Impact of body mass index on the one-year clinical outcome of patients undergoing multivessel revascularization with sirolimus-eluting stents (from the Arterial Revascularization Therapies Study Part II)

The differential safety and efficacy profiles of sirolimus-eluting stents when implanted in patients with multivessel coronary artery disease who have increased body mass indexes (BMIs) compared with those with normal BMIs are largely unknown. This study evaluated the impact of BMI on 1-year outcomes in patients with multivessel coronary artery disease treated with sirolimus-eluting stents as part of the Arterial Revascularization Therapies Study Part II (ARTS II). From February to November 2003, 607 patients were included at 45 centers; 176 patients had normal BMIs (<25 kg/m(2)), 289 were overweight (> or =25 and < or =30 kg/m(2)), and 142 were obese (>30 kg/m(2)). At 30 days, the cumulative incidence of the primary combined end point of death, myocardial infarction, cerebrovascular accident, and repeat revascularization (major adverse cardiac and cerebrovascular events) was 3.4% in the group with normal BMIs, 3.1% in overweight patients, and 2.8% in obese patients (p = 0.76). At 1 year, the cumulative incidence of major adverse cardiac and cerebrovascular events was 10.8%, 11.8%, and 7.0% in the normal BMI, overweight, and obese groups, respectively (p = 0.31). In conclusion, BMI had no impact on 1-year clinical outcomes in patients with multivessel coronary artery disease treated with sirolimus-eluting stents in ARTS II.

Early clinical trial experience with vaccine therapies in non-small-cell lung cancer

Cancer immunotherapy has made great progress because of advances in immunology and molecular biology. Increased understanding of mechanisms by which lung cancer cells escape the immune system and recognition of key tumor antigens and immune system components involved in tumor ignorance have led to the development of a variety of lung cancer vaccines. Immunotherapy has advanced from using nonspecific immunomodulatory agents to lung cancer-specific tumor antigens and tumor cell-derived vaccines. While understanding of immune processes and malignancy has improved, there is great opportunity for further research of vaccine therapies in non-small-cell lung cancer. Herein, we review the development and evolution of early lung cancer vaccine trials.

[Lung protective ventilation - supportive and adjunctive therapies in acute lung injury]

Various supportive and adjunctive therapies to conventional mechanical ventilation have been evaluated in patients with acute lung injury and acute respiratory distress syndrome (e.g. nitric oxide, prone position, surfactant, glucocorticoids). Although some investigations have shown promising improvements in oxygenation and physiological variables, large randomized trials of adjunctive and supportive therapies showed no impact on survival.

Integrin alphavbeta6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies

BACKGROUND/AIMS: The integrin alphavbeta6 promotes proliferation of specialized epithelia and acts as a receptor for the activation of latent TGFbeta1. We studied alphavbeta6 expression in experimental and human liver fibrosis and the potential of its pharmacological inhibition for treatment of hepatic fibrosis. METHODS: alphavbeta6 expression was studied by quantitative PCR and immunohistochemistry in rats with cirrhosis due to bile duct ligation (BDL), administration of thioacetamide (TAA), in Mdr2(Abcb4)(-/-) mice with spontaneous biliary fibrosis, and in livers of patients with chronic hepatitis C (n=79) and end-stage liver disease due to various etiologies (n=18). The effect of a selective alphavbeta6 inhibitor was evaluated in Mdr2(Abcb4)(-/-) mice with ongoing fibrogenesis. RESULTS: Integrin beta6 mRNA increased with fibrosis stage in hepatitis C and was upregulated between 25- and 100-fold in TAA- and BDL-induced cirrhosis, in Mdr2(Abcb4)(-/-) mice and in human end-stage liver disease. alphavbeta6 protein was absent in normal livers and expressed de novo on (activated) bile duct epithelia and transitional hepatocytes. A single dose of the alphavbeta6 inhibitor injected into Mdr2(Abcb4)(-/-) mice significantly induced profibrolytic matrix metalloproteinases (MMP)-8 and -9 after 3 h, with a corresponding increase in extracellular matrix-degrading activities. In parallel profibrogenic transcripts (procollagen alpha1(I), TGFbeta2, and MMP-2) showed a trend of downregulation. CONCLUSIONS: (1) Integrin alphavbeta6 is induced de novo in rodent and human liver fibrosis, where it is expressed on activated bile duct epithelia and (transitional) hepatocytes during fibrosis progression. (2) In vivo a single dose of a small molecule alphavbeta6 inhibitor induced antifibrogenic and profibrolytic genes and activities, suggesting alphavbeta6 is a unique target for treatment of liver fibrosis.

Cardiac toxicity with anti-HER-2 therapies: what have we learned so far?

Trastuzumab, a monoclonal antibody that blocks HER-2 receptor, improves the survival of women with HER-2-positive early and advanced breast cancer when given with chemotherapy. Lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2, is approved for the treatment of metastatic breast cancer patients after failure of prior anthracycline, taxanes and trastuzumab therapies in combination with capecitabine. Importantly, cardiac toxicity, manifested as symptomatic congestive heart failure or asymptomatic left ventricular ejection fraction decline, has been reported in some of the patients receiving these novel anti-HER-2 therapies, particularly when these drugs are used following anthracyclines, whose cardiotoxic potential has been recognized for decades. This review will focus on the incidence, natural history, underlying mechanisms, management, and areas of uncertainty regarding trastuzumab-and lapatinib-induced cardiotoxicity.

Lipids as targets for novel anti-inflammatory therapies

Lipids serve important functions as membrane constituents and also as energy storing molecules. Besides these functions certain lipid species have now been recognized as signalling molecules that regulate a multitude of cellular responses including cell growth and death, and also inflammatory reactions. Bioactive lipids are generated by hydrolysis from membrane lipids mainly by phospholipases giving rise to fatty acids and lysophospholipids that either directly exert their function or are further converted to active mediators. This review will summarize the present knowledge about bioactive lipids that either promote or attenuate inflammatory reactions. These lipids include polyunsaturated fatty acids (PUFA), eicosanoids including the epoxyeicosatrienoic acids (EET), peroxisome proliferation activating receptor (PPAR) activators, cannabinoids and the sphingolipids ceramide, sphingosine 1-phosphate and sphingosylphosphorylcholine.

EpCAM-targeted delivery of nanocomplexed siRNA to tumor cells with designed ankyrin repeat proteins

Specific delivery to tumors and efficient cellular uptake of nucleic acids remain major challenges for gene-targeted cancer therapies. Here we report the use of a designed ankyrin repeat protein (DARPin) specific for the epithelial cell adhesion molecule (EpCAM) as a carrier for small interfering RNA (siRNA) complementary to the bcl-2 mRNA. For charge complexation of the siRNA, the DARPin was fused to a truncated human protamine-1 sequence. To increase the cell binding affinity and the amount of siRNA delivered into cells, DARPin dimers were generated and used as fusion proteins with protamine. All proteins expressed well in Escherichia coli in soluble form, yet, to remove tightly bound bacterial nucleic acids, they were purified under denaturing conditions by immobilized metal ion affinity chromatography, followed by refolding. The fusion proteins were capable of complexing four to five siRNA molecules per protamine, and fully retained the binding specificity for EpCAM as shown on MCF-7 breast carcinoma cells. In contrast to unspecific LipofectAMINE transfection, down-regulation of antiapoptotic bcl-2 using fusion protein complexed siRNA was strictly dependent on EpCAM binding and internalization. Inhibition of bcl-2 expression facilitated tumor cell apoptosis as shown by increased sensitivity to the anticancer agent doxorubicin.

Cannabinoid receptor ligands as potential anticancer agents--high hopes for new therapies?

OBJECTIVES: The endocannabinoid system is an endogenous lipid signalling network comprising arachidonic-acid-derived ligands, cannabinoid (CB) receptors, transporters and endocannabinoid degrading enzymes. The CB(1) receptor is predominantly expressed in neurons but is also co-expressed with the CB(2) receptor in peripheral tissues. In recent years, CB receptor ligands, including Delta(9)-tetrahydrocannabinol, have been proposed as potential anticancer agents. KEY FINDINGS: This review critically discusses the pharmacology of CB receptor activation as a novel therapeutic anticancer strategy in terms of ligand selectivity, tissue specificity and potency. Intriguingly, antitumour effects mediated by cannabinoids are not confined to inhibition of cancer cell proliferation; cannabinoids also reduce angiogenesis, cell migration and metastasis, inhibit carcinogenesis and attenuate inflammatory processes. In the last decade several new selective CB(1) and CB(2) receptor agents have been described, but most studies in the area of cancer research have used non-selective CB ligands. Moreover, many of these ligands exert prominent CB receptor-independent pharmacological effects, such as activation of the G-protein-coupled receptor GPR55, peroxisome proliferator-activated receptor gamma and the transient receptor potential vanilloid channels. SUMMARY: The role of the endocannabinoid system in tumourigenesis is still poorly understood and the molecular mechanisms of cannabinoid anticancer action need to be elucidated. The development of CB(2)-selective anticancer agents could be advantageous in light of the unwanted central effects exerted by CB(1) receptor ligands. Probably the most interesting question is whether cannabinoids could be useful in chemoprevention or in combination with established chemotherapeutic agents.

[Role of complementary medicine in type 1 diabetes mellitus in two Swiss centres]

Insulin replacement is the only effective treatment of type 1 Diabetes mellitus (T1DM). Nevertheless, many complementary treatments are in use for T1DM. In this study we assessed by questionnaire that out of 342 patients with T1DM, 48 (14%; 13.4% adult, 18.5% paediatric; 20 male, 28 female) used complementary medicine (CM) in addition to their insulin therapy. The purpose of the use of CM was to improve general well-being, ameliorate glucose homeostasis, reduce blood glucose levels as well as insulin doses, improve physical fitness, reduce the frequency of hypoglycaemia, and control appetite. The modalities most frequently used are cinnamon, homeopathy, magnesium and special beverages (mainly teas). Thus, good collaboration between health care professionals will allow optimal patient care.

Atorvastatin compared with simvastatin-based therapies in the management of severe familial hyperlipidaemias

We compared atorvastatin with simvastatin-based therapies in a prospective observational study of 201 patients with severe hyperlipidaemia. Atorvastatin 10 mg therapy was substituted for simvastatin 20 mg, 20 mg for 40 mg, 40 mg for simvastatin 40 mg plus resin, and 80 mg for simvastatin-fibrate-resin therapy. Lipid and safety profiles were assessed. Atorvastatin reduced total cholesterol by 31 +/- 11-40 +/- 14% vs. 25 +/- 12-31 +/- 11%; LDL by 38 +/- 16-45 +/- 18% vs. 31 +/- 18-39 +/- 18% and geometric mean triglycerides by 29.3-37.3% vs. 16.6-24.8%, but reduced HDL 11% +/- 47% at 80 mg compared with a 16% +/- 34% increase with simvastatin-based therapy. Target LDL < 3.5 mmol/l was achieved more often with atorvastatin (63% vs. 50%; p < 0.001). Atorvastatin increased geometric mean fibrinogen by 12-20% vs. a 0-6% fall with simvastatin (p << 0.001). Side effects were noted in 10-36% of patients, including one case of rhabdomyolysis, and 36% discontinued therapy. These data suggest that atorvastatin is more effective than current simvastatin-based therapies in achieving treatment targets in patients with familial hypercholesterolaemia but at the expense of a possible increase in side-effects. This issue needs further study in randomized controlled trials.