Pharmacokinetic (Pk) Activity of Cabazitaxel (Cbz) in Patients (Pts) with Renal Impairment (Ri)

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Coligation of the hepatitis C virus receptor CD81 with CD28 primes naive T lymphocytes to acquire type 2 effector function

Costimuli provide supplementary signals required by naive T cells to become fully activated upon Ag encounter. Tetraspanins are a large family of transmembrane proteins that can costimulate T cells when engaged in vitro. In this study, we describe for the first time that coligation of the tetraspanins CD81, CD82, or CD9 with the costimulatory molecule CD28 in vitro leads to proliferation of naive T cells. When activated through this pathway, both CD4+ and CD8+ naive T cells differentiate into type 2 effector cells, which produce IL-4, IL-5, IL-13, and IL-10, together with IL-2 and TNF-alpha, but little to no IFN-gamma. These effector cells descend from precursors that display early and strong production of IL-4, STAT6 phosphorylation, and up-regulation of the transcription factor GATA-3, suggesting a direct skewing toward Th2 differentiation without a Th0 intermediate. The hepatitis C virus envelope protein E2 is the only ligand known for CD81. Therefore, we propose that this new type of Ag-independent T cell activation may occur in hepatitis C virus-infected individuals, contributing to liver inflammation, impaired type 1 immune responses, and recurrent flares of type 2 immunity associated with chronic infection

Managing uncertainty: a review of food system scenario analysis and modelling

Complex socio-ecological systems like the food system are unpredictable, especially to long-term horizons such as 2050. In order to manage this uncertainty, scenario analysis has been used in conjunction with food system models to explore plausible future outcomes. Food system scenarios use a diversity of scenario types and modelling approaches determined by the purpose of the exercise and by technical, methodological and epistemological constraints. Our case studies do not suggest Malthusian futures for a projected global population of 9 billion in 2050; but international trade will be a crucial determinant of outcomes; and the concept of sustainability across the dimensions of the food system has been inadequately explored so far. The impact of scenario analysis at a global scale could be strengthened with participatory processes involving key actors at other geographical scales. Food system models are valuable in managing existing knowledge on system behaviour and ensuring the credibility of qualitative stories but they are limited by current datasets for global crop production and trade, land use and hydrology. Climate change is likely to challenge the adaptive capacity of agricultural production and there are important knowledge gaps for modelling research to address

Impact of smoking and smoking cessation on overweight and obesity: Scotland-wide, cross-sectional study on 40,036 participants

<p>Background: Weight control is cited by some people, especially adolescent girls, as a reason for commencing smoking or not quitting. The aim of this study was to explore the relationship between smoking behaviour and being overweight or obese, overall and by age and sex sub-groups.</p> <p>Methods: We used data from the six Scottish Health Surveys conducted to date (1995--2010) to undertake a population-based, cross-sectional study on 40,036 participants representative of the adult (>=16 years) Scottish population. Height and weight were measured by a trained interviewer, not self-reported.</p> <p>Results: 24,459 (63.3%) participants were overweight (BMI >=25 kg/m2) and 9,818 (25.4%) were obese (BMI >=30 kg/m2). Overall, current smokers were less likely to be overweight than never smokers. However, those who had smoked for more than 20 years (adjusted OR 1.54, 95% CI 1.41-1.69, p < 0.001) and ex-smokers (adjusted OR 1.18, 95% CI 1.11-1.25, p < 0.001) were more likely to be overweight. There were significant interactions with age. Participants 16--24 years of age, were no more likely to be overweight if they were current (adjusted OR 1.01, 95% CI 0.84-1.20, p = 0.944) or ex (adjusted OR 0.88, 95% CI 0.67-1.14, p = 0.319) smokers. The same patterns pertained to obesity.</p> <p>Conclusions: Whilst active smoking may be associated with reduced risk of being overweight among some older adults, there was no evidence to support the belief among young people that smoking protects them from weight gain. Making this point in educational campaigns targeted at young people may help to discourage them from starting to smoke.</p&gt

Failure to repair endogenous DNA damage in β-cells causes adult-onset diabetes in mice

Age is the greatest risk factor for the development of type 2 diabetes mellitus (T2DM). Age-related decline in organ function is attributed to the accumulation of stochastic damage, including damage to the nuclear genome. Islets of T2DM patients display increased levels of DNA damage. However, whether this is a cause or consequence of the disease has not been elucidated. Here, we asked if spontaneous, endogenous DNA damage in β-cells can drive β-cell dysfunction and diabetes, via deletion of Ercc1, a key DNA repair gene, in β-cells. Mice harboring Ercc1-deficient β-cells developed adult-onset diabetes as demonstrated by increased random and fasted blood glucose levels, impaired glucose tolerance, and reduced insulin secretion. The inability to repair endogenous DNA damage led to an increase in oxidative DNA damage and apoptosis in β-cells and a significant loss of β-cell mass. Using electron microscopy, we identified β-cells in clear distress that showed an increased cell size, enlarged nuclear size, reduced number of mature insulin granules, and decreased number of mitochondria. Some β-cells were more affected than others consistent with the stochastic nature of spontaneous DNA damage. Ercc1-deficiency in β-cells also resulted in loss of β-cell function as glucose-stimulated insulin secretion and mitochondrial function were impaired in islets isolated from mice harboring Ercc1-deficient β-cells. These data reveal that unrepaired endogenous DNA damage is sufficient to drive β-cell dysfunction and provide a mechanism by which age increases the risk of T2DM. </p

Platelet-activating factor receptor (PAF-R)-dependent pathways control tumour growth and tumour response to chemotherapy

<p>Abstract</p> <p>Background</p> <p>Phagocytosis of apoptotic cells by macrophages induces a suppressor phenotype. Previous data from our group suggested that this occurs via Platelet-activating factor receptor (PAF-R)-mediated pathways. In the present study, we investigated the impact of apoptotic cell inoculation or induction by a chemotherapeutic agent (dacarbazine, DTIC) on tumour growth, microenvironmental parameters and survival, and the effect of treatment with a PAF-R antagonist (WEB2170). These studies were performed in murine tumours: Ehrlich Ascitis Tumour (EAT) and B16F10 melanoma.</p> <p>Methods</p> <p>Tumour growth was assessed by direct counting of EAT cells in the ascitis or by measuring the volume of the solid tumour. Parameters of the tumour microenvironment, such as the frequency of cells expressing cyclo-oxygenase-2 (COX-2), caspase-3 and galectin-3, and microvascular density, were determined by immunohistochemistry. Levels of vascular endothelium growth factor (VEGF) and prostaglandin E2 (PGE2) were determined by ELISA, and levels of nitric oxide (NO) by Griess reaction. PAF-R expression was analysed by immunohistochemistry and flow cytometry.</p> <p>Results</p> <p>Inoculation of apoptotic cells before EAT implantation stimulated tumour growth. This effect was reversed by <it>in vivo </it>pre-treatment with WEB2170. This treatment also reduced tumour growth and modified the microenvironment by reducing PGE2, VEGF and NO production. In B16F10 melanoma, WEB2170 alone or in association with DTIC significantly reduced tumour volume. Survival of the tumour-bearing mice was not affected by WEB2170 treatment but was significantly improved by the combination of DTIC with WEB2170. Tumour microenvironment elements were among the targets of the combination therapy since the relative frequency of COX-2 and galectin-3 positive cells and the microvascular density within the tumour mass were significantly reduced by treatment with WEB2170 or DTIC alone or in combination. Antibodies to PAF-R stained the cells from inside the tumour, but not the tumour cells grown <it>in vitro</it>. At the tissue level, a few cells (probably macrophages) stained positively with antibodies to PAF-R.</p> <p>Conclusions</p> <p>We suggest that PAF-R-dependent pathways are activated during experimental tumour growth, modifying the microenvironment and the phenotype of the tumour macrophages in such a way as to favour tumour growth. Combination therapy with a PAF-R antagonist and a chemotherapeutic drug may represent a new and promising strategy for the treatment of some tumours.</p

An integrated ontology resource to explore and study host-virus relationships.

Our growing knowledge of viruses reveals how these pathogens manage to evade innate host defenses. A global scheme emerges in which many viruses usurp key cellular defense mechanisms and often inhibit the same components of antiviral signaling. To accurately describe these processes, we have generated a comprehensive dictionary for eukaryotic host-virus interactions. This controlled vocabulary has been detailed in 57 ViralZone resource web pages which contain a global description of all molecular processes. In order to annotate viral gene products with this vocabulary, an ontology has been built in a hierarchy of UniProt Knowledgebase (UniProtKB) keyword terms and corresponding Gene Ontology (GO) terms have been developed in parallel. The results are 65 UniProtKB keywords related to 57 GO terms, which have been used in 14,390 manual annotations; 908,723 automatic annotations and propagated to an estimation of 922,941 GO annotations. ViralZone pages, UniProtKB keywords and GO terms provide complementary tools to users, and the three resources have been linked to each other through host-virus vocabulary

The Lantern Vol. 50, No. 2, Spring 1984

• The Storm • Je ne sais pas • The Ghetious Blastious • An Empty Cradle • The Playing Hands • Battle Hymn • A Limerick • Parting Thoughts • The River • Miss You • De la Tristeza • Two So Special • Time of the Unicorn • The Absence • Thru The Breeze • Is the World Really a Round Ball? • Brother • To Michael • Gravity • Refuge • Der Witwer • Plastic Flowers Never Die • Book on the Shelfhttps://digitalcommons.ursinus.edu/lantern/1124/thumbnail.jp

Scenario Planning and Nanotechnological Futures

Scenario planning may assist us in harnessing the benefits of nanotechnology and managing the associated risks for the good of the society. Scenario planning is a way to describe the present state of the world and develop several hypotheses about the future of the world, thereby enabling discussions about how the world ought to be. Scenario planning thus is not only a tool for learning and foresight, but also for leadership. Informed decision-making by experts and political leaders becomes possible, while simultaneously allaying public's perception of the risks of new and emerging technologies such as nanotechnology. Two scenarios of the societal impact of nanotechnology are the mixed-signals scenario and the confluence scenario. Technoscientists have major roles to play in both scenarios