BackgroundControl 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 ResultsRandomized controlled trials (RCTs) 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 RCTs 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; I2=67%) and diastolic BP (−3.9 mm Hg, 95% CI: −5.1 to −2.8; I2=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.ConclusionsPharmacist 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.

OBJECTIVEThis systematic review and meta-analysis of randomized controlled trials (RCTs) assesses the effect of pharmacist care on cardiovascular disease (CVD) risk factors among outpatients with diabetes.RESEARCH DESIGN AND METHODSMEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials were searched. Pharmacist interventions were classified, and a meta-analysis of mean changes of blood pressure (BP), total cholesterol (TC), LDL cholesterol, HDL cholesterol, and BMI was performed using random-effects models.RESULTSThe meta-analysis included 15 RCTs (9,111 outpatients) in which interventions were conducted exclusively by pharmacists in 8 studies and in collaboration with physicians, nurses, dietitians, or physical therapists in 7 studies. Pharmacist interventions included medication management, educational interventions, feedback to physicians, measurement of CVD risk factors, or patient-reminder systems. Compared with usual care, pharmacist care was associated with significant reductions for systolic BP (12 studies with 1,894 patients; −6.2 mmHg [95% CI −7.8 to −4.6]); diastolic BP (9 studies with 1,496 patients; −4.5 mmHg [−6.2 to −2.8]); TC (8 studies with 1,280 patients; −15.2 mg/dL [−24.7 to −5.7]); LDL cholesterol (9 studies with 8,084 patients; −11.7 mg/dL [−15.8 to −7.6]); and BMI (5 studies with 751 patients; −0.9 kg/m2 [−1.7 to −0.1]). Pharmacist care was not associated with a significant change in HDL cholesterol (6 studies with 826 patients; 0.2 mg/dL [−1.9 to 2.4]).CONCLUSIONSThis meta-analysis supports pharmacist interventions—alone or in collaboration with other health care professionals—to improve major CVD risk factors among outpatients with diabetes.

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.The cellular tumor suppressor p53 exerts its tumor suppression functions largely by acting as a transcriptional transactivator. In response to a variety of stimuli, such as DNA damage and expression of cellular or viral oncoproteins, p53 is stabilized and binds to specific DNA sequences in the vicinity of the promoter of its target genes and activates their transcription. The genes activated by p53 include p21 ( also called WAF1 or Cip1) (cyclin-dependent kinase inhibitor), cyclin G, GADD45, Mdm2, and Bax1 (apoptosis inducer). The products of these genes are implicated in regulation of cell cycle progression, DNA replication, and apoptosis (13,25,31).Growth arrest or apoptosis imposed by p53 could severely hinder the replication of small DNA tumor viruses, as such replication requires host cells to enter the S phase. Thus, it is not surprising that a number of viral oncoproteins, such as the adenovirus (Ad) E1B 55-kDa protein, human papillomavirus (HPV) E6, and simian virus 40 large T antigen, bind to and repress the biological functions of p53 (30,34,49,66). The E6 proteins of highly oncogenic HPV types 16 and 18 (HPV16 and HPV18) associate with p53 and target it for ubiquitination and subsequent degradation (51). Simian virus 40 large T antigen binds to the sequence-specific DNA binding domain of p53 (52,56). This interaction interferes with sequence-specific DNA binding of p53 and therefore inhibits p53-mediated transcriptional transactivation (2, 10, 41).Inhibition of p53 transactivation function is thought to be the key step in cell transformation induced by Ad (45, 69). The transforming function of Ad maps to the early region 1 (E1) of the 36-kb Ad genome (45). The E1 region encompasses t...

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.Cancer arises from a cell that undergoes a number of specific changes. Transformation of primary human cells requires at least four genetic events: inactivation of both the p53 and pRb pathways, activation of mitogenic oncogenes such as ras, and telomere maintenance (11). These genetic changes may also underlie cell transformation induced by DNA tumor viruses. In fact, it is well known that several viral oncogenes involved in virus-induced cell transformation inactivate both the p53 and pRb pathways. These viral oncogenes include the simian virus 40 (SV40) large T antigen, the human papillomavirus (HPV) 16 E6 and E7 proteins, and the adenovirus (Ad) E1A and E1B proteins (1). Recent in vitro cell transformation experiments used the SV40 large T antigen and the HPV E6 and E7 oncogenes to inactivate the p53 and pRb pathways (11,25). Interestingly, in combination with ras and the gene for the catalytic subunit of telomerase, the SV40 large T antigen effectively transformed human primary cells (11), but HPV E6 and E7 failed to do so (25), suggesting that inactivation of cellular pathways in addition to pRb and p53 may be required in malignant transformation.

We have previously published that 2 proven treatments for acute promyelocytic leukemia, As 2 O 3 and retinoic acid, can be antagonistic in vitro. We now report that As 2 O 3 inhibits ligand-induced transcription of the retinoic acid receptor, as well as other nuclear receptors that heterodimerize with the retinoid X receptor α (RXRα). As 2 O 3 did not inhibit transactivation of the estrogen receptor or the glucocorticoid receptor, which do not heterodimerize with RXRα. We further show that As 2 O 3 inhibits expression of several target genes of RXRα partners. Phosphorylation of RXRα has been reported to inhibit nuclear receptor signaling, and we show by in vivo labeling and phosphoamino acid detection that As 2 O 3 phosphorylated RXRα in the N-terminal ABC region exclusively on serine residues. Consistent with our previous data implying a role for JNK in As 2 O 3 -induced apoptosis, we show that pharmacologic or genetic inhibition of JNK activation decreased As 2 O 3 -induced RXRα phosphorylation and blocked the effects of As 2 O 3 on RXRα-mediated transcription. A mutational analysis indicated that phosphorylation of a specific serine residue, S32, was primarily responsible for inhibition of RXRα-mediated transcription. These data may provide some insight into the rational development of chemotherapeutic combinations involving As 2 O 3 as well as into molecular mechanisms of arsenicinduced carcinogenesis resulting from environmental exposure.