Pathogenesis and management issues for non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has, although it is a very common disorder, only relatively recently gained broader interest among physicians and scientists. Fatty liver has been documented in up to 10 to 15 percent of normal individuals and 70 to 80 percent of obese individuals. Although the pathophysiology of NAFLD is still subject to intensive research, several players and mechanisms have been suggested based on the substantial evidence. Excessive hepatocyte triglyceride accumulation resulting from insulin resistance is the first step in the proposed 'two hit' model of the pathogenesis of NAFLD. Oxidative stress resulting from mitochondrial fatty acids oxidation, NF-κB-dependent inflammatory cytokine expression and adipocytokines are all considered to be the potential factors causing second hits which lead to hepatocyte injury, inflammation and fibrosis. Although it was initially believed that NAFLD is a completely benign disorder, histologic follow-up studies have showed that fibrosis progression occurs in about a third of patients. A small number of patients with NAFLD eventually ends up with end-stage liver disease and even hepatocellular carcinoma. Although liver biopsy is currently the only way to confirm the NAFLD diagnosis and distinguish between fatty liver alone and NASH, no guidelines or firm recommendations can still be made as for when and in whom it is necessary. Increased physical activity, gradual weight reduction and in selected cases bariatric surgery remain the mainstay of NAFLD therapy. Studies with pharmacologic agents are showing promising results, but available data are still insufficient to make specific recommendations; their use therefore remains highly individual.

Effect of superoxide dismutase and malondialdehyde metabolic changes on carcinogenesis of gastric carcinoma

AIM： To investigate the relationship between the superoxide dismutase （SOD）, malondialdehyde （MDA） metabolic changes and the gastric carcinogenesis.METHODS： The SOD activity and MDA content were measured in the gastric tissues from the focus center, peripheral and far-end areas of gastric carcinoma （n = 52） arid gastric ulcer （n = 10）. All the tissues were subjected to routine histological examinations and classifications.RESULTS： The SOD activity was greatly reduced but the MDA content was markedly increased in the center areas of the non-mucous gastric carcinoma （non-MGC）; and the poorly differentiated gastric carcinoma varied. The SOD activity was gradually decreased and the MDA content was gradually increased in the tissues from the focus far-end, peripheral to center areas of non-MGC. Both of the SOD activity and the MDA content were significantly declined and were respectively at same low level in the tissues from the focus center, peripheral, and far-end area with the mucous gastric carcinoma （MGC）. In contrast to the gastric ulcer and grade I or II of non-MGC, the same level of the SOD activity and the MDA content were found in the focus center areas. Between non-MGC （groups A-D） and gastric ulcer （group F）, the differences of SOD activity and MDA content were very noticeable in the gastric tissues from the focus peripheral and far-end areas, in which the SOD activity showed noticeable increase and the MDA content showed noticeable decreasein the gastric ulcer.CONCLUSION： The active free radical reaction in the gastric tissues can induce the carcinogenesis of non-MGC. The utmost low ability of antioxidation in the gastric tissues can induce the carcinogenesis of MGC. The metabolic change of the free radicals centralized mostly in the center of ulcerated lesions only, which suggested the ability of antioxidation was declined only in these lesions. However, the metabolism of free radicals varied significantly and the ability of antioxidation declined not only in the local focus area but also in the abroad gastric tissues with gastric carcinoma.

The efficacy of capecitabine and temozolomide against neuroendocrine carcinomas

Objective Neuroendocrine carcinomas(NECs) are resistant to currently available chemotherapy agents, and its therapeutic options are limited. Preclinical data have suggested synergy between capecitabine and temozolomide(CAPTEM). Therefore, we evaluated the efficacy and safety of CAPTEM in patients with metastatic NECs who have failed prior therapies.Methods A retrospective review was conducted on seven patients with metastatic NECs for whom platinum-based chemotherapies and hepatic chemoembolization failed. Patients received capecitabine(1000 mg twice daily on days 1-14) and temozolomide(150–200 mg/m^2 once daily on days 10–14) every 28 days. Tumor assessments were performed every two cycles.Results Among the seven patients treated, two achieved partial remission and four achieved stable disease. The total response rate was 29%, and the clinical benefit was 86%. Median progression-free survival was 10(range: 8–14) months. The most common toxicities were grade 1 and 2 neutropenia, grade 1 fatigue, and grade 1 and 2 hand-foot syndrome. No grade 4 toxicities or treatment-related deaths were observed.Conclusion Our study showed that the CAPTEM regimen is an effective and well-tolerated salvage option for NECs. Further prospective studies are warranted to evaluate optimal combinations of the CAPTEM regimen for NECs.

A MULTI-AGENT LOCAL-LEARNING ALGORITHM UNDER GROUP ENVIROMENT

In this paper,a local-learning algorithm for multi-agent is presented based on the fact that individual agent performs local perception and local interaction under group environment.As for in-dividual-learning,agent adopts greedy strategy to maximize its reward when interacting with envi-ronment.In group-learning,local interaction takes place between each two agents.A local-learning algorithm to choose and modify agents' actions is proposed to improve the traditional Q-learning algorithm,respectively in the situations of zero-sum games and general-sum games with unique equi-librium or multi-equilibrium.And this local-learning algorithm is proved to be convergent and the computation complexity is lower than the Nash-Q.Additionally,through grid-game test,it is indicated that by using this local-learning algorithm,the local behaviors of agents can spread to globe.

MULTI-AGENT BASED MODELING AND SIMULATING FOR EVACUATION PROCESS IN STADIUM

A multi-agent evacuation model is proposed in this paper to simulate the pedestrian evacuation process in stadium with or without obstacles.The authors give a multi-agent individual decisionmaking framework,in which the action direction of each pedestrian(called agent) is affected by the distance of the agent to the exits and the occupant number and density within the view field of the agent.Different from the existing results,the authors divide all the pedestrians in the stadium into four classes:Young male,young female,old male,and old female.In evacuation process,the weighting that affects individual decision-making between each class of agents is different.In the simulation,the authors present the effects of obstacles,crowd distribution and the exit position in evacuation process.Simulation results show that the proposed model can reproduce exactly the real evacuation process in stadium.Therefore,this method might be useful to assess public buildings design.

G protein-coupled receptors in energy homeostasis

G-protein coupled receptors(GPCRs)compromise the largest membrane protein superfamily which play vital roles in physiological and pathophysiological processes including energy homeostasis.Moreover,they also represent the up-to-date most successful drug target.The gut hormone GPCRs,such as glucagon receptor and GLP-1 receptor,have been intensively studied for their roles in metabolism and respective drugs have developed for the treatment of metabolic diseases such as type 2 diabetes(T2D).Along with the advances of biomedical research,more GPCRs have been found to play important roles in the regulation of energy homeostasis from nutrient sensing,appetite control to glucose and fatty acid metabolism with various mechanisms.The investigation of their biological functions will not only improve our understanding of how our body keeps the balance of energy intake and expenditure,but also highlight the possible drug targets for the treatment of metabolic diseases.The present review summarizes GPCRs involved in the energy control with special emphasis on their pathophysiological roles in metabolic diseases and hopefully triggers more intensive and systematic investigations in the field so that a comprehensive network control of energy homeostasis will be revealed,and better drugs will be developed in the foreseeable future.