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.

The present study evaluated the acute effects of radiation dose, dose rate and fractionation as well as the energy of protons in hematopoietic cells of irradiated mice. The mice were irradiated with a single dose of 51.24 MeV protons at a dose of 2 Gy and a dose rate of 0.05–0.07 Gy/min or 1 GeV protons at doses of 0.1, 0.2, 0.5, 1, 1.5 and 2 Gy delivered in a single dose at dose rates of 0.05 or 0.5 Gy/min or in five daily dose fractions at a dose rate of 0.05 Gy/min. Sham-irradiated animals were used as controls. The results demonstrate a dose-dependent loss of white blood cells (WBCs) and lymphocytes by up to 61% and 72%, respectively, in mice irradiated with protons at doses up to 2 Gy. The results also demonstrate that the dose rate, fractionation pattern and energy of the proton radiation did not have significant effects on WBC and lymphocyte counts in the irradiated animals. These results suggest that the acute effects of proton radiation on WBC and lymphocyte counts are determined mainly by the radiation dose, with very little contribution from the dose rate (over the range of dose rates evaluated), fractionation and energy of the protons.

The Integrated Stress Response (ISR) is a signaling program that enables cellular adaptation to stressful conditions like hypoxia and nutrient deprivation in the tumor microenvironment. An important effector of the ISR is activating transcription factor 4 (ATF4), a transcription factor that regulates genes involved in redox homeostasis and amino acid metabolism and transport. Because both inhibition and overactivation of the ISR can induce tumor cell death, modulators of ATF4 expression could prove to be clinically useful. In this study, chemical libraries were screened for modulators of ATF4 expression. We identified one compound, E235, that activated the ISR and dosedependently increased levels of ATF4 in transformed cells. A dose-dependent decrease in viability was observed in several mouse and human tumor cell lines, and knockdown of ATF4 significantly increased the antiproliferative effects of E235. Interestingly, low mM doses of E235 induced senescence in many cell types, including HT1080 human fibrosarcoma and B16F10 mouse melanoma cells. E235-mediated induction of senescence was not dependent on p21 or p53; however, p21 conferred protection against the growth inhibitory effects of E235. Treatment with E235 resulted in an increase in cells arrested at the G2/M phase with a concurrent decrease in S-phase cells. E235 also activated DNA damage response signaling, resulting in increased levels of Ser15-phosphorylated p53, g-H2AX, and phosphorylated checkpoint kinase 2 (Chk2), although E235 does not appear to cause physical DNA damage. Induction of g-H2AX was abrogated in ATF4 knockdown cells. Together, these results suggest that modulation of the ISR pathway with the small molecule E235 could be a promising antitumor strategy.

Spontaneous canine osteosarcoma is increasingly recognized as an informative model for human osteosarcoma research. However, additional knowledge is needed to appreciate how well canine osteosarcoma recapitulates the disease in humans, given the significant heterogeneity and genomic complexity of this tumor. Here we show in one of the largest clinically annotated canine osteosarcoma datasets that two previously reported gene signatures cluster the data into two groups that are prognostic for both disease-free interval and overall survival. Furthermore, these signatures are similarly predictive of progression-free and overall survival when applied to a comparable human dataset, NCI-TARGET. Further analysis of both the human and canine clusters reveals similar patterns of activities among immune related pathways and populations of immune cells such as T-cells and macrophages. Collectively these findings further validate the naturally occurring osteosarcoma of the pet dog as a translationally relevant patient model for humans and improve our understanding of the immunologic and genomic landscape of the disease in both species.