Factors affecting the retention of methyl iodide by iodide-impregnated carbon

Iodide-impregnated activated carbon that had been in use for up to 30 months was studied to characterize those factors that affect its interaction with and retention of methyl iodide. Humidity and competing organic sorbents were observed to decrease the residence time of the methyl iodide on the carbon bed. Additionally, changes in the effective surface area and the loss of iodide from the surface are both important in determining the effectiveness of the carbon for retaining radioactive iodine from methyl iodide. A simple model incorporating both factors gave a fairly good fit to the experimental data

Adverse outcomes and correlates of change in the Short Physical Performance Battery over 36 months in the African American health project

BACKGROUND: The Short Physical Performance Battery (SPPB) is a well-established measure of lower body physical functioning in older persons but has not been adequately examined in African Americans or younger persons. Moreover, factors associated with changes in SPPB over time have not been reported. METHODS: A representative sample of 998 African Americans (49-65 years old at baseline) living in St. Louis, Missouri were followed for 36 months to examine the predictive validity of SPPB in this population and identify factors associated with changes in SPPB. SPPB was calibrated to this population, ranged from 0 (worst) to 12 (best), and required imputation for about 50% of scores. Adverse outcomes of baseline SPPB included death, nursing home placement, hospitalization, physician visits, incident basic and instrumental activity of daily living disabilities, and functional limitations. Changes in SPPB over 36 months were modeled. RESULTS: Adjusted for appropriate covariates, weighted appropriately, and using propensity scores to address potential selection bias, baseline SPPB scores were associated with all adverse outcomes except physician visits, and were marginally associated with hospitalization. Declines in SPPB scores were associated with low falls efficacy (b = -1.311), perceived income adequacy (-0.121), older age (-0.073 per year), poor vision (-0.754), diabetes mellitus (-0.565), refusal to report household income (1.48), ever had Medicaid insurance (-0.610), obesity (-0.437), hospitalization in the prior year (-0.521), and kidney disease (-.956). CONCLUSIONS: The effect of baseline SPPB on adverse outcomes in this late middle-age African American population confirms reports involving older, primarily white participants. Alleviating deterioration in lower body physical functioning guided by the associated covariates may avoid or delay multiple age-associated adverse outcomes

Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.National Institutes of Health (U.S.) (NIH grant R01 GM56203)National Institutes of Health (U.S.) (grant NIH 5P01CA120964)Dana-Farber/Harvard Cancer Center (NIH 5P30CA006516)National Institutes of Health (U.S.) (NIH grant R03MH085679)National Human Genome Research Institute (U.S.) (Intramural Research Program)National Institutes of Health (U.S.) (Molecular Libraries Initiative of the NIH Roadmap for Medical Research

Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer

BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.United States. Dept. of Defense (Grant W81-XWH-13-1-0323)National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051

Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. PKM2 interaction with phosphotyrosine-containing proteins inhibits enzyme activity and increases availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors. Structural studies reveal that small molecule activators bind PKM2 at the subunit interaction interface, a site distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small molecule activation of PKM2 can interfere with anabolic metabolism

Deletion of PKBα/Akt1 Affects Thymic Development

BACKGROUND: The thymus constitutes the primary lymphoid organ for the majority of T cells. The phosphatidyl-inositol 3 kinase (PI3K) signaling pathway is involved in lymphoid development. Defects in single components of this pathway prevent thymocytes from progressing beyond early T cell developmental stages. Protein kinase B (PKB) is the main effector of the PI3K pathway. METHODOLOGY/PRINCIPAL FINDINGS: To determine whether PKB mediates PI3K signaling in the thymus, we characterized PKB knockout thymi. Our results reveal a significant thymic hypocellularity in PKBalpha(-/-) neonates and an accumulation of early thymocyte subsets in PKBalpha(-/-) adult mice. Using thymic grafting and fetal liver cell transfer experiments, the latter finding was specifically attributed to the lack of PKBalpha within the lymphoid component of the thymus. Microarray analyses show that the absence of PKBalpha in early thymocyte subsets modifies the expression of genes known to be involved in pre-TCR signaling, in T cell activation, and in the transduction of interferon-mediated signals. CONCLUSIONS/SIGNIFICANCE: This report highlights the specific requirements of PKBalpha for thymic development and opens up new prospects as to the mechanism downstream of PKBalpha in early thymocytes

VIBRONIC ASSIGNMENTS IN THE 1Au−1Ag^{1}A_{u}-^{1}A_{g} ABSORPTION SPECTRUM OF GLYOXAL BY TIME-RESOLVED SVL FLUORESCENCE

$^{1}$ E. Photos and G. H. Atkinson, Chem. Phys. Let. 36, 34 (1975).""This work was supported by U.S. Amay Research Office, the Am. Chem. Soc., and the Research Corporation.""Author Institution: Department of ChemistryFluorescence spectra from single vibronic levels (SVL) In glyoxal vapor have been analysed in order to (1) experimentally establish the vibrational modes populated during absorption transitions and (2) provide information about excited-state structure through the analyses of Franck-Condon factors. Since such spectra are comprised of ground-state vibrational frequencies which are well established from infrared and Raman spectroscopy, these data can often provide unique identification of absorption transitions. Time-resolved SVL (TRSVL) techniques utilize box car integration and pulsed laser excitation to observe emission before a significant degree of collisional perturbation can redistribute excited-state energy to vibrational modes not initially-populated in $absorption^{1}$ TRSVL techniques have been used to reveal the activity of $\nu_{6}$ for the first time and to confirm more than twenty other vibronic transitions. A low resolution analysis of fluorescence band contours is included in this work. A Franck-Condon analysis of these fluorescence spectra has also been performed and provides new information about the geometry of the $^{1}A_{u}$ state