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

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The Phase Behavior of Mixed Lipid Membranes in Presence of the Rippled Phase

We propose a model describing liquid-solid phase coexistence in mixed lipid membranes by including explicitly the occurrence of a rippled phase. For a single component membrane, we employ a previous model in which the membrane thickness is used as an order parameter. As function of temperature, this model properly accounts for the phase behavior of the three possible membrane phases: solid, liquid and the rippled phase. Our primary aim is to explore extensions of this model to binary lipid mixtures by considering the composition dependence of important model parameters. The obtained phase diagrams show various liquid, solid and rippled phase coexistence regions, and are in quantitative agreement with the experimental ones for some specific lipid mixtures.Comment: 8pages, 5figure

PET imaging of the normal human auditory system: responses

Abstract The neural mechanisms involved in listening to sentences, and then detecting and verbalizing a specific word are poorly understood, but most likely involve complex neural networks. We used positron emission tomography to identify the areas of the human brain that are activated when young, normal hearing males and females were asked to listen to a sentence and repeat the last word from the Speech in Noise (SPIN) test. Listening conditions were (1) Quiet, (2) Speech, (3) Noise, and (4) SPIN with stimuli presented monaurally to either the left ear or the right ear. The least difficult listening task, Speech, resulted in bilateral activation of superior and middle temporal gyrus and pre-central gyrus. The Noise and SPIN conditions activated many of the same regions as Speech alone plus additional sites within the cerebellum, thalamus and superior/middle frontal gyri. Comparison of the SPIN condition versus Speech revealed additional activation in the right anterior lobe of the cerebellum and right medial frontal gyrus, near the cingulate. None of the left ear^right ear stimulus comparison revealed any significant differences except for the SPIN condition that showed greater activation in the left superior temporal gyrus for stimuli presented to the right ear. No gender differences were observed. These results demonstrate that repeating the last word in a sentence activates mainly auditory and motor areas of the brain when Speech is presented, whereas more difficult tasks, such as SPIN or multi-talker Noise, activate linguistic, attentional, cognitive, working memory, and motor planning areas.

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

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

Production of CXC and CC chemokines by human antigen-presenting cells in response to Lassa virus or closely related immunogenic viruses, and in cynomolgus monkeys with lassa fever.

International audienceThe pathogenesis of Lassa fever (LF), a hemorrhagic fever endemic to West Africa, remains unclear. We previously compared Lassa virus (LASV) with its genetically close, but nonpathogenic homolog Mopeia virus (MOPV) and demonstrated that the strong activation of antigen-presenting cells (APC), including type I IFN production, observed in response to MOPV probably plays a crucial role in controlling infection. We show here that human macrophages (MP) produce large amounts of CC and CXC chemokines in response to MOPV infection, whereas dendritic cells (DC) release only moderate amounts of CXC chemokines. However, in the presence of autologous T cells, DCs produced CC and CXC chemokines. Chemokines were produced in response to type I IFN synthesis, as the levels of both mediators were strongly correlated and the neutralization of type I IFN resulted in an inhibition of chemokine production. By contrast, LASV induced only low levels of CXCL-10 and CXCL-11 production. These differences in chemokine production may profoundly affect the generation of virus-specific T-cell responses and may therefore contribute to the difference of pathogenicity between these two viruses. In addition, a recombinant LASV (rLASV) harboring the NP-D389A/G392A mutations, which abolish the inhibition of type I IFN response by nucleoprotein (NP), induced the massive synthesis of CC and CXC chemokines in both DC and MP, confirming the crucial role of arenavirus NP in immunosuppression and pathogenicity. Finally, we confirmed, using PBMC samples and lymph nodes obtained from LASV-infected cynomolgus monkeys, that LF was associated with high levels of CXC chemokine mRNA synthesis, suggesting that the very early synthesis of these mediators may be correlated with a favourable outcome

Soluble Serum CD81 Is Elevated in Patients with Chronic Hepatitis C and Correlates with Alanine Aminotransferase Serum Activity

Aim: Cellular CD81 is a well characterized hepatitis C virus (HCV) entry factor, while the relevance of soluble exosomal CD81 in HCV pathogenesis is poorly defined. We performed a case-control study to investigate whether soluble CD81 in the exosomal serum fraction is associated with HCV replication and inflammatory activity. Patients and Methods: Four cohorts were investigated, patients with chronic hepatitis C (n = 37), patients with chronic HCV infection and persistently normal ALT levels (n = 24), patients with long term sustained virologic response (SVR, n = 7), and healthy volunteers (n = 23). Concentration of soluble CD81 was assessed semi-quantitatively after differential centrifugation ranging from 200 g to 100,000 g in the fifth centrifugation fraction by immunoblotting and densitometry. Results: Soluble CD81 was increased in patients with chronic hepatitis C compared to healthy subjects (p = 0.03) and cured patients (p = 0.017). Patients with chronic HCV infection and persistently normal ALT levels and patients with long term SVR had similar soluble CD81 levels as healthy controls (p>0.2). Overall, soluble CD81 levels were associated with ALT levels (r = 0.334, p = 0.016) and severe liver fibrosis (p = 0.027). Conclusion: CD81 is increased in the exosomal serum fraction in patients with chronic hepatitis C and appears to be associated with inflammatory activity and severity of fibrosis

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