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1.
Am J Dermatopathol ; 41(11): 794-798, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30702455

RESUMO

Intraoral cutaneous hamartomas (ICHs) are uncommon mucosal lesions characterized microscopically by a combination of cutaneous structures, including various stages of follicular and sebaceous elements. Due to their rarity, the clinicopathologic and immunohistochemical attributes of ICHs have not been thoroughly delineated. Three cases of ICH were identified from our records, and formalin-fixed paraffin-embedded sections were immunohistochemically stained with antibodies against androgen receptor, estrogen receptor, and progesterone receptor, p63, factor XIIIα, and CD34. All 3 ICHs involved the buccal mucosa with an M:F ratio = 2:1 and mean age = 42.3 years (age range: 27-61 years). ICHs presented as thickened, painless, white and yellow plaques or nodules of long duration, measuring 0.6-1.5 cm. No history of skin graft in the area of the lesions was reported. Histopathologically, the lesions showed aggregates of rudimentary folliculosebaceous structures. Although well-defined piloerector muscles were present in all cases of ICH, bona fide hair follicles and isolated hair shafts were identified only in 1 case. The overlying oral epithelium exhibited epidermis-like morphological features, while inflammation was generally absent. Immunohistochemically, strong and diffuse nuclear staining for androgen receptor and factor XIIIα was observed in the sebaceous glands, and estrogen receptor and p63 reactivity were confined exclusively to the peripheral basal cells, while progesterone receptor staining was negative in ICHs. CD34 diffusely decorated the lesional stroma. In conclusion, ICH is a rare lesion composed of cutaneous elements in an abnormal location. A predilection for the buccal mucosa is reported in the current study.

2.
PLoS One ; 13(9): e0203404, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30188920

RESUMO

Bone remodeling occurs via coupling between bone resorption by osteoclasts and bone formation by osteoblasts. The mechanisms that regulate osteoclast signals to osteoblasts are not well understood. Published studies have reported that BMP signaling in osteoclasts regulate osteoclast coupling targets. To investigate the necessity of canonical BMP signaling on osteoclast differentiation and coupling, we mated Smad1fl/fl; Smad5fl/fl mice to c-Fms-Cre mice. We analyzed male mice at 3 months of age to determine the skeletal phenotype of the Smad1fl/fl; Smad5fl/fl;c-Fms-Cre (SMAD1/5 cKO) mice. There was a 1.2-fold decrease in trabecular BV/TV in SMAD1/5 cKO. Analyses of osteoclast serum markers in SMAD1/5 cKO mice, showed a significant increase in CTX-1 (1.5 fold) and TRAP ELISA (3 fold) compared to control mice. In these same mice, there was a 1.3-fold increase in cortical thickness. Consistent with the increase in cortical thickness, we found a 3-fold increase in osteoblast activity as measured by P1NIP ELISA assay from SMAD1/5 cKO mice. To explain the changes in cortical thickness and P1NP activity, we determined conditioned media from SMAD1/5 cKO osteoclast cultures enhanced mineralization of an osteoblast cell line and coupling factors expressed by osteoclasts that regulate osteoblast activity Wnt1 (4.5-fold increase), Gja1 (3-fold increase) and Sphk1 (1.5-fold increase) were all upregulated in osteoclasts from SMAD1/5 cKO compared to control osteoclasts. Lastly osteoclasts treated with dorsomorphin, a chemical inhibitor of SMAD1/5 signaling, demonstrates an increase in Wnt1 and Gja1 expression similar to the SMAD1/5 cKO mice. Previous studies demonstrated that TGF-ß signaling in osteoclasts leads to increases in WNT1 expression by osteoclasts. Therefore, our data suggest that TGF-ß and BMP signaling pathways in osteoclasts could act in an antagonistic fashion to regulate osteoblast activity through WNT1 and other coupling factors.

3.
Head Neck Pathol ; 12(1): 136-144, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28721660

RESUMO

Cherubism is a rare autosomal dominant condition affecting the jaws and caused by mutations in the gene encoding for the adapter protein SH3BP2 that maps to chromosome 4p16.3. Cherubism is characterized by symmetrically developing bone lesions in the maxilla and mandible. The lesions have been radiographically and histopathologically well-described. Here, we present a family with cherubism with two of its members featuring odontogenic tumorous proliferations in association with persistent central giant cell lesions (CGCL). Specifically, the proband, a 25-year-old male, developed a radiolucent lesion characterized histologically by central odontogenic fibroma-like proliferation in association with a CGCL component, while his mother, at age 57, was diagnosed with primary intraosseous odontogenic carcinoma with areas of benign fibro-osseous lesions. In both patients the lesions occurred in the anterior mandible and presented with clinical enlargement. The son underwent incisional biopsy and did not have additional treatment. His mother underwent extensive mandibulectomy due to widespread tumor. The son has two affected children with classic cherubism while a third child at age 5, had not shown any features of the disease. Mutation analysis of three affected members resulted in the identification of a heterozygous mutation in SH3BP2 (c.1244G>C; p.Arg415Pro). To the best of our knowledge, association of cherubism with odontogenic neoplastic lesions has hitherto not been reported in the literature, thus suggesting a relationship between cherubism with disturbed odontogenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Querubismo/complicações , Neoplasias Mandibulares/patologia , Tumores Odontogênicos/patologia , Adulto , Proliferação de Células , Querubismo/genética , Feminino , Humanos , Masculino , Neoplasias Mandibulares/genética , Pessoa de Meia-Idade , Mutação , Tumores Odontogênicos/genética , Linhagem
4.
PLoS One ; 12(9): e0185441, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28953929

RESUMO

Histone deacetylases (HDACs) are negative regulators of transcription and have been shown to regulate specific changes in gene expression. In vertebrates, eighteen HDACs have thus far been identified and subdivided into four classes (I-IV). Key roles for several HDACs in bone development and biology have been elucidated through in vitro and in vivo models. By comparison, there is a paucity of data on the roles of individual HDACs in osteoclast formation and function. In this study, we investigated the gene expression patterns and the effects of suppressing individual class II (Hdac4, 5, 6, 9, and 10) and class IV (Hdac11) HDACs during osteoclast differentiation. We demonstrated that HDAC class II and IV members are differentially expressed during osteoclast differentiation. Additionally, individual shRNA-mediated suppression of Hdac4, 5, 9, 10 and 11 expression resulted in increased multinucleated osteoclast size and demineralization activity, with little to no change in the overall number of multinucleated osteoclasts formed compared with control shRNA-treated cells. We also detected increased expression of genes highly expressed in osteoclasts, including c-Fos, Nfatc1, Dc-stamp and Cathepsin K. These observations indicate that HDACs cooperatively regulate shared targets in a non-redundant manner.


Assuntos
Diferenciação Celular/fisiologia , Histona Desacetilases/fisiologia , Osteoclastos/citologia , Osteogênese/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real
5.
Sci Rep ; 7(1): 7603, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-28790434

RESUMO

Osteoclasts begin as mononuclear cells that fuse to form multinuclear cells able to resorb bone. The mechanisms that regulate all the steps of osteoclast differentiation are not entirely known. MYO10, an unconventional myosin, has previously been shown in mature osteoclasts to play a role in attachment and podosome positioning. We determined that MYO10 is also expressed early during osteoclast differentiation. Loss of MYO10 expression in osteoclast precursors inhibits the ability of mononuclear osteoclasts to fuse into multinuclear osteoclasts. Expression of Nfatc1, Dc-stamp, Ctsk, and ß 3 integrin is reduced in the osteoclasts with reduced MYO10 expression. A slight reduction in the osteoclasts ability to migrate, as well as a reduction in SMAD 1/5/8 phosphorylation are also noted with reduced MYO10 expression. Interestingly we also detected a change in the ability of the osteoclast precursors to form tunneling nanotubes (TNTs), which suggests that MYO10 may regulate the presence of TNTs through its interaction with the cytoskeletal proteins.

6.
PLoS Genet ; 13(6): e1006820, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28640813

RESUMO

Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.


Assuntos
2',5'-Oligoadenilato Sintetase/genética , Interferon Tipo I/genética , Locos de Características Quantitativas/genética , Síndrome de Sjogren/genética , 2',5'-Oligoadenilato Sintetase/biossíntese , Alelos , Processamento Alternativo/genética , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Interferon Tipo I/metabolismo , Masculino , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia , Viroses/genética , Viroses/virologia
7.
Oral Oncol ; 56: 25-31, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27086483

RESUMO

OBJECTIVES: In recent years, the incidence of Human Papilloma Virus (HPV)-positive head and neck squamous cell carcinomas (HNSCC) has markedly increased. Our aim was to design a novel therapeutic agent through the use of conditionally replicative adenoviruses (CRAds) that are targeted to the HPV E6 and E7 oncoproteins. METHODS: Each adenovirus included small deletion(s) in the E1a region of the genome (Δ24 or CB016) intended to allow for selective replication in HPV-positive cells. In vitro assays were performed to analyze the transduction efficiency of the vectors and the cell viability following viral infection. Then, the UPCI SCC090 cell line (HPV-positive) was used to establish subcutaneous tumors in the flanks of nude mice. The tumors were then treated with either one dose of the virus or four doses (injected every fourth day). RESULTS: The transduction analysis with luciferase-expressing viruses demonstrated that the 5/3 fiber modification maximized virus infectivity. In vitro, both viruses (5/3Δ24 and 5/3CB016) demonstrated profound oncolytic effects. The 5/3CB016 virus was more selective for HPV-positive HNSCC cells, whereas the 5/3Δ24 virus killed HNSCC cells regardless of HPV status. In vivo, single injections of both viruses demonstrated anti-tumor effects for only a few days following viral inoculation. However, after four viral injections, there was statistically significant reductions in tumor growth when compared to the control group (p<0.05). CONCLUSION: CRAds targeted to HPV-positive HNSCCs demonstrated excellent in vitro and in vivo therapeutic effects, and they have the potential to be clinically translated as a novel treatment modality for this emerging disease.


Assuntos
Alphapapillomavirus/patogenicidade , Carcinoma de Células Escamosas/virologia , Neoplasias de Cabeça e Pescoço/virologia , Terapia Viral Oncolítica , Adenoviridae/genética , Animais , Linhagem Celular Tumoral , Vetores Genéticos , Humanos , Injeções Intralesionais , Camundongos , Camundongos Nus , Replicação Viral
9.
Arthritis Rheumatol ; 68(3): 724-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26636433

RESUMO

OBJECTIVE: Autoantibodies reactive with Ro52 (tripartite motif-containing protein 21 [TRIM21]) are detected in 70% of patients with primary Sjögren's syndrome (SS). TRIM21 belongs to a 34-member C-IV family of TRIM proteins. Although autoantibodies against other TRIM proteins within the C-IV family have been detected in the sera of patients with primary SS, their clinical relevance remains unclear. This study was undertaken to investigate the frequency of anti-TRIM38 in patients with primary SS and evaluate its association with various clinical measures of the disease. METHODS: Serum samples from patients with primary SS (n = 235) and controls (n = 50) were analyzed for reactivity with in vitro-transcribed and -translated (35) S-methionine-labeled TRIM38 protein. The associations of anti-TRIM38 with various laboratory and clinical measures of primary SS were evaluated. Reactivity of anti-TRIM38 with different structural domains of TRIM38 was analyzed. Affinity-purified anti-TRIM38 antibodies were used to immunoprecipitate TRIM21. RESULTS: TRIM38-reactive autoantibodies were detected in the sera of 24 of the 235 patients with primary SS and 2 of the 50 controls. Anti-TRIM38 positivity was significantly associated with the presence of anti-Ro60, anti-Ro52, anti-La, rheumatoid factor, and hypergammaglobulinemia. Clinically, anti-TRIM38 was associated with significantly higher ocular surface staining scores, lower Schirmer's test scores, and minor labial salivary gland biopsy focus scores of ≥3.0. Anti-TRIM38 antibodies mainly recognized the cortactin-binding protein 2 (CortBP-2; amino acids 128-238) and the B30.2/SPRY (amino acids 268-465) domains on TRIM38. Affinity-purified antibodies to TRIM38-CortBP-2 and TRIM38-B30.2/SPRY domains reacted with TRIM21. CONCLUSION: Our data demonstrate that anti-TRIM38 specificity arising in a subset of patients with primary SS is associated with increased severity of the disease.


Assuntos
Autoanticorpos/sangue , Proteínas de Transporte/imunologia , Índice de Gravidade de Doença , Síndrome de Sjogren/imunologia , Feminino , Humanos , Hipergamaglobulinemia/imunologia , Imunoprecipitação , Masculino , Metionina , Pessoa de Meia-Idade , Fator Reumatoide/sangue , Ribonucleoproteínas/imunologia , Síndrome de Sjogren/fisiopatologia , Radioisótopos de Enxofre
10.
Head Neck Pathol ; 10(2): 237-44, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26156422

RESUMO

The most recent A.F.I.P. fascicle defines primordial odontogenic cyst (POC) as a distinct, nonkeratinized, odontogenic cyst of "undetermined origin" forming in the place of a developing normal or supernumerary tooth. However, the majority of examples reported in the literature under this term represent odontogenic keratocysts (keratocystic odontogenic tumors). In addition, there are rare reported cases of cystic odontomas. An 18-year-old Caucasian male presented with a unilocular mandibular radiolucent lesion in the place of a congenitally missing molar. Histologically, it featured nonkeratinizing, thin stratified squamous epithelial lining with areas of spongiosis and foci of vacuolization of individual basal cells without significant nuclear palisading. Focally, budding of the basal cell layer was identified. A zone of increased cellularity featuring induction-type fibroblasts was present subepithelially as well as dentinoid deposits with odontogenic epithelial nests. Immunohistochemically, the epithelial lining was negative for calretinin and the induction-like zone negative for S100 protein, smooth muscle actin, and CD34. The case was externally reviewed by five oral pathologists who provided various diagnostic interpretations including primordial cyst, odontogenic cyst not otherwise specified (NOS), cyst with ameloblastic changes, and unicystic ameloblastoma. At that time, a final diagnosis of odontogenic cyst NOS was rendered with a comment that it may represent a true example of POC or a cystic odontoma. The lesion has not recurred within a 13 year follow-up period after initial excision. An unusual cystic lesion is presented that may represent a true example of POC with dentinoid formation or an archegonous cystic odontoma.


Assuntos
Cistos Odontogênicos/diagnóstico , Cistos Odontogênicos/patologia , Odontoma/diagnóstico , Odontoma/patologia , Adolescente , Biomarcadores Tumorais/análise , Humanos , Imuno-Histoquímica , Masculino
11.
J Oral Maxillofac Surg ; 74(4): 738-46, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26501428

RESUMO

PURPOSE: To analyze serum markers of bone turnover, angiogenesis, endocrine function, and inflammation in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) who discontinued long-term intravenous bisphosphonate (BP) therapy. PATIENTS AND METHODS: Serum samples were obtained from 25 BRONJ patients who had discontinued long-term intravenous BP therapy for an average of 11.4 ± 8.7 months and 48 non-BRONJ controls who continued receiving intravenous BP therapy. Samples were analyzed for total alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin, C-telopeptide, vascular endothelial growth factor, triiodothyronine, thyroxine, thyroid-stimulating hormone, 25-hydroxyvitamin D, and C-reactive protein. RESULTS: The mean number of BP infusions was significantly higher in BRONJ patients compared with controls (38.4 ± 26.3 infusions vs 18.8 ± 7.2 infusions, P < .0001); however, the duration of BP therapy was not significantly different between the groups (P = .23). Overall, there were no significant differences in any of the markers between BRONJ patients and controls (all P values ≥ .16). In a subgroup analysis that matched BRONJ patients and controls according to mean age and number of BP infusions (10 BRONJ patients and 48 controls), log10 vascular endothelial growth factor (2.9 ± 0.4 pg/mL vs 2.4 ± 0.4 pg/mL, P < .001) and C-reactive protein (34 ± 26 mg/L vs 13 ± 8 mg/L, P < .01) levels were significantly higher in BRONJ patients compared with controls. Within BRONJ patients, none of the serum markers were correlated with duration of BP discontinuation. CONCLUSIONS: Levels of bone turnover and endocrine markers in BRONJ patients who discontinue long-term intravenous BP therapy are similar to those in non-BRONJ controls receiving intravenous BP therapy. However, levels of angiogenesis and inflammation markers are higher in BRONJ patients who discontinue long-term intravenous BP therapy. The prolonged skeletal half-life of BPs may suppress bone turnover markers in BRONJ patients for several years after discontinuation of intravenous BP therapy, suggesting an extended effect on bone homeostasis.


Assuntos
Proteínas Angiogênicas/sangue , Biomarcadores/sangue , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/sangue , Conservadores da Densidade Óssea/administração & dosagem , Osso e Ossos/metabolismo , Difosfonatos/administração & dosagem , Administração Intravenosa , Idoso , Fosfatase Alcalina/sangue , Proteína C-Reativa/análise , Estudos de Casos e Controles , Colágeno Tipo I/sangue , Feminino , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Osteocalcina/sangue , Peptídeos/sangue , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Vitamina D/análogos & derivados , Vitamina D/sangue
12.
Arthritis Rheumatol ; 68(5): 1290-1300, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26713507

RESUMO

OBJECTIVE: More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ∼1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. METHODS: All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. RESULTS: We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients. CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was ∼2.5 and ∼2.9 times higher, respectively, than that in women with 46,XX and ∼25 and ∼41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.


Assuntos
Artrite Reumatoide/epidemiologia , Cirrose Hepática Biliar/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/epidemiologia , Síndrome de Sjogren/epidemiologia , Doenças Autoimunes/epidemiologia , Estudos de Casos e Controles , Cromossomos Humanos X , Feminino , Dosagem de Genes , Humanos , Hibridização in Situ Fluorescente , Prevalência , Sarcoidose/epidemiologia , Aberrações dos Cromossomos Sexuais , Distribuição por Sexo , Trissomia
13.
PLoS One ; 10(4): e0123843, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25875108

RESUMO

Molecular regulators of osteoclast formation and function are an important area of research due to the central role of osteoclasts in bone resorption. Transcription factors such as MITF are essential for osteoclast generation by regulating expression of the genes required for cellular differentiation and resorptive function. We recently reported that histone deacetylase 7 (HDAC7) binds to and represses the transcriptional activity of MITF in osteoclasts, and that loss of HDAC7 in vitro accelerated osteoclastogenesis. In the current study, we extend this initial observation by showing that conditional deletion of HDAC7 in osteoclasts of mice leads to an in vivo enhancement in osteoclast formation, associated with increased bone resorption and lower bone mass. Expression of multiple MITF target genes is increased in bone marrow derived osteoclast cultures from the HDAC7 knockout mice. Interestingly, multiple regions of the HDAC7 amino-terminus can bind to MITF or exert repressive activity. Moreover, mutation or deletion of the HDAC7 conserved deacetylase catalytic domain had little effect on repressive function. These observations identify HDAC7 in osteoclasts as an important molecular regulator of MITF activity and bone homeostasis, but also highlight a gap in our understanding of exactly how HDAC7 functions as a corepressor.


Assuntos
Densidade Óssea/genética , Reabsorção Óssea/genética , Histona Desacetilases/genética , Fator de Transcrição Associado à Microftalmia/genética , Osteoclastos/metabolismo , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Domínio Catalítico , Diferenciação Celular , Feminino , Fêmur/citologia , Fêmur/metabolismo , Regulação da Expressão Gênica , Histona Desacetilases/deficiência , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição Associado à Microftalmia/metabolismo , Osteoclastos/citologia , Ligação Proteica , Transdução de Sinais , Transcrição Genética
14.
J Cell Biochem ; 116(10): 2239-46, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25808976

RESUMO

Proper regulation of osteoclast (OCL) function is critical for normal bone homeostasis. Bone morphogenetic protein (BMP) signaling and its regulation have been shown to have direct effects on OCL differentiation and activity. One of the major modulators of BMP signaling in the extracellular space is the secreted protein twisted gastrulation (TWSG1), which can inhibit BMP signaling and OCL differentiation. In this study we examine specific N-terminal regions of TWSG1 protein that have been previously proposed as BMP binding sites to determine whether TWSG1 binding to BMPs is required for its inhibitory effects on OCLs. We demonstrate that overexpression of wild type TWSG1 suppresses osteoclastogenesis, while overexpression of mutant TWSG1 proteins (W66A and N80Q/N146Q mutants), which cannot bind BMPs, leads to increased BMP signaling, enhanced osteoclastogenesis, increased resorptive activity, and expression of OCL-specific genes. Our results show that BMP binding is required for TWSG1-mediated inhibition of OCL formation and function, and validate the critical functional regions within the TWSG1 protein for these interactions.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular/genética , Osteoclastos/metabolismo , Proteínas/genética , Animais , Sítios de Ligação , Proteínas Morfogenéticas Ósseas/genética , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Ligação Proteica , Proteínas/metabolismo , Transdução de Sinais
15.
Int J Surg Pathol ; 23(4): 298-304, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25673632

RESUMO

Ameloblastomas can present in various clinical and histomorphologic patterns. The granular cell variant accounts for only 3.5% to 5% of ameloblastomas. The aim of this case report is to present an example of ameloblastoma with unusual granular cell component, affecting a 63-year-old woman, in which both the inner and peripheral layers of follicles composed exclusively by eosinophilic granular cells. Assessment of the immunohistochemical and histochemical profile of the lesion was performed and the challenges of such a diagnosis were also addressed.


Assuntos
Ameloblastoma/patologia , Tumor de Células Granulares/patologia , Neoplasias Mandibulares/patologia , Recidiva Local de Neoplasia/patologia , Biomarcadores Tumorais/análise , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade
16.
Dis Model Mech ; 8(2): 139-46, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25468951

RESUMO

Holoprosencephaly (HPE) is a developmental anomaly characterized by inadequate or absent midline division of the embryonic forebrain and midline facial defects. It is believed that interactions between genes and the environment play a role in the widely variable penetrance and expressivity of HPE, although direct investigation of such effects has been limited. The goal of this study was to examine whether mice carrying a mutation in a gene encoding the bone morphogenetic protein (BMP) antagonist twisted gastrulation (Twsg1), which is associated with a low penetrance of HPE, are sensitized to retinoic acid (RA) teratogenesis. Pregnant Twsg1(+/-) dams were treated by gavage with a low dose of all-trans RA (3.75 mg/kg of body weight). Embryos were analyzed between embryonic day (E)9.5 and E11.5 by microscopy and geometric morphometric analysis by micro-computed tomography. P19 embryonal carcinoma cells were used to examine potential mechanisms mediating the combined effects of increased BMP and retinoid signaling. Although only 7% of wild-type embryos exposed to RA showed overt HPE or neural tube defects (NTDs), 100% of Twsg1(-/-) mutants exposed to RA manifested severe HPE compared to 17% without RA. Remarkably, up to 30% of Twsg1(+/-) mutants also showed HPE (23%) or NTDs (7%). The majority of shape variation among Twsg1(+/-) mutants was associated with narrowing of the midface. In P19 cells, RA induced the expression of Bmp2, acted in concert with BMP2 to increase p53 expression, caspase activation and oxidative stress. This study provides direct evidence for modifying effects of the environment in a genetic mouse model carrying a predisposing mutation for HPE in the Twsg1 gene. Further study of the mechanisms underlying these gene-environment interactions in vivo will contribute to better understanding of the pathogenesis of birth defects and present an opportunity to explore potential preventive interventions.


Assuntos
Face/anormalidades , Holoprosencefalia/patologia , Mutação/genética , Proteínas/genética , Tretinoína/farmacologia , Animais , Proteína Morfogenética Óssea 2/metabolismo , Caspase 3/metabolismo , Caspase 7/metabolismo , Embrião de Mamíferos/anormalidades , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/patologia , Ativação Enzimática/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Defeitos do Tubo Neural/patologia , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Teratogênese/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos
17.
Oral Surg Oral Med Oral Pathol Oral Radiol ; 118(6): e198-204, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25311166

RESUMO

Angioimmunoblastic T-cell lymphoma (AITL) is a rare neoplastic process constituting 15% to 20% of peripheral T-cell lymphomas. We report the clinicopathologic and molecular characteristics of an unusual intraoral manifestation of AITL. A 35-year-old white man with a history of AITL presented with a 2.5-cm, poorly circumscribed, erythematous, exophytic lesion occupying the free and attached buccal gingiva of the right maxillary lateral incisor and canine. Histopathologically, the tumor showed diffuse and intense polymorphic infiltration by small to medium-sized lymphocytes admixed with numerous eosinophils. The neoplastic cells showed strong and diffuse reactivity for CD2, CD3, CD4, CD10, and PD-1 (programmed cell death 1 [PDCD1]). Rare immunopositivity was seen with BCL6 (B-cell CLL/lymphoma 6) and CXCL13 (chemokine [C-X-C motif] ligand 13). Neoplastic cells were negative for CD7 and EBER ISH (Epstein-Barr virus-encoded small RNA in situ hybridization). CD21 did not show any increased follicular dendritic cell component. Polymerase chain reaction-based assay found monoclonal T-cell receptor γ (TRG) gene rearrangements. Diagnosis of recurrent/residual AITL was rendered. Chemotherapy was administered, with the intraoral tumor resolving completely 3 months later.


Assuntos
Rearranjo Gênico do Linfócito T , Genes Codificadores da Cadeia gama de Receptores de Linfócitos T , Neoplasias Gengivais/genética , Neoplasias Gengivais/patologia , Linfadenopatia Imunoblástica/genética , Linfadenopatia Imunoblástica/patologia , Linfoma de Células T/genética , Linfoma de Células T/patologia , Adulto , Biomarcadores Tumorais/análise , Neoplasias Gengivais/tratamento farmacológico , Humanos , Linfadenopatia Imunoblástica/tratamento farmacológico , Linfoma de Células T/tratamento farmacológico , Masculino , Reação em Cadeia da Polimerase
18.
Artigo em Inglês | MEDLINE | ID: mdl-24268388

RESUMO

Examples of multiple minor salivary gland tumors, synchronous or metachronous, are uncommon. We report a patient who initially presented with polymorphous low-grade adenocarcinoma (PLGA) and subsequently with myoepithelioma. A 91-year-old white woman presented in 2009 with a 1-cm, firm, nontender, well-circumscribed nodule of the left side of the upper lip extending to the anterior buccal mucosa. Excisional biopsy revealed PLGA. While the margins were positive, further treatment was not recommended due to the patient's age. In 2011, the patient returned with a 1.5-cm, asymptomatic mass of the left buccal vestibule. Excision of the lesion revealed a circumscribed proliferation of epithelioid and plasmacytoid cells arranged in spherical or whorl-like islands and immersed in a mucinous stroma, consistent with myoepithelioma. The PLGA recurred 3 years after initial diagnosis. Excision was again associated with positive margins, and again no further treatment was recommended. A few months later, at a scheduled follow-up appointment, she presented with a painless nodule of the left upper lip, consistent with recurrent PLGA. One month later, the patient died of unrelated causes. We also present a literature review of multiple minor salivary gland tumors.


Assuntos
Neoplasias Labiais/patologia , Mioepitelioma/patologia , Segunda Neoplasia Primária/patologia , Neoplasias das Glândulas Salivares/patologia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Labiais/cirurgia , Mioepitelioma/cirurgia , Gradação de Tumores , Segunda Neoplasia Primária/cirurgia , Neoplasias das Glândulas Salivares/cirurgia
19.
Ann Rheum Dis ; 73(1): 31-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23968620

RESUMO

OBJECTIVE: To compare the performance of the American-European Consensus Group (AECG) and the newly proposed American College of Rheumatology (ACR) classification criteria for Sjögren's Syndrome (SS) in a well-characterised sicca cohort, given ongoing efforts to resolve discrepancies and weaknesses in the systems. METHODS: In a multidisciplinary clinic for the evaluation of sicca, we assessed features of salivary and lacrimal gland dysfunction and autoimmunity as defined by tests of both AECG and ACR criteria in 646 participants. Global gene expression profiles were compared in a subset of 180 participants. RESULTS: Application of the AECG and ACR criteria resulted in classification of 279 and 268 participants with SS, respectively. Both criteria were met by 244 participants (81%). In 26 of the 35 AECG+/ACR participants, the minor salivary gland biopsy focal score was ≥1 (74%), while nine had positive anti-Ro/La (26%). There were 24 AECG-/ACR+ who met ACR criteria mainly due to differences in the scoring of corneal staining. All patients with SS, regardless of classification, had similar gene expression profiles, which were distinct from the healthy controls. CONCLUSIONS: The two sets of classification criteria yield concordant results in the majority of cases and gene expression profiling suggests that patients meeting either set of criteria are more similar to other SS participants than to healthy controls. Thus, there is no clear evidence for increased value of the new ACR criteria over the old AECG criteria from the clinical or biological perspective. It is our contention, supported by this report, that improvements in diagnostic acumen will require a more fundamental understanding of the pathogenic mechanisms than is at present available.


Assuntos
Síndrome de Sjogren/classificação , Transcriptoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Consenso , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/genética , Estados Unidos , Adulto Jovem
20.
J Periodontol ; 85(2): 226-33, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23786404

RESUMO

BACKGROUND: Previous case reports and animal studies suggest that periodontitis is associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ). This case-control study is conducted to evaluate the association between clinical and radiographic measures of periodontal disease and BRONJ. METHODS: Twenty-five patients with BRONJ were matched with 48 controls. Trained examiners measured probing depth, clinical attachment level (CAL), and bleeding on probing on all teeth except third molars and gingival and plaque indices on six index teeth. Alveolar bone height was measured from orthopantomograms. Most patients with BRONJ were using antibiotics (48%) or a chlorhexidine mouthrinse (84%) at enrollment. Adjusted comparisons of patients with BRONJ versus controls used multiple linear regression. RESULTS: The average number of bisphosphonate (BP) infusions was significantly higher in patients with BRONJ compared with controls (38.4 versus 18.8, P = 0.0001). In unadjusted analyses, patients with BRONJ had more missing teeth (7.8 versus 3.1, P = 0.002) and higher average CAL (2.18 versus 1.56 mm, P = 0.047) and percentage of sites with CAL ≥3 mm (39.0 versus 23.3, P = 0.039) than controls. Also, patients with BRONJ had lower average bone height (as a fraction of tooth length, 0.59 versus 0.62, P = 0.004) and more teeth with bone height less than half of tooth length (20% versus 6%, P = 0.001). These differences remained significant after adjusting for age, sex, smoking, and number of BP infusions. CONCLUSIONS: BRONJ patients have fewer teeth, greater CAL, and less alveolar bone support compared with controls after adjusting for number of BP infusions. Group differences in antibiotics and chlorhexidine rinse usage may have masked differences in the other clinical measures.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/complicações , Periodontite/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Perda do Osso Alveolar/classificação , Perda do Osso Alveolar/diagnóstico por imagem , Antibacterianos/uso terapêutico , Anti-Infecciosos Locais/uso terapêutico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico , Estudos de Casos e Controles , Clorexidina/uso terapêutico , Índice de Placa Dentária , Difosfonatos/administração & dosagem , Feminino , Hemorragia Gengival/classificação , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Antissépticos Bucais/uso terapêutico , Perda da Inserção Periodontal/classificação , Índice Periodontal , Bolsa Periodontal/classificação , Periodontite/classificação , Radiografia Panorâmica , Fatores de Risco , Perda de Dente/classificação
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