Antivirale Kombinationstherapie mit einem Protease-Inhibitor (Telaprevir, VX-950) und pegyliertem Interferon alfa-2a bei Patienten mit chronischer Hepatitis-C-Infektion, Genotyp 1

Bei dieser Studie wurde die antivirale Effektivität, sowie die Verträglichkeit von einem selektiven NS3/4A Protease-Inhibitor als Monotherapie und in Kombination mit Peginterferon alfa-2a über einen Behandlungszeitraum von 14 Tagen evaluiert. Bezüglich der Hepatitis unvorbehandelte Patienten mit einer Genotyp 1 Infektion wurden in unterschiedliche Therapiearme randomisiert: (i) Placebo und Peginterferon alfa-2a (n=4), (ii) Telaprevir Monotherapie (n=8) oder (iii) Telaprevir in Kombination mit Peginterferon alfa-2a (n=8). Telaprevir wurde in oraler Tablettenform mit jeweils 750 mg alle 8 Stunden verabreicht und Peginterferon alfa-2a wurde einmal wöchentlich 180 μg subkutan injiziert. Bei der Studie zeigte sich ein medianer Abfall der HCV RNA von Beginn der Therapie bis zu letztem Behandlungstag 15 von -1.09 log10 (Bereich: -2.08 log10 und -0.46 log10) in der Placebo und Peginterferon alfa-2a-Gruppe; -3.99-log10 (Bereich: -5.28 und -1.26) in der Telaprevir-Gruppe, und -5.49-log10 (Bereich: -6.54 und -4.30) in der Kombinations- Gruppe mit Telaprevir plus Peginterferon alfa-2a. Bei 4 Patienten, die mit Telaprevir und Peginterferon alfa-2a behandelt wurden, war die HCV RNA an Tag 15 nicht mehr nachweisbar und bei einem Patienten, der initial mit Telaprevir behandelt wurde. Insgesamt kam es unter der Therapie zu keinem viralen Durchbruch unter der Kombination mit Telaprevir und Peginterferon alfa-2a während der 14-tägigen Behandlung innerhalb der Studie. Die meisten Nebenwirkungen waren von milder Intensität und es kam zu keinen schwerwiegenden Nebenwirkungen oder vorzeitigen Therapieabbrüchen. Die Studie zeigte eine potente antivirale Wirksamkeit von Telaprevir als Monotherapie und bei der Kombination mit Peginterferon alfa-2a kam es zu einer gesteigerten antiviralen Aktivität. Bereits aufgrund dieser Ergebnisse initiierte, größere Studien werden nun evaluieren, ob Telaprevir in Kombination mit Peginterferon alfa und Ribavirin die dauerhaften antiviralen Ansprechraten verbessern kann.In the present study viral efficacy, safety and tolerability of a HCV-NS3 serine protease inhibitor alone and in combination with peginterferon alfa-2a for 14 days was evaluated. Previously untreated patients with genotype 1 hepatitis C were randomized to receive (i) placebo and peginterferon alfa-2a (n=4), (ii) telaprevir alone (n=8) or (iii) telaprevir and peginterferon alfa-2a (n=8). Telaprevir was given as 750 mg oral doses every 8 hours and peginterferon alfa-2a was given as weekly 180 μg subcutaneous injections. The median change in HCV RNA from baseline to day 15 was -1.09 log10 (range: -2.08 log10 to -0.46 log10) in the placebo and peginterferon alfa-2a group; -3.99-log10 (range: -5.28 to -1.26) in the telaprevir group, and -5.49-log10 (range: -6.54 to -4.30) in the telaprevir plus peginterferon alfa-2a group. Day 15 HCV RNA levels were undetectable in 4 patients who received telaprevir and peginterferon alfa-2a and in 1 patient who received telaprevir alone. No viral breakthrough occurred in patients who received telaprevir and peginterferon alfa-2a during the 14 days dosing period. The majority of adverse events were generally mild and there were no serious adverse events or premature discontinuations. The study showed substantial antiviral efficacy of telaprevir and showed an enhanced antiviral effect of telaprevir in combination with peginterferon alfa-2a. Ongoing larger trials will investigate, whether telaprevir, in combination with peginterferon alfa and ribavirin will improve sustained virologic response rates

Assessment of liver fibrosis and associated risk factors in HIV-infected individuals using transient elastography and serum biomarkers

Background: Liver fibrosis in human immunodeficiency virus (HIV)-infected individuals is mostly attributable to co-infection with hepatitis B or C. The impact of other risk factors, including prolonged exposure to combined antiretroviral therapy (cART) is poorly understood. Our aim was to determine the prevalence of liver fibrosis and associated risk factors in HIV-infected individuals based on non-invasive fibrosis assessment using transient elastography (TE) and serum biomarkers (Fibrotest [FT]). Methods: In 202 consecutive HIV-infected individuals (159 men; mean age 47 ± 9 years; 35 with hepatitis-C-virus [HCV] co-infection), TE and FT were performed. Repeat TE examinations were conducted 1 and 2 years after study inclusion. Results: Significant liver fibrosis was present in 16% and 29% of patients, respectively, when assessed by TE (≥ 7.1 kPa) and FT (> 0.48). A combination of TE and FT predicted significant fibrosis in 8% of all patients (31% in HIV/HCV co-infected and 3% in HIV mono-infected individuals). Chronic ALT, AST and γ-GT elevation was present in 29%, 20% and 51% of all cART-exposed patients and in 19%, 8% and 45.5% of HIV mono-infected individuals. Overall, factors independently associated with significant fibrosis as assessed by TE (OR, 95% CI) were co-infection with HCV (7.29, 1.95-27.34), chronic AST (6.58, 1.30-33.25) and γ-GT (5.17, 1.56-17.08) elevation and time on dideoxynucleoside therapy (1.01, 1.00-1.02). In 68 HIV mono-infected individuals who had repeat TE examinations, TE values did not differ significantly during a median follow-up time of 24 months (median intra-patient changes at last TE examination relative to baseline: -0.2 kPa, p = 0.20). Conclusions: Chronic elevation of liver enzymes was observed in up to 45.5% of HIV mono-infected patients on cART. However, only a small subset had significant fibrosis as predicted by TE and FT. There was no evidence for fibrosis progression during follow-up TE examinations

Plant processing experiments and use-wear analysis of Tabon Cave artefacts question the intentional character of denticulated stone tools in prehistoric Southeast Asia

The presence of notches on European Palaeolithic flaked stone tools termed ‘denticulates’ has been variously ascribed to cultural, functional and taphonomic factors. In Southeast Asia prehistoric stone tool assemblages are dominated by unretouched flakes, so the rare retouched lithics, including denticulates, can be considered unique testimonies of the intention of the tool makers to control the shape and properties of tool edges. Here we report the results of plant processing experiments with modern unretouched flakes made of red jasper. Splitting plants with the help of a specific hand and arm movement (“twist-of-the-wrist”) resulted in a series of use-wear traces that included large crescent-break micro-scars. These are very similar in shape and appearance to the notches of prehistoric denticulated tools. These results suggest that some denticulated pieces in prehistoric Southeast Asia could be less intentional than previously thought, being instead the result of plant processing activities. We also report here the analysis of 41 denticulates from Tabon Cave, Philippines. While some are clearly intentionally retouch, others exhibit use-wear and nocth micro-morphology characteristic of plant splitting. The notches of others result from utilisation and taphonomy or trampling. Altogether, our observations raise the following question: should the term denticulates be restricted to the tools intentionally retouched or encompass all the tools with adjacent notches whatever the origin of the latter is

The Human Phenotype Ontology project:linking molecular biology and disease through phenotype data

The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online

Serum MicroRNA-21 as Marker for Necroinflammation in Hepatitis C Patients with and without Hepatocellular Carcinoma

Background: MicroRNA-21 (miR-21) is up-regulated in tumor tissue of patients with malignant diseases, including hepatocellular carcinoma (HCC). Elevated concentrations of miR-21 have also been found in sera or plasma from patients with malignancies, rendering it an interesting candidate as serum/plasma marker for malignancies. Here we correlated serum miR-21 levels with clinical parameters in patients with different stages of chronic hepatitis C virus infection (CHC) and CHC-associated HCC. Methodology/Principal Findings: 62 CHC patients, 29 patients with CHC and HCC and 19 healthy controls were prospectively enrolled. RNA was extracted from the sera and miR-21 as well as miR-16 levels were analyzed by quantitative real-time PCR; miR-21 levels (normalized by miR-16) were correlated with standard liver parameters, histological grading and staging of CHC. The data show that serum levels of miR-21 were elevated in patients with CHC compared to healthy controls (P<0.001); there was no difference between serum miR-21 in patients with CHC and CHC-associated HCC. Serum miR-21 levels correlated with histological activity index (HAI) in the liver (r = −0.494, P = 0.00002), alanine aminotransferase (ALT) (r = −0.309, P = 0.007), aspartate aminotransferase (r = −0.495, P = 0.000007), bilirubin (r = −0.362, P = 0.002), international normalized ratio (r = −0.338, P = 0.034) and γ-glutamyltransferase (r = −0.244, P = 0.034). Multivariate analysis revealed that ALT and miR-21 serum levels were independently associated with HAI. At a cut-off dCT of 1.96, miR-21 discriminated between minimal and mild-severe necroinflammation (AUC = 0.758) with a sensitivity of 53.3% and a specificity of 95.2%. Conclusions/Significance: The serum miR-21 level is a marker for necroinflammatory activity, but does not differ between patients with HCV and HCV-induced HCC

Hemimethylation of CpG dyads is characteristic of secondary DMRs associated with imprinted loci and correlates with 5-hydroxymethylcytosine at paternally methylated sequences

Background In mammals, the regulation of imprinted genes is controlled by differential methylation at imprinting control regions which acquire parent of origin-specific methylation patterns during gametogenesis and retain differences in allelic methylation status throughout fertilization and subsequent somatic cell divisions. In addition, many imprinted genes acquire differential methylation during post-implantation development; these secondary differentially methylated regions appear necessary to maintain the imprinted expression state of individual genes. Despite the requirement for both types of differentially methylated sequence elements to achieve proper expression across imprinting clusters, methylation patterns are more labile at secondary differentially methylated regions. To understand the nature of this variability, we analyzed CpG dyad methylation patterns at both paternally and maternally methylated imprinted loci within multiple imprinting clusters. Results We determined that both paternally and maternally methylated secondary differentially methylated regions associated with imprinted genes display high levels of hemimethylation, 29–49%, in comparison to imprinting control regions which exhibited 8–12% hemimethylation. To explore how hemimethylation could arise, we assessed the differentially methylated regions for the presence of 5-hydroxymethylcytosine which could cause methylation to be lost via either passive and/or active demethylation mechanisms. We found enrichment of 5-hydroxymethylcytosine at paternally methylated secondary differentially methylated regions, but not at the maternally methylated sites we analyzed in this study. Conclusions We found high levels of hemimethylation to be a generalizable characteristic of secondary differentially methylated regions associated with imprinted genes. We propose that 5-hydroxymethylcytosine enrichment may be responsible for the variability in methylation status at paternally methylated secondary differentially methylated regions associated with imprinted genes. We further suggest that the high incidence of hemimethylation at secondary differentially methylated regions must be counteracted by continuous methylation acquisition at these loci

Identification et impact de la sarcopénie chez les patients en surpoids et obèses avec un carcinome à cellules rénales localisé.

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Impact of Body Composition in Overweight and Obese Patients With Localised Renal Cell Carcinoma

International audienceBackground/aim: To investigate the impact of body composition on morbidity and mortality at the initial diagnosis of localised renal cell carcinoma (RCC) in patients with overweight or obesity. Patients and methods: Sarcopenia was defined using sex-specific cut-off points and other body composition parameters by median values with computed tomography imaging. Results: Among the 96 patients, 40 had sarcopenia (43.0%) at diagnosis. Body composition had no effect on morbidity and 5-year disease-free survival contrary to the classic factors (p<0.05). In the subgroup of obese patients, those with sarcopenia had a poor prognosis (p=0.04) but not in the population with overweight (p=0.9). Conclusion: Sarcopenia was frequently associated with localised RCC at the initial diagnosis. Body composition did not affect morbidity or outcomes. BMI was involved in morbidity and there was paradoxically longer survival in the obesity group