Novartis

About: Novartis is a company organization based out in Basel, Switzerland. It is known for research contribution in the topics: Alkyl & Population. The organization has 41930 authors who have published 50566 publications receiving 1978996 citations. The organization is also known as: Novartis International AG.

Vaccine manufacturing: challenges and solutions

Abstract: The recent influenza vaccine shortages have provided a timely reminder of the tenuous nature of the world's vaccine supply and the potential for manufacturing issues to severely disrupt vital access to important vaccines. The application of new technologies to the discovery, assessment, development and production of vaccines has the potential to prevent such occurrences and enable the introduction of new vaccines. Gene-based vaccines, virus-like particles, plant-derived vaccines and novel adjuvants and delivery systems represent promising approaches to creating safer, more potent vaccines. As a consequence, more people will have faster access to more effective vaccines against a broader spectrum of infectious diseases. However, the increased cost of producing new vaccines and regulatory uncertainty remain challenges for vaccine manufacturers.

Hormone replacement therapy and risk of venous thromboembolism: population based case-control study

Abstract: Objective: To evaluate the association between use of hormone replacement therapy and the risk of idiopathic venous thromboembolism. Design: Population based case-control study. Setting: Population enrolled in the General Practice Research Database, United Kingdom. Subjects: A cohort of 347 253 women aged 50 to 79 without major risk factors for venous thromboembolism was identified. Cases were 292 women admitted to hospital for a first episode of pulmonary embolism or deep venous thrombosis; 10 000 controls were randomly selected from the source cohort. Main outcome measures: Adjusted relative risks estimated from unconditional logistic regression. Results: The adjusted odds ratio of venous thromboembolism for current use of hormone replacement therapy compared with non-users was 2.1 (95% confidence interval 1.4 to 3.2). This increased risk was restricted to first year users, with odds ratios of 4.6 (2.5 to 8.4) during the first six months and 3.0 (1.4 to 6.5) 6-12 months after starting treatment. No major risk differences were observed between users of low and high doses of oestrogens, unopposed and opposed treatment, and oral and transdermal preparations. The risk of idiopathic venous thromboembolism among non-users of replacement therapy was estimated to be 1.3 per 10 000 women per year. Among current users, idiopathic venous thromboembolism occurs at two to three times the rate in non-users, resulting in one to two additional cases per 10 000 women per year. Conclusions: Current use of hormone replacement therapy was associated with a higher risk of venous thromboembolism, although the risk seemed to be restricted to the first year of use.

Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway.

Abstract: Sirt1, an NAD-dependent protein deacetylase has emerged as important regulator of mammalian transcription in response to cellular metabolic status and stress 1 . Here we demonstrate that Sirt1 plays a neuroprotective role in models of Huntington’s disease (HD), an inherited neurodegenerative disorder caused by a glutamine repeat expansion in huntingtin protein 2 . Brainspecific knockout of Sirt1 results in exacerbation of brain pathology in HD mice, whereas overexpression of Sirt1 improves survival, neuropathology and BDNF expression in HD mice. We show that Sirt1 deacetylase activity directly targets neurons to mediate neuroprotection from mutant huntingtin. The neuroprotective effect of Sirt1 requires the presence of TORC1, a brainspecific modulator of CREB activity 3 . We show that under normal conditions Sirt1 deacetylates and activates TORC1 by promoting its dephoshorylation and interaction with CREB. We identified BDNF as an important target of Sirt1 and TORC1 transcriptional activity in normal and HD neurons. Mutant huntingtin interferes with the TORC1-CREB interaction to repress BDNF transcription and Sirt1 rescues this defect in vitro and in vivo. These studies suggest a key role of Sirt1 in transcriptional networks in normal and HD brain and offer an opportunity for therapeutic development.

Combining multiple comparisons and modeling techniques in dose-response studies.

Abstract: The analysis of data from dose-response studies has long been divided according to two major strategies: multiple comparison procedures and model-based approaches. Model-based approaches assume a functional relationship between the response and the dose, taken as a quantitative factor, according to a prespecified parametric model. The fitted model is then used to estimate an adequate dose to achieve a desired response but the validity of its conclusions will highly depend on the correct choice of the a priori unknown dose-response model. Multiple comparison procedures regard the dose as a qualitative factor and make very few, if any, assumptions about the underlying dose-response model. The primary goal is often to identify the minimum effective dose that is statistically significant and produces a relevant biological effect. One approach is to evaluate the significance of contrasts between different dose levels, while preserving the family-wise error rate. Such procedures are relatively robust but inference is confined to the selection of the target dose among the dose levels under investigation. We describe a unified strategy to the analysis of data from dose-response studies which combines multiple comparison and modeling techniques. We assume the existence of several candidate parametric models and use multiple comparison techniques to choose the one most likely to represent the true underlying dose-response curve, while preserving the family-wise error rate. The selected model is then used to provide inference on adequate doses.

Drug-induced liver injury: recent advances in diagnosis and risk assessment

Abstract: Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI. New emerging biomarkers which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122. From the numerous in vitro test systems that are available, monocyte-derived hepatocytes generated from patients with DILI show promise in identifying the DILI-causing agent from among a panel of coprescribed drugs. Several computer-based algorithms are available that rely on cumulative scores of known risk factors such as the administered dose or potential liabilities such as mitochondrial toxicity, inhibition of the bile salt export pump or the formation of reactive metabolites. A novel DILI cluster score is being developed which predicts DILI from multiple complimentary cluster and classification models using absorption-distribution-metabolism-elimination-related as well as physicochemical properties, diverse substructural descriptors and known structural liabilities. The provision of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public-private partnerships.