Mechanisms of Resistance to Sorafenib and the Corresponding Strategies in Hepatocellular Carcinoma.

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma.

World J Hepatol. 2013 Jul 27; 5(7): 345-52
Zhai B, Sun XY

Sorafenib, the unique drug as first-line treatment for advanced hepatocellular carcinoma (HCC), has opened a window of hope after searching for effective agents to combat HCC for decades. However, the overall outcomes are far from satisfactory. One of the explanations is the genetic heterogeneity of HCC, which has led to identifying predictive biomarkers for primary resistance to sorafenib, and then applying the concept of personalized medicine, or seeking therapeutic strategies such as combining sorafenib with other anticancer agents. Some of the combinations have demonstrated a better effectiveness than sorafenib alone, with good tolerance. The acquired resistance to sorafenib has also drawn attention. As a multikinase inhibitor, sorafenib targets several cellular signaling pathways but simultaneously or sequentially the addiction switches and compensatory pathways are activated. Several mechanisms are involved in the acquired resistance to sorafenib, such as crosstalks involving PI3K/Akt and JAK-STAT pathways, hypoxia-inducible pathways, epithelial-mesenchymal transition, etc. Based on the investigated mechanisms, some other molecular targeted drugs have been applied as second-line treatment for treat HCC after the failure of sorafenib therapy and more are under evaluation in clinical trials. However, the exact mechanisms accounting for sorafenib resistance remains unclear. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms and help to find effective strategies for overcoming sorafenib resistance in HCC. HubMed – addiction

Not so Cool? Menthol’s discovered actions on the nicotinic receptor and its implications for nicotine addiction.

Front Pharmacol. 2013; 4: 95
Kabbani N

Nicotine cigarette smoke is a large public health burden worldwide, contributing to various types of disease. Anti-tobacco media campaigns and control programs have significantly reduced smoking in the United States, yet trends for menthol cigarette smoking have not been as promising. Menthol cigarette smoking is particularly prevalent among young adults and African Americans, with implications for long-term impacts on health care. Continuing high rates of menthol cigarette addiction call into question the role of menthol in nicotine addiction. To date, a biological basis for the high rate of addiction and relapse among menthol cigarette smokers has not been defined. Studies have demonstrated a role for menthol in the metabolism of nicotine in the body. More recent findings now reveal an interaction between menthol and the nicotinic acetylcholine (nACh) receptor in cells. This receptor is central to the actions of nicotine in the brain, and plays an important role in nicotine addiction. The newly discovered effect of menthol on nACh receptors may begin to explain the unique addictive properties of menthol cigarettes. HubMed – addiction

Positive environmental modification of depressive phenotype and abnormal hypothalamic-pituitary-adrenal axis activity in female C57BL/6J mice during abstinence from chronic ethanol consumption.

Front Pharmacol. 2013; 4: 93
Pang TY, Du X, Catchlove WA, Renoir T, Lawrence AJ, Hannan AJ

Depression is a commonly reported co-morbidity during rehabilitation from alcohol use disorders and its presence is associated with an increased likelihood of relapse. Interventions which impede the development of depression could be of potential benefit if incorporated into treatment programs. We previously demonstrated an ameliorative effect of physical exercise on depressive behaviors in a mouse model of alcohol abstinence. Here, we show that environmental enrichment (cognitive and social stimulation) has a similar beneficial effect. The hypothalamic-pituitary-adrenal (HPA) axis is a key physiological system regulating stress responses and its dysregulation has been separably implicated in the pathophysiology of depression and addiction disorders. We performed a series of dexamethasone challenges and found that mice undergoing 2 weeks of alcohol abstinence had significantly greater corticosterone and ACTH levels following a DEX-CRH challenge compared to water controls. Environmental enrichment during alcohol abstinence corrected the abnormal DEX-CRH corticosterone response despite a further elevation of ACTH levels. Examination of gene expression revealed abstinence-associated alterations in glucocorticoid receptor (Gr), corticotrophin releasing hormone (Crh) and pro-opiomelanocortin (Pomc1) mRNA levels which were differentially modulated by environmental enrichment. Overall, our study demonstrates a benefit of environmental enrichment on alcohol abstinence-associated depressive behaviors and HPA axis dysregulation. HubMed – addiction

Video Game Use in Boys With Autism Spectrum Disorder, ADHD, or Typical Development.

Pediatrics. 2013 Jul 29;
Mazurek MO, Engelhardt CR

OBJECTIVES:The study objectives were to examine video game use in boys with autism spectrum disorder (ASD) compared with those with ADHD or typical development (TD) and to examine how specific symptoms and game features relate to problematic video game use across groups.METHODS:Participants included parents of boys (aged 8-18) with ASD (n = 56), ADHD (n = 44), or TD (n = 41). Questionnaires assessed daily hours of video game use, in-room video game access, video game genres, problematic video game use, ASD symptoms, and ADHD symptoms.RESULTS:Boys with ASD spent more time than did boys with TD playing video games (2.1 vs 1.2 h/d). Both the ASD and ADHD groups had greater in-room video game access and greater problematic video game use than the TD group. Multivariate models showed that inattentive symptoms predicted problematic game use for both the ASD and ADHD groups; and preferences for role-playing games predicted problematic game use in the ASD group only.CONCLUSIONS:Boys with ASD spend much more time playing video games than do boys with TD, and boys with ASD and ADHD are at greater risk for problematic video game use than are boys with TD. Inattentive symptoms, in particular, were strongly associated with problematic video game use for both groups, and role-playing game preferences may be an additional risk factor for problematic video game use among children with ASD. These findings suggest a need for longitudinal research to better understand predictors and outcomes of video game use in children with ASD and ADHD. HubMed – addiction

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