Genome-wide association study of hepatocellular carcinoma in Southern Chinese patients with chronic hepatitis B virus infection

One of the most relevant risk factors for hepatocellular carcinoma (HCC) development is chronic hepatitis B virus (HBV) infection, but only a fraction of chronic HBV carriers develop HCC, indicating that complex interactions among viral, environmental and genetic factors lead to HCC in HBV-infected patients. So far, host genetic factors have incompletely been characterized. Therefore, we performed a genome-wide association (GWA) study in a Southern Chinese cohort consisting of 95 HBV-infected HCC patients (cases) and 97 HBV-infected patients without HCC (controls) using the Illumina Human610-Quad BeadChips. The top single nucleotide polymorphisms (SNPs) were then validated in an independent cohort of 500 cases and 728 controls. 4 SNPs (rs12682266, rs7821974, rs2275959, rs1573266) at chromosome 8p12 showed consistent association in both the GWA and replication phases (OR combined = 1.31-1.39; p combined = 2.71×10 -5-5.19×10 -4; PAR combined = 26-31%). We found a 2.3-kb expressed sequence tag (EST) in the region using in-silico data mining and verified the existence of the full-length EST experimentally. The expression level of the EST was significantly reduced in human HCC tumors in comparison to the corresponding non-tumorous liver tissues (P<0.001). Results from sequence analysis and in-vitro protein translation study suggest that the transcript might function as a long non-coding RNA. In summary, our study suggests that variations at chromosome 8p12 may promote HCC in patients with HBV. Further functional studies of this region may help understand HBV-associated hepatocarcinogenesis. © 2011 Chan et al.published_or_final_versio

Hedgehog/notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans

Hirschsprung (HSCR) disease is a complex genetic disorder attributed to a failure of the enteric neural crest cells (ENCCs) to form ganglia in the hindgut. Hedgehog and Notch are implicated in mediating proliferation and differentiation of ENCCs. Nevertheless, how these signaling molecules may interact to mediate gut colonization by ENCCs and contribute to a primary etiology for HSCR are not known. Here, we report our pathway- based epistasis analysis of data generated by a genome-wide association study on HSCR disease, which indicates that specific genotype constellations of Patched (PTCH1) (which encodes a receptor for Hedgehog) and delta-like 3 (DLL3) (which encodes a receptor for Notch) SNPs confer higher risk to HSCR. Importantly, deletion of Ptch1 in mouse ENCCs induced robust Dll1 expression and activation of the Notch pathway, leading to premature gliogenesis and reduction of ENCC progenitors in mutant bowels. Dll1 integrated Hedgehog and Notch pathways to coordinate neuronal and glial cell differentiation during enteric nervous system development. In addition, Hedgehog-mediated gliogenesis was found to be highly conserved, such that Hedgehog was consistently able to promote gliogenesis of human neural crest-related precursors. Collectively, we defined PTCH1 and DLL3 as HSCR susceptibility genes and suggest that Hedgehog/Notch-induced premature gliogenesis may represent a new disease mechanism for HSCR.published_or_final_versio

Lactobacillus rhamnosus GG modulates intestinal barrier function and inflammation in BALB/C mice following dietary exposure to deoxynivalenol and zearalenone through changes in gut

Oral Presentation 2Conference Theme: From Experience to PerspectivesDeoxynivalenol (DON) and zearalenone are mycotoxins produced by Fusarium species, which naturally co-occur in foods and feeds. The gastrointestinal tract represents the first barrier met by exogenous food/feed compounds. The purpose of the present study was to investigate the ability of Lactobacillus rhamnosus GG (LGG) to improve intestinal barrier functions and ameliorate inflammation in Balb/c mice (6 weeks old) fed diets containing mycotoxin mixtures (i.e. DON and ZEA) through modulation of intestinal bacterial …published_or_final_versio

Modulation of 11β-hydroxysteroid dehydrogenase as a strategy to reduce vascular inflammation

Atherosclerosis is a chronic inflammatory disease in which initial vascular damage leads to extensive macrophage and lymphocyte infiltration. Although acutely glucocorticoids suppress inflammation, chronic glucocorticoid excess worsens atherosclerosis, possibly by exacerbating systemic cardiovascular risk factors. However, glucocorticoid action within the lesion may reduce neointimal proliferation and inflammation. Glucocorticoid levels within cells do not necessarily reflect circulating levels due to pre-receptor metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs). 11β-HSD2 converts active glucocorticoids into inert 11-keto forms. 11β-HSD1 catalyses the reverse reaction, regenerating active glucocorticoids. 11β-HSD2-deficiency/ inhibition causes hypertension, whereas deficiency/ inhibition of 11β-HSD1 generates a cardioprotective lipid profile and improves glycemic control. Importantly, 11β-HSD1-deficiency/ inhibition is atheroprotective, whereas 11β-HSD2-deficiency accelerates atherosclerosis. These effects are largely independent of systemic risk factors, reflecting modulation of glucocorticoid action and inflammation within the vasculature. Here, we consider whether evidence linking the 11β-HSDs to vascular inflammation suggests these isozymes are potential therapeutic targets in vascular injury and atherosclerosis

Revealing Real-Time Emotional Responses: a Personalized Assessment based on Heartbeat Dynamics

Emotion recognition through computational modeling and analysis of physiological signals has been widely investigated in the last decade. Most of the proposed emotion recognition systems require relatively long-time series of multivariate records and do not provide accurate real-time characterizations using short-time series. To overcome these limitations, we propose a novel personalized probabilistic framework able to characterize the emotional state of a subject through the analysis of heartbeat dynamics exclusively. The study includes thirty subjects presented with a set of standardized images gathered from the international affective picture system, alternating levels of arousal and valence. Due to the intrinsic nonlinearity and nonstationarity of the RR interval series, a specific point-process model was devised for instantaneous identification considering autoregressive nonlinearities up to the third-order according to the Wiener-Volterra representation, thus tracking very fast stimulus-response changes. Features from the instantaneous spectrum and bispectrum, as well as the dominant Lyapunov exponent, were extracted and considered as input features to a support vector machine for classification. Results, estimating emotions each 10 seconds, achieve an overall accuracy in recognizing four emotional states based on the circumplex model of affect of 79.29%, with 79.15% on the valence axis, and 83.55% on the arousal axis

Heparan sulfate proteoglycans: structure, protein interactions and cell signaling

Heparan sulfate proteoglycans are ubiquitously found at the cell surface and extracellular matrix in all the animal species. This review will focus on the structural characteristics of the heparan sulfate proteoglycans related to protein interactions leading to cell signaling. The heparan sulfate chains due to their vast structural diversity are able to bind and interact with a wide variety of proteins, such as growth factors, chemokines, morphogens, extracellular matrix components, enzymes, among others. There is a specificity directing the interactions of heparan sulfates and target proteins, regarding both the fine structure of the polysaccharide chain as well precise protein motifs. Heparan sulfates play a role in cellular signaling either as receptor or co-receptor for different ligands, and the activation of downstream pathways is related to phosphorylation of different cytosolic proteins either directly or involving cytoskeleton interactions leading to gene regulation. The role of the heparan sulfate proteoglycans in cellular signaling and endocytic uptake pathways is also discussed.Proteoglicanos de heparam sulfato são encontrados tanto superfície celular quanto na matriz extracelular em todas as espécies animais. Esta revisão tem enfoque nas características estruturais dos proteoglicanos de heparam sulfato e nas interações destes proteoglicanos com proteínas que levam à sinalização celular. As cadeias de heparam sulfato, devido a sua variedade estrutural, são capazes de se ligar e interagir com ampla gama de proteínas, como fatores de crescimento, quimiocinas, morfógenos, componentes da matriz extracelular, enzimas, entreoutros. Existe uma especificidade estrutural que direciona as interações dos heparam sulfatos e proteínas alvo. Esta especificidade está relacionada com a estrutura da cadeia do polissacarídeo e os motivos conservados da cadeia polipeptídica das proteínas envolvidas nesta interação. Os heparam sulfatos possuem papel na sinalização celular como receptores ou coreceptores para diferentes ligantes. Esta ligação dispara vias de sinalização celular levam à fosforilação de diversas proteínas citosólicas ou com ou sem interações diretas com o citoesqueleto, culminando na regulação gênica. O papel dos proteoglicanos de heparam sulfato na sinalização celular e vias de captação endocítica também são discutidas nesta revisão.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo (UNIFESP) Departamento de BioquímicaUniversidade Federal de São Paulo (UNIFESP) Departamento de OftalmologiaUNIFESP, Depto. de BioquímicaUNIFESP, Depto. de OftalmologiaSciEL

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

The frequency of missed test results and associated treatment delays in a highly computerized health system

<p>Abstract</p> <p>Background:</p> <p>Diagnostic errors associated with the failure to follow up on abnormal diagnostic studies ("missed results") are a potential cause of treatment delay and a threat to patient safety. Few data exist concerning the frequency of missed results and associated treatment delays within the Veterans Health Administration (VA).</p> <p>Objective:</p> <p>The primary objective of the current study was to assess the frequency of missed results and resulting treatment delays encountered by primary care providers in VA clinics.</p> <p>Methods:</p> <p>An anonymous on-line survey of primary care providers was conducted as part of the health systems ongoing quality improvement programs. We collected information from providers concerning their clinical effort (e.g., number of clinic sessions, number of patient visits per session), number of patients with missed abnormal test results, and the number and types of treatment delays providers encountered during the two week period prior to administration of our survey.</p> <p>Results:</p> <p>The survey was completed by 106 out of 198 providers (54 percent response rate). Respondents saw and average of 86 patients per 2 week period. Providers encountered 64 patients with missed results during the two week period leading up to the study and 52 patients with treatment delays. The most common missed results included imaging studies (29 percent), clinical laboratory (22 percent), anatomic pathology (9 percent), and other (40 percent). The most common diagnostic delays were cancer (34 percent), endocrine problems (26 percent), cardiac problems (16 percent), and others (24 percent).</p> <p>Conclusion:</p> <p>Missed results leading to clinically important treatment delays are an important and likely underappreciated source of diagnostic error.</p

Assessing the accuracy of an inter-institutional automated patient-specific health problem list

<p>Abstract</p> <p>Background</p> <p>Health problem lists are a key component of electronic health records and are instrumental in the development of decision-support systems that encourage best practices and optimal patient safety. Most health problem lists require initial clinical information to be entered manually and few integrate information across care providers and institutions. This study assesses the accuracy of a novel approach to create an inter-institutional automated health problem list in a computerized medical record (MOXXI) that integrates three sources of information for an individual patient: diagnostic codes from medical services claims from all treating physicians, therapeutic indications from electronic prescriptions, and single-indication drugs.</p> <p>Methods</p> <p>Data for this study were obtained from 121 general practitioners and all medical services provided for 22,248 of their patients. At the opening of a patient's file, all health problems detected through medical service utilization or single-indication drug use were flagged to the physician in the MOXXI system. Each new arising health problem were presented as 'potential' and physicians were prompted to specify if the health problem was valid (Y) or not (N) or if they preferred to reassess its validity at a later time.</p> <p>Results</p> <p>A total of 263,527 health problems, representing 891 unique problems, were identified for the group of 22,248 patients. Medical services claims contributed to the majority of problems identified (77%), followed by therapeutic indications from electronic prescriptions (14%), and single-indication drugs (9%). Physicians actively chose to assess 41.7% (n = 106,950) of health problems. Overall, 73% of the problems assessed were considered valid; 42% originated from medical service diagnostic codes, 11% from single indication drugs, and 47% from prescription indications. Twelve percent of problems identified through other treating physicians were considered valid compared to 28% identified through study physician claims.</p> <p>Conclusion</p> <p>Automation of an inter-institutional problem list added over half of all validated problems to the health problem list of which 12% were generated by conditions treated by other physicians. Automating the integration of existing information sources provides timely access to accurate and relevant health problem information. It may also accelerate the uptake and use of electronic medical record systems.</p