Tumor-Suppressor Role of the α1-Na/K-ATPase Signalosome in NASH Related Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide, with an estimate of 0.84 million cases every year. In Western countries, because of the obesity epidemic, non-alcoholic steatohepatitis (NASH) has become the major cause of HCC. Intriguingly, the molecular mechanisms underlying tumorigenesis of HCC from NASH are largely unknown. We hypothesized that the growing uncoupled metabolism during NASH progression to HCC, manifested by lower cell redox status and an apoptotic 'switch' activity, follows a dysregulation of α1-Na/K-ATPase (NKA)/Src signalosome. Our results suggested that in NASH-related malignancy, α1-NKA signaling causes upregulation of the anti-apoptotic protein survivin and downregulation of the pro-apoptotic protein Smac/DIABLO via the activation of the PI3K → Akt pro-survival pathway with concomitant inhibition of the FoxO3 circuit, favoring cell division and primary liver carcinogenesis. Signalosome normalization using an inhibitory peptide resets apoptotic activity in malignant cells, with a significant decrease in tumor burden in vivo. Therefore, α1-NKA signalosome exercises in HCC the characteristic of a tumor suppressor, suggesting α1-NKA as a putative target for clinical therapy.

The Role of Histone Acetylation-/Methylation-Mediated Apoptotic Gene Regulation in Hepatocellular Carcinoma.

Epigenetics, an inheritable phenomenon, which influences the expression of gene without altering the DNA sequence, offers a new perspective on the pathogenesis of hepatocellular carcinoma (HCC). Nonalcoholic steatohepatitis (NASH) is projected to account for a significant share of HCC incidence due to the growing prevalence of various metabolic disorders. One of the major molecular mechanisms involved in epigenetic regulation, post-translational histone modification seems to coordinate various aspects of NASH which will further progress to HCC. Mounting evidence suggests that the orchestrated events of cellular and nuclear changes during apoptosis can be regulated by histone modifications. This review focuses on the current advances in the study of acetylation-/methylation-mediated histone modification in apoptosis and the implication of these epigenetic regulations in HCC. The reversibility of epigenetic alterations and the agents that can target these alterations offers novel therapeutic approaches and strategies for drug development. Further molecular mechanistic studies are required to enhance information governing these epigenetic modulators, which will facilitate the design of more effective diagnosis and treatment options.

The Impact of BMI on Adult Blunt Trauma Outcomes.

Traumatic injuries account for 10% of all mortalities in the United States. Globally, it is estimated that by the year 2030, 2.2 billion people will be overweight (BMI ≥ 25) and 1.1 billion people will be obese (BMI ≥ 30). Obesity is a known risk factor for suboptimal outcomes in trauma; however, the extent of this impact after blunt trauma remains to be determined. The incidence, prevalence, and mortality rates from blunt trauma by age, gender, cause, BMI, year, and geography were abstracted using datasets from 1) the Global Burden of Disease group 2) the United States Nationwide Inpatient Sample databank 3) two regional Level II trauma centers. Statistical analyses, correlations, and comparisons were made on a global, national, and state level using these databases to determine the impact of BMI on blunt trauma. The incidence of blunt trauma secondary to falls increased at global, national, and state levels during our study period from 1990 to 2015, with a corresponding increase in BMI at all levels (P < 0.05). Mortality due to fall injuries was higher in obese patients at all levels (P < 0.05). Analysis from Nationwide Inpatient Sample database demonstrated higher mortality rates for obese patients nationally, both after motor vehicle collisions and mechanical falls (P < 0.05). In obese and nonobese patients, regional data demonstrated a higher blunt trauma mortality rate of 2.4% versus 1.2%, respectively (P < 0.05) and a longer hospital length of stay of 4.13 versus 3.26 days, respectively (P = 0.018). The obesity rate and incidence of blunt trauma secondary to falls are increasing, with a higher mortality rate and longer length of stay in obese blunt trauma patients.