Immunogenicity of mAbs in non-human primates during nonclinical safety assessment

The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we accessed the drug registration files of all mAbs registered in the European Union to establish the relative immunogenicity of mAbs in NHPs and humans. The incidence of formation of antidrug-antibodies in NHPs and patients was comparable in only 59% of the cases. In addition, the type of antidrug-antibody response was different in NHP and humans in 59% of the cases. Humanization did not necessarily reduce immunogenicity in humans. Immunogenicity interfered with the safety assessment during non-clinical drug development when clearing or neutralizing antibodies were formed. While important to interpret the study results, immunogenicity reduced the quality of NHP data in safety assessment. These findings confirm that the ability to compare relative immunogenicity of mAbs in NHPs and humans is low. Furthermore, immunogenicity limits the value of informative NHP studies.     

Roles of Wnt8a during formation and patterning of the mouse inner ear

Fgf and Wnt signalling have been shown to be required for formation of the otic placode in vertebrates. Whereas several Fgfs including Fgf3, Fgf8 and Fgf10 have been shown to participate during early placode induction, Wnt signalling is required for specification and maintenance of the otic placode, and dorsal patterning of the otic vesicle. However, the requirement for specific members of the Wnt gene family for otic placode and vesicle formation and their potential interaction with Fgf signalling has been poorly defined. Due to its spatiotemporal expression during placode formation in the hindbrain Wnt8a has been postulated as a potential candidate for its specification. Here we have examined the role of Wnt8a during formation of the otic placode and vesicle in mouse embryos. Wnt8a expression depends on the presence of Fgf3 indicating a serial regulation between Fgf and Wnt signalling during otic placode induction and specification. Wnt8a by itself however is neither essential for placode specification nor redundantly required together with Fgfs for otic placode and vesicle formation. Interestingly however, Wnt8a and Fgf3 are redundantly required for expression of Fgf15 in the hindbrain indicating additional reciprocal interactions between Fgf and Wnt signalling. Further reduction of Wnt signalling by the inactivation of Wnt1 in a Wnt8a mutant background revealed a redundant requirement for both genes during morphogenesis of the dorsal portion of the otic vesicle.     

Sexual dimorphism of body size and sternopleural bristle number: a comparison of geographic populations of an invasive cosmopolitan drosophilid

Zaprionus indianus is a cosmopolitan drosophilid, of Afrotropical origin, which has recently colonized South America. The sexual dimorphism (SD) of body size is low, males being almost as big as females. We investigated 10 natural populations, 5 from America and 5 from Africa, using the isofemale line technique. Three traits were measured on each fly: wing and thorax length and sternopleural bristle number. Two indices of SD were compared, and found to be highly correlated (r > 0.99). For the sake of simplicity, only the female/male (F/M) ratio was further considered. A significant genetic variability of SD was found in all cases, although with a low heritability (intra-class correlation of 0.13), about half the value found for the traits themselves. For size SD, we did not find any variation among continents or any latitudinal trend, and average values were 1.02 for wing length and 1.01 for thorax length. Bristle number SD was much greater (1.07). Among mass laboratory strains, SD was genetically much more variable than in recently collected populations, a likely consequence of laboratory drift. Altogether, SD, although genetically variable and prone to laboratory drift, is independent of size variations and presumably submitted to a stabilizing selection in nature.     

Eco-efficiency

Goal, Scope and Background The eco-efficiency analysis and portfolio is a powerful decision support tool for various strategic and marketing issues. Since its original academic development, the approach has been refined during the last decade and applied to a multitude of projects. BASF, as possibly the most prominent company using and developing this tool, has applied the eco-efficiency approach to more than 300 projects in the last 7 years. One of the greatest difficulties is to cover both dimensions of eco-efficiency (costs or value added and environmental impact) in a comparable manner. This is particularly a challenge for the eco-efficiency analyses of products. Methods In this publication, an important approach and field of application dealing with product decisions based on the combination of Life Cycle Cost (LCC) and Life Cycle Assessment (LCA) is described in detail. Special emphasis is put on the quantitative assessment of the relation of costs and environmental impacts. In conventional LCA an assessment of environmental impact categories is often made by normalization with inhabitant equivalents. This is necessary to be able to compare the different environmental impact categories, because of each different unit. For the proposed eco-efficiency analysis, the costs of products or processes are also normalized with adapted gross domestic product figures. Results and Discussion The ratio between normalized environmental impact categories and normalized costs (R_E,C) is used for the graphical presentation of the results in an eco-efficiency portfolio. For the interpretation of the results of an eco-efficiency analysis, it is important to distinguish ratios R_E,C which are higher than one from ratios lower than one. In the first case, the environmental impact is higher than the cost impact, while the inverse is true in the second case. This is very important for defining which kind of improvement is needed and defining strategic management decisions. The paper shows a statistical evaluation of the R_E,C factor based on the results of different eco-efficiency analyses made by BASF. For industries based on large material flows (e.g. chemicals, steel, metals, agriculture), the R_E,C factor is typically higher than one. Conclusions and Recommendations This contribution shows that LCC and LCA may be combined in a way that they mirror the concept of eco-efficiency. LCAs that do not consider LCC may be of very limited use for company management. For that very reason, corporations should install a data management system that ensures equal information on both sides of the eco-efficiency coin.     

Host Modulators of H1N1 Cytopathogenicity

Influenza A virus infects 5-20% of the population annually, resulting in ～35,000 deaths and significant morbidity. Current treatments include vaccines and drugs that target viral proteins. However, both of these approaches have limitations, as vaccines require yearly development and the rapid evolution of viral proteins gives rise to drug resistance. In consequence additional intervention strategies, that target host factors required for the viral life cycle, are under investigation. Here we employed arrayed whole-genome siRNA screening strategies to identify cell-autonomous molecular components that are subverted to support H1N1 influenza A virus infection of human bronchial epithelial cells. Integration across relevant public data sets exposed druggable gene products required for epithelial cell infection or required for viral proteins to deflect host cell suicide checkpoint activation. Pharmacological inhibition of representative targets, RGGT and CHEK1, resulted in significant protection against infection of human epithelial cells by the A/WS/33 virus. In addition, chemical inhibition of RGGT partially protected against H5N1 and the 2009 H1N1 pandemic strain. The observations reported here thus contribute to an expanding body of studies directed at decoding vulnerabilities in the command and control networks specified by influenza virulence factors.     

Resurgence of HIV Infection among Men Who Have Sex with Men in Switzerland: Mathematical Modelling Study

Background

New HIV infections in men who have sex with men (MSM) have increased in Switzerland since 2000 despite combination antiretroviral therapy (cART). The objectives of this mathematical modelling study were: to describe the dynamics of the HIV epidemic in MSM in Switzerland using national data; to explore the effects of hypothetical prevention scenarios; and to conduct a multivariate sensitivity analysis.

Methodology/Principal Findings

The model describes HIV transmission, progression and the effects of cART using differential equations. The model was fitted to Swiss HIV and AIDS surveillance data and twelve unknown parameters were estimated. Predicted numbers of diagnosed HIV infections and AIDS cases fitted the observed data well. By the end of 2010, an estimated 13.5% (95% CI 12.5, 14.6%) of all HIV-infected MSM were undiagnosed and accounted for 81.8% (95% CI 81.1, 82.4%) of new HIV infections. The transmission rate was at its lowest from 1995–1999, with a nadir of 46 incident HIV infections in 1999, but increased from 2000. The estimated number of new infections continued to increase to more than 250 in 2010, although the reproduction number was still below the epidemic threshold. Prevention scenarios included temporary reductions in risk behaviour, annual test and treat, and reduction in risk behaviour to levels observed earlier in the epidemic. These led to predicted reductions in new infections from 2 to 26% by 2020. Parameters related to disease progression and relative infectiousness at different HIV stages had the greatest influence on estimates of the net transmission rate.

Conclusions/Significance

The model outputs suggest that the increase in HIV transmission amongst MSM in Switzerland is the result of continuing risky sexual behaviour, particularly by those unaware of their infection status. Long term reductions in the incidence of HIV infection in MSM in Switzerland will require increased and sustained uptake of effective interventions.     

The sensory modality used for learning affects grades

Second-year undergraduated students from 2008, 2009, and 2010 cohorts were asked to respond a questionnaire to determine their learning style preferences, the VARK questionnaire (where V is visual, A is aural, R is reading-writing, and K is kinesthetic), which was translated into Spanish by the author. The translated questionnaire was tested for wording comprehension before its application in the actual study. Using the results of the VARK questionnaire, students were classified as unimodal or multimodal and according to the first preferred sensory modality used for learning as V, A, R, or K learners. Multiple-choice questions (MCQs) and problems that required simple arithmetic calculations (arithmetic-type questions) were applied to the students. The relation between the main sensory modality used for learning and the grades obtained in each question type was analyzed both in unimodal and multimodal students. It was found that R unimodal students performed significantly better in arithmetic questions than A and K unimodal students (P < 0.001 by a Bonferroni multiple-comparison test after ANOVA). R unimodal students also performed better than R multimodal students in arithmetic questions (P = 0.02 by a Mann-Whitney U-test). However, no differences were observed after MCQs in either unimodal or multimodal students with different first sensory modalities used for learning. When MCQ scores between unimodal and multimodal students were compared, no differences were detected. It was concluded that the sensory learning style used for learning affects student outcome when students receive arithmetic questions but not when MCQs are applied.