Francesca Rappa - Academia.edu (original) (raw)

Papers by Francesca Rappa

International Journal of Molecular Sciences

Thyroid cancers are the most common of the endocrine system malignancies and progress must be mad... more Thyroid cancers are the most common of the endocrine system malignancies and progress must be made in the areas of differential diagnosis and treatment to improve patient management. Advances in the understanding of carcinogenic mechanisms have occurred in various fronts, including studies of the chaperone system (CS). Components of the CS are found to be quantitatively increased or decreased, and some correlations have been established between the quantitative changes and tumor type, prognosis, and response to treatment. These correlations provide the basis for identifying distinctive patterns useful in differential diagnosis and for planning experiments aiming at elucidating the role of the CS in tumorigenesis. Here, we discuss studies of the CS components in various thyroid cancers (TC). The chaperones belonging to the families of the small heat-shock proteins Hsp70 and Hsp90 and the chaperonin of Group I, Hsp60, have been quantified mostly by immunohistochemistry and Western blo...

Exosomes have recently been proposed as novel elements in the study of intercellular communicatio... more Exosomes have recently been proposed as novel elements in the study of intercellular communication in normal and pathological conditions. The biomolecular composition of exosomes reflects the specialized functions of the original cells. Heat shock proteins (Hsps) are a group of chaperone proteins with diverse biological roles. In recent years, many studies have focused on the extracellular roles played by Hsps that appear to be involved in cancer development and immune system stimulation. Hsps localized on the surface of exosomes, secreted by normal and tumour cells, could be key players in intercellular cross-talk, particularly during the course of different diseases, such as cancer. Exosomal Hsps offer significant opportunities for clinical applications, including their use as potential novel biomarkers for the diagnoses or prognoses of different diseases, or for therapeutic applications and drug delivery.

Endocrine research, Jan 23, 2016

The purpose of the present study was to investigate the influence of endogenous glucagon-like pep... more The purpose of the present study was to investigate the influence of endogenous glucagon-like peptide-2 (GLP-2) on lipid profile in mice fed a standard diet (STD) or a high-fat diet (HFD). HFD- and age-matched STD mice were injected once a day with GLP-2 (3-33), a GLP-2 receptor (GLP-2R) antagonist, or vehicle for 4 weeks. HFD mice displayed increased intrahepatic lipid concentration and hepatic steatosis and higher plasma concentrations of cholesterol, LDL, AST, and ALT than STD mice. No difference was observed in lipid fecal elimination. In STD mice, the chronic treatment with GLP-2 (3-33) did not affect any parameter, while in HFD mice, it enhanced plasma triglycerides, cholesterol, ALT, and AST and reduced HDL, it increased intrahepatic lipid concentration, and it worsened the hepatic steatosis degree, without affecting lipid fecal elimination. The present results suggest that GLP-2R antagonism worsens lipid disorders in HFD mice, and endogenous GLP-2 might even exert a defensiv...

Journal of Cellular Physiology, 2016

Mild exercise training may positively affect the course of Duchenne Muscular Dystrophy (DMD). Tra... more Mild exercise training may positively affect the course of Duchenne Muscular Dystrophy (DMD). Training causes mild bronchial epithelial injury in both humans and mice, but no study assessed the effects of exercise in mdx mice, a well known model of DMD. The airway epithelium was examined in mdx (C57BL/10ScSn-Dmdmdx) mice, and in wild type (WT, C57BL/10ScSc) mice either under sedentary conditions (mdx-SD, WT-SD) or during mild exercise training (mdx-EX, WT-EX). At baseline, and after 30 and 45 days of training (5 d/wk for 6 weeks), epithelial morphology and markers of regeneration, apoptosis, and cellular stress were assessed. The number of goblet cells in bronchial epithelium was much lower in mdx than in WT mice under all conditions. At 30 days, epithelial regeneration (PCNA positive cells) was higher in EX than SD animals in both groups; however, at 45 days, epithelial regeneration decreased in mdx mice irrespective of training, and the percentage of apoptotic (TUNEL positive) cells was higher in mdx-EX than in WT-EX mice. Epithelial expression of HSP60 (marker of stress) progressively decreased, and inversely correlated with epithelial apoptosis (r = -0.66, p = 0.01) only in mdx mice. Lack of dystrophin in mdx mice appears associated with defective epithelial differentiation, and transient epithelial regeneration during mild exercise training. Hence, lack of dystrophin might impair repair in bronchial epithelium, with potential clinical consequences in DMD patients. This article is protected by copyright. All rights reserved.

Objectives: Alcoholism is one of the most devastating diseases with high incidence, but knowledge... more Objectives: Alcoholism is one of the most devastating diseases with high incidence, but knowledge of its pathology and treatment is still plagued with gaps mostly because of the inherent limitations of research with patients. We developed an animal model for studying liver histopathology, Hsp (heat-shock protein)-chaperones involvement, and response to treatment. Methods: The system was standardized using mice to which ethanol was orally administered alone or in combination with Lactobacillus fermentum following a precise schedule over time and applying, at predetermined intervals, a battery of techniques (histology, immunohistochemistry, western blotting, real-time PCR, immunoprecipitation, 3-nitrotyrosine labeling) to assess liver pathology (e.g., steatosis, fibrosis), and Hsp60 and iNOS (inducible form of nitric oxide synthase) gene expression and protein levels, and post-translational modifications. Results: Typical ethanol-induced liver pathology occurred and the effect of the probiotic could be reliably monitored. Steatosis score, iNOS levels, and nitrated proteins (e.g., Hsp60) decreased after probiotic intake. Conclusions: We describe a mouse model useful for studying liver disease induced by chronic ethanol intake and for testing pertinent therapeutic agents, e.g., probiotics. We tested L. fermentum, which reduced considerably ethanol-induced tissue damage and deleterious post-translational modifications of the chaperone Hsp60. The model is available to test other agents and probiotics with therapeutic potential in alcoholic liver disease.

Cancer research, Jan 15, 2016

Aging is a major risk factor for progression of liver diseases to hepatocellular carcinoma (HCC).... more Aging is a major risk factor for progression of liver diseases to hepatocellular carcinoma (HCC). Cellular senescence contributes to age-related tissue dysfunction, but the epigenetic basis underlying drug-induced senescence remains unclear. macroH2A1, a variant of histone H2A, is a marker of senescence-associated heterochromatic foci that synergizes with DNA methylation to silence tumor-suppressor genes in human fibroblasts. In this study, we investigated the relationship between macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, and liver carcinogenesis. We found that protein levels of both macroH2A1 isoforms were increased in the livers of very elderly rodents and humans, and were robust immunohistochemical markers of human cirrhosis and HCC. In response to the chemotherapeutic and DNA-demethylating agent 5-aza-deoxycytidine (5-aza-dC), transgenic expression of macroH2A1 isoforms in HCC cell lines prevented the emergence of a senescent-like phenotype and induced synergistic ...

European Respiratory Journal, Sep 1, 2014

Cell Stress and Chaperones, 2015

CD1a is involved in presentation to the immune system of lipid antigen derived from tumor cells w... more CD1a is involved in presentation to the immune system of lipid antigen derived from tumor cells with subsequent T cell activation. Hsp60 is a molecular chaperone implicated in carcinogenesis by, for instance, modulating the immune reaction against the tumor. We have previously postulated a synergism between CD1a and Hsp60 as a key factor in the activation of an effective antitumor immune response in squamous epithelia. Keratoacantomas (KAs) are benign tumors that however can transform into squamous cell carcinomas (SCCs), but the reasons for this malignization are unknown. In a previous study, we found that CD1a-positive cells are significantly more numerous in KA than in SCC. In this study, we analyzed a series of KAs and SCCs by immunohistochemistry for CD1a and Hsp60. Our results show that the levels of both are significantly lower in KA than in SCC and support the hypothesis that KA may evolve towards SCC if there is a failure of the local modulation of the antitumor immune response. The data also show that immunohistochemistry for CD1a and Hsp60 can be of help in differential diagnosis between KAs and well-differentiated forms of SCC.

European Respiratory Journal, 2015

European journal of histochemistry: EJH

The FASEB Journal

The epigenetic basis of age-associated progression of liver diseases towards hepatocellular carci... more The epigenetic basis of age-associated progression of liver diseases towards hepatocellular carcinoma (HCC) is unclear. MacroH2A1 is a variant of histone H2A1, present in the two isoforms, with fundamental roles in cell homeostasis. MacroH2A1 is a marker of senescence associated heterochromatic foci (SAHF) and synergizes with DNA demethylating chemotherapic agent 5-aza-2'-deoxycytidine (5-aza-dC) in silencing tumor suppressor genes in human fibroblasts. We show that protein levels of macroH2A1 isoforms are increased in the livers of old rodents and humans, and in human HCC tissue. Human HCC cells overexpressing macroH2A1 escape a 5-aza-dC-induced senescent phenotype, as determined by cell proliferation/migration/cell cycle assays and b-gal staining, and exhibit a synergistic global DNA hypomethylation. Deletion of macroH2A1 had opposite, pro-senescence effects in presence of drug dependent DNA hypomethylation. System analysis of ChIP-Seq combined with RNA-Seq data revealed compl...

Cell-to-cell communication is imperative for life. Intercellular communications are mediated thro... more Cell-to-cell communication is imperative for life. Intercellular communications are mediated through "sending" and "receiving" information via the secretion and subsequent receptor-mediated detection of biomolecular species (1). Each type of cell exhibits a particular set of receptors that allows it to respond to a corresponding number of signal molecules produced by other cells and these ligands act in combination to influence cell behavior (1). There are many pathways of intercellular communication such as the presence of signaling molecules on plasma membranes or secretion of soluble ligands. A number of evidences have now demonstrated new mechanisms of intercellular interaction through lipid vesicles (2, 3). The extracellular vesicles are constituted by a lipid bilayer that contains in its lumen both transmembrane and free proteins, RNA and microRNA; based on their composition and size these vesicles can be categorized into various classes such as exosomes, apoptotic bodies, microparticles, etc. (4). In recent years many studies have focused on exosomes, a particularly important class of extracellular vesicles (5). Exosomes are 30-100 nm wide membranous vesicles first described in 1984 by Pan and Johnstone in maturing mammalian reticulocytes as a mechanism for removal of plasma membrane proteins (6); over the years they have been observed to be secreted into the culture medium from a large number of cell types, including T cells, B cells, dendritic cells, platelets, epithelial cells and cancer cells (3,. Recent studies have reported the isolation and characterization of these vesicles in Invited Commentary © EUROMEDITERRANEAN BIOMEDICAL JOURNAL 2013, 8(22):137-139. Available on-line at: http://www.embj.org

Journal of Cellular Physiology, 2015

Glucagon like peptide-2 (GLP-2) is a gastrointestinal hormone released in response to dietary nut... more Glucagon like peptide-2 (GLP-2) is a gastrointestinal hormone released in response to dietary nutrients, which acts through a specific receptor, the GLP-2 receptor (GLP-2R). The physiological effects of GLP-2 are multiple, involving also the intestinal adaptation to high fat diet (HFD). In consideration of the well-known relationship between chronic HFD and impaired glucose metabolism, in the present study we examined if the blocking of the GLP-2 signaling by chronic treatment with the GLP-2R antagonist, GLP-2 (3-33), leads to functional consequences in the regulation of glucose metabolism in HFD-fed mice. Compared with animals fed standard diet (STD), mice at the tenth week of HFD showed hyperglycaemia, glucose intolerance, high plasma insulin level after glucose load, increased pancreas weight and β cell expansion, but not insulin resistance. In HFD fed mice, GLP-2 (3-33) treatment for four weeks (from the sixth to the tenth week of diet) did not affect fasting glycaemia, but it significantly increased the glucose intolerance, both fasting and glucose-induced insulin levels, and reduced the sensitivity to insulin leading to insulin-resistance. In GLP-2 (3-33)-treated HFD mice pancreas was significantly heavier and displayed a significant increase in β-cell mass in comparison with vehicle-treated HFD mice. In STD mice, the GLP-2 (3-33) treatment did not affect fasted or glucose-stimulated glycemia, insulin, insulin sensitivity, pancreas weight and beta cell mass. The present study suggests that endogenous GLP-2 may act as a protective factor against the dysregulation of the glucose metabolism that occurs in HFD mice, because GLP-2 (3-33) worsens glucose metabolism disorders. This article is protected by copyright. All rights reserved.

BMC cancer, Jan 26, 2004

A case of Primitive Neuroectodermal Tumor (PNET) of the kidney in a 27-year-old woman is presente... more A case of Primitive Neuroectodermal Tumor (PNET) of the kidney in a 27-year-old woman is presented. Few cases are reported in the literature with a variable, nonspecific presentation and an aggressive behaviour. In our case, a radical nephrectomy with lymphadenectomy was performed and there was no residual or recurrent tumour at 24-month follow-up. The surgical specimens were formalin-fixed and paraffin embedded. The sections were stained with routinary H&E. Immunohistochemistry was performed. The immunohistochemical evaluation revealed a diffuse CD99 positivity in the cytoplasm of the neoplastic cells. Pankeratin, cytokeratin AE1/AE3, vimentin, desmin, S100, cromogranin were negative. The clinical presentation and the macroscopic aspect, together with the histological pattern, the cytological characteristic and the cellular immunophenotype addressed the diagnosis towards primary PNET of kidney. Since sometimes it is difficult to discriminate between PNET and Ewing's tumour, we ...

European journal of histochemistry : EJH, 2003

We selected 63 prostate tumors with Gleason's grade 6 (3+3), commonly showing both tubular an... more We selected 63 prostate tumors with Gleason's grade 6 (3+3), commonly showing both tubular and cribrous patterns. We compared in both patterns the expression of two of the most used biologic markers: PCNA and p53, with the aim to verify the validity of the Gleason's grading system to compare the morphologic grade with biologic aggressiveness and prognostic value. We did not find any statistical difference in the protein immunopositivity, indicating that both patterns could have identical biologic behaviour; then we confirmed the validity of Gleason's system for considering both tubular and cribrous patterns as an intermediate grade of tumoral differentiation. Moreover, we found a linear relationship between the increase of PCNA and the accumulation of mutated p53; this datum could confirm the hypothesis that p53 mutation is a late event in prostate carcinogenesis.