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Hepatocellular carcinoma (HCC) is a highly invasive malignancy. Recently, GATOR1 (Gap Activity TOward Rags 1) complexes have been shown to play an important role in regulating tumor growth. NPRL2 is a critical component of the GATOR1 complex. Therefore, this study used NPRL2 knockdown to investigate how GATORC1 regulates the prognosis and development of HCC via the mammalian target of rapamycin (mTOR) and autophagy signaling pathways. We established HepG2 cells with NPRL2 knockdown using small interfering RNA (siRNA) and short hairpin RNA (shRNA) systems. The siRNA-mediated and shRNA-mediated NPRL2 down-regulation significantly reduced the expression of NPRL2 and two other GATPOR1 complex components, NPRL3 and DEPDC5, in HepG2 cells; furthermore, the efficient down-regulation of NPRL2 protein expression by both the shRNA and siRNA systems enhanced the proliferation, migration, and colony formation in vitro. Additionally, the NPRL2 down-regulation significantly increased HCC growth in the subcutaneous and orthotopic xenograft mouse models. The NPRL2 down-regulation increased the Rag GTPases and mTOR activation and inhibited autophagy in vitro and in vivo. Moreover, the NPRL2 level in the tumors was significantly associated with mortality, recurrence, the serum alpha fetoprotein level, the tumor size, the American Joint Committee on Cancer stage, and the Barcelona Clinic Liver Cancer stage. Low NPRL2, NPRL3, DEPDC5, and LC3, and high p62 and mTOR protein expression in the tumors was significantly associated with disease-free survival and overall survival in 300 patients with HCC after surgical resection. Conclusion: The efficient down-regulation of NPRL2 significantly increased HCC proliferation, migration, and colony formation in vitro, and increased HCC growth in vivo. Low NPRL2 protein expression in the tumors was closely correlated with poorer clinical outcomes in patients with HCC. These results provide a mechanistic understanding of HCC and aid the development of treatments for HCC.

INTRODUCTION: The incidence of early-onset colorectal cancer is increasing. This study explored the feasibility of fecal immunochemical test (FIT) and risk factors for predicting colorectal neoplasm in younger adults. METHODS: This single-center study included 6,457 participants who underwent health examination from 2013 to 2016 including index colonoscopy (3,307 individuals aged 30–49 years as the younger adult group and 3,150 aged ≥50 years as the average-risk group). Primary outcomes were adenoma detection rate (ADR) and advanced ADR (AADR). Findings of younger participants were stratified by the results of FIT and clinical risk factors and were compared with those of the average-risk group. RESULTS: Among participants aged 30–49 years, a positive FIT was associated with significantly higher ADR (28.5% vs 15.5, P < 0.001) and AADR (14.5% vs 3.7%, P < 0.001) than a negative FIT. Moreover, a positive FIT was associated with higher AADR in younger participants than in average-risk counterparts (14.5% vs 9.8%, P = 0.028). Although no single risk factor predicted FIT positivity in younger participants, nonalcoholic fatty liver disease was independently associated with higher ADR (odds ratio = 2.60, 95% confidence interval = 1.27–5.34, P = 0.001), and metabolic syndrome was independently predictive of higher AADR in younger participants than in average-risk participants (odds ratio = 3.46, 95% confidence interval = 1.66–7.21, P = 0.001). DISCUSSION: A positive FIT in people aged 30–49 years implies a higher risk of colorectal neoplasm, particularly among patients with nonalcoholic fatty liver disease and metabolic syndrome.

The accumulation of autophagosomes in the terminal step of the autophagic process has recently emerged as a potentially maladaptive process in the septic heart and lung. However, the role of autophagy in the septic liver has not been ascertained. This study was investigated by first examining the entire sequence of the autophagic process in the liver of septic mice. Second, a novel pharmacotherapeutic approach was utilized to treat sepsis with autophagy enhancer/inhibitor. Sepsis was induced by cecal ligation and puncture (CLP). C57BL/6 mice received autophagy enhancer carbamazepine (CBZ), autophagy inhibitor 3-methyladenine (inhibition of autophagosomal formation), or chloroquine (impairment of autophagosomal clearance). We found that the whole autophagic process was activated at 4 h after CLP; however, it did not proceed to completion during the 4- to 24-h time period, as indicated by accumulated autophagosomes and decreased autophagic flux. Carbamazepine, which induced complete activation of the autophagic process, improved CLP survival. This protective effect was also associated with decreased cell death, inflammatory responses, and hepatic injury. However, disruption of autophagosomal clearance with chloroquine abolished the above protective effects in CBZ-treated CLP mice. 3-Methyladenine, which resulted in inhibition of the autophagosomal formation, did not show any above beneficial effects in CLP mice. Impaired autophagosome-lysome fusion resulting in incomplete activation of autophagy may contribute to sepsis-induced liver injury. Treatment with CBZ may serve a protective role in the septic liver, possibly through the effect of complete activation of autophagic process.

The efficacy of sorafenib in combination with transarterial chemoembolization (TACE) or multiple-line therapies in patients with advanced hepatocellular carcinoma (HCC) remains unclear. This study aimed to investigate the overall survival (OS) of patients with advanced HCC in response to different combination therapies. We analyzed the treatment and OS of 401 patients with Barcelona clinic liver cancer stage C HCC between 2012 and 2017. Mortality was analyzed using multivariate Cox regression, and OS was analyzed by the Kaplan–Meier method. The mean age was 59 years and males were predominant. During a median follow-up time of 8.6 months (range, 1–80 months), 346 (86.2%) patients died. In the multivariate Cox regression analysis, primary tumor size ≥5 cm, serum alpha-fetoprotein ≥200, and serum albumin ≥3.5 were significantly associated with mortality. In addition, compared with sorafenib alone, multiple-line treatments with sorafenib and multiple-line treatments without sorafenib yielded significantly decreased mortality. In the Kaplan–Meier analysis, sorafenib with TACE, multiple-line treatments with sorafenib, third-line treatments with sorafenib, and multiple-line treatments without sorafenib yielded a significantly better median OS than sorafenib alone. Sorafenib with concurrent multiple-line therapies significantly improved OS. These combination therapies will provide important information for immunotherapy combination with locoregional therapies in advanced HCC.

Background The role of autophagy-related markers as the prognostic factor of post-operative hepatocellular carcinoma (HCC) recurrence remained controversial. Methods Overall, 535 consecutive HCC patients undergoing curative resection from 2010 to 2014 were followed and classified with early (ER

There has been a surge in the academic publication output based on secondary analyses of the data from the Taiwan's National Health Insurance claim records. It has become a challenge to comprehend such a rapid expansion of the literature. Therefore, this study aimed to explore the conceptual content of National Health Insurance Research Database-based cancer research, using the abstract of articles extracted from PubMed between 2002 and 2015. Search terms including "National Health Insurance Research Database (NHIRD) AND Taiwan," "Taiwan AND population-based," and "Taiwan AND nationwide" were used to search in PubMed with the publication date limited to between 1997 and 2015. The retrieved articles were manually screened to retain only those that were cancer-related and were based on secondary data analysis of the NHIRD. A total 589 articles were selected for subsequent text mining using the R software. Among the 589 articles, the top 5 most studied cancer types were breast (16.3%), lung (11.4%), colorectal (10.4%), liver (8.3%), and prostate (7.5%). The articles that received the highest number of citations by PubMed Central articles were cited 92 times. The top 3 most frequently occurred keywords in the abstracts of the 589 articles were cancer, patient, and risk, with 3670, 2535, and 1652 times, respectively. Analysis of key conception indicated that the most common conceptions were diabetes, survival, breast cancer, lung cancer, and colorectal cancer. In conclusion, in this study of 589 published articles on secondary data analysis of the NHIRD, indexed by PubMed between 2002 and 2015, we found that while the risk factors of cancer, treatment of cancer, and survival of cancer patients were popular research topics, end-of-life cancer care issues were less studied. Further studies should explore these areas since they are as important as treatment of the disease itself for many patients.