RalA signaling pathway as a therapeutic target in hepatocellular carcinoma (HCC)

Ral (Ras like) leads an important proto‐oncogenic signaling pathway down‐stream of Ras. In this work, RalA was found to be significantly overactivated in hepatocellular carcinoma (HCC) cells and tissues as compared to non‐malignant samples. Other elements of RalA pathway such as RalBP1 and RalGDS were also expressed at higher levels in malignant samples. Inhibition of RalA by gene‐specific silencing caused a robust decrease in the viability and invasiveness of HCC cells. Additionally, the use of geranyl–geranyl transferase inhibitor (GGTI, an inhibitor of Ral activation) and Aurora kinase inhibitor II resulted in a significant decrease in the proliferation of HCC cells. Furthermore, RalA activation was found to be at a higher level of activation in HCC stem cells that express CD133. Transgenic mouse model for HCC (FXR‐Knockout) also revealed an elevated level of RalA‐GTP in the liver tumors as compared to background animals. Finally, subcutaneous mouse model for HCC confirmed effectiveness of inhibition of aurora kinase/RalA pathway in reducing the tumorigenesis of HCC cells in vivo. In conclusion, RalA overactivation is an important determinant of malignant phenotype in differentiated and stem cells of HCC and can be considered as a target for therapeutic intervention.     

Molecular mechanisms of A3 adenosine receptor-induced G1 cell cycle arrest and apoptosis in androgen-dependent and independent prostate cancer cell lines: involvement of intrinsic pathway

Purpose  

A3 adenosine receptor has shown several physiological and pathological activities, including cell proliferation and apoptosis in various cancer cell lines. This study is designed to investigate molecular mechanism and apoptotic pathway of A3 adenosine receptor in DU-145, PC3 and LNcap-FGC10 human prostate cancer cells.     

Randomized controlled trial of bilateral intrapleural block in cardiac surgery

The aim of this study was to determine the efficacy of bilateral intrapleural block with bupivacaine as a preemptive analgesic for postoperative pain in coronary artery bypass graft surgery. In a double-blind prospective clinical trial, 70 patients were randomly divided into a bupivacaine group (20 mL bupivacaine 0.25% and 0.5 mL adrenaline 1/200,000 each side) and a control group (20.5 mL normal saline each side). Evaluation of the severity of pain was performed using the visual analog scale at 12 and 24 h after entering the intensive care unit and again during chest tube removal. Pain scores at 12 and 24 h after intensive care unit admission were significantly lower in the bupivacaine group. There were no side-effects related to intrapleural block, such as pneumothorax or emphysema. In coronary artery bypass graft candidates, preemptive analgesia with bilateral intrapleural block using bupivacaine provided relatively less painful conditions during the first 24 h after surgery, but it did not improve the clinical outcome.     

Alteration of hepatic nuclear receptor-mediated signaling pathways in hepatitis C virus patients with and without a history of alcohol drinking

The current study tests a hypothesis that nuclear receptor signaling is altered in chronic hepatitis C patients and that the altered pattern is specific to alcohol drinking history. The expression of a panel of more than 100 genes encoding nuclear receptors, coregulators, and their direct/indirect targets was studied in human livers. Gene expression pattern was compared between 15 normal donor livers and 23 hepatitis C virus (HCV) genotype 1-positive livers from patients without a drinking history (matched for age, sex, and body mass index). HCV infection increased the expression of nuclear receptors small heterodimer partner and constitutive androstane receptor (CAR) as well as genes involved in fatty acid trafficking, bile acid synthesis and uptake, and inflammatory response. However, the expression of retinoid X receptor (RXR) α, peroxisomal proliferator-activated receptor (PPAR) α and β as well as steroid regulatory element-binding protein (SREBP)-1c was decreased in HCV-infected livers. Gene expression pattern was compared in chronic hepatitis C patients with and without a drinking history. Alcohol drinking increased the expression of genes involved in fatty acid uptake, trafficking, and oxidation, but decreased the expression of genes responsible for gluconeogenesis. These changes were consistent with reduced fasting plasma glucose levels and altered expression of upstream regulators that include RXRα, PPARα, and CAR. The messenger RNA levels of fibroblast growth factor 21, interleukin-10, and fatty acid synthase, which are all regulated by nuclear receptors, showed independent correlation with hepatic HCV RNA levels. Conclusion: Our findings suggest that those genes and pathways that showed altered expression could potentially be therapeutic targets for HCV infection and/or alcohol drinking-induced liver injury.     

Effects of apomorphine and β-carbolines on firing rate of neurons in the ventral pallidum in the rats

The ventral pallidum (VP) is a critical element of the mesocorticolimbic system that is inter-connected with motor and limbic structures and may be considered as an interface between motivational and effector neural signals. Dopamine is important in behavioral output of the VP, and dysfunctioning its dopamine quantity leads to various neuropsychiatric disorders. Understanding neural substrate underlying this phenomenon has become an important affair in recent years. In this study, neuronal activities were recorded from the VP in presence or absence of the mixed dopamine D1/D2 receptor agonist, apomorphine, and/or β-carbolines, using an extracellular single-unit recording technique. We reported that subcutaneous administration of apomorphine (0.5 mg/kg) decreased neural activity in the VP. In addition, neither harmine (7.8 mg/kg; i.p.) nor harmane (4 mg/kg; i.p.) and norharmane (2.5 mg/kg; i.p.) had any effect on neural firing in the VP. Finally, pretreatment with β-carbolines prevented the apomorphine-induced inhibition on VP firing rate. Thus, according to the results of aforementioned study and our results in the present study, we can conclude that presumably most responses in the VP are D2 dopamine dependent. Although the β-carbolines were unable to alter neural activity in the VP, interestingly, pretreatment with β-carbolines protect decreasing in firing rate of neurons in the VP followed by apomorphine administration. This protective effect could be explained by interaction between β-carbolines and dopaminergic mechanisms.     

Period dependent branching process and its applications in epidemiology

In this paper we introduce a new technical development of branching processes that can potentially model spread of epidemics by including various stages of infection. In fact, we present an epidemic model that the disease spreads from an individual to another one in such a way that the ability of individual u to infect a susceptible individual depends only on how long u has been infected. For analysis of this model, we introduce a new and special model of the Crump–Mode–Jagers branching processes in discrete time and obtain some of its fundamental properties.