Effects of ubiquitin-proteasome system deregulation on the vascular senescence and atherosclerosis process in elderly patients.

BACKGROUND: The role of the ubiquitin-proteasome system in the vascular senescence and atherosclerotic progression of elderly patients is unclear. We evaluated ubiquitin-proteasome activity in carotid plaques of asymptomatic elderly and adult patients. METHODS: Plaques were obtained from 28 elderly and 18 adult patients undergoing carotid endarterectomy. Plaques were analyzed for ubiquitin levels, proteasome 20S activity, p16 and p53, nitrotyrosine, matrix metalloproteinase-9 (MMP-9) and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay). Serial sections were incubated with specific antibodies anti-human leukocyte antigen (HLA)-DR, anti CD68 and anti-CD3. RESULTS: Compared to plaques obtained from adult patients, plaques of elderly patients had more ubiquitin levels (257.4 +/- 118.9 ng/mg vs 110 +/- 14.4 ng/mg, p <.001), nitrotyrosine (3.8 +/- 0.55 nmol/pg vs 1.1 +/- 0.19 nmol/pg, p <.001), p53 and p16 staining (p <.01), and MMP-9 levels (14.6 +/- 2.5 microg/mg vs 3.2 +/- 0.1.8 microg/mg, p <.001), along with a lesser collagen content (21.9 +/- 4.8% vs 7.1 +/- 2.8%, p <.05) and less proteasome 20S activity (24.2 +/- 6.9 pmol/mg vs 78.4 +/- 10.3 pmol/mg, p <.001). CONCLUSIONS: Our data suggest that reduction of proteasome activity promotes vascular cell senescence, thereby contributing to the pathogenesis of human atherosclerosis.

Adjuvant electrochemotherapy for the treatment of incompletely excised spontaneous canine sarcomas.

Electrochemotherapy (ECT) is a new therapeutical technique that combines the administration of trains of biphasic pulses with the local application of poorly permeant anticancer molecules, thus obtaining increased chemotherapy uptake. The purpose of this study was to prospectively assess the adjuvant potentialities of ECT for the treatment of different incompletely excised canine sarcomas. Twenty-two privately owned dogs with incomplete surgical excision of high grade sarcomas were treated with bleomycin injected within the tumor bed (1.5 IU/mg) followed by the sequential application of trains of biphasic pulses (8 pulses, 1300 V/cm, 50+50 micros duration, 1 Hz frequency). The overall response rate was 95% (21 out of 22 patients) with a mean time to recurrence of 730 days. At the time of writing 11 dogs were still in remission, three dogs had died of unrelated causes, one had local recurrence and the owner declined further treatment, one had limb amputation following recurrence, four had both local recurrence and distant metastases that led to euthanasia, and two were retreated following tumor recurrence and are disease free at 850 and 1947 days. The only observed toxicity was wound dehiscence in three patients. Electrochemotherapy is well tolerated and has effectiveness against incompletely excised sarcomas in companion animals. Further investigations are warranted to improve the currently available protocols.

Local control and distant metastasis after electrochemotherapy of a canine anal melanoma.

Canine anal melanoma is an aggressive neoplasm that rapidly leads to constipation in dogs, thus mimicking the behavior of their human counterpart. In this paper, the successful local palliation of this neoplasm is described using cisplatin selectively driven within the tumor cells by trains of biphasic pulses. The dog experienced tumor reduction with restoration of normal defecation for three months, then experienced massive dissemination to the sublumbar lymph nodes that led to intestinal obstruction and euthanasia. Electrochemotherapy (ECT) is a safe palliative therapy for such neoplasm and warrants further investigations in dogs as well humans.