Single nucleotide polymorphisms in DNA glycosylases: From function to disease.

Oxidative stress is associated with a growing number of diseases that span from cancer to neurodegeneration. Most oxidatively induced DNA base lesions are repaired by the base excision repair (BER) pathway which involves the action of various DNA glycosylases. There are numerous genome wide studies attempting to associate single-nucleotide polymorphisms (SNPs) with predispositions to various types of disease; often, these common variants do not have significant alterations in their biochemical function and do not exhibit a convincing phenotype.

Overexpression of parkin rescues the defective mitochondrial phenotype and the increased apoptosis of Cockayne Syndrome A cells.

The ERCC8/CSA gene encodes a WD-40 repeat protein (CSA) that is part of a E3-ubiquitin ligase/COP9 signalosome complex. When mutated, CSA causes the Cockayne Syndrome group A (CS-A), a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. CS-A cells features include ROS hyperproduction, accumulation of oxidative genome damage, mitochondrial dysfunction and increased apoptosis that may contribute to the neurodegenerative process.

Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and specific tumor infiltration.

Purpose: Immunotherapy is a promising antitumor strategy, which can be successfully combined with current anticancer treatments, as suggested by recent studies showing the paradoxical chemotherapy-induced enhancement of the immune response. The purpose of the present work is to dissect the biological events induced by chemotherapy that cooperate with immunotherapy in the success of the combined treatment against cancer. In particular, we focused on the following: (a) cyclophosphamide-induced modulation of several cytokines, (b) homeostatic proliferation of adoptively transferred lymphocytes, and (c) homing of transferred lymphocytes to secondary lymphoid organs and tumor mass.

[HIV protease inhibitors for the treatment of Kaposi's sarcoma].

A reduced incidence or the regression of Kaposi's sarcoma (KS) has been described in HIV-infected patients treated with HIV-protease inhibitors (PI). We have recently demonstrated that PI block the angiogenesis and the development of KS lesions induced experimentally in vivo by the inoculation of angiogenic factors or human primary KS cells. These effects of PI occur at the same drug concentrations in plasma of treated individuals, and they are due to the inhibition of cell invasion and of the activation of matrix metalloprotease-2, an enzyme that is key to angiogenesis and tumor growth and invasion.

Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin.

Background: The role of dietary components in cancer progression and metastasis is an emerging field of clinical importance. Many stages of cancer progression involve carbohydrate-mediated recognition processes. We therefore studied the effects of high pH- and temperature-modified citrus pectin (MCP), a nondigestible, water-soluble polysaccharide fiber derived from citrus fruit that specifically inhibits the carbohydrate-binding protein galectin-3, on tumor growth and metastasis in vivo and on galectin-3-mediated functions in vitro.

Treatment of Kaposi's sarcoma--an update.

Kaposi's sarcoma (KS) is an angioproliferative disease of multifactorial origin arising in different clinic-epidemiologic forms, which show the same histopathological features. It generally starts as a hyperplastic reactive-inflammatory and angiogenic process, which may evolve into monomorphic nodules of KS cells that can be clonal (late-stage lesions) and resemble a true sarcoma. Infection with the human herpesvirus 8, cytokine- and angiogenic factor-induced growth together with an immuno-dysregulated state represent fundamental conditions for the development of this tumor.

NK cell activity controls human herpesvirus 8 latent infection and is restored upon highly active antiretroviral therapy in AIDS patients with regressing Kaposi's sarcoma.

Kaposi's sarcoma (KS) develops upon reactivation of human herpesvirus 8 (HHV8) infection and virus dissemination to blood and tissue cells, including endothelial and KS spindle cells where the virus is mostly present in a latent form. However, this may likely require the presence of compromised host immune responses and/or the evasion of infected cells from the host immune response. In this regard, mechanisms of evasion of productively infected cells from both CTL and NK cell responses, and resistance of latently infected cells from specific CTL, have already been shown.

HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma.

Treatment with HIV-1 protease inhibitors (PI) is associated with a reduced incidence or regression of Kaposi sarcoma (KS). Here we show that systemic administration of the PIs indinavir or saquinavir to nude mice blocks the development and induces regression of angioproliferative KS-like lesions promoted by primary human KS cells, basic fibroblast growth factor (bFGF), or bFGF and vascular endothelial growth factor (VEGF) combined. These PIs also block bFGF or VEGF-induced angiogenesis in the chorioallantoic membrane assay with a potency similar to paclitaxel (Taxol).