Identification of a novel phosphorylation site in hepatitis C virus NS5A

Hepatitis C virus (HCV) NS5A protein is phosphorylated on multiple residues; however, despite extensive study, the precise identity of these sites has not been determined unambiguously. In this study, we have used a combination of immunoprecipitation and mass spectrometry to identify these phosphorylation sites. This analysis revealed the presence of a major phosphorylated residue within NS5A from the genotype 1b Con1 isolate – serine 249 (serine 2221 in polyprotein numbering). However, mutation of this residue (or the corresponding threonine in the JFH-1 isolate) to either a phosphomimetic (aspartate) or a phosphoablative (alanine) residue resulted in no phenotype. We conclude that phosphorylation of this residue, in the context of a highly culture-adapted HCV genome, does not play a role in either viral RNA replication or virus assembly. It is possible that it might be important in an aspect of virus biology that is not recapitulated faithfully in the Huh-7 cell-culture system

The PRINTS database: a fine-grained protein sequence annotation and analysis resource—its status in 2012

The PRINTS database, now in its 21st year, houses a collection of diagnostic protein family ‘fingerprints’. Fingerprints are groups of conserved motifs, evident in multiple sequence alignments, whose unique inter-relationships provide distinctive signatures for particular protein families and structural/functional domains. As such, they may be used to assign uncharacterized sequences to known families, and hence to infer tentative functional, structural and/or evolutionary relationships. The February 2012 release (version 42.0) includes 2156 fingerprints, encoding 12 444 individual motifs, covering a range of globular and membrane proteins, modular polypeptides and so on. Here, we report the current status of the database, and introduce a number of recent developments that help both to render a variety of our annotation and analysis tools easier to use and to make them more widely available

Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer

Background:Tasquinimod is a quinoline-3-carboxamide derivative with anti-angiogenic activity. Two open-label phase I clinical trials in patients were conducted to evaluate the safety and tolerability of tasquinimod, with additional pharmacokinetic and efficacy assessments.Methods:Patients with castration-resistant prostate cancer with no previous chemotherapy were enrolled in this study. The patients received tasquinimod up to 1 year either at fixed doses of 0.5 or 1.0 mg per day or at an initial dose of 0.25 mg per day that escalated to 1.0 mg per day.Results:A total of 32 patients were enrolled; 21 patients were maintained for >/=4 months. The maximum tolerated dose was determined to be 0.5 mg per day; but when using stepwise intra-patient dose escalation, a dose of 1.0 mg per day was well tolerated. The dose-limiting toxicity was sinus tachycardia and asymptomatic elevation in amylase. Common treatment-emergent adverse events included transient laboratory abnormalities, anaemia, nausea, fatigue, myalgia and pain. A serum prostate-specific antigen (PSA) decline of >/=50% was noted in two patients. The median time to PSA progression (>25%) was 19 weeks. Only 3 out of 15 patients (median time on study: 34 weeks) developed new bone lesions.Conclusion:Long-term continuous oral administration of tasquinimod seems to be safe, and the overall efficacy results indicate that tasquinimod might delay disease progression.British Journal of Cancer advance online publication, 15 September 2009; doi:10.1038/sj.bjc.6605322 www.bjcancer.com

A Randomized Phase II/III Study of Naptumomab Estafenatox + IFNα versus IFNα in Renal Cell Carcinoma: Final Analysis with Baseline Biomarker Subgroup and Trend Analysis

Purpose: To prospectively determine the efficacy of naptumomab estafenatox (Nap) þ IFNa versus IFN in metastatic renal cell carcinoma (RCC). Experimental Design: In a randomized, open-label, multicenter, phase II/III study, 513 patients with RCC received Nap (15 mg/ kg i. v. in three cycles of four once-daily injections) + IFN (9 MU s. c. three times weekly), or the same regimen of IFN monotherapy. The primary endpoint was overall survival (OS). Results: This phase II/III study did notmeetits primary endpoint. Median OS/PFS for Nap + IFN patients was 17.1/5.8 months versus 17.5/5.8 months for the patients receiving IFN alone (P = 0.56; HR, 1.08/P = 0.41; HR, 0.92). Post hoc exploratory subgroup and trend analysis revealed that the baseline plasma concentrations of antiSEA/E-120 (anti-Nap antibodies) for drug exposure and IL6 for immune status could be used as predictive biomarkers. A subgroup of patients (SG; n = 130) having concentrations below median of anti-SEA/E-120 and IL6 benefitted greatly from the addition of Nap. In SG, median OS/PFS for the patients treated with Nap þ IFN was 63.3/13.7 months versus 31.1/5.8 months for the patients receiving IFN alone (P = 0.02; HR, 0.59/P = 0.02; HR, 0.62). Addition of Nap to IFN showed predicted and transient immune related AEs and the treatment had an acceptable safety profile. Conclusions: The study did not meet its primary endpoint. Nap + IFN has an acceptable safety profile, and results from post hoc subgroup analyses showed that the treatment might improve OS/PFS in a baseline biomarker-defined RCC patient subgroup. The results warrant further studies with Nap in this subgroup

Solubilization and Characterization of Phosphoprotein Phosphatase(s) from Bovine Corpus-Luteum Plasma Membranes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65607/1/j.1432-1033.1975.tb02186.x.pd

A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma

In a phase II study, 43 renal cell carcinoma patients were treated with individualised doses of ABR-214936; a fusion of a Fab recognising the antigen 5T4, and Staphylococcal enterotoxin A. Drug was given intravenously on 4 consecutive days, treatment was repeated 1 month later. Treatment was associated with moderate fever and nausea, but well tolerated. Of 40 evaluable patients, 28 had disease control at 2 months, and at 4 months, one patient showed partial response (PR) and 16 patients stable disease. Median survival, with minimum follow-up of 26 months was 19.7 months with 13 patients alive to date. Stratification by the Motzer's prognostic criteria highlights prolonged survival compared to published expectation. Patients receiving higher drug exposure had greater disease control and lived almost twice as long as expected, whereas the low-exposure patients survived as expected. Sustained interleukin-2 (IL-2) production after a repeated injection appears to be a biomarker for clinical effect, as the induced-IL-2 level on the day 2 of treatment correlated with survival. The high degree of disease control and the prolonged survival suggest that this treatment can be effective. These findings will be used in the trial design for the next generation of drug, with reduced antigenicity and toxicity

Ethics in Iran: Jacques Lacan and the Films of Abbas Kiarostami\u27s Koker Trilogy

In 1900, Sigmund Freud published The Interpretation of Dreams, establishing climacteric concepts for psychoanalysis and creating a structure upon which he built the theory and his career. 20 years later, he had entirely revised these concepts that solidified the foundation of psychoanalysis. In Beyond the Pleasure Principle (1920), Freud notably theorizes the ‘death drive’ for the first time, a radical but necessary break from the economics of the pleasure principle. Often, the death drive is taken to be the most important contribution of this essay, but I argue that the lasting message to be gleaned from Freud is what he concludes Beyond the Pleasure Principle with: “We must be ready, too, to abandon a path that we have followed for a time, if it seems to be leading to no good end. Only believers, who demand that science shall be a substitute for the catechism they have given up, will blame an investigator for developing or even transforming his views.” In this thesis, I argue that we can develop a necessary Ethic from this way that Freud approached the formation of his work. Drawing on the further developments from Jacques Lacan, I claim that one can take theory of the gaze as an ethical moment: the point at which one is faced with a disruption that they are tasked to carry out “to see where it will lead,” as Freud puts it. Further, I utilize this formation of the Ethic to read the films of Abbas Kiarostami’s “Koker trilogy” to highlight the points at which we can locate the characters, form, and content of these films as realizations of such ethical moments

Människors upplevelse av livskvalitet och relationer före och efter stomioperation : en litteraturstudie

Validerat; 20101217 (root

Analysis and mathematical modelling of industrial truck silencers

The currently low requirements on sound emissions for industrial trucks are expected to be raised in the near future. The company Kalmar Industries AB, which develop, produce and market industrial trucks, want to improve their truck silencers as a precaution to the future harder restrictions and also to improve their competitiveness. The sound emission produced by a vehicle depends on type and range of application it is designed for but the dominant part of the sound is usually produced by the engine and silencer. A new measuring method is developed for studying sound emanating through the silencer system. The analysis of the measurement data establishes that the silencers are not working well. The simulations made with SIDLAB, which is a computer programme for calculating the propagation of sound in ducts, confirms that the silencers are inefficient and that they are simply too small. A simulation which implements a parallel resonator in the main silencer shows that it is possible to make great improvements in reducing the noise from the truck as well as meeting requirements on space. Mathematical modelling based on linearity and one-dimensional interaction between the silencer elementsis advantageous and gives very good results when understanding, analysing and simulating the silencer. The simulation tool SIDLAB works well and saves a lot of time by its fast modelling and easy interface