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.

Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC‐1α

Abstract: In mammals, maintenance of energy and nutrient homeostasis during food deprivation is accomplished through an increase in mitochondrial fatty acid oxidation in peripheral tissues. An important component that drives this cellular oxidative process is the transcriptional coactivator PGC‐1α. Here, we show that fasting induced PGC‐1α deacetylation in skeletal muscle and that SIRT1 deacetylation of PGC‐1α is required for activation of mitochondrial fatty acid oxidation genes. Moreover, expression of the acetyltransferase, GCN5, or the SIRT1 inhibitor, nicotinamide, induces PGC‐1α acetylation and decreases expression of PGC‐1α target genes in myotubes. Consistent with a switch from glucose to fatty acid oxidation that occurs in nutrient deprivation states, SIRT1 is required for induction and maintenance of fatty acid oxidation in response to low glucose concentrations. Thus, we have identified SIRT1 as a functional regulator of PGC‐1α that induces a metabolic gene transcription program of mitochondrial fatty acid oxidation. These results have implications for understanding selective nutrient adaptation and how it might impact lifespan or metabolic diseases such as obesity and diabetes.

Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden.

Abstract: BACKGROUND Recent breakthroughs regarding gastrointestinal stromal tumors (GIST) and their pathogenesis have redefined diagnostic criteria and have led to the development of molecularly targeted drug therapy. New treatment options mandate more accurate information regarding the incidence, prevalence, clinical behavior, and prognostic factors of GIST. METHODS All patients (n = 1460) who potentially had GIST diagnosed from 1983 to 2000 in western Sweden (population, 1.3–1.6 million) were reviewed, and 288 patients with primary GIST were identified. The incidence and prevalence of GIST were determined, and predictive prognostic factors, including current risk-group stratifications, were analyzed statistically. RESULTS Ninety percent of GISTs were detected clinically due to symptoms (69%) or were incidental findings at surgery (21%); the remaining 10% of GISTs were found at autopsy. Forty-four percent of symptomatic, clinically detected GISTs were categorized as high risk (29%) or overtly malignant (15%), with tumor-related deaths occurring in 63% of patients and 83% of patients, respectively (estimated median survival, of 40 months and 16 months, respectively). Tumor-related deaths occurred in only 2 of 170 of patients (1.2%) with very-low-risk, low-risk, or intermediate-risk tumors. The annual incidence of GIST was 14.5 per million. The prevalence of all GIST risk groups was 129 per million (31 per million for the high-risk group and the overtly malignant group). CONCLUSIONS GIST has been under recognized: Its incidence, prevalence, and clinical aggressiveness also have been underestimated. Currently existing risk-group stratification systems based on tumor size and mitotic rate delineate GIST patients who have a poor prognosis. Prognostication in patients with GIST can be refined using a proposed risk score based solely on tumor size and proliferative index. Cancer 2005. © 2005 American Cancer Society.

HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS

Abstract: A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.

Inhibition of the Abl Protein-Tyrosine Kinase in Vitro and in Vivo by a 2-Phenylaminopyrimidine Derivative

Abstract: Oncogenic activation of Abl proteins due to structural modifications can occur as a result of viral transduction or chromosomal translocation The tyrosine protein kinase activity of oncogenic Abl proteins is known to be essential for their transforming activity Therefore, we have attempted to identify selective inhibitors of the Abl tyrosine protein kinase Herein we describe an inhibitor (CGP 57148) of the Abl and platelet-derived growth factor (PDGF) receptor protein-tyrosine kinases from the 2-phenylaminopyrimidine class, which is highly active in vitro and in vivo Submicromolar concentrations of the compound inhibited both v-Abl and PDGF receptor autophosphorylation and PDGF-induced c-fos mRNA expression selectively in intact cells In contrast, ligand-induced growth factor receptor autophosphorylation in response to epidermal growth factor (EGF), insulin-like growth factor-I, and insulin showed no or weak inhibition by high concentrations of CGP 57148 c-fos mRNA expression induced by EGF, fibroblast growth factor, or phorbol ester was also insensitive to inhibition by CGP 57148 In antiproliferative assays, the compound was more than 30-100-fold more potent in inhibiting growth of v-abl-transformed PB-3c cells and v-sis-transformed BALB/c 3T3 cells relative to inhibition of EGF-dependent BALB/MK cells, interleukin-3-dependent FDC-P1 cells, and the T24 bladder carcinoma line Furthermore, anchorage-independent growth of v-abl- and v-sis-transformed BALB/c 3T3 cells was inhibited potently by CGP 57148 When tested in vivo, CGP 57148 showed antitumor activity at tolerated doses against tumorigenic v-abl- and v-sis-transformed BALB/c 3T3 cells In contrast, CGP 57148 had no antitumor activity when tested using src-transformed BALB/c 3T3 cells These findings suggest that CGP 57148 may have therapeutic potential for the treatment of diseases that involve abnormal cellular proliferation induced by Abl protein-tyrosine kinase deregulation or PDGF receptor activation