Role of Irbesartan in Prevention of Post-Coronary Artery Bypass Graft Atrial Fibrillation

Background and Objective

Atrial fibrillation (AF) is a common complication of cardiothoracic surgery (CTS). Existing evidence about the potential protective role of angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) for post-CTS AF has been limited and conflicting. In this single-blind, open-label, randomized prospective pilot study, we evaluated the potential protective role of irbesartan (an ARB) in post-coronary artery bypass graft (CABG) AF.

Methods

A total of 100 consecutive patients undergoing CABG were randomly assigned to irbesartan (n = 50) versus no irbesartan (n = 50) for 5 days prior to the scheduled surgery. Data were collected for imaging studies, laboratory values, and peri-operative details. Patients were monitored post-operatively for in-hospital AF episodes. Unadjusted and adjusted logistic regression analysis was performed to assess the effect of irbesartan on the incidence of post-CABG AF.

Results

A total of 14 patients developed AF during their post-operative hospital stay. The incidence of AF in patients who received irbesartan was 6% (n = 3) compared with 22% (n = 11) in patients who did not receive irbesartan (p = 0.021). Univariate logistic regression analysis identified irbesartan and age as statistically significant variables. An adjusted multivariate logistic model identified irbesartan as an important protective factor against development of post-CABG AF (adjusted odds ratio [OR] 0.20; 95% confidence interval [CI] 0.04, 0.94; p = 0.04). Increasing age (adjusted OR 1.09, 95% CI 1.01, 1.17; p = 0.03) was also identified as an independent risk factor for development of post-CABG AF.

Conclusion

Pretreatment with irbesartan tends to have a significant protective effect against the occurrence of AF during the post-operative period in patients undergoing CABG.     

The combination of alisertib,an investigational Aurora kinase A inhibitor,and docetaxel promotes cell death and reduces tumor growth in preclinical cell models of upper gastrointestinal adenocarcinomas

BACKGROUND:

Upper gastrointestinal adenocarcinomas (UGCs) respond poorly to current chemotherapeutic regimes. The authors and others have previously reported frequent Aurora kinase A (AURKA) gene amplification and mRNA and protein overexpression in UGCs. The objective of the current study was to determine the therapeutic potential of alisertib (MLN8237) alone and in combination with docetaxel in UGCs.

METHODS:

After treatment with alisertib and/or docetaxel, clonogenic cell survival, cell cycle analyses, Western blot analyses, and tumor xenograft growth assays were carried out to measure cell survival, cell cycle progression, apoptotic protein expression, and tumor xenograft volumes, respectively.

RESULTS:

By using the AGS, FLO‐1, and OE33 UGC cell lines, which have constitutive AURKA overexpression and variable tumor protein 53 (p53) status, significantly enhanced inhibition of cancer cell survival was observed with alisertib and docetaxel treatment in combination (P < .001), compared with single‐agent treatments. Cell cycle analyses, after 48 hours of treatment with alisertib, produced a significant increase in the percentage of polyploidy in UGC cells (P < .01) that was further enhanced by docetaxel (P < .001). In addition, an increase in the percentage of cells in sub‐G1‐phase observed with alisertib (P < .01) was significantly enhanced with the combination treatment (P < .001). Western blot analysis demonstrated higher induction of cleaved caspase 3 protein expression with the combined treatment compared with single‐agent treatments. In addition, FLO‐1 and OE33 cell xenograft models demonstrated enhanced antitumor activity for the alisertib and docetaxel combination compared with single‐agent treatments (P < .001).

CONCLUSIONS:

The current study demonstrated that alisertib combined with docetaxel can mediate a better therapeutic outcome in UGC cell lines. Cancer 2013. © 2012 American Cancer Society.     

PIK3CA alterations in Middle Eastern ovarian cancers

Background  

PI3K/AKTsignaling pathway plays an important role in cell growth, proliferation, and tumorgenesis of various malignancies. This signaling pathway has been shown to be frequently altered in several human cancers including ovarian cancers. However the role of this oncogenic signaling pathway has not been explored in the Middle Eastern epithelial ovarian cancer (EOC). Therefore, we investigated PI3K/AKT genetic alterations such as PIK3CA amplification, PIK3CA mutation, PTEN protein loss and their relationships with various clinicopathological characteristics in 156 EOCs.     

Proprotein Convertase Subtilisin/Kexin Type 9 Deficiency Reduces Melanoma Metastasis in Liver

High circulating cholesterol is associated with hypercholesterolemia, atherosclerosis, and stroke. However, the relation between cholesterol and tumorigenesis/metastasis is controversial. The proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein cholesterol homeostasis by targeting the low-density lipoprotein receptor (LDLR) for degradation. PCSK9 is mostly expressed in liver, which is one of the most common sites for metastatic disease. To reveal the function of PCSK9 and also evaluate the impact of cholesterol in liver metastasis development, B16F1 melanoma cells were injected into wild-type (WT) and Pcsk9^-/- mice to induce liver metastasis. On chow diet, Pcsk9^-/- mice harbored two-fold less liver metastases than WT mice. This decrease is related to low cholesterol levels in Pcsk9^-/- mice, as the protection was lost after normalizing Pcsk9^-/- cholesterol levels by a 2-week high cholesterol diet. Furthermore, a prolongation of this diet strongly increased metastasis in both genotypes, suggesting that high cholesterol levels promote metastatic progression. The protective effect of the PCSK9 deficiency is also associated with increased apoptosis in liver stroma and metastases. Tumor necrosis factor.α (TNFα) mRNA and protein were, respectively, higher in liver stroma and plasma of injected mice, likely increasing the apoptotic TNFα signaling. Furthermore, the anti-apoptotic factor B-cell lymphoma 2 was downregulated. TNFα regulation is LDLR-independent, as its mRNA level was similarly upregulated in mice lacking both PCSK9 and LDLR. Our findings show that PCSK9 deficiency reduces liver metastasis by its ability to lower cholesterol levels and by possibly enhancing TNFα-mediated apoptosis.     

BRCA1-IRIS inactivation overcomes paclitaxel resistance in triple negative breast cancers

Introduction

Intrinsic or acquired chemoresistance is a major problem in oncology. Although highly responsive to chemotherapies such as paclitaxel, most triple negative breast cancer (TNBC) patients develop chemoresistance. Here we investigate the role of BRCA1-IRIS as a novel treatment target for TNBCs and their paclitaxel-resistant recurrences.

Methods

We analyzed the response of BRCA1-IRIS overexpressing normal mammary cells or established TNBC cells silenced from BRCA1-IRIS to paclitaxel in vitro and in vivo. We analyzed BRCA1-IRIS downstream signaling pathways in relation to paclitaxel treatment. We also analyzed a large cohort of breast tumor samples for BRCA1-IRIS, Forkhead box class O3a (FOXO3a) and survivin expression. Finally, we analyzed the effect of BRCA1-IRIS silencing or inactivation on TNBCs formation, maintenance and response to paclitaxel in an orthotopic model.

Results

We show that low concentrations of paclitaxel triggers BRCA1-IRIS expression in vitro and in vivo, and that BRCA1-IRIS activates two autocrine signaling loops (epidermal growth factor (EGF)/EGF receptor 1 (EGFR)-EGF receptor 2 (ErbB2) and neurogulin 1 (NRG1)/ErbB2-EGF receptor 3 (ErbB3), which enhances protein kinase B (AKT) and thus survivin expression/activation through promoting FOXO3a degradation. This signaling pathway is intact in TNBCs endogenously overexpressing BRCA1-IRIS. These events trigger the intrinsic and acquired paclitaxel resistance phenotype known for BRCA1-IRIS-overexpressing TNBCs. Inactivating BRCA1-IRIS signaling using a novel inhibitory mimetic peptide inactivates these autocrine loops, AKT and survivin activity/expression, in part by restoring FOXO3a expression, and sensitizes TNBC cells to low paclitaxel concentrations in vitro and in vivo. Finally, we show BRCA1-IRIS and survivin overexpression is correlated with lack of FOXO3a expression in a large cohort of primary tumor samples, and that BRCA1-IRIS overexpression-induced signature is associated with decreased disease free survival in heavily treated estrogen receptor alpha-negative patients.

Conclusions

In addition to driving TNBC tumor formation, BRCA1-IRIS overexpression drives their intrinsic and acquired paclitaxel resistance, partly by activating autocrine signaling loops EGF/EGFR-ErbB2 and NRG1/ErbB2-ErbB3. These loops activate AKT, causing FOXO3a degradation and survivin overexpression. Taken together, this underscores the need for BRCA1-IRIS-specific therapy and strongly suggests that BRCA1-IRIS and/or signaling loops activated by it could be rational therapeutic targets for advanced TNBCs.     

Block copolymers of the type poly(caprolactone)-b-poly(ethylene oxide) for the preparation and stabilization of nanoemulsions

Block copolymers poly(caprolactone)-block-poly(ethylene oxide) are promising non-ionic macromolecular surfactants for the stabilization of emulsions because they display a stronger adsorption and provide an increased long-term stability. But such amphiphilic copolymers should also allow the fabrication of the suspensions according to the emulsification process used. An evaluation of such block copolymers was done regarding the nanoprecipitation and the miniemulsion polymerization processes that both afford aqueous suspensions of nanoparticles. Both the fabrication and the long-term stability were investigated. It was found that the emulsification by means of the nanoprecipitation process was successful when the amphiphilic block copolymer was added into the organic phase. The studies on the structure-activity relationships have shown that a minimum length of the poly(ethylene oxide) block was necessary in order to ensure both the long-term colloidal stability of the suspensions and the instantaneous stability during the preparation process. The length of the hydrophobic block was a parameter of less relevance, but a minimum length was required for the copolymers to be soluble in the organic phase. The miniemulsion polymerization process using block copolymer emulsifiers could be adapted to the incorporation of large loads of vitamin E acetate used as a hydrophobe stabilizer.     

Organochlorine pesticide contaminations in human milk samples from women living in Amman,Jordan

Concentrations of 15 organochlorine pesticides were determined by capillary gas chromatography in 59 human milk samples collected from the general population during 1989/1990 in the Jordanian capital of Amman. In addition to hexachlorbenzene (HCB), three groups of organochlorine compounds namely, DDT and its metabolites, hexachlorcyclohexane (HCH-isomers) and the cyclopentadiene group (aldrin, dieldrin, endrin, heptachlor, and heptachlor epoxide) were analyzed.The results show that almost all samples contained HCB, -HCH, p,p-DDE and p,p-DDT, whereas p,p-DDD, heptachlor, -HCH, -HCH and o,pDDT were found in 42, 40, 33, 22 and 20 analyzed samples, respectively. The concentration of HCB, -HCH, p,p-DDE, p,p-DDT and heptachlor expressed on a milk-fat basis (median in mg/kg milk fat): 0.29, 0.4, 2.04, and 0.7 respectively.For the comparative purposes and in order to try to find the possible sources of mother-milk contaminations, different types of locally produced and imported cow milk samples were also analyzed for the same organochlorine compounds. Almost all types of tested milk were contaminated with p,p-DDE.     

Effect of selenium-containing compounds on hepatic chemoprotective enzymes in mice

Selenite and organoselenium compounds have been examined at supranutritional levels for their ability to influence the activity and mRNA levels of chemoprotective enzymes in the livers of selenium-sufficient mice and the changes compared to those elicited by oltipraz. Compounds investigated included novel selenocysteine prodrugs that have previously been evaluated for their ability to reduce the tumorigenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mice. Following seven daily doses (i.g.), all compounds except 2-methylselenazolidine-4(R)-carboxylic acid (MSCA) increased thioredoxin reductase activity (43–92%) but only for 2-oxoselenazolidine-4(R)-carboxylic acid (OSCA) was there an accompanying increase in mRNA. No compound enhanced glutathione peroxidase activity, although sodium selenite significantly elevated the mRNA of this enzyme. Oltipraz was an efficacious inducer of both thioredoxin reductase and glutathione peroxidase mRNAs. Sodium selenite, selenazolidine-4(R)-carboxylic acid (SCA), and OSCA elevated NAD(P)H-quinone oxidoreductase mRNA but only for OSCA was the elevation in mRNA accompanied by an increase in enzyme activity. l-Selenocystine significantly increased this activity without increasing mRNA levels. Sodium selenite, l-selenocystine, l-selenomethionine, and Se-methyl-l-selenocysteine all enhanced glutathione S-transferase activity. The increased activity with sodium selenite was accompanied by increases in mRNAs of Gst , Gst μ and Gst π classes, while for l-selenocystine and Se-methyl-l-selenocysteine, only an elevation in the mRNA for the Gst class was observed. Gst and Gst μ class mRNAs were elevated by OSCA without a significant elevation in enzyme activity. SCA and MSCA both elevated a Gst π mRNA and MSCA elevated Gst μ in addition. By comparison, oltipraz only significantly elevated the mRNA of Gst μ, adding to the conclusion that across the entire study, no selenium compound appears to be acting purely through the antioxidant response typified by oltipraz. Despite their chemical similarity, the three cysteine prodrugs, SCA, MSCA, and OSCA, each produced its own unique pattern of effects on protective enzymes and none was identical to the pattern elicited by sodium selenite, l-selenocystine, l-selenomethionine, and Se-methyl-l-selenocysteine. The study also shows that after 7 days of administration, there was only occasional concordance between elevations in mRNA and enzyme activity for any selenium compound and for any protective enzyme, there was no response in common for all selenium compounds.     

Impact of the cyclosporine-ketoconazole interaction in children with steroid-dependent idiopathic nephrotic syndrome

Background Children with steroid-dependent nephrotic syndrome experience serious side effects from steroid therapy. Cyclosporine A (CsA), which is an effective agent in the treatment of steroid-dependent nephrotic syndrome, is expensive and, consequently, often unaffordable in developing countries. Many studies have documented the benefit of ketoconazole administration in transplant adults treated with CsA. We have conducted a retrospective study with the objective of addressing cost-savings, safety, and the efficacy of the co-administration of ketoconazole and CsA to children with steroid-dependent nephrotic syndrome. Methods This study included 102 nephrotic patients who were steroid-dependent and who received cyclosporine therapy. The commonest pathologic lesions were focal segmental glomerulosclerosis (64 patients) and minimal change disease (36 patients). Among the patients participating in the study, 78 received daily ketoconazole therapy (ketoconazole group) in the form of a 50-mg dose accompanied by an initial one-third decrease in the CsA dose, while 24 received CsA alone (non- ketoconazole group). All of the patients were children (below 18 years), and the male-to-female ratio was 3:1. The mean duration of treatment was 22.9 months. The characteristics of both groups were comparable. Results Co-administration of ketoconazole significantly reduced mean doses of CsA by 48% with a net cost savings of 38%. It also resulted in a significant improvement in the CsA response and a more successful steroid withdrawal as well as a decrease in the frequency of renal impairment. Liver function tests remained normal in both groups up to and including the final follow-up (mean of 33.6 months). Conclusions The co-administration of ketoconazole to CsA in children with idiopathic steroid-dependent nephrotic syndrome safely results in a significant reduction in CsA cost, which causes great concern in developing countries. It may also improve CsA response.     

Inhibition of α-glucosidase and α-amylase by diaryl derivatives of imidazole-thione and 1,2,4-triazole-thiol

The in vivo and in vitro effects of 4,5-diphenylimidazole-2-thione (1), 4,5-diphenyl-1,2,4-triazole-3-thiol (2) and 5-(2-hydroxyphenyl)-4-phenyl-1,2,4-triazole-3-thiol (3) on α-glucosidase and α-amylase were investigated. The in vivo inhibition has been found to be dose-dependent and to occur at a value less than LD50. The in vitro treatment of the enzymes by 4,5-diphenylimidazole-2-thione exhibited a reversible inhibition of the non-competitive type with Ki value of 3.5 and 6.5×10(-5) M for α-glucosidase and α-amylase, respectively. 4,5-diphenyl-1,2,4-triazole-3-thione showed a reversible inhibition of the competitive and non-competitive types, with Ki value of 10(-5) M magnitude, for α-glucosidase and α-amylase. On the other hand, 5-(o-hydroxyphenyl)-4-phenyl-1,2,4-triazole-3-thione did not display an inhibitory effect towards α-amylase but showed a potent inhibition of the competitive type for hepatic α-glucosidase with 10(-5) M magnitude of Ki value.