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IntroductionThe shape of the glucose curve during an oral glucose tolerance test (OGTT) reflects β-cell function in populations without diabetes but has not been as well studied in those with diabetes. A monophasic shape has been associated with higher risk of diabetes, while a biphasic pattern has been associated with lower risk. We sought to determine if phenotypic or metabolic characteristics were associated with glucose response curve shape in adults with type 2 diabetes treated with metformin alone.Research design and methodsThis is a cross-sectional analysis of 3108 metformin-treated adults with type 2 diabetes diagnosed ResultsThe monophasic profile was the most common (67.8% monophasic, 5.5% biphasic, 26.7% continuous rise). The monophasic subgroup was younger, more likely male and white, and had higher body mass index (BMI), while the continuous rise subgroup was more likely female and African American/black. HOMA2-S and fasting glucose did not differ among the subgroups. The biphasic subgroup had the highest early, late, and total insulin and C peptide responses (all pConclusionsBased on the large multiethnic GRADE cohort, sex, race, age, and BMI were found to be important determinants of the shape of the glucose response curve. A pattern of a continuously rising glucose at 2 hours reflected reduced β-cell function and may portend increased glycemic failure rates.Trial registration numberNCT01794143.

We have previously published that 2 proven treatments for acute promyelocytic leukemia, As2O3 and retinoic acid, can be antagonistic in vitro. We now report that As2O3 inhibits ligand-induced transcription of the retinoic acid receptor, as well as other nuclear receptors that heterodimerize with the retinoid X receptor alpha (RXRalpha). As2O3 did not inhibit transactivation of the estrogen receptor or the glucocorticoid receptor, which do not heterodimerize with RXRalpha. We further show that As2O3 inhibits expression of several target genes of RXRalpha partners. Phosphorylation of RXRalpha has been reported to inhibit nuclear receptor signaling, and we show by in vivo labeling and phosphoamino acid detection that As2O3 phosphorylated RXRalpha in the N-terminal ABC region exclusively on serine residues. Consistent with our previous data implying a role for JNK in As2O3-induced apoptosis, we show that pharmacologic or genetic inhibition of JNK activation decreased As2O3-induced RXRalpha phosphorylation and blocked the effects of As2O3 on RXRalpha-mediated transcription. A mutational analysis indicated that phosphorylation of a specific serine residue, S32, was primarily responsible for inhibition of RXRalpha-mediated transcription. These data may provide some insight into the rational development of chemotherapeutic combinations involving As2O3 as well as into molecular mechanisms of arsenic-induced carcinogenesis resulting from environmental exposure.

Background Control of blood pressure ( BP ) remains a major challenge in primary care. Innovative interventions to improve BP control are therefore needed. By updating and combining data from 2 previous systematic reviews, we assess the effect of pharmacist interventions on BP and identify potential determinants of heterogeneity. Methods and Results Randomized controlled trials ( RCT s) assessing the effect of pharmacist interventions on BP among outpatients with or without diabetes were identified from MEDLINE , EMBASE , CINAHL , and CENTRAL databases. Weighted mean differences in BP were estimated using random effect models. Prediction intervals ( PI ) were computed to better express uncertainties in the effect estimates. Thirty‐nine RCT s were included with 14 224 patients. Pharmacist interventions mainly included patient education, feedback to physician, and medication management. Compared with usual care, pharmacist interventions showed greater reduction in systolic BP (−7.6 mm Hg, 95% CI : −9.0 to −6.3; I 2 = 67%) and diastolic BP (−3.9 mm Hg, 95% CI : −5.1 to −2.8; I 2 = 83%). The 95% PI ranged from −13.9 to −1.4 mm Hg for systolic BP and from −9.9 to +2.0 mm Hg for diastolic BP . The effect tended to be larger if the intervention was led by the pharmacist and was done at least monthly. Conclusions Pharmacist interventions – alone or in collaboration with other healthcare professionals – improved BP management. Nevertheless, pharmacist interventions had differential effects on BP , from very large to modest or no effect; and determinants of heterogeneity could not be identified. Determining the most efficient, cost‐effective, and least time‐consuming intervention should be addressed with further research.

The adenovirus E1B 55-kDa protein binds to cellular tumor suppressor p53 and inactivates its transcriptional transactivation function. p53 transactivation activity is dependent upon its ability to bind to specific DNA sequences near the promoters of its target genes. It was shown recently that p53 is acetylated by transcriptional coactivators p300, CREB bidning protein (CBP), and PCAF and that acetylation of p53 by these proteins enhances p53 sequence-specific DNA binding. Here we show that the E1B 55-kDa protein specifically inhibits p53 acetylation by PCAF in vivo and in vitro, while acetylation of histones and PCAF autoacetylation is not affected. Furthermore, the DNA-binding activity of p53 is diminished in cells expressing the E1B 55-kDa protein. PCAF binds to the E1B 55-kDa protein and to a region near the C terminus of p53 encompassing Lys-320, the specific PCAF acetylation site. We further show that the E1B 55-kDa protein interferes with the physical interaction between PCAF and p53, suggesting that the E1B 55-kDa protein inhibits PCAF acetylase function on p53 by preventing enzyme-substrate interaction. These results underscore the importance of p53 acetylation for its function and suggest that inhibition of p53 acetylation by viral oncoproteins prevent its activation, thereby contributing to viral transformation.

Very little is known concerning the toxicity of antimony, despite its commercial use as a flame retardant and medical use as a treatment for parasitic infections. Our previous studies show that antimony trioxide (Sb(2)O(3)) induces growth inhibition in patient-derived acute promyelocytic leukemia (APL) cell lines, a disease in which a related metal, arsenic trioxide (As(2)O(3)), is used clinically. However, signaling pathways initiated by Sb(2)O(3) treatment remain undefined. Here, we show that Sb(2)O(3) treatment of APL cells is associated with increased apoptosis as well as differentiation markers. Sb(2)O(3)-induced reactive oxygen species (ROS) correlated with increased apoptosis. In addition, when we decreased the buffering capacity of the cell by depleting glutathione, ROS production and apoptosis was enhanced. Arsenic-resistant APL cells with increased glutathione levels exhibited increased cross-resistance to Sb(2)O(3). Based on studies implicating c-jun kinase (JNK) in the mediation of the response to As(2)O(3), we investigated the role for JNK in Sb(2)O(3)-induced apoptosis. Sb(2)O(3) activates JNK and its downstream target, AP-1. In fibroblasts with a genetic deletion in SEK1, an upstream regulator of JNK, Sb(2)O(3)-induced growth inhibition as well as JNK activation was decreased. These data suggest roles for ROS and the SEK1/JNK pathway in the cytotoxicity associated with Sb(2)O(3) exposure.

Some success in overcoming retinoic acid (RA)-resistance has been reported for acute promyelocytic leukemia in cell lines and the clinic by combining histone deacetylase inhibitors, like sodium butyrate (NaB), with RA. This epigenetic therapy counteracts the effects of nuclear corepressors, causing a DNA conformation that facilitates RA-induced gene transcription and cell differentiation. In an effort to improve delivery of each drug, we have synthesized retinoyloxymethyl butyrate (RN1), a mutual prodrug of both RA and butyric acid. RN1 targets both drugs to the same cells or cellular compartments to achieve differentiation at lower concentrations than using RA and NaB alone. In an RA-resistant cell line, which is not responsive to RA and NaB given together at the same concentration, RN1 inhibited growth substantially. This growth inhibition is caused by an increase in apoptosis and a minimal induction of differentiation, rather than the more complete granulocytic differentiation as seen in the RA-sensitive cell line. The different phenotypes induced by RN1 in RA-sensitive versus RA-resistant cells are reflected by altered patterns of gene expression. In addition to acute promyelocytic leukemia cells, RN1 induces apoptosis of other RA-resistant leukemic cell lines with blocked transcriptional pathways, but not normal human peripheral blood mononuclear cells. RN1, therefore, is a novel retinoid that may be more widely active in hematologic malignancies than RA alone.

The adenovirus E1B 55-kDa protein impairs the p53 pathway and enhances transformation, although the underlying mechanisms remain to be defined. We found that Daxx binds to the E1B 55-kDa protein in a yeast two-hybrid screen. The two proteins interact through their C termini. Mutation of three potential phosphorylation sites (S489/490 and T494 to alanine) within the E1B 55-kDa protein did not affect its interaction with Daxx, although such mutations were previously shown to inhibit E1B's ability to repress p53-dependent transcription and to enhance transformation. In addition to their coimmunoprecipitation in 293 extracts, purified Daxx interacted with the E1B 55-kDa protein in vitro, indicating their direct interaction. In 293 cells, Daxx colocalized with the E1B 55-kDa protein within discrete nuclear dots, where p53 was also found. Such structures were distinct from PML (promyelocytic leukemia protein) bodies, and it appeared that Daxx was displaced from PML bodies. Thus, the Daxx concentration was diminished in dots with a prominent presence of PML and vice versa. Indeed, PML overexpression led to dramatic redistribution of Daxx from p53-E1B 55-kDa protein complexes to PML bodies. Additionally, expression of the E1B 55-kDa protein in Saos2 osteosarcoma cells reduced the number of PML bodies. Our data suggest that E1B and PML compete for available Daxx in the cell. Surprisingly, Daxx significantly augmented p53-mediated transcription and the E1B 55-kDa protein eliminated this effect. Thus, it is likely that the E1B 55-kDa protein sequesters Daxx and p53 in specific nuclear locations, where p53 cannot activate transcription. One consequence of the Daxx-E1B interaction might be an alteration of normal interactions of Daxx, PML, and p53, which may contribute to cell transformation.

Background Pharmacists may improve the clinical management of major risk factors for cardiovascular disease (CVD) prevention. A systematic review was conducted to determine the impact of pharmacist care on the management of CVD risk factors among outpatients. Methods The MEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled Trials databases were searched for randomized controlled trials that involved pharmacist care interventions among outpatients with CVD risk factors. Two reviewers independently abstracted data and classified pharmacists' interventions. Mean changes in blood pressure, total cholesterol, low-density lipoprotein cholesterol, and proportion of smokers were estimated using random effects models. Results Thirty randomized controlled trials (11 765 patients) were identified. Pharmacist interventions exclusively conducted by a pharmacist or implemented in collaboration with physicians or nurses included patient educational interventions, patient-reminder systems, measurement of CVD risk factors, medication management and feedback to physician, or educational intervention to health care professionals. Pharmacist care was associated with significant reductions in systolic/diastolic blood pressure (19 studies [10 479 patients]; −8.1 mm Hg [95% confidence interval {CI}, −10.2 to −5.9]/−3.8 mm Hg [95% CI,−5.3 to −2.3]); total cholesterol (9 studies [1121 patients]; −17.4 mg/L [95% CI,−25.5 to −9.2]), low-density lipoprotein cholesterol (7 studies [924 patients]; −13.4 mg/L [95% CI,−23.0 to −3.8]), and a reduction in the risk of smoking (2 studies [196 patients]; relative risk, 0.77 [95% CI, 0.67 to 0.89]). While most studies tended to favor pharmacist care compared with usual care, a substantial heterogeneity was observed. Conclusion Pharmacist-directed care or in collaboration with physicians or nurses improve the management of major CVD risk factors in outpatients.