Therapeutic angiogenesis: a new treatment approach for ischemic heart disease--Part II

Angiogenesis is the biologic process of forming new blood vessels and is being investigated as an innovative therapeutic approach to help manage ischemic heart disease and peripheral vascular disease. Research studies have identified various angiogenic growth factors and progenitor cells that can enhance new blood vessel formation. This is Part II of an article that began publication in the July/August issue of Cardiology in Review. Preclinical investigations in animal models have explored the potential use of growth factors with and without progenitor cells to treat myocardial ischemia. The results of clinical trials with growth factor infusions and gene therapy techniques to enhance growth factor production have shown some promise, but therapeutic angiogenesis remains at an early stage of development.     

Temozolomide Combined with Irradiation as Postoperative Treatment of Primary Glioblastoma Multiforme Phase I/II Study

Background and Purpose:   

The role of radiochemotherapy in the treatment of primary glioblastoma multiforme is still discussed controversially. To evaluate the feasibility and toxicity of irradiation and concomitant administration of 50 mg/m² temozolomide in patients with primary malignant glioma, this phase I/II study was conducted.     

Paradoxical sleep and memory: Long-term disruptive effects of anisomycin

The effects of the protein synthesis inhibitor Anisomycin (ANI) on Paradoxical Sleep (PS or REM sleep), slow wave sleep (SWS), and retention of one-trial inhibitory avoidance training was examined in mice in three separate experiments. In Experiment 1, mice injected with ANI 120 mg/kg and 210 mg/kg exhibited reductions in PS for 9 consecutive hours and ANI 40 mg/kg treated mice for 6 consecutive hours with no PS rebound in all three groups. ANI increased SWS commencing 3 hr postinjection, continuing for 9 consecutive hours and then returning to saline control levels. There were no significant differences between ANI-treated groups in the degree of SWS augmentation. In Experiment 2, Part A, ANI 120 mg/kg and 210 mg/kg but not ANI 40 mg/kg impaired retention measured 72 hr after training. In Experiment 2, Part B, ANI 120 mg/kg and 210 mg/kg induced amnesia from 3 to 9 hr post-training but ANI 40 mg/kg was effective only from 3 to 6 hr. In Experiment 3, the gradient of memory trace susceptibility to disruption by ECS was extended to 3 hr post-training in mice given immediate post-training injections of ANI 40 mg/kg. ANI 20 mg/kg and ANI 10 mg/kg alone or in combination with ECS was ineffective in extending the lability of the memory trace. The results of this study indicate that PS in the 3 hr period after aversively motivated training is not essential for memory processing. We suggest that memory stability and maintenance is dependent on PS occurring over a protracted time period.     

L1 on ovarian carcinoma cells is a binding partner for Neuropilin-1 on mesothelial cells

The progression of ovarian cancer is driven by a variety of cellular factors that are incompletely understood. Binding of tumor cells to normal cells and to soluble factors influence tumor growth, angiogenesis and the stimulation of vascular permeability leading to ascites production. L1 adhesion molecule is overexpressed in ovarian carcinoma and is associated with bad prognosis. One receptor for L1 is Neuropilin-1 (NRP-1) that is also known as a receptor for VEGF(165). In the nervous system a complex of NRP-1 and L1 transmits signals by the neurorepellant Sem3A that is critical for the control of neurite outgrowth. NRP-1 has also been detected in human carcinomas but its function remains unknown. Here, we have examined NRP-1 expression in ovarian carcinoma cell lines and tissue. We report that little NRP-1 protein was detected in primary ovarian carcinoma tissues or established cell lines although mRNA for soluble and transmembrane NRP-1 were detected by RT-PCR. Instead, we observed strong expression of NRP-1 in mesothelial cells, which form the lining of the peritoneum. NRP-1 could serve as an isolation marker for primary mesothelial cells present in ascites fluid. We demonstrate that ovarian cancer cells expressing L1 can bind to NRP-1 overexpressing cells and mesothelial cells. Likewise, soluble L1 isolated from ascites of patients or produced as a fusion protein could bind to NRP-1 overexpressing cells and a direct interaction was demonstrated at the protein level. These findings suggest that L1 can support the binding of ovarian carcinoma cells to mesothelial cells via NRP-1. The L1-NRP-1 binding pathway could contribute to the growth of ovarian carcinomas and to reciprocal signalling between mesothelial cells and tumors.     

MicroRNA-145 Targets the Metalloprotease ADAM17 and Is Suppressed in Renal Cell Carcinoma Patients

A disintegrin and metalloproteinase 17 (ADAM17) is a metalloprotease that is overexpressed in many cancer types, including renal cancers. However, the regulatory mechanisms of ADAM17 in cancer development and progression are poorly understood. In the present work, we provide evidence using overexpression and inhibition of microRNA 145 (miR-145) that miR-145 negatively regulates ADAM17 expression. Furthermore, we show that ADAM17 negatively regulates miR-145 through tumor necrosis factor-α, resulting in a reciprocal negative feedback loop. In this study, the expression of ADAM17 and miR-145 correlated negatively in renal cancer tumor tissues and cell lines, suggesting an important regulatory mechanism. Additionally, we showed that the regulation of ADAM17 is partly involved in the effects of miR-145 on proliferation and migration, whereas no involvement in chemosensitivity was observed. Importantly, in the healthy kidney, miR-145 was detected in different cell types including tubular cells, which are considered the origin of renal cancer. In renal cancer cell lines, miR-145 expression was strongly suppressed by methylation. In summary, miR-145 is downregulated in renal cancer patients, which leads to the up-regulation of ADAM17 in renal cancer. Importantly, miR-145 and ADAM17 are regulated in a reciprocal negative feedback loop.     

Reirradiation of Recurrent WHO Grade III Astrocytomas Using Fractionated Stereotactic Radiotherapy (FSRT)

PURPOSE: To assess the effect of reirradiation in recurrent WHO grade III astrocytomas. PATIENTS AND METHODS: From January 1995 to July 2003, 40 patients with grade III gliomas were treated with fractionated stereotactic reirradiation at the time point of recurrence. Median size of planning target volume for reirradiation was 56.2 ml (range 25.1-296.2 ml). A median target total dose of 36 Gy (range 20-57.6 Gy) was applied using a median fractionation of 5 x 2 Gy/week with a 6-MeV linear accelerator. RESULTS: Radiotherapy was well tolerated by all patients. No toxicities > CTC grade 2 developed. Median overall survival calculated from the time point of primary diagnosis was 48 months (range 7-180 months). The 5- and 10-year overall survival rates were 49.5% and 24.7%, respectively. From the time point of reirradiation, median survival was 16 months (range 1-98 months). Median progression-free survival from the time point of reirradiation was 8 months (range 1-72 months). No prognosticators for survival or progression-free survival after reirradiation could be identified. CONCLUSION: Fractionated stereotactic radiotherapy is well tolerated and effective in patients with recurrent grade III astrocytomas.