Project description:The purpose of the study is to assess a new treatment for patients with liver tumor metastases from colorectal cancer. The treatment has never been used in humans before. The treatment foresees the use of two compounds: AvdinOX and [177Lu]DOTA-biotin.
AvidinOX is a new compound, essentially a natural protein obtained from hen eggs, while [177Lu]DOTA-biotin is a new chemical compound resulting from the combination of the DOTA-biotin (also deriving from a natural vitamin which is biotin) with the 177Lutetium, an atom which emits radiation.
AvidinOX will be injected directly into the metastases in the liver and [177Lu]DOTA-biotin will be injected into the arm vein.
One specific property of AvidinOX is that it chemically links to the tumor tissues when it is injected while maintaining the capacity to take up [177Lu]DOTA-biotin. Once locally bound in tumor tissue, AvidinOX becomes an "artificial receptor" for intravenously injected [177Lu]DOTA-biotin, which allows an internal radiation therapy of the tumor tissue.
The treatment of liver metastases with local injection of AvidinOX and the following intra-venous injection of [177Lu]DOTA-biotin could be simpler and more tolerable than the current available treatments.
Project description:In addition to its essential metabolic functions biotin is suggested a critical role in regulating gene expression. The first committed enzyme in biotin biosynthesis in Arabidopsis, 7-keto-8-aminopelargonic acid synthase is encoded by At5g04620 (BIO4). We isolated a novel T-DNA insertion mutant of BIO4 (bio4-1) showing a spontaneous cell death phenotype that could be rescued both by exogenous biotin and genetic complementation. The bio4-1 plants exhibited massive accumulation of hydrogen peroxide. The T-DNA insertion in the bio4-1 mutant contains a Methionine Sulfoxide Reductase B9 (AT4G21850) under a constitutive 35S CaMV promoter. To dissect the specific effects of biotin defiency on gene expression on a genome wide scale, we compared expression of wt Col-0 leaves with bio4-1 mutants and bio4-1 mutants complemented with D-biotin.
Project description:Biotin is cofactor of crucial enzymes for intermediary metabolism, and its deficiency affects the transcription of some critical genes of mammalian glucose metabolism. However, the precise mechanisms of biotin starvation on gene expression are unknown. Here we show that metabolic changes ushered by deficiency of this vitamin sets in motion extensive reorganization of carbon metabolism gene expression, consistent across three diverse eukaryotes, that is mediated through a regulatory circuitry at the genome level similar in the three species. We used affymetrix microarrays to detail the global gene expression underlying the effects of biotin deficiency in Rattus norvegicus liver, Caenorhabditis elegans and Saccharomyces cerevisiae and identified distinct classes of up-regulated genes during this event.
Project description:We have identified a methanol- and biotin-starvation-inducible zinc finger protein named ROP [repressor of phosphoenolpyruvate carboxykinase (PEPCK)] in the methylotrophic yeast Pichia pastoris. When P.pastoris strain GS115 (wild-type, WT) is cultured in biotin-deficient, glucose ammonium (Bio-) medium, growth is suppressed due to the inhibition of anaplerotic synthesis of oxaloacetate, catalysed by the biotin-dependent enzyme pyruvate carboxylase (PC). Deletion of ROP results in a strain (∆ROP) that can grow under biotin-deficient conditions due to derepression of a biotin- and PC-independent pathway of anaplerotic synthesis of oxaloacetate. Northern analysis as well as microarray expression profiling of RNA isolated from WT and ∆ROP strains cultured in Bio(-) medium indicate that expression of the phosphoenolpyruvate carboxykinase gene (PEPCK) is induced in ∆ROP during biotin- or PC-deficiency even under glucose-abundant conditions. There is an excellent correlation between PEPCK expression and growth of ∆ROP in Bio(-) medium, suggesting that ROP-mediated regulation of PEPCK may have a crucial role in the biotin- and PC-independent growth of the ∆ROP strain. To our knowledge, ROP is the first example, of a zinc finger transcription factor involved in the catabolite repression of PEPCK in yeast cells cultured under biotin- or PC-deficient and glucose-abundant conditions.
Project description:In addition to its essential metabolic functions biotin is suggested a critical role in regulating gene expression. The first committed enzyme in biotin biosynthesis in Arabidopsis, 7-keto-8-aminopelargonic acid synthase is encoded by At5g04620 (BIO4). We isolated a novel T-DNA insertion mutant of BIO4 (bio4-1) showing a spontaneous cell death phenotype that could be rescued both by exogenous biotin and genetic complementation. The bio4-1 plants exhibited massive accumulation of hydrogen peroxide. The T-DNA insertion in the bio4-1 mutant contains a Methionine Sulfoxide Reductase B9 (AT4G21850) under a constitutive 35S CaMV promoter. To dissect the specific effects of biotin defiency on gene expression on a genome wide scale, we compared expression of wt Col-0 leaves with bio4-1 mutants and bio4-1 mutants complemented with D-biotin. Expression in leaves of Col-0 wt, bio4-1 mutants with a T-DNA insertion in the 5`-UTR of BIO4, and bio4-1 mutants complemented with watering with 200µM D-biotin.
Project description:Confluent U2OS cells were released to serum-free medium, and continued to grow for 36 h (Per2-dLuc peak), then added biotin-DRB (40uM) treatment for 0.5, then fixed the cells, harvested genomic DNA by Strepavidin agarose beads, and conducted hi-seq sequencing
Project description:This study aimed to establish molecular endotypes in osteoarthritis soft joint tissue driven by obesity in both load-bearing and non-load bearing joints. Transcriptomic analysis found the inflammatory landscape of OA synovial fibroblasts (SF) are independently impacted by obesity, joint loading, and anatomical site with significant heterogeneity between obese and normal weight patients. These findings demonstrate the significance of obesity in changing the inflammatory landscape of synovial fibroblasts in both load bearing and non-load bearing joints. The molecular endotypes identified may provide a route for the stratification of patients in clinical trials, providing a rational for the therapeutic targeting of specific SF subsets in specific patient populations with arthritic conditions.