duration. Our findings demonstrate that the CC genotype of the p22 phox gene is a risk factor for the progression of atherosclerosis in diabetic patients.

Role of the serotonin transporter gene in susceptibility to mood disorders in children of depressed parents

Objective The aim of the study was to explore psychological and behavioral disturbances in a sample of Egyptian children with depressed parents and investigate the potential role of the short (s) alleles of the serotonin transporter-linked polymorphic region in developing depressive symptoms in both parents and their offspring. Subjects and methods The study included 20 families with depressed parents and their offspring (age 6-18 years), who were compared with 20 control families with healthy parents. The Child Behavior Check List was filled by parents for children to detect syndromal and subsyndromal symptoms of mood disorders and other psychiatric disorders in the offspring. Blood samples were drawn from all groups and PCR analysis was conducted to investigate the polymorphism of interest. Results The children of depressed parents scored higher than the children of control parents in almost all Child Behavior Check List internalizing and externalizing problem parameters. A significantly higher percentage of depressed parents (70%) were found to carry the risk allele (s) compared with control parents (35%) (P = 0.03). A similar, but nonsignificant, pattern of asymmetric allele distribution was also found among the offspring of the two groups (77.3 vs. 50%). Conclusion Parental depression must be recognized as a major risk factor of psychiatric morbidity in children. Greater emphasis should be placed on developing large-scale effective preventive interventions for families with parental depression.