Unleash Multifunctional Role of miRNA Biogenesis Gene Variants (XPO5*rs34324334 and RAN*rs14035) with Susceptibility to Hepatocellular Carcinoma.

Numerous reports have explored the roles of different genetic variants in miRNA biogenesis mechanisms and the progression of various types of carcinomas. The goal of this study is to explore the association between XPO5*rs34324334 and RAN*rs14035 gene variants and susceptibility to hepatocellular carcinoma (HCC). In a cohort of 234 participants (107 HCC patients and 127 unrelated cancer-free controls) from the same geographic region, we characterized allelic discrimination using PCR-RFLP and performed subgroup analysis and multivariate regression. We found that the frequency of the XPO5*rs34324334 (A) variant was correlated with elevated risk of HCC under allelic (OR = 10.09, p-value < 0.001), recessive (OR = 24.1, p-value < 0.001), and dominant (OR = 10.1, p-value < 0.001) models. A/A genotype was associated with hepatitis C cirrhosis (p-value = 0.012), ascites (p-value = 0.003), and higher levels of alpha-fetoproteins (p-value = 0.011). Carriers of the RAN*rs14035 (T) variant were more likely to develop HCC under allelic (OR = 1.76, p-value = 0.003) and recessive (OR = 3.27, p-value < 0.001) models. Our results suggest that XPO5*rs34324334 and RAN*rs14035 variants are independent risk factors for developing HCC.

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.

The interaction between insulin resistance, liver fibrosis and early virological response in Egyptian patients with chronic hepatitis C.

BACKGROUND: Hepatitis C virus (HCV) infection may induce insulin resistance (IR) irrespective of the severity of liver disease, and there is evidence of a central role for IR in failure to achieve sustained virological response (SVR) in HCV patients. OBJECTIVE: To assess IR as a predictor of the severity of hepatic fibrosis in Egyptian HCV patients, and its effect on early viral kinetics and virological response to HCV therapy. METHODS: A total of 140 chronic HCV patients were divided into two groups according to the homeostasis model assessment-IR (HOMA-IR). Group 1 consisted of 48 chronic HCV patients with HOMA-IR >=2, and group 2 consisted of 92 chronic HVC patients without IR (HOMA IR <2). All patients were treated with combination therapy (pegylated interferon-alpha 2a plus ribavirin) for 48 weeks and studied for viral kinetics throughout the period of therapy. RESULTS: The study revealed that older age, higher body mass index and HOMA-IR >=2 were significantly associated with advanced fibrosis. Rapid virological response, complete early virological response and SVR were significantly lower in the IR-HCV group compared with the non-IR-HCV group. Univariate and multivariate analyses revealed that older age, fibrosis (F>=3), high viral load (>600,000 IU/mL) and HOMA-IR >=2 were significantly associated with a lack of viral kinetics as well as SVR. However, HOMA-IR >=2 was the main independent variable associated with lack of SVR. On the other hand, body mass index, plasma insulin level and HOMA-IR decreased significantly compared with starting levels in patients who achieved SVR. This suggests a cause and effect relationship between HCV infection and IR. CONCLUSION: IR in chronic HCV patients is associated with progressive fibrosis and slow viral kinetics, and could be a predictor for lack of rapid and early virological response. Therefore, HOMA-IR levels should be measured and improved before starting antiviral treatment.

Tissue Doppler and strain rate imaging detect improvement of myocardial function in iron deficient patients with congestive heart failure after iron replacement therapy.

BACKGROUND: Iron deficiency may contribute to diminished exercise tolerance in patients with congestive heart failure (CHF) even in absence of anemia. The aim of this study was to evaluate the effect of correction of iron deficiency on functional capacity and myocardial function in patients with CHF. METHODS: We studied 40 patients with ejection fraction <40%, hemoglobin% >12 g/dL, serum ferritin <100 ug/L, and transferrin saturation <20%. Patients received 200 mg weekly doses of iron dextran complex until serum ferritin level was between 200 and 300 ug/L or transferrin saturation level was between 30% and 40%. Transthoracic echocardiogram, tissue Doppler imaging, peak systolic strain rate, and 6 minute walk test were performed before iron therapy and at 12-week follow up. Peak early diastolic myocardial tissue velocity (E'), peak late diastolic myocardial tissue velocity (A'), and peak systolic myocardial tissue velocity (S') were measured. RESULTS: There was a significant improvement of New York Heart Association functional class (3.0 ± 0.4 vs. 2.1 ± 0.3, P < 0.05) and 6minutes walk distance (322 ± 104 vs. 377 ± 76, P < 0.01) from rest to follow up, respectively. Ejection fraction did not change significantly (32 ± 8% vs. 34 ± 9%, respectively). There was a significant improvement of S'-wave (3.0 ± 0.8 cm/sec vs. 6.0 ± 1.2 cm/sec, P < 0.05), E/E' ratio (22 ± 3 vs. 13 ± 3, P < 0.05), and peak systolic strain rate (-0.72 ± 0.11/s vs. -1.09 ± 0.37/s, P < 0.05) from baseline to follow-up, respectively. CONCLUSION: Correction of iron deficiency improves functional class and walking distance in nonanemic iron deficient patients with systolic heart failure. Tissue Doppler and strain rate demonstrated a significant improvement of diastolic and systolic function after therapy despite lack of improvement of ejection fraction. (Echocardiography 2012;29:13-18).

Serum pentraxin 3 and interleukin-6 are associated with subclinical atherosclerosis in recent-onset rheumatoid arthritis.

Subclinical atherosclerosis is increased in patients with rheumatoid arthritis (RA), as chronic systemic inflammation leads to accelerate atherosclerosis and increase arterial stiffness in theses patients. This study aimed to evaluate the association of serum interleukin-6 (sIL-6) and serum pentraxin 3(sPTX3) with subclinical atherosclerotic in patients with recent-onset rheumatoid arthritis. Sixty patients with recent onset RA (12-24 months) and 20 controls were investigated. Carotid ultrasound examination, assays for lipid profile, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor, sPTX3 and sIL-6 were done. RA patients demonstrated significantly higher carotid intima-media thickness (cIMT) values and increased carotid plaques than the control (P < 0.001 and P = 0.02, respectively). Levels of ESR, CRP, sPTX 3 and sIL-6 were significantly higher in RA patients than controls. RA related risk factors (disease duration, CRP, ESR, and duration of treatment with steroids), as well as sPTX 3, sIL-6 and cIMT were significantly higher in RA with atherosclerotic carotid plaques compared to those without atherosclerotic carotid plaques (all < 0.05). It is concluded that accelerated atherosclerosis in patients with recent-onset RA is associated with elevated levels of CRP, sPTX 3 and sIL-6.