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American Journal of Medical Genetics Part A 03/2013; · 2.39 Impact Factor
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ABSTRACT: The aim of this study was to evaluate the influence of the γ-aminobutyric acid receptor type A β-3 subunit (GABRB3) polymorphisms in patients with nonsyndromic cleft lip and/or palate (NSCL/P). We carried out a structured case-control analysis of three GABRB3 polymorphisms (rs4477673, rs6576618, and rs981778) in 229 patients with nonsyndromic cleft lip with or without cleft palate (CL±P) and in 314 unaffected controls from Brazil. The polymorphisms were genotyped by the TaqMan 5'-exonuclease allelic discrimination assay, and each sample was independently typed for 40 biallelic short insertion/deletion markers (INDELs) to characterize the genomic ancestry. The genotype distributions of the three polymorphisms were as expected by the Hardy-Weinberg equilibrium test. After adjustment to ancestry contribution, the minor A allele of rs981778 was associated with NSCL/P, but significant results did not persist after Bonferroni correction for multiple tests. Similarly, the haplotype analysis revealed that the CCA haplotype (C allele of rs4477673, C allele of rs6576618, and A allele of rs981778) was correlated with NSCL/P, but this association did not remain statistically significant after Bonferroni correction. With a weak association, our data do not support the hypothesis that the GABRB3 variants are a cause of NSCL/P, but further studies are warranted.
DNA and cell biology 03/2013; 32(3):125-9. · 2.28 Impact Factor
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ABSTRACT: OBJECTIVE: The aim of this study was to describe the clinicopathological and immunohistochemical features of 19 cases of oral eosinophilic ulcers and discuss the hypothesis that this entity could represent a spectrum of the CD30(+) lymphoproliferative disorder. MATERIAL AND METHODS: Clinical data concerning gender, age, affected site, and clinical presentation of 19 patients were collected and a broad immunohistochemical panel was carried out. Eosinophil distribution in relation to muscular tissue was evaluated using an Aperio ScanScope CS scanner. RESULTS: The mean age of the patients was 58.6 years, with a male preponderance. A single painful ulcer in the tongue was the most common clinical presentation. There was no predilection of eosinophils for surrounding muscular fibers because this population was equally distributed in areas adjacent to and distant from these structures. The inflammatory infiltrate was mainly formed by cytotoxic T lymphocytes and CD30 expression was not limited to large atypical cells; it also stained small reactive lymphocytes. CONCLUSIONS: Considering the clinical, histopathological, and immunohistochemical characteristics, oral eosinophilic ulcers must be considered a self-limiting reactive condition.
Oral surgery, oral medicine, oral pathology and oral radiology. 01/2013;
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ABSTRACT: Myofibroblasts are frequent in the stroma of neoplasm and by the expression of proteinases they can influence tumor infiltration
and progression. In the present study, presence of myofibroblasts and expression of matrix metalloproteinase-2 (MMP-2) and
urokinase plasminogen activator (uPA) were examined in intra-osseous solid multicystic ameloblastomas to determine their roles
in the clinicopathological features of the tumors. Fifty seven ameloblastomas were analyzed immunohistochemically with antibodies
against the isoform α of the smooth muscle actin (α-SMA), a specific marker of myofibroblasts, MMP-2 and uPA. Myofibroblasts
were found in the stroma, in close contact with neoplastic cell islands, of ~58% (n = 33) of the ameloblastomas. MMP-2 and uPA were found in the cytoplasm of both neoplastic and stromal cells. A significant
correlation between presence of myofibroblasts and MMP-2 expression was observed. Abundant presence of myofibroblast in the
stroma of the tumors and expression of MMP-2 in the neoplastic or stromal cells were significantly correlated with rupture
of the osseous cortical, which has been considered an important prognostic marker of ameloblastoma aggressiveness. Ours results
suggest that abundant presence of myofibroblasts and expression of MMP-2 in solid ameloblastomas may be associated with a
more aggressive infiltrative behavior.
Pathology & Oncology Research 04/2012; 15(2):231-240. · 1.37 Impact Factor
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ABSTRACT: HOX genes encode homeodomain-containing transcription factors involved in the regulation of cellular proliferation and differentiation during embryogenesis. However, members of this family demonstrated oncogenic properties in some malignancies. The present study investigated whether genes of the HOXA cluster play a role in oral cancer.
In order to identify differentially expressed HOXA genes, duplex RT-PCR in oral samples from healthy mucosa and squamous cell carcinoma was used. The effects of HOXA1 on proliferation, apoptosis, adhesion, invasion, epithelial-mesenchymal transition (EMT) and anchorage-independent growth were assessed in cells with up- and down-regulation of HOXA1. Immunohistochemical analysis using a tissue microarray (TMA) containing 127 oral squamous cell carcinomas (OSCC) was performed to determine the prognostic role of HOXA1 expression.
We showed that transcripts of HOXA genes are more abundant in OSCC than in healthy oral mucosa. In particular, HOXA1, which has been described as one of the HOX members that plays an important role in tumorigenesis, was significantly more expressed in OSCCs compared to healthy oral mucosas. Further analysis demonstrated that overexpression of HOXA1 in HaCAT human epithelial cells promotes proliferation, whereas downregulation of HOXA1 in human OSCC cells (SCC9 cells) decreases it. Enforced HOXA1 expression in HaCAT cells was not capable of modulating other events related to tumorigenesis, including apoptosis, adhesion, invasion, EMT and anchorage-independent growth. A high number of HOXA1-positive cells was significantly associated with T stage, N stage, tumor differentiation and proliferative potential of the tumors, and was predictive of poor survival. In multivariate analysis, HOXA1 was an independent prognostic factor for OSCC patients (HR: 2.68; 95% CI: 1.59-2.97; p = 0.026).
Our findings indicate that HOXA1 may contribute to oral carcinogenesis by increasing tumor cell proliferation, and suggest that HOXA1 expression might be helpful as a prognostic marker for patients with OSCC.
BMC Cancer 04/2012; 12:146. · 3.01 Impact Factor
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ABSTRACT: Buccal bifurcation cyst (BBC) is a rare inflammatory odontogenic cyst that typically occurs at the buccal region of the first or second mandibular molars of children. In the current case, a 9-year-old boy complained of an extraoral soft tissue painful swelling. Intraoral examination revealed a partial eruption of the right permanent mandibular first molar with drainage of purulent material and clinical absence of the left mandibular first molar. Panoramic radiographic and computed tomography showed two well-defined areas surrounding the mandibular first molars consistent with cystic lesions. Surgical enucleations were performed and histopathologic analysis revealed inflammatory cysts. Based on the clinical, microscopic, radiographic, and CT images, the diagnosis of bilateral BBC was established. Patient has been under follow-up for about 1 year showing normal bone repair and eruption of the involved teeth. Although BBC is uncommon, it is important to recognize this entity.
Head and Neck Pathology 03/2012;
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Histopathology 03/2012; 60(4):662-5. · 3.08 Impact Factor
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ABSTRACT: Amelogenesis imperfecta (AI) is due to many inherited defects of enamel formation that affect the quantity and quality of enamel, leading to delay in tooth eruption and cosmetic consequences. AI has been described in association with nephrocalcinosis, which is called the enamel-renal syndrome. The aim of this case report is to describe typical features of AI in 2 patients with Bartter's syndrome (BS) for the first time.
-Eight patients with confirmed BS were systematically screened for dental abnormalities as part of protocol. Those with suggestive clinical features of AI were submitted to panoramic X-ray and decayed teeth were analyzed by scanning electron microscopy.
Typical features of AI were detected in 2 girls with BS. These 2 patients showed nephrocalcinosis, and diagnosis and adequate clinical control were delayed. Genetic analysis detected the mutation responsible for BS in 1 of these patients. In this case, BS was due to a homozygous mutation of exon 5 of the KCNJ1 gene resulting in a substitution of valine for alanine at the codon 214 (A214V).
The finding of typical features of AI in BS might constitute preliminary evidence that abnormalities of the biomineralization process found in patients with renal tubular disorders might also affect calcium deposition in dental tissues.
Nephron extra. 01/2012; 2(1):319-25.
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ABSTRACT: Abstract Objective: Many studies have demonstrated a high frequency of dental anomalies in patients with cleft lip and/or palate (CL/P). Since dental anomalies may complicate dental treatment, we investigated the prevalence of dental anomalies in a group of Brazilian patients with nonsyndromic CL/P (NSCL/P). Design, Participants, Setting: Retrospective analysis was performed using clinical records of 296 patients with repaired NSCL/P aged between 12 and 30 years without history of tooth extraction and orthodontic treatment. Associations between oral clefts and presence of dental anomalies outside the cleft area were investigated. Results: Dental anomalies were identified in 39.9% of the NSCL/P patients, and tooth agenesis (47.5%), impacted tooth (13.1%) and microdontia (12.7%) were the most common anomalies. CL patients were less affected by dental anomalies compared with CP or CLP patients (p=0.057). Specifically, unilateral CLP patients were significantly more affected by dental anomalies than bilateral CLP patients (p=0.00002), and individuals with unilateral complete CLP (p=0.002) and complete CP (p=0.01) were significantly more affected by tooth agenesis than other cleft types. Ageneses of the premolars (p=0.043) and maxillary lateral incisors (p=0.03) were significantly more frequent in unilateral complete CLP patients. Conclusions: The present study revealed a high frequency of dental anomalies in NSCL/P patients, and further demonstrated that patients with unilateral CLP were frequently more affected by dental anomalies than bilateral CLP. Moreover, our results demonstrate that dental anomalies should be considered during dental treatment planning of individuals affected by NSCL/P. Keywords: Cleft lip and palate; dental anomaly; tooth agenesis; dental treatment.
The Cleft Palate-Craniofacial Journal 10/2011; · 0.82 Impact Factor
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ABSTRACT: Myofibroblasts are essential during wound healing and are often found in the stroma of oral squamous cell carcinomas (OSCC). Although the molecular mechanisms by which myofibroblasts influence OSCC remain largely unknown, previous studies demonstrated that presence of myofibroblast in OSCC stroma is an important risk factor of patient's shortened survival. Here we showed that some growth factors are produced in higher levels by tumor-associated myofibroblasts compared to tumor-associated fibroblasts, including activin A. Myofibroblast-conditioned media containing activin A significantly increased OSCC cell proliferation and tumor volume, whereas down-regulation of activin A in the conditioned media decreased proliferation. In addition, myofibroblasts induced in vitro invasion of OSCC cells, which was accompanied by an increased production of matrix metalloproteinases (MMP). In vivo, a significant correlation between presence of myofibroblasts and activities of MMP-2 and MMP-9 was observed in OSCC samples. However, blockage of activin A synthesis by myofibroblasts did not affect invasion and MMP production by OSCC cells. Together, our data demonstrate that activin A is required for the proliferative effects of myofibroblasts on OSCC cells. We conclude that myofibroblasts in the stroma of OSCC may influence proliferation and invasion, resulting in more aggressive tumor.
Oral Oncology 07/2011; 47(9):840-6. · 2.86 Impact Factor
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James O'Sullivan,
Carolina C Bitu,
Sarah B Daly,
Jill E Urquhart,
Martin J Barron,
Sanjeev S Bhaskar,
Hercilio Martelli-Júnior,
Pedro Eleuterio dos Santos Neto,
Maria A Mansilla,
Jeffrey C Murray, Ricardo D Coletta,
Graeme C M Black,
Michael J Dixon
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ABSTRACT: Amelogenesis imperfecta (AI) describes a clinically and genetically heterogeneous group of disorders of biomineralization resulting from failure of normal enamel formation. AI is found as an isolated entity or as part of a syndrome, and an autosomal-recessive syndrome associating AI and gingival hyperplasia was recently reported. Using whole-exome sequencing, we identified a homozygous nonsense mutation in exon 2 of FAM20A that was not present in the Single Nucleotide Polymorphism database (dbSNP), the 1000 Genomes database, or the Centre d'Etude du Polymorphisme Humain (CEPH) Diversity Panel. Expression analyses indicated that Fam20a is expressed in ameloblasts and gingivae, providing biological plausibility for mutations in FAM20A underlying the pathogenesis of this syndrome.
The American Journal of Human Genetics 05/2011; 88(5):616-20. · 10.60 Impact Factor
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Pediatric Dermatology 05/2011; 28(3):333-4. · 1.07 Impact Factor
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ABSTRACT: Fatty acid synthase (FASN) is the metabolic enzyme responsible for the endogenous synthesis of the saturated long-chain fatty acid, palmitate. In contrast to most normal cells, FASN is overexpressed in a variety of human cancers, including cutaneous melanoma, in which its levels of expression are associated with tumor invasion and poor prognosis. We have previously shown that FASN inhibition with orlistat significantly reduces the number of spontaneous mediastinal lymph node metastases following the implantation of B16-F10 mouse melanoma cells in the peritoneal cavity of C57BL/6 mice. In this study, we investigate the biological mechanisms responsible for the FASN inhibition-induced apoptosis in B16-F10 cells. Both FASN inhibitors, cerulenin and orlistat, significantly reduced melanoma cell proliferation and activated the intrinsic pathway of apoptosis, as demonstrated by the cytochrome c release and caspase-9 and -3 activation. Further, apoptosis was preceded by an increase in both reactive oxygen species production and cytosolic calcium concentrations and independent of p53 activation and mitochondrial permeability transition. Taken together, these findings demonstrate the mitochondrial involvement in FASN inhibition-induced apoptosis in melanoma cells.
Laboratory Investigation 02/2011; 91(2):232-40. · 3.64 Impact Factor
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ABSTRACT: Oral squamous cell carcinoma (OSCC) invasion is followed by several stromal events such as inflammatory and immune cell infiltration, neo-vascularization, fibroblast activation and occasionally myofibroblast emergence. Our previous studies demonstrated that myofibroblasts in the stroma of OSCC are associated with a more aggressive behavior, leading to shorter patient overall survival. Therefore, we evaluated whether OSCC-associated myofibroblasts have different characteristics compared to OSCC-associated fibroblasts. OSCC myofibroblast cell lines were isolated, cultured and characterized on the basis of the expression of specific isoform α of smooth muscle actin (α-SMA) and of the excessive production of type I collagen. To assess the proliferative potential of the cell lines, growth curves were constructed, whereas the production and activity of matrix metalloproteinases (MMP) were analyzed by ELISA and enzymography, respectively. Myofibroblast clones were positive for α-SMA and vimentin, and negative for pan-cytokeratin and CD34. In long time cultures, western blotting, flow cytometry and ELISA analysis revealed constant α-SMA expression and elevated production of type I collagen. There were no differences on proliferative potential between fibroblast and myofibroblast clones, but myofibroblast cells secreted significantly higher levels of MMP-1, -2, -9 and -13. Furthermore, MMP-2 gelatinolytic activity was significantly higher in myofibroblast clones. The results of this study suggest that myofibroblasts may contribute to OSCC invasion through elevation of MMP synthesis.
Oncology Reports 01/2011; 25(4):1013-20. · 1.84 Impact Factor
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ABSTRACT: Gingiva fibromatosis is a relatively rare condition characterized by diffuse enlargement of the gingiva, which is caused by expansion and accumulation of the connective tissue.
The aim of the present study was to investigate proliferative and apoptotic biomarker expression in normal gingiva and two forms of gingival fibromatosis.
Archived tissue specimens of hereditary gingival fibromatosis, gingival fibromatosis and dental abnormality syndrome and normal gingiva were subject to morphological analysis and immunohistochemical staining. The results were analyzed statistically.
Proteins associated with proliferation were found in the nuclei of epithelial cells from the basal and suprabasal layers, whereas apoptotic proteins were detected in the cytoplasm of the upper layers of the epithelium. Increased expressions of minichromosome maintenance proteins 2 and 5 were observed in the gingival fibromatosis and dental abnormality syndrome samples. In contrast, geminin expression was higher in normal gingiva samples. No difference in the expression of apoptotic proteins was observed among the groups.
Our findings support a role for augmented proliferation of epithelial cells within the overgrown tissues associated with gingival fibromatosis or dental abnormality syndrome. However, our data suggest that different biological mechanisms may account for the pathogenesis of different types of gingival fibromatosis.
Clinics (São Paulo, Brazil) 01/2011; 66(5):753-7. · 1.59 Impact Factor
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ABSTRACT: Amelogenesis imperfecta (AI) is a group of hereditary disorders that affect the quality and/or quantity of dental enamel. This paper describes the clinicopathological features of a patient who was born of consanguineous parents and who presented with oral alterations, including yellow and misshapen teeth, intrapulpal calcifications, delayed tooth eruption, and gum enlargement. Scanning electron microscopy of the teeth revealed hypoplastic enamel, and a renal ultrasound detected bilateral nephrocalcinosis, leading to a diagnosis of AI and nephrocalcinosis syndrome. Since nephrocalcinosis is often asymptomatic and can be associated with impaired renal function, dentists who see children with generalized and thin hypoplastic AI should consider a renal ultrasound scan and referral to a nephrologist, if appropriate. Children with nephrocalcinosis should also be considered for a dental check.
Nephron Physiology 01/2011; 118(3):p62-5. · 2.55 Impact Factor
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ABSTRACT: Goldenhar syndrome (GS) is a relatively common developmental disorder characterized by craniofacial anomalies in association with vertebral, cardiac, renal, and central nervous system defects. This paper describes GS features with special emphasis on oral characteristics.
The clinical features of 6 patients with GS aged 3 months to 12 years are described, and a brief review of the literature about this genetic disorder is presented.
All patients demonstrated the classical triad of GS, including mandibular hypoplasia resulting in facial asymmetry, ear and/or eye malformation, and vertebral anomalies. In addition, renal and gastrointestinal abnormalities were observed in 2 patients. Regarding the oral involvement, 2 patients presented cleft lip and palate, and 1 patient had temporomandibular joint malformation. Malocclusion was found in all patients.
Our orofacial findings correlate with the reported cases in the literature, and point out that after diagnosis GS patients need to be examined for systemic abnormalities.
Journal of applied oral science: revista FOB 12/2010; 18(6):646-9. · 0.39 Impact Factor
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ABSTRACT: Transforming growth factor-β1 (TGF-β1), its downstream signaling mediators (Smad proteins), and specific targets, including connective tissue growth factor (CTGF), play important roles in tissue remodeling and fibrosis via myofibroblast activation. We investigated the effect of overexpression of Smad7, a TGF-β1 signaling inhibitor, on transition of gingival fibroblast to myofibroblast. Moreover, we analyzed the participation of CTGF on TGF-β1-mediated myofibroblast transformation.
To study the inhibitory effect of Smad7 on TGF-β1/CTGF-mediating gingival fibroblast transition into myofibroblasts, we stably overexpressed Smad7 in normal gingival fibroblasts and in myofibroblasts from hereditary gingival fibromatosis (HGF). Myofibroblasts were characterized by the expression of the specific marker isoform α of the smooth muscle actin (α-SMA) by Western blot, flow cytometry, and immunofluorescence. Enzyme-linked immunosorbent assay for type I collagen was performed to measure myofibroblast activity. CTGF's role on myofibroblast transformation was examined by enzyme-linked immunosorbent assay and small interference RNA.
TGF-β1 induced the expression of α-SMA and CTGF, and small interference RNA-mediating CTGF silencing prevented fibroblast-myofibroblast switch induced by TGF-β1. In Smad7-overexpressing fibroblasts, ablation of TGF-β1-induced Smad2 phosphorylation marked decreased α-SMA, CTGF, and type I collagen expression. Similarly, HGF transfectants overexpressing Smad7 demonstrated low levels of α-SMA and phospho-Smad2 and significant reduction on CTGF and type I collagen production.
CTGF is critical for TGF-β1-induced gingival fibroblast-myofibroblast transition, and Smad7 overexpression is effective in the blockage of myofibroblast transformation and activation, suggesting that treatments targeting myofibroblasts by Smad7 overexpression may be clinically effective in gingival fibrotic diseases, such as HGF.
Journal of Periodontology 11/2010; 82(4):642-51. · 2.60 Impact Factor
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ABSTRACT: Polymorphisms in genes that are involved in folic acid metabolism may be important maternal risk factors for the birth of a child with nonsyndromic cleft lip and/or palate (NSCL/P). The aim of this study was to determine the involvement of polymorphic variants in four genes (MTHFR, MTHFD1, MTR, and SLC19A1) that encode proteins related to folic acid metabolism in the women with susceptibility for having a child with NSCL/P.
DNA samples from 106 mothers of children with NSCL/P (case group) and from 184 mothers of healthy children (control group) were genotyped by polymerase chain reaction associated with restriction fragment length polymorphism (PCR-RFLP).
One of 29 polymorphisms was associated with significantly increased maternal risk for NSCL/P. Mothers exhibiting the A variant allele (GA genotype) of the MTHFR rs2274976 polymorphism demonstrated a ~6 times increased risk for having a child with NSCL/P compared to G allele carriers (OR, 5.76; 95% CI, 3.32-9.99, p = 0.000001). Among mothers who did not use vitamins, the OR of NSCL/P was increased to 8.34 (95% CI, 3.75-18.55, p = 0.000001) in the presence of the GA genotype of the MTHFR rs2274976 polymorphism compared to those with the GG genotype. Gene-gene interaction analysis showed that the combination of MTHFR rs2274976, MTHFD1 rs2236225, and SLC19A1 rs1051266 was the best model for prediction of maternal risk for NSCL/P.
The findings of the present study suggested that genetic variants of folic acid metabolic genes may modulate maternal susceptibility for having an offspring with NSCL/P.
Birth Defects Research Part A Clinical and Molecular Teratology 10/2010; 88(11):980-6. · 2.27 Impact Factor
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ABSTRACT: Proliferative verrucous leukoplakia (PVL) is a distinct and aggressive type of oral leukoplakia which affects elderly women without risk behavior and presents high rates of malignant transformation. The objective of the present study was to evaluate the clinicopathological characteristics and the distribution of cell proliferation markers, aiming to elucidate the distinct biological behavior of the PVL.
Clinical and microscopical features of 12 patients with PVL were reviewed. Immunohistochemical analysis for p53, Ki-67, Mcm-2 and Mcm-5 were performed and the data were correlated.
All patients were women, above 50 years of age, 91.7% were non-smoker and 100% were non-habitual drinker. Alveolar ridge (66.6%), tongue (50%) and buccal mucosa (41.6%) were the most affected sites. Four patients developed squamous cell carcinoma (SCC). The immunohistochemical findings showed higher positivity for p53, Ki-67, Mcm-2 and Mcm-5 in SCCs. However, some patients with mild or moderate dysplasia, specially the patients who developed SCC, presented high expression of Mcm-2 and Mcm-5.
High immunoexpression of Mcm-2 and Mcm-5 in mild and moderate dysplasia could be helpful to predict the malignant transformation of PVL.
Journal of Oral Pathology and Medicine 07/2010; 39(6):447-52. · 1.63 Impact Factor
