Genetic variability in the precore and core promoter regions of hepatitis B virus strains in Karachi

BACKGROUND: Hepatitis B virus (HBV) genotypes have distinct geographic distribution. Moreover, much genetic variability has been described in the precore (PC) and basal core promoter (BCP) regions of the HBV genome. The local prevalence of HBV genotypes and mutations has not been well studied. The aim of the present study is to determine the prevalence of HBV genotypes and mutations in the PC and BCP region in HBV strains in Karachi. METHODS: A total of 109 chronic hepatitis B patients with detectable HBV DNA by a PCR assay were enrolled in the study. Sera were tested for HBeAg, anti-HBe antibody and liver profile. HBV genotypes and mutations in the PC and BCP regions were detected by INNO-LiPA line-probe assays. RESULTS: Of the 109 patients investigated, 38 (35%) were HBeAg positive while 71 (65%) were HBeAg negative. Genotype D was present in 100% of the patients. Two patients had co-infection with genotype A. There was no significant difference in the baseline characteristics, mean ALT levels, and presence of clinical cirrhosis in patients with HBeAg positive or negative strains with or without PC and BCP mutations. Of the 38 HBeAg positive patients, 9 (24%) had PC and BCP mutations. In the HBeAg negative patient group, mutations were detected in 44 (62%) of the strains investigated. More than one mutation was common, seen in 26 (37%) patients with HBeAg negative disease and 6 (16%) patients with HBeAg positive disease. Twelve (17%) HBeAg negative patients had dual T1762 and A1764 mutations. None of the HBeAg positive patients had T1762 mutation. Mutations were undetectable in 27 (38%) of patients with HBeAg negative disease. CONCLUSION: Our study shows that type D is the main HBV genotype in Karachi, Pakistan. Significant numbers of patients infected with this genotype have PC and BCP variants. Mutations at more than one site are common. Patients harboring these mutants do not differ significantly in their clinical presentation from patients having wild type infection

HBsAg Inhibits the Translocation of JTB into Mitochondria in HepG2 Cells and Potentially Plays a Role in HCC Progression

Background and Aims: The expression of the jumping translocation breakpoint (JTB) gene is upregulated in malignant liver tissues; however, JTB is associated with unbalanced translocations in many other types of cancer that suppress JTB expression. No comprehensive analysis on its function in human hepatocellular carcinoma (HCC) has been performed to date. We aimed to define the biological consequences for interaction between JTB and HBsAg in HCC cell lines. Methods: We employed the stable transfection to establish small HBsAg expressing HepG2 cell line, and stably silenced the JTB expression using short hairpin RNA in HepG2 cell line. The effects of JTB and small HBsAg in vitro were determined by assessing cell apoptosis and motility. Results: Silencing of JTB expression promoted cancer cell motility and reduced cell apoptosis, which was significantly enhanced by HBs expression. Expression of HBsAg inhibited the translocation of JTB to the mitochondria. Furthermore, silencing of the JTB resulted in an increase in the phosphorylation of p65 in HepG2 cells and HepG2-HBs cells, whereas HBsAg expression decreased the phosphorylation of p65. The silencing of JTB in HepG2-HBs cells conferred increased advantages in cell motility and anti-apoptosis. Conclusion: HBsAg inhibited the translocation of JTB to the mitochondria and decreased the phosphorylation of p65 through the interaction with JTB, After JTB knockdown, HBsAg exhibited a stronger potential to promote tumor progression. Our data suggested that JTB act as a tumor suppressor gene in regards to HBV infection and its activation might be applied as a therapeutic strategy for in control of HBV related HCC development.National Natural Science Foundation of China [30971362, 81072013]; Fundamental Research Funds for the Central Universities in China [2010111082]; Key Projects for Technology Plan of Fujian Province in China [2009D020]; Foundation of Health Bureau of Fujian in China [2007CXB8, 3502z20077046]; Foundation of Health Bureau of Xiamen in China [2007CXB8, 3502z20077046

HURP Expression-Assisted Risk Scores Identify Prognosis Distinguishable Subgroups in Early Stage Liver Cancer

Hepatoma up-regulated protein (HURP) is a component of the chromatin-dependent pathway for spindle assembly. We examined the prognostic predictive value of HURP in human hepatocellular carcinoma (HCC).HURP expression was evaluated by immunocytochemistry of fine needle aspirated hepatoma cells in 97 HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage A. Subsequently, these patients underwent partial hepatectomy (n = 18) or radiofrequency ablation (n = 79) and were followed for 2 to 35 months. The clinicopathological parameters were submitted for survival analysis.HURP expression in aspirated HCC cells was detected in 19.6% patients. Kaplan-Meier survival analysis showed that positive HURP expression (P = 0.023), cytological grading ≥3 (P = 0.008), AFP ≥35 ng/mL (P = 0.039), bilirubin ≥1.3 mg/dL (P = 0.010), AST ≥50 U/L (P = 0.003) and ALT ≥35 U/L (P = 0.005) were all associated with a shorter disease-free survival. A stepwise multivariate Cox proportional hazard model revealed that positive HURP expression (HR, 2.334; 95% CI, 1.165-4.679, P = 0.017), AST ≥50 U/L (HR, 3.697; 95% CI, 1.868-7.319, p<0.001), cytological grade ≥3 (HR, 4.249; 95% CI, 2.061-8.759, P<0.001) and tumor number >1 (HR, 2.633; 95% CI, 1.212-5.722, P = 0.014) were independent predictors for disease-free survival. By combining the 4 independent predictors, patients with different risk scores (RS) showed distinguishable disease-free survival (RS≤1 vs. RS = 2, P = 0.001; RS = 2 vs. RS = 3, P<0.001). In contrast, the patients cannot be separated into prognosis distinguishable subgroups by using AJCC/UICC TNM staging system.HCC patients with BCLC stage A can be separated into three prognosis-distinguishable groups by use of a risk score that is based upon HURP expression in aspirated HCC cells, ALT, cytological grade and tumor number

Homeostatic regulation of the endoneurial microenvironment during development, aging and in response to trauma, disease and toxic insult

The endoneurial microenvironment, delimited by the endothelium of endoneurial vessels and a multi-layered ensheathing perineurium, is a specialized milieu intérieur within which axons, associated Schwann cells and other resident cells of peripheral nerves function. The endothelium and perineurium restricts as well as regulates exchange of material between the endoneurial microenvironment and the surrounding extracellular space and thus is more appropriately described as a blood–nerve interface (BNI) rather than a blood–nerve barrier (BNB). Input to and output from the endoneurial microenvironment occurs via blood–nerve exchange and convective endoneurial fluid flow driven by a proximo-distal hydrostatic pressure gradient. The independent regulation of the endothelial and perineurial components of the BNI during development, aging and in response to trauma is consistent with homeostatic regulation of the endoneurial microenvironment. Pathophysiological alterations of the endoneurium in experimental allergic neuritis (EAN), and diabetic and lead neuropathy are considered to be perturbations of endoneurial homeostasis. The interactions of Schwann cells, axons, macrophages, and mast cells via cell–cell and cell–matrix signaling regulate the permeability of this interface. A greater knowledge of the dynamic nature of tight junctions and the factors that induce and/or modulate these key elements of the BNI will increase our understanding of peripheral nerve disorders as well as stimulate the development of therapeutic strategies to treat these disorders

The impact of currently licensed therapies on viral and immune responses in Chronic Hepatitis B: considerations for future novel therapeutics.

Despite the availability of a preventative vaccine, chronic hepatitis B (CHB) remains a global healthcare challenge with the risk of disease progression due to cirrhosis and hepatocellular carcinoma. Although current treatment strategies, interferon and nucleos(t)ide analogues have contributed to reducing morbidity and mortality related to CHB, these therapies are limited in providing functional cure. The treatment paradigm in CHB is rapidly evolving with a number of new agents in the developmental pipeline. However, until novel agents with functional cure capability are available in the clinical setting, there is a pressing need to optimize currently licensed therapies. Here, we discuss current agents used alone and/or in combination strategies along with the impact of these therapies on viral and immune responses. Novel treatment strategies are outlined, and the potential role of current therapies in the employment of pipeline agents is discussedWellcome Trust Clinical Research Training Fellowship (107389/Z/15/Z)NIHR Academic Clinical LectureshipBarts Charity Project Grants (723/1795 and MGU/0406NIHR Research for patient benefit award (PB‐PG‐0614‐34087) to PTF

Cost of cerebellar ataxia in Hong Kong : a retrospective cost-of-illness analysis

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