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111.
Xiaoyu Yang Wei Xu Svetlana Dukleska Sabrina Benchaar Selina Mengisen Valentyn Antochshuk Jason Cheung Leslie Mann Zulfia Babadjanova Jason Rowand Rico Gunawan Alexander McCampbell Maribel Beaumont David Meininger Daisy Richardson Alexandre Ambrogelly 《MABS-AUSTIN》2013,5(5):787-794
Monoclonal antibodies constitute a robust class of therapeutic proteins. Their stability, resistance to stress conditions and high solubility have allowed the successful development and commercialization of over 40 antibody-based drugs. Although mAbs enjoy a relatively high probability of success compared with other therapeutic proteins, examples of projects that are suspended due to the instability of the molecule are not uncommon. Developability assessment studies have therefore been devised to identify early during process development problems associated with stability, solubility that is insufficient to meet expected dosing or sensitivity to stress. This set of experiments includes short-term stability studies at 2−8 þC, 25 þC and 40 þC, freeze-thaw studies, limited forced degradation studies and determination of the viscosity of high concentration samples. We present here three case studies reflecting three typical outcomes: (1) no major or unexpected degradation is found and the study results are used to inform early identification of degradation pathways and potential critical quality attributes within the Quality by Design framework defined by US Food and Drug Administration guidance documents; (2) identification of specific degradation pathway(s) that do not affect potency of the molecule, with subsequent definition of proper process control and formulation strategies; and (3) identification of degradation that affects potency, resulting in program termination and reallocation of resources. 相似文献
112.
Petra Dieker Claudia Drees Thomas Schmitt Thorsten Assmann 《Conservation Genetics》2013,14(1):231-236
The burnet moth Zygaena anthyllidis, endemic to the high elevations of the Pyrenees, is vulnerable to land-use. In order to identify conservation priorities based on an assessment of genetic diversity within populations and gene flow among populations, we examined Z. anthyllidis’ genetic variability and differentiation based on allozyme electrophoresis from seven populations scattered across its entire range. In comparison to other mountain Lepidoptera, the populations studied exhibit a low level of genetic diversity. Remarkable between-population differentiation (F ST = 0.053), the presence of private alleles, and the lack of significant isolation-by-distance pattern characterises the genetic make-up of the species. We interpreted the pattern of genetic differentiation as a consequence of low dispersal power in combination with insufficient landscape connectivity. Ongoing land-use change might reinforce genetic differentiation due to habitat fragmentation and additionally affect negatively allozyme variability at shifting range margins, i.e. the capacity to adapt to changing environments. We therefore suggest creating a network of suitable habitats at the landscape scale to facilitate genetic exchange and to conserve the species’ overall genetic variability. 相似文献
113.
Beate Wieseler Natalia Wolfram Natalie McGauran Michaela F. Kerekes Volker Verv?lgyi Petra Kohlepp Marloes Kamphuis Ulrich Grouven 《PLoS medicine》2013,10(10)
Background
Access to unpublished clinical study reports (CSRs) is currently being discussed as a means to allow unbiased evaluation of clinical research. The Institute for Quality and Efficiency in Health Care (IQWiG) routinely requests CSRs from manufacturers for its drug assessments.Our objective was to determine the information gain from CSRs compared to publicly available sources (journal publications and registry reports) for patient-relevant outcomes included in IQWiG health technology assessments (HTAs) of drugs.Methods and Findings
We used a sample of 101 trials with full CSRs received for 16 HTAs of drugs completed by IQWiG between 15 January 2006 and 14 February 2011, and analyzed the CSRs and the publicly available sources of these trials. For each document type we assessed the completeness of information on all patient-relevant outcomes included in the HTAs (benefit outcomes, e.g., mortality, symptoms, and health-related quality of life; harm outcomes, e.g., adverse events). We dichotomized the outcomes as “completely reported” or “incompletely reported.” For each document type, we calculated the proportion of outcomes with complete information per outcome category and overall.We analyzed 101 trials with CSRs; 86 had at least one publicly available source, 65 at least one journal publication, and 50 a registry report. The trials included 1,080 patient-relevant outcomes. The CSRs provided complete information on a considerably higher proportion of outcomes (86%) than the combined publicly available sources (39%). With the exception of health-related quality of life (57%), CSRs provided complete information on 78% to 100% of the various benefit outcomes (combined publicly available sources: 20% to 53%). CSRs also provided considerably more information on harms. The differences in completeness of information for patient-relevant outcomes between CSRs and journal publications or registry reports (or a combination of both) were statistically significant for all types of outcomes.The main limitation of our study is that our sample is not representative because only CSRs provided voluntarily by pharmaceutical companies upon request could be assessed. In addition, the sample covered only a limited number of therapeutic areas and was restricted to randomized controlled trials investigating drugs.Conclusions
In contrast to CSRs, publicly available sources provide insufficient information on patient-relevant outcomes of clinical trials. CSRs should therefore be made publicly available. Please see later in the article for the Editors'' Summary 相似文献114.
Sibylle Bernard-Stoecklin Céline Gommet Aurélien B. Corneau Sabrina Guenounou Claire Torres Nathalie Dejucq-Rainsford Antonio Cosma Nathalie Dereuddre-Bosquet Roger Le Grand 《PLoS pathogens》2013,9(12)
The mucosal events of HIV transmission have been extensively studied, but the role of infected cells present in the genital and rectal secretions, and in the semen, in particular, remains a matter of debate. As a prerequisite to a thorough in vivo investigation of the early transmission events through infected cells, we characterized in detail by multi-parameter flow cytometry the changes in macaque seminal leukocytes during SIVmac251 infection, focusing on T cells, macrophages and dendritic cells. Using immunocytofluorescence targeting SIV proteins and real-time quantitative PCR targeting SIV DNA, we investigated the nature of the infected cells on sorted semen leukocytes from macaques at different stages of infection. Finally, we cocultured semen CD4+ T cells and macrophages with a cell line permissive to SIV infection to assess their infectivity in vitro. We found that primary infection induced strong local inflammation, which was associated with an increase in the number of leukocytes in semen, both factors having the potential to favor cell-associated virus transmission. Semen CD4+ T cells and macrophages were productively infected at all stages of infection and were infectious in vitro. Lymphocytes had a mucosal phenotype and expressed activation (CD69 & HLA-DR) and migration (CCR5, CXCR4, LFA-1) markers. CD69 expression was increased in semen T cells by SIV infection, at all stages of infection. Macrophages predominated at all stages and expressed CD4, CCR5, MAC-1 and LFA-1. Altogether, we demonstrated that semen contains the two major SIV-target cells (CD4+ T cells and macrophages). Both cell types can be productively infected at all stages of SIV infection and are endowed with markers that may facilitate transmission of infection during sexual exposure. 相似文献
115.
Benjamin Steeb Beatrice Claudi Neil A. Burton Petra Tienz Alexander Schmidt Hesso Farhan Alain Mazé Dirk Bumann 《PLoS pathogens》2013,9(4)
Pathogen access to host nutrients in infected tissues is fundamental for pathogen growth and virulence, disease progression, and infection control. However, our understanding of this crucial process is still rather limited because of experimental and conceptual challenges. Here, we used proteomics, microbial genetics, competitive infections, and computational approaches to obtain a comprehensive overview of Salmonella nutrition and growth in a mouse typhoid fever model. The data revealed that Salmonella accessed an unexpectedly diverse set of at least 31 different host nutrients in infected tissues but the individual nutrients were available in only scarce amounts. Salmonella adapted to this situation by expressing versatile catabolic pathways to simultaneously exploit multiple host nutrients. A genome-scale computational model of Salmonella in vivo metabolism based on these data was fully consistent with independent large-scale experimental data on Salmonella enzyme quantities, and correctly predicted 92% of 738 reported experimental mutant virulence phenotypes, suggesting that our analysis provided a comprehensive overview of host nutrient supply, Salmonella metabolism, and Salmonella growth during infection. Comparison of metabolic networks of other pathogens suggested that complex host/pathogen nutritional interfaces are a common feature underlying many infectious diseases. 相似文献
116.
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118.
Francesco Marabita Malin Almgren Maléne E. Lindholm Sabrina Ruhrmann Fredrik Fagerstr?m-Billai Maja Jagodic Carl J. Sundberg Tomas J. Ekstr?m Andrew E. Teschendorff Jesper Tegnér David Gomez-Cabrero 《Epigenetics》2013,8(3):333-346
The proper identification of differentially methylated CpGs is central in most epigenetic studies. The Illumina HumanMethylation450 BeadChip is widely used to quantify DNA methylation; nevertheless, the design of an appropriate analysis pipeline faces severe challenges due to the convolution of biological and technical variability and the presence of a signal bias between Infinium I and II probe design types. Despite recent attempts to investigate how to analyze DNA methylation data with such an array design, it has not been possible to perform a comprehensive comparison between different bioinformatics pipelines due to the lack of appropriate data sets having both large sample size and sufficient number of technical replicates. Here we perform such a comparative analysis, targeting the problems of reducing the technical variability, eliminating the probe design bias and reducing the batch effect by exploiting two unpublished data sets, which included technical replicates and were profiled for DNA methylation either on peripheral blood, monocytes or muscle biopsies. We evaluated the performance of different analysis pipelines and demonstrated that: (1) it is critical to correct for the probe design type, since the amplitude of the measured methylation change depends on the underlying chemistry; (2) the effect of different normalization schemes is mixed, and the most effective method in our hands were quantile normalization and Beta Mixture Quantile dilation (BMIQ); (3) it is beneficial to correct for batch effects. In conclusion, our comparative analysis using a comprehensive data set suggests an efficient pipeline for proper identification of differentially methylated CpGs using the Illumina 450K arrays. 相似文献
119.
Wolfgang Retz Samir S. T. Boureghda Petra Retz-Junginger Florence Philipp-Wiegmann Michael Rösler 《Attention deficit and hyperactivity disorders》2013,5(1):47-57
ADHD and psychopathy are both associated with poor social adaptation and antisocial behavior. Previous studies have also suggested that ADHD and psychopathy share some symptomatology. The current study attempted to further uncover the relationship between ADHD and psychopathy in perpetrators by investigating the possibility of underlying common factors of ADHD and psychopathy using standardized instruments. Correlation analyses and principal component analyses were performed on ADHD-SB self-rating questionnaires and the PCL-SV from a population of 314 offenders. Further, subjects without ADHD, full ADHD and partially remitted ADHD according to DSM-IV were compared regarding psychopathic traits. ADHD and psychopathy rating scores were found to be correlated. Only psychopathic features related to unstable and antisocial lifestyle, but not related to affective features of psychopathy accounted to this association. Findings on the principal component analysis suggest that ADHD and psychopathy are unrelated on a symptomatic level, with the exception of impulsivity, which is a common feature that seems to combine both constructs. 相似文献
120.
Sébastien Fritz Aurelien Capitan Anis Djari Sabrina C. Rodriguez Anne Barbat Aurélia Baur Cécile Grohs Bernard Weiss Mekki Boussaha Diane Esquerré Christophe Klopp Dominique Rocha Didier Boichard 《PloS one》2013,8(6)
The regular decrease of female fertility over time is a major concern in modern dairy cattle industry. Only half of this decrease is explained by indirect response to selection on milk production, suggesting the existence of other factors such as embryonic lethal genetic defects. Genomic regions harboring recessive deleterious mutations were detected in three dairy cattle breeds by identifying frequent haplotypes (>1%) showing a deficit in homozygotes among Illumina Bovine 50k Beadchip haplotyping data from the French genomic selection database (47,878 Holstein, 16,833 Montbéliarde, and 11,466 Normande animals). Thirty-four candidate haplotypes (p<10−4) including previously reported regions associated with Brachyspina, CVM, HH1, and HH3 in Holstein breed were identified. Haplotype length varied from 1 to 4.8 Mb and frequencies from 1.7 up to 9%. A significant negative effect on calving rate, consistent in heifers and in lactating cows, was observed for 9 of these haplotypes in matings between carrier bulls and daughters of carrier sires, confirming their association with embryonic lethal mutations. Eight regions were further investigated using whole genome sequencing data from heterozygous bull carriers and control animals (45 animals in total). Six strong candidate causative mutations including polymorphisms previously reported in FANCI (Brachyspina), SLC35A3 (CVM), APAF1 (HH1) and three novel mutations with very damaging effect on the protein structure, according to SIFT and Polyphen-2, were detected in GART, SHBG and SLC37A2 genes. In conclusion, this study reveals a yet hidden consequence of the important inbreeding rate observed in intensively selected and specialized cattle breeds. Counter-selection of these mutations and management of matings will have positive consequences on female fertility in dairy cattle. 相似文献