Ferone G.,Netherlands Cancer Institute |
Mollo M.R.,CEINGE Biotecnologie Avanzate Scarl |
Mollo M.R.,University of Naples Federico II |
Missero C.,University of Naples Federico II
Cell and Tissue Research | Year: 2015
As the outermost tissue of the body, the epidermis is the first physical barrier for any pressure, stress or trauma. Several specialized cell–matrix and cell–cell adhesion structures, together with an intracellular network of dedicated intermediate filaments, are required to confer critical resilience to mechanical stress. The transcription factor p63 is a master regulator of gene expression in the epidermis and in other stratified epithelia. It has been extensively demonstrated that p63 positively controls a large number of tissue-specific genes, including those encoding a large fraction of tissue-restricted cell adhesion molecules. Consistent with p63 functions in cell adhesion and in epidermal differentiation, heterozygous mutations clustered mainly in the p63 C-terminus are causative of AEC syndrome, an autosomal dominant disorder characterized by cleft palate, ankyloblepharon and ectodermal dysplasia associated with severe skin erosions, bleeding and infections. The molecular basis of skin erosions in AEC patients is not fully understood, although defects in desmosomes and in other cell junctions are likely to be involved. Here, we provide an extensive review of the different epidermal cell junctions that cooperate to withstand mechanical stress and on the mechanisms by which p63 regulates gene expression of their components in healthy skin and in AEC syndrome. Collectively, advancement in understanding the molecular mechanisms by which epidermal cell junctions precisely exert their functions and how p63 orchestrates their coordinated expression, will ultimately lead to insight into developing future strategies for the treatment of AEC syndrome and more in generally for diseases that share an overlapping phenotype. © 2015, Springer-Verlag Berlin Heidelberg. Source
Ilardi G.,University of Naples Federico II |
Zambrano N.,CEINGE Biotecnologie Avanzate Scarl |
Merolla F.,University of Naples Federico II |
Siano M.,University of Naples Federico II |
And 5 more authors.
Current Medicinal Chemistry | Year: 2014
Intrinsic and acquired drug resistance of tumor cells still causes the failure of treatment regimens in advanced human cancers. It may be driven by intrinsic tumor cells features, or may also arise from micro environmental influences. Hypoxia is a microenvironment feature associated with the aggressiveness and metastasizing ability of human solid cancers. Hypoxic cancer cells overexpress Carbonic Anhydrase IX (CA IX). CA IX ensures a favorable tumor intracellular pH, while contributing to stromal acidosis, which facilitates tumor invasion and metastasis. The overexpression of CA IX is considered an epiphenomenon of the presence of hypoxic, aggressive tumor cells. Recently, a relationship between CA IX overexpression and the cancer stem cells (CSCs) population has been hypothesized. CSCs are strictly regulated by tumor hypoxia and drive a major non-mutational mechanism of cancer drug-resistance. We reviewed the current data concerning the role of CA IX overexpression in human malignancies, extending such information to the expression of the stem cells markers CD44 and nestin in solid cancers, to explore their relationship with the biological behavior of tumors. CA IX is heavily expressed in advanced tumors. A positive trend of correlation between CA IX overexpression, tumor stage/grade and poor outcome emerged. Moreover, stromal CA IX expression was associated with adverse events occurrence, maybe signaling the direct action of CA IX in directing the mesenchymal changes that favor tumor invasion; in addition, membranous/cytoplasmic co-overexpression of CA IX and stem cells markers were found in several aggressive tumors. This suggests that CA IX targeting could indirectly deplete CSCs and counteract resistance of solid cancers in the clinical setting. © 2014 Bentham Science Publishers. Source
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.1.4-1;HEALTH.2012.2.3.2-1 | Award Amount: 7.81M | Year: 2013
Worldwide, 200 million people are infected with the hepatitis C virus (HCV). An estimated 15 million individuals are living with HCV infection within the EU. The economic, health and societal costs of chronic HCV infection are significant. HCV is the principal cause of death from liver disease and the leading indication for liver transplantation. The only treatment for end-stage liver disease is a liver transplant, yet the transplanted liver becomes rapidly re-infected and is frequently destroyed within 5 years after transplantation. In this cohort of patients current antiviral treatments are too toxic - there is an urgent need to develop safe and effective treatments for use in this setting. Human monoclonal antibodies (MAbs) that target virus entry, are as yet an underutilised and potentially highly effective and safe weapon in the armoury against HCV infection. The consortium has identified MAb leads which, in pre-clinical analyses, potently block HCV infection. HCV exhibits a high degree of genetic and antigenic variability, which enables the virus to escape protective immune responses. Crucially, the lead antibodies identified by the consortium are capable of preventing infection by a wide range of genetically distinct isolates because they target highly conserved epitopes on the virus or host receptor molecules. This limits the chances of virus resistance. Also, each lead antibody targets a unique component of the viral entry pathway, thereby paving the way for powerful combinatorial approaches which maximises clinical potency. HepaMAb harnesses leading expertise in MAb technology, preclinical efficacy and safety testing, biomanufacture and clinical trial to progress at least one anti-viral and one anti-receptor human MAb to phase I/IIa proof of concept clinical trial in the liver transplant setting for the prevention of graft reinfection. We will establish a much-needed therapeutic MAb pipeline for use in this solid organ transplant setting.
Nigro E.,CEINGE Biotecnologie Avanzate Scarl |
Scudiero O.,CEINGE Biotecnologie Avanzate Scarl |
Scudiero O.,University of Naples Federico II |
Sarnataro D.,CEINGE Biotecnologie Avanzate Scarl |
And 5 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2013
Adiponectin (Acrp30) exerts protective functions on metabolic and cellular processes as energy metabolism, cell proliferation and differentiation by two widely expressed receptors, AdipoR1 and AdipoR2. To date, the biological role of Acrp30 in lung has not been completely assessed but altered levels of Acrp30 and modulated expression of both AdipoRs have been related to establishment and progression of chronic obstructive pulmonary disease (COPD) and lung cancer. Here, we investigated the effects of Acrp30 on A549, a human alveolar epithelial cell line, showing how, in a time and dose-dependent manner, it decreases cell viability and increases apoptosis through ERK1/2 and AKT. Furthermore, we examined the effects of Acrp30 on A549 cells exposed to TNFa and/or IL-1ß, two potent lung inflammatory cytokines. We showed that Acrp30, in dose- and time-dependent manner, reduces cytotoxic effects of TNFa and/or IL-1ß improving cell viability and decreasing apoptosis. In addition, Acrp30 inhibits NF-?B nuclear trans-activation and induces the expression of the anti-inflammatory IL-10 cytokine without modifying that of pro-inflammatory IL-6, IL-8, and MCP-1 molecules via ERK1/2 and AKT. Finally, specifically silencing AdipoR1 or AdipoR2, we observed that NF-?B inhibition is mainly mediated by AdipoR1. Taken together, our data provides novel evidence for a direct effect of Acrp30 on the proliferation and inflammation status of A549 cells strongly supporting the hypothesis for a protective role of Acrp30 in lung. Further studies are needed to fully elucidate the Acrp30 lung effects in vivo but our results confirm this adipokine as a promising therapeutic target in lung diseases. © 2013 Elsevier Ltd. Source
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.1.2-5 | Award Amount: 3.42M | Year: 2009
This project aims to elucidate the molecular coding of meso-diencephalic dopaminergic (mdDA) neurons forming the complex meso-limbic and nigro-striatal dopaminergic system in the vertebrate central nervous system. Recent advances in molecular and developmental biology have shown that this system harbors u multitude of functional units that are defined by spatial and temporal cues and are represented by specific molecular codes. These codes are essential to understand specific mdDA neuronal pathology as Parkinsons diseases and schizophrenia. In this collaborative project we gather the expertise on early and late development, cross species molecular-coding conservation, migration and axonal pathfinding to capture the significance of the understanding of mdDA neuronal development to generate a real advance in clinical understanding and treatment of mdDA pathology.