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Biomedical subjects

Furio Pezzetti

Publications and source records attributed to Furio Pezzetti.

At least 19 recordsLinked to original sources
PubMed2006

TGFbeta3 expression in non-syndromic orofacial clefts.

BACKGROUND: Genetic studies have demonstrated that non-syndromic cleft is composed of two separate entities - cleft palate only (CPO) and cleft of lip, alveolus with or without cleft palate (CL+/-P) -, both have a heterogeneous genetic background and environmental factors contribute to the onset of these malformations. Previous studies have shown that TGFbeta3 could be involved in these diseases, but no conclusive results have been reached. PURPOSE: In order to detect if TGFbeta3 has a role in cleft diseases, a series of non-syndromic cleft patients and controls are analyzed for TGFbeta3 protein expression. MATERIAL AND METHODS: Forty-three non-syndromic cleft patients and 21 unaffected subjects were involved in this study. Paraffin-embedded specimens were matched with the TGFbeta3 antibody and then scanned with a computerized image analyzer. TGFbeta3 was found to be absent (less than 10%), moderate (from 10% to 30%) and highly expressed (higher than 30%) in epithelium (EP), minor palatal salivary gland (GL) and fibres of elevator palati muscle (MU). Data was statistically analyzed with a Kruskal-Wallis test. RESULTS: Only GL and EP have a statistically significant lower expression in non-syndromic cleft compared to unaffected subjects. A subsequent comparison between CL+/-P and CPO groups demonstrates a statistically significant difference only for GL, with a lower expression in GL of CPO patients. CONCLUSIONS: TGFbeta3 is decreasingly expressed in GL of unaffected CL+/-P and CPO patients and thus further strength is given to a pathogenetic role of TGFbeta3 in the onset of clefts.

Case-Control Studies↗
PubMed2006

Study of four genes belonging to the folate pathway: transcobalamin 2 is involved in the onset of non-syndromic cleft lip with or without cleft palate.

Cleft lip with or without cleft palate (CL/P) is the most common inborn craniofacial anomaly. Affected individuals require extensive medical and psychosocial support. Although CL/P has a complex and poorly understood etiology, increasing evidence of folate pathway involvement has been collected. So far, only the MTHFR gene has been extensively investigated as a risk factor for CL/P, while little has been done to test genetic variations in the folate biosynthetic pathways that may influence the infant's susceptibility to these birth defects. To date, this paper presents the first attempt to verify the involvement of four genes belonging to the folate pathway in nonsyndromic cleft onset. We used a case-parent triad design to test for linkage disequilibrium in the case of seven SNPs mapping on four different genes: transcobalamin 1 and 2 (TCN1 and TCN2), methionine synthase (MTR), and MTR reductase (MTRR). Our finding suggests that TCN2 is involved in causing CL/P. Indeed, significant overtransmission of the C allele was observed at the polymorphism c.776C>G (p.Pro259Arg) to the affected offspring (P=0.01). Results obtained with additional TCN2 polymorphisms suggest that c.776C>G may be functionally related to CL/P. However, because conflicting data exist with regard to the effect of the polymorphism in transcobalamin 2 function or in perturbing plasma levels of key molecules in the folate pathway, further investigation is warranted to confirm our data.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2006

Genetic effects of Medpor on osteoblast-like cells.

Porous polyethylene (PP or Medpor) is an alloplastic material used worldwide for craniofacial reconstruction. Although several clinical studies are available, there is a lack as regard the genetic effects. Because PP is always fixed on bone and the mechanism by which PP acts on osteoblasts is unknown, we therefore attempted to address this question by using microarray techniques to identify genes that are differently regulated in osteoblasts exposed to PP. By using DNA microarrays containing 19,200 genes, we identified in osteoblast-like cell lines (i.e. MG-63) cultured on PP several genes where expression was differentially regulated. The differentially expressed genes cover a broad range of functional activities: 1) signal transduction, 2) transcription, 3) translation, 4) cell cycle regulation, 5) vesicular transport, and 6) production of cytoskeletal elements, cell-adhesion molecules and extracellular matrix components. The data reported are, to our knowledge, the first genetic portrait of osteoblast-like cells cultured on PP. They are relevant to better understanding of the molecular mechanism of bone-PP interaction and as a model for comparing other materials used for bone reconstruction.

Bone Substitutes↗
PubMed2005

Genetic effects of anorganic bovine bone (Bio-Oss) on osteoblast-like MG63 cells.

Bio-Oss (Geistlich, Wolhusen, Switzerland) is composed by anorganic bovine bone and is widely used in several bone regeneration procedures in oral surgery. How this biomaterial alters osteoblast gene expression to promote bone formation is poorly understood. We therefore attempted to address this question by using microarray techniques to identify genes that are differentially regulated in osteoblasts exposed to Bio-Oss. By using DNA microarrays containing 20,000 genes, we identified in osteoblast-like cells line (MG-63) cultured with Bio-Oss several genes which expression was significantly up- and down-regulated. The differentially expressed genes cover a broad range of functional activities: (a) signaling transduction, (b) transcription, (c) cell cycle regulation, (d) vesicular transport, (e) apoptosis, and (f) immunity. These results could explain the reported bioaffinity of Bio-Oss to host animals, its biological affinity to osteogenic cells and its capability to stimulate osteoblastic differentiation. The data reported are, to our knowledge, the first genetic portrait of Bio-Oss effects. They can be relevant to our improved understanding of the molecular mechanism underlying bone regenerative procedures and as a model for comparing other materials with similar clinical effects.

Animals↗
PubMed2005

Study of folate receptor genes in nonsyndromic familial and sporadic cleft lip with or without cleft palate cases.

Folate receptor family members (FOLRs) mediate the delivery of 5-methyltetrahydrofolate to the interior of, out of within, or between cells in a process known as potocytosis. Three FOLRs and a pseudogene map to 11q13.4. The aim of this study was to verify whether FOLRs could be responsible for the onset of nonsyndromic cleft lip with or without cleft palate (CL/P). Linkage and linkage disequilibrium between genetic markers and disorder were analyzed. Patients and their mothers from 71 familial CL/P pedigrees and 75 sporadic cases from Italian population were investigated by PCR-SSCP analysis. Data from mutation scanning allowed us to find only a silent mutation in FOLR1 present in a mother and her child. Our findings do not support FOLR1 and FOLR2 genes in the onset of CL/P.

Carrier Proteins↗
PubMed2005

Effect of Vitamin C on pre-osteoblast gene expression.

Ascorbic acid (AA), also known as Vitamin C, is a cofactor required for the function of several hydroxylases. It is not synthesised in humans and has to be provided by diet. Its absence is responsible for scurvy, a condition related to the defective synthesis of collagen by the reduced function of prolylhydroxylase. AA is also a risk factor for periodontal disease. Recently, it has been shown that AA induces embryonic stem cells to differentiate into osteoblasts. The mechanism by which AA sustains pre-osteoblast proliferation and commitment is mediated through the synthesis of collagen type I, interaction with alpha2- and beta1-integrin, activation of the mitogen-activated protein kinase pathway, and phosphorylation of osteoblast-specific transcription factors. However, the multifunctional role of AA is not fully elucidated. MC3T3-E1 mouse calvaria-derived cell line is a well-defined in vitro model of pre-osteoblast differentiation, and AA is essential for the proliferation and differentiation of MC3T3-E1. By using DNA micro-arrays containing 15,000 genes, we identified several genes in MC3T3-E1 cultured with AA for 24h whose expression was significantly up or downregulated. The differentially expressed genes covered a broad range of functional activities: (1) cell growth; (2) metabolism; (3) morphogenesis; (4) cell death; (5) cell communication. The data reported are, to our knowledge, the first genetic portrait of early stage stimulation of pre-osteoblasts by AA, and may be relevant to better understand the molecular mechanism of pre-osteoblast proliferation and commitment. Elucidation of the molecular mechanism has important clinical implications because it may facilitate the correct use of AA to accelerate bone regeneration.

3T3 Cells↗
PubMed2005

P253R fibroblast growth factor receptor-2 mutation induces RUNX2 transcript variants and calvarial osteoblast differentiation.

Unregulated fibroblast growth factor 2 (FGF2) signaling caused by mutations in the fibroblast growth factor receptor (FGFR2) leads to human craniosynostosis such as the Apert syndrome. In an in vitro control model of calvarial osteoblasts from Apert patients carrying the FGFR2 P253R mutation, we studied the changes in cellular phenotype and evaluated the effects of FGF2. Compared with wild-type controls, osteocalcin mRNA was down-regulated in Apert osteoblasts, Runt-related transcription factor-2 (RUNX2) mRNA was differentially spliced, and FGF2 secretion was greater. Total protein synthesis, fibronectin and type I collagen secretion were up-regulated, while protease and glycosidase activities and matrix metalloproteinase-13 (MMP-13) transcription were decreased, suggesting an altered ECM turnover. Adding FGF2 increased protease and glycosidase activities and down-regulated fibronectin and type I collagen secretion in Apert osteoblasts. High affinity FGF2 receptors were up-regulated in Apert osteoblasts and analysis of signal transduction showed elevated levels of Grb2 tyrosine phosphorylation and the Grb2-p85 beta association, which FGF2 stimulation strongly reduced. All together these findings suggest increased constitutive receptor activity in Apert mutant osteoblasts and an autocrine loop involving the FGF2 pathway in modulation of Apert osteoblast behavior.

Acrocephalosyndactylia↗
PubMed2005

Genetic portrait of mild and severe lingual dysplasia.

Squamous cell carcinoma is the most frequent malignant tumor of the oral cavity and often arises from premalignant lesions. Traditional methods used by the pathologist are subjective and lack the sensitivity to predict accurately which precancers may progress with time. Therefore, it is important to search for markers that may identify progression of premalignant lesions. Microarray technology can be use with this aim. Here, we define the genetic expression profile of lingual dysplasia (DS) progression. By using cDNA microarray containing 19.2K clones and a baseline of 11 normal tissues, we compared 5 mild and 4 severe DS. We identified 270 genes differentially expressed in normal tissue vs. mild DS (i.e. 161 up- and 109 down-regulated) and 181 genes differentially expressed in mild vs. severe DS (i.e. 63 up- and 118 down-regulated). The described genes cover a broad range of functional activities: (a) anti-oxidative, (b) DNA-repair, (c) inflammatory response, (d) cell-adhesion/mobility, (e) extracellular matrix depolymerization, and (f) cell-cycle regulation. The data reported better define DS progression and can help in classifying premalignant lesions.

Adult↗
PubMed2005

An in vitro model for dissecting distraction osteogenesis.

Distraction osteogenesis (DO) is a mechanotransduction process capable of generating viable osseous tissue by the gradual separation of osteotomized bone edges. Several variables are implicated in DO: magnitude of mechanical strain, distraction rate, and type of distracted bone. The combination of these factors acts on different types of cells inducing apoptosis, cell proliferation, and differentiation. The elucidation of the molecular mechanisms has important clinical implications because it may facilitate the use of recombinant proteins or gene therapy to accelerate bone regeneration. Previous reports have analyzed several molecules such as extracellular matrix proteins, cytokines, bone morphogenetic proteins, hormones, and angiogenic factors. Moreover, a single protein can have multifunctional roles. With such a huge number of mechanical, histologic, cellular, and molecular variables, there is the need to have a cell culture model that enables the selection of the effect of a specific strength to a single cell type at different time points and with or without cytokines. The analysis of the genetic profiling of a cell line cultured on an equibiaxial stretch device has such characteristic. Because there is a recruitment and commitment of preosteoblastic cells during bone lengthening and no previous report has focus on them, the authors used a preosteoblast MC3T3-E1 cell line to detect the early molecular effects of distraction on mesenchymal cells. By using DNA microarrays containing 15,000 clones, the authors identified several genes the expression of which was significantly up- or down-regulated. The differentially expressed genes cover a broad range of biological processes: cell growth, metabolism, morphogenesis, cell communication, response to stress, and cell death. The data reported are the first genetic portrait of stretched preosteoblasts. They can be relevant in the better understanding of the molecular mechanism of DO and as a model for comparing the effect of distraction on different cell lines and primary cultures, rate and strength of distraction, and with or without cytokines.

3T3 Cells↗
PubMed2005

Apert and Crouzon syndromes: clinical findings, genes and extracellular matrix.

Apert and Crouzon syndromes are well known craniostenosis. In the last 10 years several studies were performed to provide a better understanding of the etiology and pathogenesis of these diseases. Both have an autosomal dominant mode of transmission, and a mutation in the gene encoding for the fibroblast growth factor receptor 2 (FGFR2) is the cause in most patients. However, the fact that the same mutation can produce a wide range of phenotypic expression makes the mechanism of anomalous development more complex. The extracellular matrix (ECM) is composed of proteins, glycosaminoglycans, and cytokines that are secreted in an autocrine and paracrine manner and are able to modify the ECM. Fibroblast growth factors are complexed with heparan sulfate, a component of the ECM, before binding the FGFR2. Data exist about different expressions of cytokines and ECM macromolecule in craniostenosis-derived fibroblasts and osteoblasts. Changes in ECM composition could explain the altered osteogenic process and account for pathologic variations in cranial development in addition to the FGFR2 mutations.

Acrocephalosyndactylia↗
PubMed2005

Genetic profiling of central giant cell granuloma of the jaws.

Central giant cell granuloma (CGCG) of the jaws is a central osteolytic lesion characterized histologically by multinucleated giant cells in a background of ovoid to spindle-shaped mesenchymal cells. Whether CGCG is a reactive lesion or a truly benign neoplasm remains undetermined, and the mechanism determining the onset of the disease remains unknown. To have more information regarding the genetic events involved in CGCG, the authors decided to perform an expression profile. Samples were derived from two surgically resected CGCG of the mandible. RNA extracted from a pool of three normal bone tissues was used as control. By using DNA microarrays containing 19,200 genes, the authors identified several genes whose expression was significantly up- or down-regulated. The differentially expressed genes cover a broad range of functional activities: cell cycle regulation; signal transduction; and vesicular transport. It was also possible to detect some genes whose function is unknown. The authors believe the data reported to be the first genetic portrait of CGCG of the jaws. Several markers have been identified that can potentially help in identifying some biological behavior (ie, quiescent versus aggressive lesions), as well as genes whose products could be potentially disease-specific targets for therapy. However, the authors think that more cases are needed, especially those comparing quiescent and aggressive lesions, before the exact profile of CGCG is known.

Gene Expression↗
PubMed2005

Bcl-2 as prognostic factor in head and neck squamous cell carcinoma.

A series of 66 cases of oral squamous cell carcinoma (OSCC) was retrospectively analyzed by immunohisto-chemistry for bcl-2 expression to verify its predictive value for clinical outcome in patients with OSCC. After grouping for bcl-2 expression, OSCCs were statistically analyzed for the variables age, gender, histological grading (G), TNM, staging, recurrence, and overall survival rate. Univariate and multivariate (Cox regression) analyses were performed. Thirty-six OSCC (54.5%) showed expression for bcl-2, whereas 30 (44.5%) were negative. No statistical association was found between bcl-2 expression and any variables considered at baseline. Overall disease-specific survival rate at 72 months was 51%, independently from the extent of the tumor. In terms of prognostic significance, the bcl-2-positive group showed more than 60% survival at 72 months whereas the bcl-2-negative group showed none. An independent association of bcl-2 expression was found with an improved overall survival rate (p = 0.048), although grading and staging were established to be the best baseline markers of prognosis. On the basis of these results, it is possible to suggest bcl-2 as an early marker of prognosis: lack of bcl-2 expression could constitute a hallmark of aggressive biological behavior in OSCC.

Adolescent↗
PubMed2004

Survivin as prognostic factor in squamous cell carcinoma of the oral cavity.

A series of 78 cases of oral squamous cell carcinoma was analysed by immunohistochemistry for expression of survivin, a recent apoptosis inhibitor. All cases were positive for survivin expression and were divided into two groups using a system of scores. Disease-specific survival curves were calculated according to Kaplan-Meier algorithm, and log rank test was used to compare survival curves. Then, Cox regression analysis was applied to determine the single contribution of covariates on survival rate. So, Cox analysis allowed us to detect the variables most associated to survival. Among the studied variables, such as grade of differentiation, tumor size, stage, recurrence of disease, lymph node presence, only stage and recurrence of disease were predictors of outcome; however, when we analyzed the survival without considering recurrence (that was the stronger predictor of death), a stepwise Cox analysis showed that Survivin, stage and grade of differentiation are significantly associated to survival, with a higher value for Survivin. These data suggest that survivin expression may identify cases of oral squamous cell carcinoma with more aggressive and invasive phenotype and, therefore, could influence the decision for the therapy at the time of diagnosis.

Adolescent↗
PubMed2004

Strong evidence of linkage disequilibrium between polymorphisms at the IRF6 locus and nonsyndromic cleft lip with or without cleft palate, in an Italian population.

Cleft lip with or without cleft palate (CL/P) is one of the most common birth defects, but its etiology is largely unknown. It is very likely that both genetic and environmental factors contribute to this malformation. Mutations in the gene for interferon regulatory factor 6 (IRF6) have been shown to be the cause of Van der Woude syndrome, a dominant disorder that has CL/P as a common feature. Recently, it has been reported that genetic polymorphisms at the IRF6 locus are associated with nonsyndromic CL/P, with stronger association in Asian and South American populations. We investigated four markers spanning the IRF6 locus, using the transmission/disequilibrium test. A sample of 219 Italian triads of patients and their parents were enrolled in the study. Strong evidence of linkage disequilibrium was found between markers and disease in both single-allele (P=.002 at marker rs2235375) and haplotype (P=.0005) analyses. These findings confirm the contribution of IRF6 in the etiology of nonsyndromic CL/P and strongly support its involvement in populations of European ancestry.

Cleft Lip↗
PubMed2004

Calcium sulfate: analysis of MG63 osteoblast-like cell response by means of a microarray technology.

Calcium sulfate (CaS) is an highly biocompatible material that has the characteristic of being one of the simplest as well as one of the synthetic bone-like graft with the longest clinical history, spanning more than 100 years. Solidified or crystallized CaS is very osteogenic in vivo. As the surface CaS dissolves in body fluid, the calcium ions form calcium phosphate that reprecipitates on the surface forming an osteoblast "friendly" environment. How this "friendly" environment alters osteoblast activity to promote bone formation is poorly understood. We therefore attempted to address this question by using microarray techniques to identified genes that are differently regulated in osteoblasts exposed to CaS. By using DNA microarrays containing 19,200 genes, we identified in osteoblast-like cells line (MG-63) cultured with CaS (Surgiplaster, Classimplant, Roma, Italy) several genes that expression was significantly upregulated. The differentially expressed genes cover a broad range of functional activities: (a) immunity, (b) lysosomal enzymes production, (c) cell cycle regulation, (d) and signaling transduction. It was also possible to detect some genes whose function is unknown. The data reported are, to our knowledge, the first genetic portrait of CaS effects. They can be relevant to better understand the molecular mechanism of bone regeneration and as a model for comparing other materials with similar clinical effects.

Calcium Sulfate↗
PubMed2004

Zirconium oxide: analysis of MG63 osteoblast-like cell response by means of a microarray technology.

Zirconium oxide ceramics have outstanding mechanical properties, a high biocompatibility and a high resistance to scratching. Expression profiling by DNA microarray is a molecular technology that allows the analysis of gene expression in a cell system. By using DNA microarrays containing 19,200 genes, we identified in osteoblast-like cells line (MG-63) cultured on zirconium oxide discs (Cercon, Degussa Dental, Hanau, Germany) several genes whose expression was significantly up or down-regulated. The differentially expressed genes cover a broad range of functional activities: (a) immunity, (b) vesicular transport and (c) cell cycle regulation. It was also possible to detect some genes whose function is unknown. The data reported are, to our knowledge, the first genetic portrait of a zirconium oxide surface. They can be relevant to better understand the molecular mechanism of biocompatibility and as a model for comparing other materials.

Animals↗
PubMed2004

Expression profiling of ameloblastic carcinoma.

Ameloblastic carcinoma (AC) is a malignant epithelial odontogenic tumor that histologically retains the features of ameloblastic differentiation and exhibits cytological features of malignancy in the primary or recurrent tumor. It may develop within a preexisting ameloblastoma or arise de novo or from an odontogenic cyst. Expression profiling by DNA microarray is a new molecular technology that allows the analysis of cell and tissue gene expression. By using DNA microarrays containing 19,200 genes, several genes whose expression was significantly upregulated or downregulated were identified in a case of AC. The differentially expressed genes cover a broad range of functional activities: 1) transcription, 2) signaling transduction, 3) cell cycle regulation, 4) apoptosis control, and 5) differentiation. The data reported are, to our knowledge, the first genetic portrait of an AC. No final conclusion can be drawn; however, this portrait will be useful in investigating the biological behavior and in identifying possible gene targets for cancer therapy when more cases of this rare tumor are reported and compared.

Aged↗