Genistein inhibits p38 map kinase activation, matrix metalloproteinase type 2, and cell invasion in human prostate epithelial cells

Epidemiologic studies associate consumption of genistein, in the form of dietary soy, with lower rates of metastatic prostate cancer. We have previously shown that genistein inhibits prostate cancer cell detachment in vitro, that it is well tolerated in an older cohort of men with prostate cancer, and that it alters cell signaling in that same cohort. We have also shown that p38 mitogen-activated protein kinase (MAPK) is necessary for transforming growth factor beta (TGF-beta)-mediated increases in prostate cancer adhesion. Although cell invasion is closely linked to metastatic behavior, little is known about how this process is regulated in prostate cancer or what effect, if any, genistein has on associated processes. We now show that genistein inhibits matrix metalloproteinase type 2 (MMP-2) activity in six of seven prostate cell lines tested, blocks MMP-2 induction by TGF-beta, and inhibits cell invasion. Efficacy was seen at low nanomolar concentrations, corresponding to blood concentrations of free genistein attained after dietary consumption. Inhibition of p38 MAPK by either SB203580 or dominant-negative construct blocked induction of MMP-2 and cell invasion by TGF-beta. Genistein exerted similar effects and was found to block activation of p38 MAPK by TGF-beta. This study shows that p38 MAPK is necessary for TGF-beta-mediated induction of MMP-2 and cell invasion in prostate cancer and that genistein blocks activation of p38 MAPK, thereby inhibiting processes closely linked to metastasis, and does so at concentrations associated with dietary consumption. Any potential causal link to epidemiologic findings will require further investigation.     

Molecular mechanisms in chronic venous insufficiency

Chronic venous disease (CVD) is common. Its manifestations include varicose veins; skin changes such as dermatitis, hyperpigmentation, and lipodermatosclerosis; and chronic leg ulcers. Recent advances in the understanding of its pathophysiology have shown how molecular mechanisms in the inflammatory cascade are involved in these diverse findings. Venous hypertension and associated fluid shear stress alterations on the endothelial surface may initiate this cascade and may lead to adverse changes in the venous wall, venous valves, and skin that can eventually result in varicose veins and in venous ulcers.     

Endovascular Stent-Graft Treatment of Traumatic Arterial Lesions

Twenty-nine cases of post-traumatic false aneurysms and arteriovenous fistulas (AVF), with a mean follow-up of 24 months (1-65 months), are presented here. Diagnosis was established by color duplex and arteriogram. The time between injury and treatment varied between 3 days and 61 months. Endovascular treatment was accomplished using a covered Palmaz stent [vein, polytetrafluoroethylene (PTFE), or polyester], Corvita endoluminal graft, or a Wallgraft. Complimentary treatment of a branch injury was performed using a detachable balloon in one patient. The initial result was favorable for all patients. One case of asymptomatic stenosis of an iliac stent graft and three occlusions of the stent (one subclavian, one axillary, and one internal carotid) were registered during the follow-up period, and no clinical manifestations of the occlusions were reported. Endovascular treatment of post-traumatic false aneurysms and AVF appears to be a promising alternative for treatment of these lesions. Less pain and disability as well as rapid recovery time and lower cost after endovascular treatment compare favorably to the standard surgical technique.     

Characterization of Atlantic halibut (Hippoglossus hippoglossus) Mx protein expression

Mx proteins are antiviral GTPases that are induced by type I interferons in vertebrates. An Atlantic halibut Mx cDNA (HHMx) was recently cloned. In this work, a polyclonal antiserum against HHMx protein was generated that detected a 71 kDa protein in the nuclei of Chinook salmon embryo cells transfected with the HHMx cDNA. Mx protein expression in organs of halibut was studied by immunoblot analysis after injection with the double-stranded RNA poly I:C or infectious pancreatic necrosis virus. Poly I:C stimulated increased Mx protein expression in liver, kidney, heart, spleen, gills and intestine. The Mx protein level in liver reached a maximum after 3 days and remained elevated for 14 days after treatment. IPNV infection resulted in increased Mx protein in liver from 4 to at least 35 days. Immunocytochemical detection of Mx proteins in blood smears from poly I:C treated halibut indicated that a cytoplasmic Mx form might exist in this species. Detection of Mx proteins in blood leukocytes could thus work as an early non-lethal test for viral infections.     

Left Iliac Vein Occlusion: Its Clinical Spectrum

The cases reported here demonstrate the variability of the clinical manifestations of left common iliac venous occlusive disease. In each instance, therapy must be adjusted to meet the symptomatic needs of the individual patient. The experience reported here should reinforce the fact that occlusions even 25 months or longer in duration may be reopened. Continuing patency can be enhanced by stent placement.     

Magnetic-resonance-guided percutaneous cryoablation of hepatic tumours.

OBJECTIVE: To study the feasibility of percutaneous cryoablation of hepatic tumours monitored by magnetic resonance imaging (MRI). DESIGN: Prospective study SETTING: University hospital, Norway PATIENTS: Six patients with hepatic metastases from colorectal cancer. INTERVENTIONS: Percutaneous cryoprobe positioning under general anaesthesia. Positioning and freezing monitored by near-real-time MRI using an open 0.5 Tesla MRI configuration system. MAIN OUTCOME MEASURES: Safety and feasibility of the procedure. Measurement of volumes of cryolesions. RESULTS: One patient developed a biliary leakage that had to be drained. Four patients developed pleural fluid. Two small tumours were adequately cryoablated. In the remaining 4 patients with large (>4 cm) tumours, an adequate cryolesion could not be formed. Cryolesion volumes larger than 105 cm3 were not produced even using 3-4 probes. MRI visualised the growing cryolesion well, but positioning of the cryoprobes was time-consuming. CONCLUSION: MR guided cryoablation is clinically feasible and gives good visualisation of the procedure. Patients with small tumours (<3 cm) seem to be best suited to this percutaneous approach as cryolesion volumes claimed to be adequate for tumour destruction can be produced. Measurement of tumour volume preoperatively may help to select patients who will respond.     

Bilateral Pharmacokinetic Interaction Between Cyclosporine A and Atorvastatin in Renal Transplant Recipients

Atorvastatin is increasingly used as a cholesterol-lowering agent in solid organ transplant recipients receiving cyclosporine A (CsA). However, the potential bilateral pharmacokinetic interaction between atorvastatin and CsA in renal transplant recipients has not previously been examined. Baseline 12-h CsA pharmacokinetic investigation was performed in 21 renal transplant recipients and repeated after 4 weeks of atorvastatin treatment (10 mg/ d). At week 4, 24-h pharmacokinetics of atorvastatin was also performed. All patients received basiliximab induction followed by CsA and prednisolone immunosuppression. Compared with historic controls, CsA-treated patients showed, on average, sixfold higher plasma HMG-CoA reductase inhibitory activity after 4 weeks of atorvastatin treatment (p < 0.05). Atorvastatin had a moderate effect on the pharmacokinetics of CsA and reduced the AUC0-12 (area under curve, 0-12h) by 9.5 +/- 18% (p = 0.013) and Cmax (maximal concentration) by 13.5 +/- 24% (p =0.009), while C12 (trough level) was unchanged (p =0.42). Total and LDL cholesterol decreased by 26.8 +/- 8.4% (p < 0.0001) and 41.5 +/- 11.0% (p < 0.0001), respectively. Bilateral pharmacokinetic interaction between atorvastatin and CsA resulted in sixfold higher plasma HMG-CoA reductase inhibitory activity, but only a moderate decrease in systemic exposure of CsA.