Outbreaks of Aleutian mink disease in farmed mink (Neovison vison) in Denmark: molecular characterization by partial NS1 gene sequencing

Référence bibliographique : Rol, 107031Appartient à l’ensemble documentaire : Pho20RolAppartient à l’ensemble documentaire : FrancComt1Image de press

Association Testing of Novel Type 2 Diabetes Risk Alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 Loci With Insulin Release, Insulin Sensitivity, and Obesity in a Population-Based Sample of 4,516 Glucose-Tolerant Middle-Aged Danes

OBJECTIVE— We evaluated the impact on diabetes-related intermediary traits of common novel type 2 diabetes–associated variants in the JAZF1 (rs864745), CDC123/CAMK1D (rs12779790), TSPAN8 (rs7961581), THADA (rs7578597), ADAMTS9 (rs4607103), and NOTCH2 (rs10923931) loci, which were recently identified by meta-analysis of genome-wide association data

Hepatitis C prevalence in Denmark in 2016—An updated estimate using multiple national registers

Background: Chronic hepatitis C (CHC) can be eliminated as a public health threat by meeting the WHO targets: 90% of patients diagnosed and 80% treated by 2030. To achieve and monitor progress towards elimination, an updated estimate of the size of the CHC population is needed, but Denmark has no complete national CHC register. By combining existing registers in 2007, we estimated the population living with CHC to be 16,888 (0.38% of the adult population). Aim: To estimate the population living with diagnosed and undiagnosed CHC in Denmark on 31 December 2016. Among additional aims were to estimate the proportion of patients attending specialised clinical care. Methods: People with diagnosed CHC were identified from four national registers. The total diagnosed population was estimated by capture-recapture analysis. The undiagnosed population was estimated by comparing the register data with data from two cross-sectional surveys. Results: The population living with diagnosed CHC in Denmark was 7,581 persons (95%CI: 7,416–12,661) of which 6,116 (81%) were identified in the four registers. The estimated undiagnosed fraction was 24%, so the total CHC infected population was 9,975 corresponding to 0.21% of the adult population (95%CI: 9,758–16,659; 0.21%-0.36%). Only 48% of diagnosed patients had received specialised clinical care. Conclusion: CHC prevalence in Denmark is declining and 76% of patients have been diagnosed. Linking diagnosed patients to care and increasing efforts to test people with former or current drug use will be necessary to achieve CHC elimination

Effectiveness of treatment with pegylated interferon and ribavirin in an unselected population of patients with chronic hepatitis C: A Danish nationwide cohort study

<p>Abstract</p> <p>Background</p> <p>The effect of peginterferon and ribavirin treatment on chronic hepatitis C virus (HCV) infection has been established in several controlled clinical studies. However, the effectiveness of treatment and predictors of treatment success in routine clinical practice remains to be established. Our aim was to estimate the effectiveness of peginterferon and ribavirin treatment in unselected HCV patients handled in routine clinical practice. The endpoint was sustained virological response (SVR), determined by the absence of HCV RNA 24 weeks after the end of treatment.</p> <p>Methods</p> <p>We determined the proportion of SVR in a nationwide, population-based cohort of 432 patients with chronic HCV infection who were starting treatment, and analyzed the impact of known covariates on SVR by using a logistic regression analysis.</p> <p>Results</p> <p>The majority of treated patients had genotype 1 (133 patients) and genotype 2/3 (285 patients) infections, with 44% and 72%, respectively, obtaining SVR. Other than genotype, the predictors of SVR were age ≤ 45 years at the start of treatment, completion of unmodified treatment, the absence of cirrhosis and non-European origin.</p> <p>Conclusions</p> <p>The effectiveness of peginterferon and ribavirin treatment for chronic hepatitis C in a routine clinical practice is comparable to that observed in controlled clinical trials, with a higher SVR rate in genotype 2 and 3 patients compared to genotype 1 patients. Our data further indicate that age at start of treatment is a strong predictor of SVR irrespective of HCV genotype, with patients 45 years or younger having a higher SVR rate.</p

Benefit of pazopanib in advanced gastrointestinal stromal tumours : results from a phase II trial (SSG XXI, PAGIST)

Background: Patients with advanced gastrointestinal stromal tumours (GISTs) resistant to the tyrosine kinase inhibitors imatinib and sunitinib may be treated with regorafenib, which resulted in a median progression-free survival (PFS) of 4.8 months in the GRID trial. Also, pazopanib, another tyrosine kinase inhibitor, has been studied in a randomized, placebo-controlled trial (PAZOGIST) in the third line, which showed a PFS of 45.2% 4 months after study entry, but patients intolerant to sunitinib were also included. We designed another trial evaluating pazopanib, enrolling only patients with progression on both imatinib and sunitinib. Patients and methods: Since all eligible patients had progressive disease, we preferred a non-randomized, phase II multicentre trial so that all patients could receive a potentially active drug. Patients had a progressive metastatic or locally advanced GIST and were >= 18 years of age, with a performance status of 0-2, and sufficient organ functions. The primary endpoint was disease control rate (defined as complete remission thorn partial remission thorn stable disease) at 12 weeks on pazopanib. A Simon's two-stage analysis was used with an interim analysis 12 weeks after enrollment of the first 22 patients, and if passed, there was a full enrolment of 72 patients. GIST mutational analysis was done, and most patients had pazopanib plasma concentration measured after 12 weeks. Results: Seventy-two patients were enrolled. The disease control rate after 12 weeks was 44%, and the median PFS was 19.6 weeks (95% confidence interval 12.6-23.4 weeks). Pazopanib-related toxicity was moderate and manageable. No statistically significant differences were found related to mutations. Plasma concentrations of pazopanib had a formal but weak correlation with outcome. Conclusion: Pazopanib given in the third line to patients with GIST progressing on both imatinib and sunitinib was beneficial for about half of the patients. The PAGIST trial confirms the results from the PAZOGIST trial, and the median PFS achieved seems comparable to the PFS achieved with regorafenib in the third-line setting.Peer reviewe

Erythropoietin overrides the triggering effect of DNA platination products in a mouse model of Cisplatin-induced neuropathy

<p>Abstract</p> <p>Background</p> <p>Cisplatin mediates its antineoplastic activity by formation of distinct DNA intrastrand cross links. The clinical efficacy and desirable dose escalations of cisplatin are restricted by the accumulation of DNA lesions in dorsal root ganglion (DRG) cells leading to sensory polyneuropathy (PNP). We investigated in a mouse model by which mechanism recombinant erythropoietin (rhEPO) protects the peripheral nervous system from structural and functional damage caused by cisplatin treatment with special emphasis on DNA damage burden.</p> <p>Results</p> <p>A cumulative dose of 16 mg cisplatin/kg resulted in clear electrophysiological signs of neuropathy, which were significantly attenuated by concomitant erythropoietin (cisplatin 32,48 m/s ± 1,68 m/s; cisplatin + rhEPO 49,66 m/s ± 1,26 m/s; control 55,01 m/s ± 1,88 m/s; p < 0,001). The co-application of rhEPO, however, did not alter the level of unrepaired cisplatin-DNA lesions accumulating in DRG target cells. Micro-morphological analyses of the sciatic nerve from cisplatin-exposed mice showed damaged myelin sheaths and mitochondria. Co-administered rhEPO inhibited myelin sheaths from structural injuries and resulted in an increased number of intact mitochondria.</p> <p>Conclusion</p> <p>The protective effect of recombinant erythropoietin is not mediated by reducing the burden of DNA platination in the target cells, but it is likely to be due to a higher resistance of the target cells to the adverse effect of DNA damage. The increased frequency of intact mitochondria might also contribute to this protective role.</p

Phase II study of gemcitabine and vindesine in patients with previously untreated non-resectable non-small-cell lung cancer

Because both vindesine and gemcitabine are active drugs in advanced non-small-cell lung cancer (NSCLC), with different modes of action and only partly overlapping toxicity, a phase II study was performed. Gemcitabine 1000 mg m−2 was given on days 1, 8 and 15 every 4 weeks, while vindesine 3 mg m−2 was administered weekly for 7 weeks, then every 2 weeks. A total of 42 patients with nonresectable NSCLC were included. The median age of patients was 56 years; 57% were men, 52% had adenocarcinoma, 31% squamous cell carcinoma and 17% had large-cell carcinoma. The performance status ranged from 0 to 2 with 83% in performance status 1. The majority (55%) had stage IV disease, while 40% had stage III B and 5% stage III A disease. WHO grade 3–4 leucopenia occurred in five patients (12%) and 9% had grade 4 neutropenia. Thrombocytopenia grade 3–4 was observed in six patients (15%). There were no septic death or bleeding episodes. One patient had a transient WHO grade 4 increase in bilirubin, and four patients had a decrease in glomerular filtration rate below the normal limit; one of these patients developed a non-reversible renal insufficiency. Ten patients (24%) complained of dyspnoea of uncertain mechanism, possibly involving bronchoconstriction. There were one complete and seven partial responses among 40 assessable patients (20%, 95% confidence limits 9–36%). Median response duration was 31 weeks (range 11–83 weeks) and median survival time 31 weeks (range 2–171 weeks). The current combination of gemcitabine and vindesine does not appear to be promising for further examination because of the toxicity and somewhat disappointing activity. © 1999 Cancer Research Campaig

Adaptive intrapatient dose escalation of cisplatin in combination with low-dose vp16 in patients with nonsmall cell lung cancer

The objective of this phase II and pharmacologic study was to explore the feasibility toxicity and activity of adaptive intrapatient dose escalation of cisplatin in a dose-intensive weekly schedule using predefined levels of exposure, with the ultimate aim to improve the antitumour activity of the therapy in patients with nonsmall cell lung cancer (NSCLC). Platinum DNA-adduct levels in peripheral white blood cells during treatment were used as the primary parameter for adaptive dosing. If DNA-adduct levels were not available, the area under the concentration-time curve (AUC) of unbound platinum in plasma was used for dose adaptation. Target levels for DNA-adducts and AUC have been defined in a previously performed pharmacologic study. The feasibility of adaptive dosing was tested in 76 patients with stage IIIB and IV NSCLC, who were planned to receive 6 weekly courses of cisplatin at a starting dose of 70 mg m-2, together with daily low oral dose of 50 mg VP16. In total, 37 patients (49%) who were given more than one course received a dose increase varying from 10 to 55%. The majority of patients reached the defined target levels by a dose increase during course two. Relevant grade 2 neurotoxicity was observed in eight (10%) patients and reversible ototoxicity grade 2 in 14 (18%) patients. The strategy of adaptive intrapatient dose adjustment of cisplatin is practically feasible in a research setting even when results for dose adaptation have to be reported within a short time-period of I week. The toxicity appeared to be manageable in this cohort of patients. In some patients, exposure after the standard dose was substantially lower than the defined target level and significant dose escalations of more than 50% had to be applied. The response rate (RR) was relatively high: overall 40% (29 out of 72 patients) partial remission (PR), in patients with stage IIIB the RR was 60% (15 out of 25 patients) and with stage IV 30% (14 out of 47 patients). Randomised studies are needed to determine whether the adaptive dosing strategy results in better efficacy than standard dosing

Bioinformatics-Driven Identification and Examination of Candidate Genes for Non-Alcoholic Fatty Liver Disease

ObjectiveCandidate genes for non-alcoholic fatty liver disease (NAFLD) identified by a bioinformatics approach were examined for variant associations to quantitative traits of NAFLD-related phenotypes.Research Design and MethodsBy integrating public database text mining, trans-organism protein-protein interaction transferal, and information on liver protein expression a protein-protein interaction network was constructed and from this a smaller isolated interactome was identified. Five genes from this interactome were selected for genetic analysis. Twenty-one tag single-nucleotide polymorphisms (SNPs) which captured all common variation in these genes were genotyped in 10,196 Danes, and analyzed for association with NAFLD-related quantitative traits, type 2 diabetes (T2D), central obesity, and WHO-defined metabolic syndrome (MetS).Results273 genes were included in the protein-protein interaction analysis and EHHADH, ECHS1, HADHA, HADHB, and ACADL were selected for further examination. A total of 10 nominal statistical significant associations (P&lt;0.05) to quantitative metabolic traits were identified. Also, the case-control study showed associations between variation in the five genes and T2D, central obesity, and MetS, respectively. Bonferroni adjustments for multiple testing negated all associations.ConclusionsUsing a bioinformatics approach we identified five candidate genes for NAFLD. However, we failed to provide evidence of associations with major effects between SNPs in these five genes and NAFLD-related quantitative traits, T2D, central obesity, and MetS