Citations

Abstract Hepatic steatosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet little is known about the molecular pathology associated with this factor. In this study, we performed a forward genetic screen using Sleeping Beauty (SB) transposon insertional mutagenesis in mice treated to induce hepatic steatosis and compared the results to human HCC data. In humans, we determined that steatosis increased the proportion of female HCC patients, a pattern also reflected in mice. Our genetic screen identified 203 candidate steatosis-associated HCC genes, many of which are altered in human HCC and are members of established HCC-driving signaling pathways. The protein kinase A/cyclic AMP signaling pathway was altered frequently in mouse and human steatosis-associated HCC. We found that activated PKA expression drove steatosis-specific liver tumorigenesis in a mouse model. Another candidate HCC driver, the N-acetyltransferase NAT10, which we found to be overexpressed in human steatosis–associated HCC and associated with decreased survival in human HCC, also drove liver tumorigenesis in a steatotic mouse model. This study identifies genes and pathways promoting HCC that may represent novel targets for prevention and treatment in the context of hepatic steatosis, an area of rapidly growing clinical significance. Cancer Res; 77(23); 6576–88. ©2017 AACR.

BACKGROUND: This review focuses on the use of peripheral nerve blocks as preoperative analgesia, as postoperative analgesia, or as a supplement to general anesthesia for hip fracture surgery and tries to determine if they offer any benefit in terms of pain on movement at 30 minutes after block placement, acute confusional state, myocardial infarction/ischemia, pneumonia, mortality, time to first mobilization, and cost of analgesic. METHODS: Trials were identified by computerized searches of Cochrane Central Register of Controlled Trials (2016, Issue 8), MEDLINE (Ovid SP, 1966 to 2016 August week 1), Embase (Ovid SP, 1988 to 2016 August week 1), and the Cumulative Index to Nursing and Allied Health Literature (EBSCO, 1982 to 2016 August week 1), trials registers, and reference lists of relevant articles. Randomized controlled trials involving the use of nerve blocks as part of the care for hip fractures in adults aged 16 years and older were included. The quality of the studies was rated according to the Cochrane tool. Two authors independently extracted the data. The quality of evidence was judged according to the Grading of Recommendations, Assessment, Development, and Evaluations Working Group scale. RESULTS: Based on 8 trials with 373 participants, peripheral nerve blocks reduced pain on movement within 30 minutes of block placement: standardized mean difference, −1.41 (95% confidence interval [CI], −2.14 to −0.67; equivalent to −3.4 on a scale from 0 to 10; I 2 statistic = 90%; high quality of evidence). The effect size was proportional to the concentration of local anesthetic used ( P < .00001). Based on 7 trials with 676 participants, no difference was found in the risk of acute confusional state: risk ratio, 0.69 (95% CI, 0.38–1.27; I 2 statistic = 48%; very low quality of evidence). Based on 3 trials with 131 participants, the risk for pneumonia was decreased: risk ratio, 0.41 (95% CI, 0.19–0.89; I 2 statistic = 3%; number needed-to-treat for additional beneficial outcome, 7 [95% CI, 5–72]; moderate quality of evidence). No difference was found for the risk of myocardial ischemia or death within 6 months but the number of participants included was well below the optimum information size for these 2 outcomes. Based on 2 trials with 155 participants, peripheral nerve blocks also reduced the time to first mobilization after surgery: mean difference, −11.25 hours (95% CI, −14.34 to −8.15 hours; I 2 statistic = 52%; moderate quality of evidence). From 1 trial with 75 participants, the cost of analgesic drugs when used as a single-shot block was lower: standardized mean difference, −3.48 (95% CI, −4.23 to −2.74; moderate quality of evidence). CONCLUSIONS: There is high-quality evidence that regional blockade reduces pain on movement within 30 minutes after block placement. There is moderate quality of evidence for a decreased risk of pneumonia, reduced time to first mobilization, and reduced cost of analgesic regimen (single-shot blocks).