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

Hedonic drinking engages a supra-spinal inhibition of thermal nociception in adult rats

The taste of sucrose is commonly used to provide pain relief in newborn humans and is innately analgesic to neonatal rodents. In adulthood, sucrose remains a strong motivator to feed, even in potentially hazardous circumstances (ie, threat of tissue damage). However, the neurobiological mechanisms of this endogenous reward–pain interaction are unclear. We have developed a simple model of sucrose drinking–induced analgesia in Sprague–Dawley rats (6-10 weeks old) and have undertaken a behavioral and pharmacological characterization using the Hargreaves' test of hind-paw thermal sensitivity. Our results reveal an acute, potent, and robust inhibitory effect of sucrose drinking on thermal nociceptive behaviour that unlike the phenomenon in neonates is independent of endogenous opioid signalling and does not seem to operate through classical descending inhibition of the spinal cord circuitry. Experience of sucrose drinking had a conditioning effect whereby the apparent expectancy of sucrose enabled water alone (in euvolemic animals) to elicit a short-lasting placebo-like analgesia. Sweet taste alone, however, was insufficient to elicit analgesia in adult rats intraorally perfused with sucrose. Instead, the sucrose analgesia phenomenon only appeared after conditioning by oral perfusion in chronically cannulated animals. This sucrose analgesia was completely prevented by systemic dosing of the endocannabinoid CB1 receptor antagonist rimonabant. These results indicate the presence of an endogenous supraspinal analgesic circuit that is recruited by the context of rewarding drinking and is dependent on endocannabinoid signalling. We propose that this hedonic sucrose-drinking model may be useful for further investigation of the supraspinal control of pain by appetite and reward

Clinical Significance of Glycolytic Metabolic Activity in Hepatocellular Carcinoma

High metabolic activity is a hallmark of cancers, including hepatocellular carcinoma (HCC). However, the molecular features of HCC with high metabolic activity contributing to clinical outcomes and the therapeutic implications of these characteristics are poorly understood. We aimed to define the features of HCC with high metabolic activity and uncover its association with response to current therapies. By integrating gene expression data from mouse liver tissues and tumor tissues from HCC patients (n = 1038), we uncovered three metabolically distinct HCC subtypes that differ in clinical outcomes and underlying molecular biology. The high metabolic subtype is characterized by poor survival, the strongest stem cell signature, high genomic instability, activation of EPCAM and SALL4, and low potential for benefitting from immunotherapy. Interestingly, immune cell analysis showed that regulatory T cells (Tregs) are highly enriched in high metabolic HCC tumors, suggesting that high metabolic activity of cancer cells may trigger activation or infiltration of Tregs, leading to cancer cells\u27 evasion of anti-cancer immune cells. In summary, we identified clinically and metabolically distinct subtypes of HCC, potential biomarkers associated with these subtypes, and a potential mechanism of metabolism-mediated immune evasion by HCC cells

Unveiling the carrier transport mechanism in epitaxial graphene for forming wafer-scale, single-domain graphene

Graphene epitaxy on the Si face of a SiC wafer offers monolayer graphene with unique crystal orientation at the wafer-scale. However, due to carrier scattering near vicinal steps and excess bilayer stripes, the size of electrically uniform domains is limited to the width of the terraces extending up to a few microns. Nevertheless, the origin of carrier scattering at the SiC vicinal steps has not been clarified so far. A layer-resolved graphene transfer (LRGT) technique enables exfoliation of the epitaxial graphene formed on SiC wafers and transfer to flat Si wafers, which prepares crystallographically single-crystalline monolayer graphene. Because the LRGT flattens the deformed graphene at the terrace edges and permits an access to the graphene formed at the side wall of vicinal steps, components that affect the mobility of graphene formed near the vicinal steps of SiC could be individually investigated. Here, we reveal that the graphene formed at the side walls of step edges is pristine, and scattering near the steps is mainly attributed by the deformation of graphene at step edges of vicinalized SiC while partially from stripes of bilayer graphene. This study suggests that the two-step LRGT can prepare electrically single-domain graphene at the wafer-scale by removing the major possible sources of electrical degradation

Reconstruction of nuclear receptor network reveals that NR2E3 is a novel upstream regulator of ESR1 in breast cancer

ESR1 is one of the most important transcription factors and therapeutic targets in breast cancer. By applying systems-level re-analysis of publicly available gene expression data, we uncovered a potential regulator of ESR1. We demonstrated that orphan nuclear receptor NR2E3 regulates ESR1 via direct binding to the ESR1 promoter with concomitant recruitment of PIAS3 to the promoter in breast cancer cells, and is essential for physiological cellular activity of ESR1 in estrogen receptor (ER)-positive breast cancer cells. Moreover, expression of NR2E3 was significantly associated with recurrence-free survival and a favourable response to tamoxifen treatment in women with ER-positive breast cancer. Our results provide mechanistic insights on the regulation of ESR1 by NR2E3 and the clinical relevance of NR2E3 in breast cancer

Positive Result in the Early Passive Phase of the Tilt-table Test: A Predictor of Neurocardiogenic Syncope in Young Men

Background/Aims: This study elucidated the prognostic factors for neurocardiogenic syncope in males in their late teens and early twenties. Methods: Tilt-table testing (TTT) was performed on 665 males (age range, 17 to 27 years) following the Italian protocol. The subjects were tilted head-up at a 70 ° angle on a table for 30 minutes during the passive phase. If the passive phase was negative, the subjects were given sublingual nitroglycerin and tilted to the same angle for 20 minutes during the drugprovocation phase. The subjects with positive results were followed without medication. We analyzed factors related to the recurrence rate of syncope. Results: Of 305 subjects (45.8%) with positive results, 223 (age range, 18 to 26 years) were followed for 12 months. The frequency of previous syncopal episodes ≥ 4 (p = 0.001) and a positive result during the passive phase (p = 0.022) were significantly related to a high recurrence rate. A positive result during the early passive phase ( ≤ 12 minutes) was significantly related to a higher recurrence rate than was that during the late passive phase (> 12 minutes; p = 0.011). Conclusions: A positive result during the early passive phase of TTT and frequent previous syncopal episodes were prognostic factors for neurocardiogenic syncope in men in their late teens and early twenties. Keywords: Syncope, vasovagal; Prognosis; Tilt-table tes

The First Very Long Baseline Interferometry Image of 44 GHz Methanol Maser with the KVN and VERA Array (KaVA)

We have carried out the first very long baseline interferometry (VLBI) imaging of 44 GHz class I methanol maser (7_{0}-6_{1}A^{+}) associated with a millimeter core MM2 in a massive star-forming region IRAS 18151-1208 with KaVA (KVN and VERA Array), which is a newly combined array of KVN (Korean VLBI Network) and VERA (VLBI Exploration of Radio Astrometry). We have succeeded in imaging compact maser features with a synthesized beam size of 2.7 milliarcseconds x 1.5 milliarcseconds (mas). These features are detected at a limited number of baselines within the length of shorter than approximately 650 km corresponding to 100 Mlambda in the uv-coverage. The central velocity and the velocity width of the 44 GHz methanol maser are consistent with those of the quiescent gas rather than the outflow traced by the SiO thermal line. The minimum component size among the maser features is ~ 5 mas x 2 mas, which corresponds to the linear size of ~ 15 AU x 6 AU assuming a distance of 3 kpc. The brightness temperatures of these features range from ~ 3.5 x 10^{8} to 1.0 x 10^{10} K, which are higher than estimated lower limit from a previous Very Large Array observation with the highest spatial resolution of ~ 50 mas. The 44 GHz class I methanol maser in IRAS 18151-1208 is found to be associated with the MM2 core, which is thought to be less evolved than another millimeter core MM1 associated with the 6.7 GHz class II methanol maser.Comment: 19 pages, 3 figure