No abstract

Core regulatory transcription factors (CR TFs) orchestrate the placement of super-enhancers (SEs) to activate transcription of cell-identity specifying gene networks, and are critical in promoting cancer. Here, we define the core regulatory circuitry of rhabdomyosarcoma (RMS) and identify critical CR TF dependencies. These CR TFs build SEs that have the largest levels of histone acetylation, yet paradoxically SEs also harbor the highest amounts of histone deacetylases Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

The purpose of this study was to determine whether a dietary supplement consisting of Lselenomethionine, vitamin C, vitamin E succinate, α-lipoic acid and N-acetyl cysteine could improve the survival of mice after total-body irradiation. Antioxidants significantly increased the 30-day survival of mice after exposure to a potentially lethal dose of X rays when given prior to or after animal irradiation. Pretreatment of animals with antioxidants resulted in significantly higher total white blood cell and neutrophil counts in peripheral blood at 4 and 24 h after 1 Gy and 8 Gy. Antioxidants were effective in preventing peripheral lymphopenia only after low-dose irradiation. Antioxidant supplementation was also associated with increased bone marrow cell counts after irradiation. Supplementation with antioxidants was associated with increased Bcl2 and decreased Bax, caspase 9 and TGF-β1 mRNA expression in the bone marrow after irradiation. Maintenance of the antioxidant diet was associated with improved recovery of the bone marrow after sublethal or potentially lethal irradiation. Taken together, oral supplementation with antioxidants appears to be an effective approach for radioprotection of hematopoietic cells and improvement of animal survival, and modulation of apoptosis is implicated as a mechanism for the radioprotection of the hematopoietic system by antioxidants.

Dietary antioxidants have radioprotective effects after γ-radiation exposure that limit hematopoietic cell depletion and improve animal survival. The purpose of this study was to determine whether a dietary supplement consisting of L-selenomethionine, vitamin C, vitamin E succinate, α-lipoic acid and N-acetyl cysteine could improve survival of mice after proton totalbody irradiation (TBI). Antioxidants significantly increased 30-day survival of mice only when given after irradiation at a dose less than the calculated LD 50/30 ; for these data, the dose-modifying factor (DMF) was 1.6. Pretreatment of animals with antioxidants resulted in significantly higher serum total white blood cell, polymorphonuclear cell and lymphocyte cell counts at 4 h after 1 Gy but not 7.2 Gy proton TBI. Antioxidants significantly modulated plasma levels of the hematopoietic cytokines Flt-3L and TGFβ1 and increased bone marrow cell counts and spleen mass after TBI. Maintenance of the antioxidant diet resulted in improved recovery of peripheral leukocytes and platelets after sublethal and potentially lethal TBI. Taken together, oral supplementation with antioxidants appears to be an effective approach for radioprotection of hematopoietic cells and improvement of animal survival after proton TBI.

Background/Objectives: Methionine synthase catalyzes the conversion of 5-methyltetrahydrofolate to tetrahydrofolate and homocysteine (Hcy) to methionine using vitamin B 12 as a cofactor. Transcobalamin is the main transporter of vitamin B 12 from blood into cells. This study was undertaken to assess the relationship between the transcobalamin P259R (TCN2 776C4G) polymorphism and both serum vitamin B 12 and total Hcy (tHcy) levels. Subjects/Methods: The population comprised 613 men from Northern Ireland, aged 30-49 years, for whom tHcy, serum vitamin B 12 and serum folate concentrations were available. TCN2 776C4G genotypes were determined using a TaqMan 5 0 nuclease Real-Time PCR assay. Standard statistical tests of association were applied to assess the relationships between the polymorphism and phenotypic variables. Results: The TCN2 776CC homozygous genotype was associated with lower serum vitamin B 12 concentrations compared with the 776CG (P unadjusted ¼ 0.01; P adjusted ¼ 0.03) and 776GG genotypes (P unadjusted ¼ 0.015; P adjusted ¼ 0.045). Among individuals with vitamin B 12 concentrations in the lower half of the distribution, tHcy concentrations were higher in TCN2 776GG homozygotes than in individuals with the other genotypes (P unadjusted ¼ 0.015; P adjusted ¼ 0.06). Conclusions: These data suggest that, relative to transcobalamin with arginine at position 259 (776G), transcobalamin with proline at this position (776C) is either more efficient at vitamin B 12 transport from blood to tissues or has higher affinity for vitamin B 12 . Furthermore, vitamin B 12 status influences the relationship between TCN2 776C4G genotype and tHcy concentrations. Thus, the TCN2 776C4G polymorphism may contribute to the risk of pathologies associated with a low B 12 , and high tHcy phenotype.