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The SCLC combination screen examined a 9-point concentration response of 180 third agents, alone and in combination with etoposide/carboplatin. The predominant effect of adding a third agent to etoposide/carboplatin was additivity. Less than additive effects occurred frequently in SCLC lines sensitive to etoposide/carboplatin. In SCLC lines with little or no response to etoposide/carboplatin, greater than additive SCLC killing occurred over the entire spectrum of SCLC lines but never occurred in all SCLC lines. Exposing SCLC lines to tubulin-targeted agents (paclitaxel or vinorelbine) simultaneously with etoposide/ carboplatin resulted primarily in less than additive cell killing. As single agents, nuclear kinase inhibitors including Aurora kinase inhibitors, Kinesin Spindle Protein/EG5 inhibitors, and Polo-like kinase-1 inhibitors were potent cytotoxic agents in SCLC lines; however, simultaneous exposure of the SCLC lines to these agents along with etoposide/carboplatin, generally, resulted in less than additive cell killing. Several classes of agents enhanced the cytotoxicity of etoposide/carboplatin toward the SCLC lines. Exposure of the SCLC lines to the MDM2 inhibitor JNJ-27291199 produced enhanced killing in 80% of the SCLC lines. Chk-1 inhibitors such as rabusertib increased the cytotoxicity of etoposide/carboplatin to the SCLC lines in an additive to greater than additive manner. The combination of GSK-3β inhibitor LY-2090314 with etoposide/carboplatin increased killing in approximately 40% of the SCLC lines. Exposure to the BET bromodomain inhibitor MK-8628 increased the SCLC cell killing by etoposide/ carboplatin in 20-25% of the SCLC lines. Only 10-15% of the SCLC lines had an increased response to etoposide/carboplatin when simultaneously exposed to the PARP inhibitor talazoparib. [ABSTRACT FROM AUTHOR]

Cardiovascular reactivity to stress and α-adrenergic receptor ( α-AR) function may contribute to the development of hypertension. As Black Americans have an increased risk of hypertension, we evaluated associations between α1A-AR ( Arg492Cys), α2A-AR ( -1291C/G), and α2B-AR ( Ins/Del301-303) gene variants and cardiovascular reactivity in 500 normotensive Black youth. Heart rate, preejection period, total peripheral resistance, and blood pressure were measured during cold and psychological stress. The Arg492Cys polymorphism in the α1A-AR gene was associated with heart rate reactivity to stress, but the association depended on sex. The -1291C/G promoter polymorphism in the α2A-AR gene was associated with vascular reactivity to stress; vasoconstriction increased as a linear function of the number of copies of the variant G allele. Thus, specific associations emerged between genetic variations in α-Ars and cardiovascular reactivity in young Blacks. [ABSTRACT FROM AUTHOR]

BACKGROUND DNA methylation patterns differ among children and adults and play an unambiguous role in several disease processes, particularly cancers. The origin of these differences is inadequately understood, and this is a question of specific relevance to childhood and adult cancer. METHODS DNA methylation levels at 26,485 autosomal CpGs were assayed in 201 newborns (107 African American and 94 Caucasian). Nonparametric analyses were performed to examine the relation between these methylation levels and maternal parity, maternal age, newborn gestational age, newborn gender, and newborn race. To identify the possible influences of confounding, stratification was performed by a second and third variable. For genes containing CpGs with significant differences in DNA methylation levels between races, analyses were performed to identify highly represented gene ontological terms and functional pathways. RESULTS 13.7% (3623) of the autosomal CpGs exhibited significantly different levels of DNA methylation between African Americans and Caucasians; 2% of autosomal CpGs had significantly different DNA methylation levels between male and female newborns. Cancer pathways, including four (pancreatic, prostate, bladder, and melanoma) with substantial differences in incidence between the races, were highly represented among the genes containing significant race-divergent CpGs. CONCLUSIONS At birth, there are significantly different DNA methylation levels between African Americans and Caucasians at a subset of CpG dinucleotides. It is possible that some of the epigenetic precursors to cancer exist at birth and that these differences partially explain the different incidence rates of specific cancers between the races. Birth Defects Research (Part A), 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Cardiovascular reactivity to stress and β-adrenergic receptor (β-AR) function may contribute to the development of hypertension. As Black Americans have an increased risk of hypertension, we evaluated associations between β1-AR (Arg389Gly) and β2-AR (Arg16Gly, Gln27Glu) gene variants and cardiovascular reactivity in 500 Black youth. Heart rate, preejection period, total peripheral resistance, and blood pressure reactivity were measured during cold and psychological stress. The Arg389Gly polymorphism in the β1-AR was associated with preejection period reactivity in males but not in females. The Arg16Gly polymorphism in the β2-AR was associated with diastolic blood pressure reactivity only during video game stress. An association between the Gln27Glu polymorphism in the β2-AR and vascular reactivity depended on sex. Thus, specific patterns of associations emerged between genetic variations in β-ARs and cardiovascular reactivity in young Blacks. [ABSTRACT FROM AUTHOR]