Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy

Prognosis for patients suffering from malignant glioma has not substantially improved. Specific immunotherapy as a novel treatment concept critically depends on target antigens, which are highly overexpressed in the majority of gliomas, but the number of such antigens is still very limited. SOX2 was identified by screening an expression database for transcripts that are overexpressed in malignant glioma, but display minimal expression in normal tissues. Expression of SOX2 mRNA was further investigated in tumour and normal tissues by real-time PCR. Compared to cDNA from pooled normal brain, SOX2 was overexpressed in almost all (9 out of 10) malignant glioma samples, whereas expression in other, non-malignant tissues was almost negligible. SOX2 protein expression in glioma cell lines and tumour tissues was verified by Western blot and immunofluorescence. Immunohistochemistry demonstrated SOX2 protein expression in all malignant glioma tissues investigated ranging from 6 to 66% stained tumour cells. Human leucocyte antigen-A*0201-restricted SOX2-derived peptides were tested for the activation of glioma-reactive CD8+ cytotoxic T lymphocytes (CTLs). Specific CTLs were raised against the peptide TLMKKDKYTL and were capable of lysing glioma cells. The abundant and glioma-restricted overexpression of SOX2 and the generation of SOX2-specific and tumour-reactive CTLs may recommend this antigen as target for T-cell-based immunotherapy of glioma

Effects of Elevated Temperature and Carbon Dioxide on the Growth and Survival of Larvae and Juveniles of Three Species of Northwest Atlantic Bivalves

Rising CO2 concentrations and water temperatures this century are likely to have transformative effects on many coastal marine organisms. Here, we compared the responses of two life history stages (larval, juvenile) of three species of calcifying bivalves (Mercenaria mercenaria, Crassostrea virginica, and Argopecten irradians) to temperatures (24 and 28°C) and CO2 concentrations (∼250, 390, and 750 ppm) representative of past, present, and future summer conditions in temperate estuaries. Results demonstrated that increases in temperature and CO2 each significantly depressed survival, development, growth, and lipid synthesis of M. mercenaria and A. irradians larvae and that the effects were additive. Juvenile M. mercenaria and A. irradians were negatively impacted by higher temperatures while C. virginica juveniles were not. C. virginica and A. irradians juveniles were negatively affected by higher CO2 concentrations, while M. mercenaria was not. Larvae were substantially more vulnerable to elevated CO2 than juvenile stages. These findings suggest that current and future increases in temperature and CO2 are likely to have negative consequences for coastal bivalve populations

Subjectivity in a context of environmental change: opening new dialogues in mental health research

In a period of unstable experimentation with challenges of globalization of associated risks, and disenchantment with ‘enduring injustice’, we bring forward a consideration of subjectivity to the study of environmental change and mental health. We begin by identifying how mainstream climate change and mental health studies are unable to explain the emergent and co-evolutionary pathways of agency. As a means of freeing these studies of their objective dimensions of linear-causation, we argue in favour of a re-positioning of subjectivity within an appreciation of recognition conflicts and beyond the over-deterministic interpretations of power centres—state, market or religion. We draw on one example of scientific research that was conducted in a region undergoing strong environmental, social and cultural changes, in the state of São Paulo/Brazil, with the aim to open mental health research to new dialogues, to which we contribute with the notion of the ‘pluriversal subject’

Association of the TNFa13 microsatellite with systemic sclerosis in Japanese patients

OBJECTIVES—To elucidate the contribution of microsatellite polymorphisms of TNFa and TNFb alleles to the pathogenesis of systemic sclerosis (SSc) by comparing the allele distribution among populations with different HLA susceptibility genes in SSc.
METHODS—TNFa and TNFb microsatellite polymorphisms were determined by PCR in 54 Japanese and 50 German SSc patients and in normal controls. HLA-DR genotyping was carried out by PCR-SSCP.
RESULTS—The frequency of TNFa13 was significantly increased in Japanese SSc (p=0.011, OR=8.53, 95% confidence intervals (95%CI)=2.46, 32.51, and p<1.0 × 10E-5, OR=10.35, 95%CI=4.88, 22.09) and SSc with antitopoisomerase I antibody (a-Scl-70) (p=0.021, OR=33.25, 95%CI=3.39, 800.76, and p<1.0 × 10E-5, OR=24.42, 95%CI=8.40, 72.83), compared with the German patient group and German controls, respectively. This increase was not only attributable to a higher prevalence of TNFa13 in Japanese compared with Germans (p=0.005, OR=3.55, 95%CI=1.60, 7.85) but was also caused by an increase in SSc, especially in the a-Scl-70 positive patients (p=0.028, OR=6.88, 95%CI=1.16, 22.60) compared with Japanese controls. TNFa13 was positively in linkage disequilibrium with HLA-DRB1*1502 (LD=0.053, t=2.69). Association analysis indicated that both TNFa13 and DRB1*1502 might have comparable probabilities of being susceptibility factors for SSc with a-Scl-70 in Japanese. Prevalences of TNFa6 and 13( )were significantly increased and prevalences of TNFa2, and 7 were significantly decreased in Japanese controls as compared with German controls.
CONCLUSION—TNFa13 is a genetic marker for SSc with a-Scl-70 in Japanese patients. Various differences in the prevalences of TNFa alleles between Japanese and German controls were established.


Incorporating safety in early (airframe) systems design and assessment

Presented is a novel framework for incorporating safety analysis in early systems architecture design.Traditionally, a systems architecture is first defined by the architects and then passed to safety experts, who manually create artefacts such as Function Hazard Analysis (FHA) or Fault Tree Analysis (FTA) for safety assessment. The problem with this manual approach is that if the architect modifies the systems architecture, then the whole safety assessment process needs to be repeated, which is tedious and time consuming. To overcome this limitation, the proposed framework automates the creation of safety models such as FHA and FTA by utilizing the Requirement, Functional, Logical, and Physical (RFLP) systems engineering paradigm. The framework supports three main activities. First, the safety targets are determined by performing a FHA of the architecture and the Requirements view is updated. Second, compliance with the safety requirements is analyzed using dynamic fault trees, automatically generated from the Logical view. Interactive visualization techniques are proposed to interpret the safety results, e.g. highlighting the greatest contributors to the probability of failure. Third, an algorithm is developed that enables the designer to interactively improve the architecture’s safety by introducing more reliable components or increasing redundancy. The concept is illustrated with a representative example, where the environmental control system of a civil aircraft is studied from a safety point of view

Climate impact response functions as impact tools in the tolerable windows approach

A critical issue for policymakers in defining mitigation strategies for climate change is the availability of appropriate evaluation tools. The development of climate impact response functions (CIRFs) is our reaction to this challenge. CIRFs depict the response of selected climate-sensitive impact sectors across a wide range of plausible futures. They consist of a limited number of climate-change-related dimensions and sensitivities of sector-specific impact models. The concept of CIRFs is defined and the procedure to develop them is presented. The use of climate change scenarios derived from various GCM experiments and the adopted impact assessment models are explained. The CIRFs presented here consider climate change impacts on natural vegetation, crop production, and water availability. They are part of the ICLIPS integrated assessment framework based on the tolerable windows approach. CIRFs can be applied both in 'forward' and in 'inverse' mode. In the latter, they help to translate thresholds for climate impacts perceived by stakeholders (so-called impact guardrails) into constraints for climate variables (so-called climate windows). This enables the results of detailed impact models to be incorporated into intertemporally optimizing integrated assessment models, such as the ICLIPS model