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Gas industry --- Rossiĭskoe akt͡sionernoe obshchestvo "Gazprom".

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Nobility --- Registers --- Archiwum Główne Akt Dawnych w Warszawie (Poland)

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The phosphatidylinositol 3-kinase (PI3K)/mTOR pathway integrates signals from growth factors with nutrient signals and other conditions and controls multiple cell responses, including proliferation, survival and metabolism. Deregulation of the PI3K pathway has been extensively investigated in connection to cancer. Somatic or inherited mutations frequently occur in tumor suppressor genes (PTEN, TSC1/2, LKB1) and oncogenes (PIK3CA, PIK3R1, AKT) in the PI3K/mTOR pathway. The fact that the PI3K/mTOR pathway is deregulated in a large number of human malignancies, and its importance for different cellular responses, makes it an attractive drug target. Pharmacological PI3K inhibitors have played a very important role in studying cellular responses involving these enzymes. Currently, a wide range of selective PI3K inhibitors have been tested in preclinical studies and some have entered clinical trials in oncology. Rapamycin and its analogs targeting mTOR are effective in many preclinical cancer models. Although rapalogs are approved for the treatment of some cancers, their efficacy in clinical trials remains the subject of debate. Due to the complexity of the PI3K/mTOR signaling pathway, developing an effective anti-cancer therapy remains a challenge. The biggest challenge in curing cancer patients with various signaling pathway abnormalities is to target multiple components of different signal transduction pathways with mechanism-based combinatorial treatments.

Cancer. --- Phosphoinositides. --- Phosphoinositide 3-kinase --- mTOR --- clinical trials --- Akt --- Cancer

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Les malformations veineuses (VM) sont des défauts localisés qui surviennent lors du développement vasculaire embryonnaire. La majorité des VM sont sporadiques. Dans 50% des cas, elles sont dues à des mutations somatiques dans le gène TEK codant pour le récepteur tyrosine kinase TIE2. TIE2 est exprimé dans les cellules endothéliales vasculaires et joue un rôle important lors de l'angiogenèse. La mutation la plus fréquemment rencontrée chez les patients souffrant de VM sporadique est une substitution d'une leucine en phénylalanine en position 914 (L914F). On retrouve aussi des mutations non-sens qui tronquent la queue C­ terminale de TIE2. Rl 099X, étant le plus proximal de ces changements, est la mutation non­ sens la plus fréquente.Toutes les mutations qui causent des VM induisent une phosphorylation du récepteur TIE2 indépendante du ligand. Dans L914F, cela cause une activation des AKT et STATI jouant un rôle dans la pathogenèse des VM. Nous avons voulu évaluer si R1099X utilise les mêmes voies moléculaires que L914F malgré l'absence de trois tyrosines phosphorylables impliquées précédemment dans leur activation.Nous avons constaté que R1099X, comme L914F, affectent l'activation de AKT et de STATI lorsqu'ils sont surexprimés in vitro. Nous voulions donc déterminer si la queue C-terminal de TIE2 et ses tyrosines, connues pour être importantes dans la signalisation par le récepteur sauvage, participe aussi dans la signalisation de L914F. Nous constatons que l'absence de la queue C-terminale affecte TIE2-WT et L914F différemment , ce qui suggère qu'il y a des différences dans leurs structures. En plus, nous avons trouvé que la régulation de STATl et de AKT par TIE2 est complexe, avec, un équilibre entre l'activation et l'inhibition de ces molécules par le récepteur. Venous malformations (VMs) are localized defects that arise during the development of the vascular system. The vast majority of VMs are sporadic. 50% of sporadic VMs are caused by somatic mutations in the gene TEK, which codes for the endothelial cell tyrosine kinase receptor TIE2. The most common mutation identified in patients is a leucine-to-phenylalanine substitution at position 914 (L914F). Nonsense mutations that cause premature truncation on the inhibitory C-terminal tail domain of TIE2 have also been identified. RI 099X is the most common, as well as the most proximal, of these truncating mutations.All VM-causative mutations induce ligand-independent phosphorylation of TIE2, of varying strengths. In the case of L914F, this causes chronic AKT and STATl activation, linked to disease pathogenesis. We wished to assess whether RI 099X works through the same molecular pathways as L914F despite lacking three phosphorylable tyrosines, previously implicated in their activation.We find that R1099X, like L914F, does indeed affect AKT and STATl activation when overexpressed in vitro. We investigated whether the C-terminal tail and its tyrosines, shown to be important in signaling by wild-type TIE2 upon Angptl ligand-binding , also participates in L914F-signaling. We find that lack of the C-terminal tail affects the wild-type and L914F forms of TIE2 differently, suggesting important differences in their structure. In addition, we find evidence for complex regulation of STATl and AKT by TIE2, with a balance between activation and inhibition of these molecules depending on different C-terminal tail tyrosines.

Arteriovenous Malformations --- Receptor, TIE-2 --- Proto-Oncogene Proteins c-akt --- STAT1 Transcription Factor

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Jews --- History --- Archival resources --- Archiwum Główne Akt Dawnych w Warszawie (Poland)