Networks of intergenic long-range enhancers and snpRNAs drive castration-resistant phenotype of prostate cancer and contribute to pathogenesis of multiple common human disorders

Biological and mechanistic relevance of intergenic disease-associated genetic loci (IDAGL) containing highly statistically significant disease-linked SNPs remains unknown. Here we present the experimental and clinical evidence revealing important role of IDAGL in human diseases. Targeted RT-PCR screen coupled with sequencing of purified PCR products detects widespread transcription at multiple intergenic disease-associated genomic loci (IDAGL) and identifies 96 small non-coding trans-regulatory RNAs of ~ 100-300 nt in length containing SNPs associated with 21 common human disorders (snpRNAs). Functionality of snpRNAs is supported by multiple independent lines of experimental evidence demonstrating their cell-type-specific expression and evolutionary conservation of sequences, genomic coordinates, and biological effects. Analysis of chromatin state signatures, expression profiling experiments using microarray and Q-PCR technologies, and luciferase reporter assays indicate that many IDAGL are Polycomb-regulated long-range enhancers. Expression of snpRNAs in human and mouse cells markedly affects cellular behavior and induces allele-specific clinically-relevant phenotypic changes: NLRP1-locus snpRNAs exert regulatory effects on monocyte/macrophage trans-differentiation, induce prostate cancer (PC) susceptibility snpRNAs, and transform low-malignancy hormone-dependent human PC cells into highly malignant androgen-independent PC. Q-PCR analysis and luciferase reporter assays demonstrate that snpRNA sequences represent allele-specific “decoy” targets of microRNAs which function as SNP-allele-specific modifiers of microRNA expression and activity. We demonstrate that trans-acting RNA molecules facilitating androgen depletion-independent growth (ADIG) in vitro and castration-resistant (CR) phenotype in vivo of PC contain intergenic 8q24-locus SNP variants which were recently linked with increased risk of developing PC. Expression level of 8q24-locus PC susceptibility snpRNAs is regulated by NLRP1-locus snpRNAs, which are transcribed from the intergenic long-range enhancer sequence located in 17p13 region at ~ 30 kb distance from the NLRP1 gene. Q-PCR analysis of clinical PC samples reveals markedly increased snpRNA expression levels in tumor tissues compared to the adjacent normal prostate [122-fold and 45-fold in Gleason 7 tumors (p = 0.03); 370-fold and 127-fold in Gleason 8 tumors (p = 0.0001); for NLRP1-locus and 8q24-locus SnpRNAs, respectively]. Highly concordant expression profiles of the NLRP1-locus snpRNAs and 8q24 CR-locus snpRNAs (r = 0.896; p < 0.0001) in clinical PC samples and experimental evidence of trans-regulatory effects of NLRP1-locus snpRNAs on expression of 8q24-locus SnpRNAs indicate that ADIG and CR phenotype of human PC cells can be triggered by RNA molecules transcribed from the NLRP1-locus intergenic enhancer and down-stream activation of the 8q24-locus snpRNAs. Our results define the intergenic NLRP1 and 8q24 regions as regulatory loci of ADIG and CR phenotype of human PC, reveal previously unknown molecular links between the innate immunity/inflammasome system and development of hormone-independent PC, and identify novel diagnostic and therapeutic targets exploration of which should be highly beneficial for clinical management of PC

Evaluation of a Laser Altimeter using the Pseudo-Random Noise Modulation Technique for Apophis Mission

Apophis is a near-Earth object with a diameter of approximately 340 m, which will come closer to the Earth than a geostationary orbit in 2029, offering a unique opportunity for characterizing the object during the upcoming encounter. Therefore, Korea Astronomy and Space Science Institute has a plan to propose a space mission to explore the Apophis asteroid using scientific instruments such as a laser altimeter. In this study, we evaluate the performance metrics of a laser altimeter using a pseudorandom noise modulation technique for the Apophis mission, in terms of detection probability and ranging accuracy. The closed-form expression of detection probability is provided using the cross correlation between the received pulse trains and pseudo-random binary sequence. And the new ranging accuracy model using Gaussian error propagation is also derived by considering the sampling rate. The operation range is significantly limited by thermal noise rather than background noise, owing to not only the low power laser but also the avalanche photodiode in the analog mode operation. However, it is demonstrated from the numerical simulation that the laser altimeter can achieve the ranging performance required for a proximity operation mode, which employs commercially available components onboard CubeSat-scale satellites for optical communications

Predicting factors of present hepatitis C virus infection among patients positive for the hepatitis C virus antibody

Background/AimsTo identify the predicting factors of present hepatitis C virus (HCV) infection among patients with positivity for antibodies to HCV (anti-HCV).MethodsWe analyzed patients who showed positive enzyme immunoassay (EIA) results and performed an HCV RNA test as a confirmatory test at Kyung Hee University Hospital at Gangdong from June 2006 to July 2012. The features distinguishing the groups with positive and negative HCV RNA results were reviewed.ResultsIn total, 490 patients were included. The results of the HCV RNA test were positive and negative in 228 and 262 patients, respectively. The index value of anti-HCV, mean age, platelet counts, total bilirubin, prothrombin time international normalized ratio, albumin and alanine transaminase (ALT) levels differed significantly between the two groups. On multivariable analysis, an index value of anti-HCV >10 [odds ratio (OR)=397.27, P40 IU/L (OR=3.64, P=0.001), and albumin <3.8 g/dL (OR=2.66, P=0.014) were related to present HCV infection.ConclusionsAlthough EIA is not a quantitative test, considering the anti-HCV titer with ALT and albumin levels may be helpful in predicting present of HCV infection

Development of the Korean Academy of Medical Sciences Guideline for Rating Physical Impairment

Systematic and effective welfare for the disabled is possible when there are scientific and objective criteria demonstrating either presence or severity of the impairment. We need our own scientific criteria suitable for our culture and society, since the impairment is influenced by them. In 2007, we established the Developing Committee of Korean Academy of Medical Sciences (KAMS) Guideline for Impairment Rating under KAMS supervision. We included all fixed and permanent physical impairments after a sufficient medical treatment. The impairment should be stable and medically measurable. If not, it should be reevaluated later. We benchmarked the American Medical Association Guides. The KAMS Guideline should be scientific, objective, valid, reasonable and practical. In particular, we tried to secure objectivity. We developed the KAMS Guideline for Impairment Rating

Anaphylactic Shock Caused by Ingestion of Polyethylene Glycol

Colonoscopy is the current standard method for evaluation of the colon. The diagnostic accuracy and therapeutic safety of colonoscopy depend on the quality of colonic cleansing and preparation. Generally, all these preparations have been demonstrated to be safe for use in healthy individuals without significant comorbid conditions. Based on safety and efficacy concerns, polyethylene glycol (PEG) is most commonly utilized as a bowel preparation solution for colonoscopy. Adverse events in patients receiving PEG are mostly clinically non-significant. However, fatal adverse events rarely have been shown to occur in the few individuals who experience vomiting or aspiration. Anaphylactic shock associated with ingestion of PEG electrolyte solution is an extremely rare fatal complication, and reported mainly in Western countries. Here, we report the first case of anaphylactic shock following the ingestion of PEG solution in Korea

A Validation Study of the Korean Version of SPAN

Purpose: The SPAN, which is acronym standing for its four components: Startle, Physiological arousal, Anger, and Numbness, is a short post-traumatic stress disorder (PTSD) screening scale. This study sought to develop and validate a Korean version of the SPAN (SPAN-K). Materials and Methods: Ninety-three PTSD patients (PTSD group), 73 patients with non-psychotic psychiatric disorders (psychiatric control group), and 88 healthy participants (normal control group) were recruited for this study. Participants completed a variety of psychiatric assessments including the SPAN-K, the Davidson Trauma Scale (DTS), the Clinician-Administered PTSD Scale (CAPS), and the State-Trait Anxiety Inventory (STAI). Results: Cronbach&#39;s alpha and test-retest reliability values for the SPAN-K were both 0.80. Mean SPAN-K scores were 10.06 for the PTSD group, 4.94 for the psychiatric control group, and 1.42 for the normal control group. With respect to concurrent validity, correlation coefficients were 0.87 for SPAN-K vs. CAPS total scores (p&lt;0.001) and 0.86 for SPAN-K vs. DTS scores (p&lt;0.001). Additionally, correlation coefficients were 0.31 and 0.42 for SPAN-K vs. STAI-S and STAI-T, respectively. Receiver operating characteristic analysis of SPAN-K showed good diagnostic accuracy with an area under the curve (AUC) of 0.87. The SPAN-K showed the highest efficiency at a cutoff score of 7, with a sensitivity of 0.83, a specificity of 0.81, positive predictive value (PPV) of 0.88, and negative predictive value (NPV) of 0.73. Conclusion: These results suggest that the SPAN-K had good psychometric properties and may be a useful instrument for rapid screening of PTSD patients.This study was supported by a grant of the Korean Academy of Anxiety Disorders, Korean Neuropsychiatric Association, and Korean Research Foundation (2006-2005152), Republic of Korea

Observation of the Baryonic Flavor-Changing Neutral Current Decay Lambda_b -> Lambda mu+ mu-

We report the first observation of the baryonic flavor-changing neutral current decay Lambda_b -> Lambda mu+ mu- with 24 signal events and a statistical significance of 5.8 Gaussian standard deviations. This measurement uses ppbar collisions data sample corresponding to 6.8fb-1 at sqrt{s}=1.96TeV collected by the CDF II detector at the Tevatron collider. The total and differential branching ratios for Lambda_b -> Lambda mu+ mu- are measured. We find B(Lambda_b -> Lambda mu+ mu-) = [1.73+-0.42(stat)+-0.55(syst)] x 10^{-6}. We also report the first measurement of the differential branching ratio of B_s -> phi mu+ mu- using 49 signal events. In addition, we report branching ratios for B+ -> K+ mu+ mu-, B0 -> K0 mu+ mu-, and B -> K*(892) mu+ mu- decays.Comment: 8 pages, 2 figures, 4 tables. Submitted to Phys. Rev. Let

Gastrodin Inhibits Expression of Inducible NO Synthase, Cyclooxygenase-2 and Proinflammatory Cytokines in Cultured LPS-Stimulated Microglia via MAPK Pathways

Microglial activation plays an important role in neurodegenerative diseases by producing several proinflammatory enzymes and proinflammatory cytokines. The phenolic glucoside gastrodin, a main constituent of a Chinese herbal medicine, has been known to display anti-inflammatory properties. The current study investigates the potential mechanisms whereby gastrodin affects the expression of potentially pro-inflammatory proteins by cultured murine microglial BV-2 cells stimulated with lipopolysaccharide (LPS).BV-2 cells were pretreated with gastrodin (30, 40, and 60 µM) for 1 h and then stimulated with LPS (1 µg/ml) for another 4 h. The effects on proinflammatory enzymes, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and proinflammatory cytokines, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), are analysed by double-immunofluorescence labeling and RT-PCR assay. To reveal the mechanisms of action of gastrodin we investigated the involvement of mitogen-activated protein kinases (MAPKs) cascades and their downstream transcription factors, nuclear factor-κB (NF-κB) and cyclic AMP-responsive element (CRE)-binding protein (CREB). Gastrodin significantly reduced the LPS-induced protein and mRNA expression levels of iNOS, COX-2, TNF-α, IL-1β and NF-κB. LPS (1 µg/ml, 30 min)-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) and this was inhibited by pretreatment of BV-2 cells with different concentrations of gastrodin (30, 40, and 60 µM). In addition, gastrodin blocked LPS-induced phosphorylation of inhibitor κB-α (IκB-α) (and hence the activation of NF-κB) and of CREB, respectively.This study indicates that gastrodin significantly attenuate levels of neurotoxic proinflammatory mediators and proinflammatory cytokines by inhibition of the NF-κB signaling pathway and phosphorylation of MAPKs in LPS-stimulated microglial cells. Arising from the above, we suggest that gastrodin has a potential as an anti-inflammatory drug candidate in neurodegenerative diseases