Launching a Novel Preclinical Infrastructure: Comparative Oncology Trials Consortium Directed Therapeutic Targeting of TNFα to Cancer Vasculature

Background: Under the direction and sponsorship of the National Cancer Institute, we report on the first pre-clinical trial of the Comparative Oncology Trials Consortium (COTC). The COTC is a novel infrastructure to integrate cancers that naturally develop in pet dogs into the development path of new human drugs. Trials are designed to address questions challenging in conventional preclinical models and early phase human trials. Large animal spontaneous cancer models can be a valuable addition to successful studies of cancer biology and novel therapeutic drug, imaging and device development. Methodology/Principal Findings: Through this established infrastructure, the first trial of the COTC (COTC001) evaluated a targeted AAV-phage vector delivering tumor necrosis factor (RGD-A-TNF) to αV integrins on tumor endothelium. Trial progress and data was reviewed contemporaneously using a web-enabled electronic reporting system developed for the consortium. Dose-escalation in cohorts of 3 dogs (n = 24) determined an optimal safe dose (5 x 1012 transducing units intravenous) of RGD-A-TNF. This demonstrated selective targeting of tumor-associated vasculature and sparing of normal tissues assessed via serial biopsy of both tumor and normal tissue. Repetitive dosing in a cohort of 14 dogs, at the defined optimal dose, was well tolerated and led to objective tumor regression in two dogs (14%), stable disease in six (43%), and disease progression in six (43%) via Response Evaluation Criteria in Solid Tumors (RECIST). Conclusions/Significance: The first study of the COTC has demonstrated the utility and efficiency of the established infrastructure to inform the development of new cancer drugs within large animal naturally occurring cancer models. The preclinical evaluation of RGD-A-TNF within this network provided valuable and necessary data to complete the design of first-in-man studies

Severe anaemia is not associated with HIV-1 <it>env </it>gene characteristics in Malawian children

Abstract Background Anaemia is the most common haematological complication of HIV and associated with a high morbidity and a poor prognosis. The pathogenesis of HIV-associated anaemia is poorly understood and may include a direct effect of HIV on erythropoiesis. In vitro studies have suggested that specific HIV strains, like X4 that uses the CXCR4 co-receptor present on erythroid precursors, are associated with diminished erythropoiesis. This co-receptor affinity is determined by changes in the hypervariable loop of the HIV-1 envelope genome. In a previous case-control study we observed an association between HIV and severe anaemia in Malawian children that could not be fully explained by secondary infections and micronutrient deficiencies alone. We therefore explored the possibility that alterations in the V1-V2-V3 fragment of HIV-1 were associated with severe anaemia. Methods Using peripheral blood nucleic acid isolates of HIV-infected children identified in the previous studied we assessed if variability of the V1-V2-V3 region of HIV and the occurrence of X4 strains were more common in HIV-infected children with (cases, n = 29) and without severe anaemia (controls, n = 30). For 15 cases bone marrow isolates were available to compare against peripheral blood. All children were followed for 18 months after recruitment. Results Phylogenetic analysis showed that HIV-1 subtype C was present in all but one child. All V1-V2-V3 characteristics tested: V3 charge, V1-V2 length and potential glycosylation sites, were not found to be different between cases and controls. Using a computer model (C-PSSM) four children (7.8%) were identified to have an X4 strain. This prevalence was not different between study groups (p = 1.00). The V3 loop characteristics for bone marrow and peripheral blood isolates in the case group were identical. None of the children identified as having an X4 strain developed a (new) episode of severe anaemia during follow up. Conclusion The prevalence of X4 strains in these young HIV-1-subtype-C-infected children that were most likely vertically infected and naïve to anti-retroviral therapy can be considered high compared to previous results from Malawi. It is unlikely that V1-V2-V3 fragment characteristics and HIV co-receptor affinity is an important feature in the development of severe anaemia in Malawian children.</p

Imputation-based meta-analysis of severe malaria in three African populations.

Combining data from genome-wide association studies (GWAS) conducted at different locations, using genotype imputation and fixed-effects meta-analysis, has been a powerful approach for dissecting complex disease genetics in populations of European ancestry. Here we investigate the feasibility of applying the same approach in Africa, where genetic diversity, both within and between populations, is far more extensive. We analyse genome-wide data from approximately 5,000 individuals with severe malaria and 7,000 population controls from three different locations in Africa. Our results show that the standard approach is well powered to detect known malaria susceptibility loci when sample sizes are large, and that modern methods for association analysis can control the potential confounding effects of population structure. We show that pattern of association around the haemoglobin S allele differs substantially across populations due to differences in haplotype structure. Motivated by these observations we consider new approaches to association analysis that might prove valuable for multicentre GWAS in Africa: we relax the assumptions of SNP-based fixed effect analysis; we apply Bayesian approaches to allow for heterogeneity in the effect of an allele on risk across studies; and we introduce a region-based test to allow for heterogeneity in the location of causal alleles

Severe anaemia is not associated with HIV-1 gene characteristics in Malawian children-4

(cases, Hb<p><b>Copyright information:</b></p><p>Taken from "Severe anaemia is not associated with HIV-1 gene characteristics in Malawian children"</p><p>http://www.biomedcentral.com/1471-2334/8/26</p><p>BMC Infectious Diseases 2008;8():26-26.</p><p>Published online 29 Feb 2008</p><p>PMCID:PMC2311312.</p><p></p

Severe anaemia is not associated with HIV-1 gene characteristics in Malawian children-1

Ases, Hb<p><b>Copyright information:</b></p><p>Taken from "Severe anaemia is not associated with HIV-1 gene characteristics in Malawian children"</p><p>http://www.biomedcentral.com/1471-2334/8/26</p><p>BMC Infectious Diseases 2008;8():26-26.</p><p>Published online 29 Feb 2008</p><p>PMCID:PMC2311312.</p><p></p

Asiakastyytyväisyystutkimus : Simon Auto Oy

Opinnäytetyön tarkoituksena oli selvittää Pihtiputaan Simon Auto Oy:n asiakkaiden tyytyväisyyttä. Asiakkaiden tyytyväisyyttä selvitettiin myymälään ja kahvioon, sijaintiin sekä asiakaspalveluun. Tutkimuksessa selvitettiin samalla myös asiakkaiden taustatietoja sekä asiointitiheyttä. Opinnäytetyön teoriaosuudessa käsitellään palvelun laatua, markkinointia yleisellä tasolla, asiakastyytyväisyyttä sekä erilaisia tutkimustyyppejä. Lähteinä opinnäytetyössä käytettiin palvelua, markkinointia, asiakastyytyväisyyttä sekä tilastollista tutkimusta käsittelevää kirjallisuutta. Asiakastyytyväisyystutkimus suoritettiin kyselylomakkeella Pihtiputaan Simon Auto Oy:ssä. Vastauksia saatiin yhteensä 29 kappaletta. Tutkimuksen tulosten perusteella asiakaspalvelun laatuun sekä myymälään ja kahvioon oltiin pääosin tyytyväisiä.The purpose of this thesis was to study the satisfaction of the customers of Simon Auto Oy. The aim was to find out customers’ satisfaction with the store, cafeteria, location and customer service. This study also examined customers’ backgrounds and density of transactions. The theoretical part of this thesis deals with the quality of service, marketing at a general level, customer satisfaction and different research types. The sources of this thesis represented literature that covered service, marketing, customer satisfaction and statistical research. The customer satisfaction research was carried out by using questionnaire which took place at the store. The total number of answers was 29. Based on the research results, the customers were mainly contented with the quality of the customer service and with the store and the cafeteria

Severe anaemia is not associated with HIV-1 gene characteristics in Malawian children-2

Mia (cases, Hb<p><b>Copyright information:</b></p><p>Taken from "Severe anaemia is not associated with HIV-1 gene characteristics in Malawian children"</p><p>http://www.biomedcentral.com/1471-2334/8/26</p><p>BMC Infectious Diseases 2008;8():26-26.</p><p>Published online 29 Feb 2008</p><p>PMCID:PMC2311312.</p><p></p