The mutational landscape of hepatocellular carcinoma

The development of hepatocellular carcinoma (HCC) is a complex process, and HCC arises from the accumulation of multiple genetic alterations leading to changes in the genomic landscape. Current advances in genomic technologies have revolutionized the search for genetic alterations in cancer genomes. Recent studies in which all coding exons in HCC were sequenced have shed new light on the genomic landscape of this malignant disease. Catalogues of these somatic mutations and systematic analysis of catalogued mutations will lead us to uncover candidate HCC driver genes, although further functional validation is needed to determine whether these genes play a causal role in the development of HCC. This review provides an overview of previously known oncogenes and new oncogene candidates in HCC that were uncovered from recent exome or whole-genome sequencing studies. This knowledge provides direction for future personalized treatment approaches for patients with HCC

Applying Regression Discontinuity Design to Social Policy: An Evaluation of the Welfare-to-Work Program in South Korea

Social policy studies focusing on poverty reduction attempt to measure poverty reductions rates and poverty gaps, but they do not provide criteria to determine whether a given social policy is a success or failure. In this study, we suggest using regression discontinuity design to establish evaluation criteria and validate estimation results in social programs. Using the dataset from the Korean Welfare Panel, first we conduct, first, a difference-in-differences comparison between welfare recipients under the National Basic Livelihood Security system and nonrecipients whose income falls under the minimum cost of living. Secondly, we establish the counterfactual effects of the program among nonrecipients whose income is below the minimum cost of living and among nonrecipients whose income is above the minimum cost of living. Last, we analyze treatment effects by comparing welfare recipients with income below the minimum cost of living and nonrecipients with income above the minimum cost of living using the regression distribution design method. We argue that the National Basic Livelihood Security system as a welfare-to-work program has positive effects on labor market participation, which has not been established by previous studies

Systems Biology Approaches to Decoding the Genome of Liver Cancer

Molecular classification of cancers has been significantly improved patient outcomes through the implementation of treatment protocols tailored to the abnormalities present in each patient's cancer cells. Breast cancer represents the poster child with marked improvements in outcome occurring due to the implementation of targeted therapies for estrogen receptor or human epidermal growth factor receptor-2 positive breast cancers. Important subtypes with characteristic molecular features as potential therapeutic targets are likely to exist for all tumor lineages including hepatocellular carcinoma (HCC) but have yet to be discovered and validated as targets. Because each tumor accumulates hundreds or thousands of genomic and epigenetic alterations of critical genes, it is challenging to identify and validate candidate tumor aberrations as therapeutic targets or biomarkers that predict prognosis or response to therapy. Therefore, there is an urgent need to devise new experimental and analytical strategies to overcome this problem. Systems biology approaches integrating multiple data sets and technologies analyzing patient tissues holds great promise for the identification of novel therapeutic targets and linked predictive biomarkers allowing implementation of personalized medicine for HCC patients

NELFE-Dependent MYC Signature Identifies a Unique Cancer Subtype in Hepatocellular Carcinoma.

The MYC oncogene is dysregulated in approximately 30% of liver cancer. In an effort to exploit MYC as a therapeutic target, including in hepatocellular carcinoma (HCC), strategies have been developed on the basis of MYC amplification or gene translocation. Due to the failure of these strategies to provide accurate diagnostics and prognostic value, we have developed a Negative Elongation Factor E (NELFE)-Dependent MYC Target (NDMT) gene signature. This signature, which consists of genes regulated by MYC and NELFE, an RNA binding protein that enhances MYC-induced hepatocarcinogenesis, is predictive of NELFE/MYC-driven tumors that would otherwise not be identified by gene amplification or translocation alone. We demonstrate the utility of the NDMT gene signature to predict a unique subtype of HCC, which is associated with a poor prognosis in three independent cohorts encompassing diverse etiologies, demographics, and viral status. The application of gene signatures, such as the NDMT signature, offers patients access to personalized risk assessments, which may be utilized to direct future care

Regulation of Gene Expression in Hepatic Cells by the Mammalian Target of Rapamycin (mTOR)

We investigated mTOR regulation of gene expression by studying rapamycin effect in two hepatic cell lines, the non-tumorigenic WB-F344 cells and the tumorigenic WB311 cells. The latter are resistant to the growth inhibitory effects of rapamycin, thus providing us with an opportunity to study the gene expression effects of rapamycin without confounding effects on cell proliferation.The hepatic cells were exposed to rapamycin for 24 hr. Microarray analysis on total RNA preparations identified genes that were affected by rapamycin in both cell lines and, therefore, modulated independent of growth arrest. Further studies showed that the promoter regions of these genes included E-box-containing transcription factor binding sites at higher than expected rates. Based on this, we tested the hypothesis that c-Myc is involved in regulation of gene expression by mTOR by comparing genes altered by rapamycin in the hepatic cells and by c-Myc induction in fibroblasts engineered to express c-myc in an inducible manner. Results showed enrichment for c-Myc targets among rapamycin sensitive genes in both hepatic cell lines. However, microarray analyses on wild type and c-myc null fibroblasts showed similar rapamycin effect, with the set of rapamycin-sensitive genes being enriched for c-Myc targets in both cases.There is considerable overlap in the regulation of gene expression by mTOR and c-Myc. However, regulation of gene expression through mTOR is c-Myc-independent and cannot be attributed to the involvement of specific transcription factors regulated by the rapamycin-sensitive mTOR Complex 1

Sleep disturbances, depressive symptoms, and cognitive efficiency as determinants of mistakes at work in shift and non-shift workers

IntroductionShift work is known to reduce productivity and safety at work. Previous studies have suggested that a variety of interrelated factors, such as mood, cognition, and sleep, can affect the performance of shift workers. This study aimed to identify potential pathways from depression, sleep, and cognition to work performance in shift and non-shift workers.Material and methodsOnline survey including the Center for Epidemiologic Studies Depression Scale (CES-D), Cognitive Failure Questionnaire (CFQ), and Pittsburgh Sleep Quality Index (PSQI), as well as two items representing work mistakes were administered to 4,561 shift workers and 2,093 non-shift workers. A multi-group structural equation model (SEM) was used to explore differences in the paths to work mistakes between shift and non-shift workers.ResultsShift workers had higher PSQI, CES-D, and CFQ scores, and made more mistakes at work than non-shift workers. The SEM revealed that PSQI, CES-D, and CFQ scores were significantly related to mistakes at work, with the CFQ being a mediating variable. There were significant differences in the path coefficients of the PSQI and CES-D between shift and non-shift workers. The direct effects of sleep disturbances on mistakes at work were greater in shift workers, while direct effects of depressive symptoms were found only in non-shift workers.DiscussionThe present study found that shift workers made more mistakes at work than non-shift workers, probably because of depressed mood, poor sleep quality, and cognitive inefficiency. Sleep influences work performance in shift workers more directly compared to non-shift workers

Resting-State Glucose Metabolism Level Is Associated with the Regional Pattern of Amyloid Pathology in Alzheimer's Disease

It has been suggested that glucose metabolism within the brain's default network is directly associated with—and may even cause—the amyloid pathology of Alzheimer's disease (AD). Here we performed 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and [11C]-labeled Pittsburgh Compound B (PIB) positron emission tomography (PET) on cognitively normal elderly subjects and on AD patients and conducted quantitative regional analysis of FDG- and PIB-PET images using an automated region of interest technique. We confirmed that resting glucose metabolism within the posterior components of the brain's default network is high in normal elderly subjects and low in AD patients, which is partially in agreement with the regional pattern of PIB uptake within the default network of AD patients. However, in several regions outside the default network, glucose metabolism was high in normal elderly subjects but was not depressed in AD patients, who exhibited significantly increased PIB uptakes in these regions. In contrast, the level of resting glucose metabolism in the default network and in regions outside the default network in normal elderly subjects was significantly correlated with the level of regional PIB uptake in AD patients. These results are discussed with experimental evidence suggesting that beta amyloid production and amyloid precursor protein regulation are dependent on neuronal activity

Effect of heat treatment of digestion-resistant fraction from soybean on retarding of bile acid transport in vitro

In this study, we investigated the heat effect of digestion-resistant fraction (RF) from soybean on retarding bile acid transport in vitro. The RFs from soybean retarded bile acid transport. A raw, unheated RF of soybean (RRF-SOY) was significantly more effective than the heated RF of soybean (HRF-SOY). The RS1 which physically trapped in milled grains and inaccessible to digestive enzyme after 18 hrs incubation level of content in RRF-SOY was found to be as high as 24.1% and after heating the RS1 of HRF-SOY was significantly reduced to 16.8%. The X-ray diffraction pattern of RF from soybean was altered after heat treatment. The RFs from soybean were characterized by peak at diffraction angles of 12.0° and 20.0° corresponding to RS content. Cellulose contents of RRF-SOY was 5% higher than that of HRF-SOY and pentosan contents of RRF-SOY was 5% higher than that of HRF-SOY, too. Whereas the hemicellulose content of RRF-SOY was 13% lower than HRF-SOY

Rab25 increases cellular ATP and glycogen stores protecting cancer cells from bioenergetic stress

Cancer cells are metabolically stressed during tumour progression due to limited tumour vascularity and resultant nutrient, growth factor and oxygen deficiency that can induce cell death and inhibit tumour growth. We demonstrate that Rab25, a small GTPase involved in endosomal recycling, that is genomically amplified in multiple tumour lineages, is a key regulator of cellular bioenergetics and autophagy. RAB25 enhanced survival during nutrient stress by preventing apoptosis and autophagy via binding and activating AKT leading to increased glucose uptake and improved cellular bioenergetics. Unexpectedly, Rab25 induced the accumulation of glycogen in epithelial cancer cells, a process not previously identified. Strikingly, an increase in basal ATP levels combined with AKT-dependent increases in glucose uptake and glycogen storage allowed maintenance of ATP levels during bioenergetic stress. The clinical relevance of these findings was validated by the ability of a Rab25-dependent expression profile enriched for bioenergetics targets to identify patients with a poor prognosis. Thus, Rab25 is an unexpected regulator of cellular bioenergetics implicated as a useful biomarker and potential therapeutic target