RESUMEN
Smooth muscle neoplasms represent an important group of lesions which is rare in the oral cavity. Leiomyoma (LM) is benign smooth muscle/pericytic tumor usually presenting as non-aggressive neoplasm, while leiomyosarcoma (LMS) represents its malignant counterpart. The rarity of these lesions, together with its unspecific clinical presentation and a variable histopathological appearance, lead to a broad list of differential diagnoses, hampering their diagnoses. Therefore, in this study we describe the clinical and microscopic features of a series of oral and maxillofacial LMs and LMSs. A retrospective search from 2000 to 2019 was performed and all cases diagnosed as LM and LMS affecting the oral cavity and gnathic bones were retrieved. Clinical and demographic data were obtained from the patients' pathology records, while microscopic features and immunohistochemistry were reviewed and completed when necessary to confirm the diagnoses. Twenty-two LMs and five LMSs were obtained. In the LM group, males predominated, with a mean age of 45.7 years. The upper lip was the most affected site, and 18 cases were classified as angioleiomyomas and four as solid LM. In the LMS group, females predominated, with a mean age of 47.6 years. The mandible was the most affected site. Diffuse proliferation of spindle cells, with necrosis and mitotic figures, were frequent microscopic findings. LMs and LMSs were positive for α-smooth muscle actin, HHF-35 and h-caldesmon. In conclusion, oral LM/LMS are uncommon neoplasms with the latter usually presenting as metastatic disease. H&E evaluation may be very suggestive of oral LMs, but h-caldesmon staining is strongly recommended to confirm LMS diagnosis.
Asunto(s)
Leiomioma , Leiomiosarcoma , Tumor de Músculo Liso , Neoplasias Uterinas , Biomarcadores de Tumor , Proteínas de Unión a Calmodulina , Femenino , Humanos , Leiomioma/diagnóstico , Leiomioma/patología , Leiomiosarcoma/diagnóstico , Leiomiosarcoma/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tumor de Músculo Liso/patología , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologíaRESUMEN
As neoplasias de glândulas salivares são um grupo heterogêneo de lesões que correspondem aproximadamente a 3-6% dos casos de neoplasias de cabeça e pescoço e apresentam características histológicas distintas. A grande variação no padrão histológico das lesões de glândulas salivares tem sido atribuída à presença de células mioepiteliais, que apresentam padrões distintos em cada neoplasia. O objetivo deste trabalho é avaliar a expressão de um painel de proteínas do citoesqueleto, adesão e proliferação celular, sendo elas: actina de músculo liso (AML), calponina, caldesmon, citoceratina 14 (CK14), E-caderina, vimentina, beta-catenina, Ki-67 e p63 em neoplasias malignas das glândulas salivares utilizando a técnica de imunoistoquímica (IHQ). Foram selecionadas retrospectivamente, um total de 15 amostras, sendo 08 amostras de carcinoma ex-adenoma pleomórfico, 04 de carcinoma mioepitelial, 03 de adenocarcinoma de células basais. Os casos foram analisados e os resultados, obtidos através da imumoistoquímica, comparados com os dados demográficos, clínicos e patológicos. A expressão das proteínas foi analisada qualitativamente e semi-quantitativamente, sendo classificada em negativo, positivo focal, positivo difuso ou positivo abundante. A actina de músculo liso (AML) foi observada em dois casos de adenocarcinoma de células basais (ACCB), três de carcinoma mioepitelial (CAME) e três de carcinoma ex-adenoma pleomórfico (CXAP). A calponina foi expressa em dois casos, tanto de ACCB quanto de CAME e em três casos de CXAP. A proteína caldesmon foi observada em dois casos de ACCB, os quatros casos de CAME e sete casos de CXAP. Três casos de ACCB e de CAME e cinco de CXAP apresentaram expressão de CK14. A E-caderina foi observada em todos os casos dos três tipos tumorais, assim como a beta-catenina. A proteína vimentina foi expressa em todos os casos de ACCB e CAME, e predominantemente nos casos de CXAP. Poucos casos, tanto de ACCB, CAME e CXAP apresentaram positividade para Ki-67. A proteína p63 foi observada em todos os casos de ACCB e CAME, sendo pouco expressa em CXAP. A análise de clusterização hierárquica demonstrou a formação de dois clusters, sendo um deles predominantemente composto por CXAP. A comparação da expressão das proteínas com as características demográficas, clínicas e patológicas demonstrou associação entre a perda de expressão das proteínas CK14 e p63 e a ocorrência de metástase. Os resultados sugerem que a expressão das proteínas beta-catenina, E-caderina, caldesmon e vimentina apresentou-se de forma muito similar, sugerindo um perfil equivalente de expressão entre essas neoplasias derivadas do ducto intercalar. Já a ausência de expressão de AML e calponina parece estar associada à separação dos grupos na análise de clusterização, sugerindo que deve ser considerada como um fator na diferenciação tumoral.
Salivary gland neoplasms are a heterogeneous group of lesions that account for approximately 3-6% of head and neck tumors, with distinct histological characteristics. The variation in the histological pattern of salivary gland lesions has been attributed to the presence of myoepithelial cells, that present different patterns in each neoplasm. The aim of the study was to evaluate the expression of a panel of cytoskeletal, cell adhesion and cell proliferation proteins, namely: smooth muscle actin (SMA), calponin, caldesmon, cytokeratin 14 (CK14), E-cadherin, vimentin, beta- catenin, Ki-67 and p63 in salivary glands malignant neoplasms, using immunohistochemical technique (IHC). Fifteen samples werer etrospectively selected, being 08 carcinoma ex-pleomorphic adenoma samples, 04 myoepithelial carcinoma samples, 03 basal cell adenocarcinoma samples. The immunohistochemical results were analyzed and compared with demographic, clinical and pathological data. Protein expression were qualitatively and semi-quantitatively analyzed and classified as negative and positive (focal, diffuse, or abundant). Smooth muscle actin (SMA) was observed in two cases of basal cell adenocarcinoma (BCAC), three cases of myoepithelial carcinoma (MECA) and three cases of carcinoma ex-pleomorphic adenocarcinoma (CXPA). Calponin was expressed in two cases of BCAC, two cases of MECA, and three cases of CXPA. Caldesmon protein was observed in two cases of BCAC, four cases of MECA and seven cases of CXPA. Three cases of BCAC and MECA and five of CXPA presented CK14 expression. E-cadherin was observed in all cases of the three tumor types, as well as beta-catenin. Vimentin protein was expressed in all BCAC and MECA cases, and predominantly in CXPA cases. Few cases of BCAC, MECA and CXPA were positive for Ki-67. p63 protein was observed in all cases of BCAC and MECA, and present low expression in CXPA. The hierarchical clustering analysis demonstrated the formation of two clusters, one of them being predominantly composed of CXPA. Protein expression comparison with demographic, clinical and pathological characteristics demonstrated an association between loss of expression of CK14 and p63 proteins and the occurrence of metastasis. The results suggest that the expression of beta-catenin, E-cadherin, caldesmon and vimentin proteins was very similar, suggesting an equivalent expression profile among these neoplasms derived from the intercalated duct of the salivary gland. The absence of SMA and calponin expression seems to be associated with the separation of groups in the clustering analysis, suggesting that it should be considered as a factor in tumor differentiation
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Neoplasias de las Glándulas Salivales/diagnóstico , Adenocarcinoma , Adenoma Pleomórfico , Vimentina , Proteínas de Unión a Calmodulina , Carcinoma , Cadherinas , Actinas , Antígeno Ki-67 , beta Catenina , QueratinasRESUMEN
Background: Exposure to ionizing radiation during childhood is a well-established risk factor for thyroid cancer. However, the genetic mechanisms of radiation-associated carcinogenesis remain not fully understood. Methods: In this study, we used targeted next-generation sequencing and RNA-Seq to study 65 papillary thyroid cancers (PTCs) from patients in the Ukrainian-American cohort with measurement-based iodine-131 (I-131) thyroid doses received as a result of the Chernobyl accident. We fitted linear regression models to evaluate differences in distribution of risk factors for PTC according to type of genetic alteration and logistic regression models to evaluate the I-131 dose response. All statistical tests were two-sided. Results: Driver mutations were identified in 96.9% of these thyroid cancers, including point mutations in 26.2% and gene fusions in 70.8% of cases. Novel driver fusions such as POR-BRAF, as well as STRN-ALK fusions that have not been implicated in radiation-associated cancer before, were found. The mean I-131 dose in cases with point mutations was 0.2 Gy (range = 0.013-1.05 Gy), statistically significantly lower than 1.4 Gy (range = 0.009-6.15 Gy) for cases with fusions (P < .001). No driver point mutations were found in tumors from individuals who received more than 1.1 Gy of radiation. Relative to tumors with point mutations, the proportion of tumors with gene fusions increased with radiation dose, reaching 87.8% among individuals exposed to 0.3 Gy or higher. With a limited study sample size, the estimated odds ratio at 1 Gy was 20.01 (95% confidence interval = 2.57 to 653.02, P < .001). In addition, after controlling for I-131 dose, we found higher odds ratios for gene fusion-positive PTCs associated with several specific demographic and geographic features. Conclusions: Our data provide support for a link between I-131 thyroid dose and generation of carcinogenic gene fusions, the predominant mechanism of thyroid cancer associated with radiation exposure from the Chernobyl accident.
Asunto(s)
Accidente Nuclear de Chernóbil , Fusión Génica , Radioisótopos de Yodo/efectos adversos , Mutación , Neoplasias Inducidas por Radiación/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Quinasa de Linfoma Anaplásico/genética , Biomarcadores de Tumor/genética , Proteínas de Unión a Calmodulina/genética , Carcinoma Papilar/etiología , Carcinoma Papilar/genética , Carcinoma Papilar/patología , Niño , Preescolar , Estudios de Cohortes , Sistema Enzimático del Citocromo P-450/genética , Femenino , Estudios de Seguimiento , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Proteínas de la Membrana/genética , Neoplasias Inducidas por Radiación/etiología , Neoplasias Inducidas por Radiación/patología , Proteínas del Tejido Nervioso/genética , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Dosis de Radiación , Neoplasias de la Tiroides/etiología , Neoplasias de la Tiroides/patología , Adulto JovenRESUMEN
OBJECTIVE: PTC-specific analysis identified novel fusions involving RET, BRAF, NTRK1, NTRK3, AGK and ALK genes in adults and pediatric PTCs. Although many novel fusions are PTC-specific events and, therefore, are ideal for diagnosis purposes, validation across additional and larger patient cohorts is essential for introducing these potential diagnostic or prognostic biomarkers into the clinical practice. As most of the BRAF, NTRK3 and ALK fusions were initially found in pediatric PTC or in more aggressive thyroid carcinomas, and there is a great disparity across population, in this study, we screened a large set of adult-sporadic PTC cases for the most prevalent kinase fusion lately described in the TCGA. DESIGN AND METHODS: The prevalence of the fusions was determined by RT-PCR in 71 classical PTC, 45 follicular variants of PTC (FVPTC), 19 follicular thyroid adenomas (FTAs) and 22 follicular thyroid carcinomas (FTCs). RESULTS: ETV6-NTRK3 was exclusively found in FVPTC, in both encapsulated and infiltrative variants, but was not found in FTAs and FTCs. STRN-ALK was found in both classical PTC and FVPTC. No AGK-BRAF fusion was identified in this series, endorsing that AGK-BRAF is a genetic event mainly associated with pediatric PTCs. CONCLUSIONS: The identification of kinase fusions in thyroid carcinomas helps to expand our knowledge about the landscape of oncogenic alterations in PTC. As ETV6-NTRK3 and STRN-ALK are recurrent and not identified in benign lesions, they can certainly help with diagnosis of thyroid nodules. Further analysis is needed to define if they can also be useful for prognosis and guiding therapy.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Proteínas de Unión a Calmodulina/metabolismo , Carcinoma Papilar/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Proto-Oncogénicas c-ets/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptor trkC/metabolismo , Proteínas Represoras/metabolismo , Neoplasias de la Tiroides/metabolismo , Adulto , Quinasa de Linfoma Anaplásico , Biomarcadores de Tumor/genética , Proteínas de Unión a Calmodulina/genética , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/genética , Estudios de Cohortes , Femenino , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Unión Proteica/fisiología , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptor trkC/genética , Proteínas Represoras/genética , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Adulto Joven , Proteína ETS de Variante de Translocación 6RESUMEN
OsWRKY47 is a divergent rice transcription factor belonging to the group II of the WRKY family. A transcriptomic analysis of the drought response of transgenic rice plants expressing P SARK ::IPT, validated by qPCR, indicated that OsWRKY47 expression was induced under drought stress in P SARK ::IPT plants. A PCR-assisted site selection assay (SELEX) of recombinant OsWRKY47 protein showed that the preferred sequence bound in vitro is (G/T)TTGACT. Bioinformatics analyses identified a number of gene targets of OsWRKY47; among these two genes encode a Calmodulin binding protein and a Cys-rich secretory protein. Using Oswrk47 knockout mutants and transgenic rice overexpressing OsWRKY47 we show that the transcription of these putative targets were regulated by OsWRKY47. Phenotypic analysis carried out with transgenic rice plants showed that Oswrky47 mutants displayed higher sensitivity to drought and reduced yield, while plants overexpressing OsWRKY47 were more tolerant.
Asunto(s)
Oryza/genética , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Secuencia de Bases , Sitios de Unión/genética , Proteínas de Unión a Calmodulina/genética , Proteínas de Unión a Calmodulina/metabolismo , ADN de Plantas/genética , ADN de Plantas/metabolismo , Sequías , Técnicas de Inactivación de Genes , Genes de Plantas , Datos de Secuencia Molecular , Oryza/crecimiento & desarrollo , Plantas Modificadas Genéticamente , Regiones Promotoras Genéticas , Estrés Fisiológico , TranscriptomaRESUMEN
Age-related macular degeneration (AMD) causes visual impairment in the elderly. In non-neovascular AMD, studies involving human subjects have suggested potential involvement of aberrant lipid metabolism. However, there have been no reports on gene expression patterns in animal models of non-neovascular AMD with abnormal lipid metabolism such as apolipoprotein E knockout and human apolipoprotein E2 transgenic mice. Transcriptome analysis was performed using retinal pigment epithelium cells of apoE knockout and apolipoprotein E2 mice using microarray analysis. C57BL/6, Rxrb, Pparbp, Vldlr, and Edf1, which are primarily related to lipid metabolism, were upregulated, while Tgfbr1 and Pdgfb, which are related to pathologic angiogenesis in AMD, were downregulated in both types of mice. Apolipoprotein E knockout and apolipoprotein E2 mice showed characteristic gene expression patterns in the transcriptome analysis of primary retinal pigment epithelium cells. These results suggest that specific genes associated with lipid metabolism and angiogenesis are involved in the pathogenesis and progression of AMD.
Asunto(s)
Apolipoproteína E2/genética , Células Epiteliales/metabolismo , Epitelio Pigmentado de la Retina/citología , Transcriptoma , Anciano , Animales , Apolipoproteínas E/genética , Proteínas de Unión a Calmodulina/genética , Proteínas de Unión a Calmodulina/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo , Humanos , Metabolismo de los Lípidos , Linfocinas/genética , Linfocinas/metabolismo , Degeneración Macular/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Análisis por Micromatrices , PPAR-beta/genética , PPAR-beta/metabolismo , Factor de Crecimiento Derivado de Plaquetas/genética , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de LDL/genética , Receptores de LDL/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: The rare cutaneous solitary fibrous tumor was initially described in the thoracic cavity in relation to the pleura and subsequently been associated with other serous membranes. It has been described in other extraserosal locations including the skin. Knowledge of its existence along with fairly typical histological features and the immunohistochemical expression pattern with intense positivity for CD34 allow the increasing diagnosis of this condition, which suggests that these cases were not previously diagnosed as such. CLINICAL CASE: We report the case of a 43 year-old male with a painless nodule in the first left finger pad clinically suggestive of pyogenic granuloma or nodular melanoma, which was diagnosed by excisional biopsy and immunohistochemical study as a solitary fibrous tumor. DISCUSSION: Only 11 cases of cutaneous solitary fibrous tumor have been published in the following locations: head, cheek, thigh, chest, back and nose. Our work describes the first case of cutaneous solitary fibrous tumor in the hand. The solitary fibrous tumor derived from mesenchymal cells expresses CD34 and hence its presentation in any location. In our case it was in the hand. It explains the problems encountered in the clinical differential diagnosis with other tumors as nodular melanoma, pyogenic granuloma, giant cell tumor of tendon sheath, fibroma, benign peripheral nerve sheath tumors, etc. As we consider the histology, differential diagnosis should be made with other tumors that also express CD34. CONCLUSIONS: Solitary fibrous tumors derived from mesenchymal cells express CD34 and hence its presentation in any location. In our case it was in the finger pad.
Antecedentes: el tumor fibroso solitario es un tumor poco común. Anteriormente se suponía que afectaba sólo la cavidad torácica, en especial la pleura; posteriormente, se relacionó con otras membranas serosas y se observó en diversas localizaciones extraserosas, entre ellas la piel. El conocimiento de este tumor, junto con el aspecto histológico característico y el patrón de expresión inmunohistoquímica con intensa positividad para CD34 permiten que cada vez se diagnostique con mayor frecuencia. Caso clínico: se comunica el caso de un varón de 43 años de edad con un nódulo indoloro en el pulpejo del primer dedo izquierdo, que sugería clínicamente un melanoma nodular o granuloma piógeno. Mediante biopsia excisional y estudio inmunohistoquímico se diagnosticó como tumor fibroso solitario. Discusión: hasta la fecha se han publicado 11 casos de tumores fibrosos solitarios cutáneos, localizados en cabeza, mejilla, muslo, pecho, espalda y vestíbulo nasal. El caso que se comunica constituye la primera lesión de estas características que afecta la mano. El diagnóstico clínico diferencial del tumor fibroso solitario incluye otros tumores como: melanoma nodular, granuloma piógeno, tumor de células gigantes tenosinovial, fibroma y tumor de vaina de nervio periférico benigno. En cuanto a la histología, se planteó el diagnóstico diferencial con otras neoplasias que también expresan CD34. Conclusiones: el tumor fibroso solitario deriva de células mesenquimatosas y expresa CD34, lo que explica su aparición en cualquier localización, como en este caso, que fue en el pulpejo del quinto dedo.
Asunto(s)
Antígenos CD34/análisis , Antígenos de Neoplasias/análisis , Biomarcadores de Tumor/análisis , Hemangiopericitoma/patología , Tumores Fibrosos Solitarios/patología , Pulgar/patología , Adulto , Apigenina/análisis , Biopsia , Proteínas de Unión a Calmodulina/análisis , Diagnóstico Diferencial , Glucósidos/análisis , Granuloma Piogénico/diagnóstico , Hemangiopericitoma/química , Hemangiopericitoma/diagnóstico , Hemangiopericitoma/cirugía , Humanos , Masculino , Melanoma/diagnóstico , Mesodermo/química , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Tumores Fibrosos Solitarios/química , Tumores Fibrosos Solitarios/diagnóstico , Tumores Fibrosos Solitarios/cirugía , Pulgar/cirugíaRESUMEN
BACKGROUND: Hyalinizing clear cell carcinoma (HCCC) is a rare low-grade malignant tumor affecting the minor salivary glands; nasopharyngeal involvement is uncommon. METHODS AND RESULTS: A 38-year-old male patient presented with a 3.2 × 4.5 × 4.4 cm expansile mass obliterating the lumen of the nasopharynx and extending into the left nasal cavity. Histopathologically, the tumor was characterized by clear round to polygonal epithelial cells arranged in anastomosing trabeculae and solid nests. The stroma consisted of fibromyxoid connective tissue with areas of intense hyalinization and desmoplasia. Immunohistochemically, strong and diffuse reactivity for AE1/AE3, CK5/6, and p63 was observed. EWSR1 gene rearrangement was confirmed by fluorescence in situ hybridization. The diagnosis of nasopharyngeal HCCC was rendered. Surgical excision was performed along with adjuvant radiotherapy and chemotherapy. CONCLUSIONS: HCCC generally demonstrates good prognosis with low metastatic potential. Identification of EWSR1 gene disruption is usefulin discerning HCCC from other neoplasms with overlapping microscopic features.
Asunto(s)
Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patología , Proteínas de Unión a Calmodulina/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Proteínas de Unión al ARN/genética , Adulto , Biomarcadores de Tumor/análisis , Carcinoma , Reordenamiento Génico , Humanos , Hialina/metabolismo , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Carcinoma Nasofaríngeo , Proteína EWS de Unión a ARNRESUMEN
PURPOSE OF REVIEW: Aldosterone's functions and mechanisms of action are different depending on the tissue and the environmental condition. The mineralocorticoid receptor is present in tissues beyond epithelial cells, including the heart and vessels. Furthermore, aldosterone has direct adverse effects by both genomic and rapid/nongenomic actions not only through a nuclear receptor but also through caveolae-mediated intracellular events. Also, multiple environmental-genetic interactions play an important role in salt-sensitive hypertension (SSH) and aldosterone modulation. These findings have reshaped our vision of aldosterone's role in cardiovascular pathophysiology. This review describes new mediators of aldosterone's mechanisms of action: lysine-specific demethylase 1 (LSD1), caveolin 1 (cav-1) and striatin. RECENT FINDINGS: LSD1, an epigenetic regulator, is involved in the pathogenesis of SSH in both humans and rodents. In addition, cav-1, the main component of caveolae, plays a substantial role in mediating aldosterone pathways of SSH. The mineralocorticoid receptor interacts with cav-1 and is modulated by sodium intake. Finally, striatin, a scaffolding protein, mediates a novel interaction between signalling molecules and mineralocorticoid receptor's rapid effects in the cardiovascular system. SUMMARY: Substantial progress in aldosterone's functions and mechanisms of action should facilitate the study of cardiovascular diseases and the role of sodium intake in aldosterone-induced damage.
Asunto(s)
Aldosterona/metabolismo , Proteínas de Unión a Calmodulina/metabolismo , Enfermedades Cardiovasculares/enzimología , Sistema Cardiovascular/enzimología , Caveolinas/metabolismo , Histona Demetilasas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Transducción de Señal , Animales , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/fisiopatología , Sistema Cardiovascular/fisiopatología , Epigenómica , Hemodinámica , Humanos , Receptores de Mineralocorticoides/metabolismo , Cloruro de Sodio Dietético/efectos adversosRESUMEN
Introducción. La hipertensión arterial es una enfermedad multifactorial influenciada por componentes genéticos y ambientales, cuya prevalencia varía entre grupos étnicos. Se han llevado a cabo numerosos estudios en genes de sistemas reguladores de la presión arterial, como el sistema renina-angiotensinaaldosterona, el sistema nervioso simpático, los factores endoteliales, y el balance de sodio, mostrando resultados incongruentes entre poblaciones. Objetivos. Evaluar el efecto de variantes en los genes AGT , AGTR1 , ACE , ADRB2 , DRD1 , ADD1 , ADD2 , ATP2B1 , TBXA2R y PTGS2 y del componente ancestral individual, sobre la hipertensión arterial y las cifras de presión arterial en una muestra de población antioqueña. Materiales y métodos. Se genotipificaron 107 casos y 253 controles para 12 variantes en los genes AGT , AGTR1 , ACE , ADRB2 , DRD1 , ADD1 , ADD2 , ATP2B1 , TBXA2R y PTGS2 , y para 20 marcadores informativos de ascendencia. Se evaluó la asociación de los polimorfismos y sus interacciones, y de la composición genética ancestral con hipertensión y cifras de presión arterial. Resultados. Los genes ADD2 , rs4852706 (OR=3,0; p=0,023); DRD1 , rs686 (OR=0,38; p=0,012) y ADRB2 , rs1042718 (OR=10,0; p=0,008); y combinaciones genotípicas de DRD1 con AGTR1 ; de AGT con ADD1 ; y de ADD1 con ATP2B1 y PTGS2 , se asociaron con hipertensión arterial. El componente ancestral amerindio se asoció con disminución en la presión arterial diastólica. Conclusiones. Variantes en los genes ADD2 , DRD1 , ADRB2 , AGTR1 , AGT , ADD1 , ATP2B1 y PTGS2 , individualmente o en su interacción, se encuentran asociadas con hipertensión. El componente ancestral amerindio tiene un efecto sobre las cifras de presión arterial.
Introduction: Hypertension is a multifactorial disease influenced by genetic and environmental components, with its prevalence varying across ethnic groups. Manifold studies on blood pressure regulatory system genes have been carried out -such as the renin-angiotensin-aldosterone system, the sympathetic nervous system, endothelial factor, and sodium balance-, but the results yielded were inconsistent among populations. Objectives: To evaluate the effect of both variants in genes AGT, AGTR1, ACE, ADRB2, DRD1, ADD1, ADD2, ATP2B1, TBXA2R PTGS2, and the result of the individual ancestry component on hypertension and blood pressure levels among population in Antioquia. Methods and materials: 107 cases and 253 controls were genotyped for 12 variants on genes AGT, AGTR1, ACE, ADRB2, DRD1, ADD1, ADD2, ATP2B1, TBXA2R y PTGS2, and for 20 ancestry informative markers. The association of polymorphisms and their interactions, and the association of ancestral genetic composition with hypertension and blood pressure levels were examined. Results: Genes ADD2, rs4852706 (OR=3.0; p=0.023); DRD1, rs686 (OR=0.38; p=0.012) and ADRB2, rs1042718 (OR=10.0; p=0.008); as well as genotypic combinations of DRD1 and AGTR1; AGT and ADD1; and ADD1 to ATP2B1 and PTGS2 were associated to hypertension. The Amerindian ancestry component was associated to some decrease in diastolic blood pressure. Conclusion: Variants on genes ADD2, DRD1, ADRB2, AGTR1, AGT, ADD1, ATP2B1 and PTGS2 individually or interacting, are associated to hypertension. The Amerindian ancestry component has an effect on blood pressure.
Asunto(s)
Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hipertensión/genética , Angiotensinógeno/genética , Presión Sanguínea/genética , Proteínas de Unión a Calmodulina/genética , Colombia , /genética , Peptidil-Dipeptidasa A/genética , ATPasas Transportadoras de Calcio de la Membrana Plasmática/genética , Receptor de Angiotensina Tipo 1/genética , /genética , Receptores de Dopamina D1/genética , /genética , Factores de RiesgoRESUMEN
Considerable effort has been invested in searching for less invasive methods of diagnosing endometriosis. Previous studies have indicated altered levels of the CALD1 gene (encoding the protein caldesmon) in endometriosis. The aims of our study were to investigate whether average CALD1 expression and caldesmon protein levels are differentially altered in the endometrium and endometriotic lesions and to evaluate the performance of the CALD1 gene and caldesmon protein as potential biomarkers for endometriosis. Paired biopsies of endometrial tissue (eutopic endometrium) and endometriotic lesions (ectopic endometrium) were obtained from patients with endometriosis to evaluate CALD1 gene expression and caldesmon protein levels by real-time PCR and Western blot analysis, respectively. In addition, immunostaining for caldesmon to determine cellular localization was also performed. Endometrium from women without endometriosis was used as a control. Increased CALD1 expression and caldesmon levels were detected in the endometriotic lesions. The electrophoretic profile of caldesmon by Western blot analysis was clearly different between the control group (endometrium of women without endometriosis) and the group of women with endometriosis (eutopic endometrium and endometriotic lesions). Caldesmon expression as determined by immunostaining showed no variation among the cell types in endometriotic lesions and eutopic endometrium. Stromal cells marked positively in eutopic endometrium from control patients and in the endometriotic lesions. The presence of caldesmon in the endometrium of patients with and without endometriosis permitted diagnoses with 95% sensitivity (specificity 100%) and 100% sensitivity (specificity 100%) for the disease and for minimal to mild endometriosis in the proliferative phase of the menstrual cycle, respectively. In the secretory phase, minimal to mild endometriosis was detected with 90% sensitivity and 93.3% specificity. Caldesmon is a possible predictor of endometrial dysregulation in patients with endometriosis. A potential limitation of our study is the fact that other endometrial diseases were not excluded, and therefore prospective studies are needed to confirm the potential of caldesmon as a biomarker exclusively for endometriosis.
Asunto(s)
Proteínas de Unión a Calmodulina/metabolismo , Endometriosis/diagnóstico , Endometrio/metabolismo , Enfermedades del Ovario/diagnóstico , Enfermedades Peritoneales/diagnóstico , Adulto , Biomarcadores/metabolismo , Proteínas de Unión a Calmodulina/genética , Estudios de Casos y Controles , Endometriosis/genética , Endometriosis/metabolismo , Endometrio/patología , Femenino , Humanos , Enfermedades del Ovario/genética , Enfermedades del Ovario/metabolismo , Enfermedades Peritoneales/genética , Enfermedades Peritoneales/metabolismo , Valor Predictivo de las Pruebas , Reacción en Cadena en Tiempo Real de la Polimerasa , Sensibilidad y Especificidad , Células del Estroma/metabolismo , Células del Estroma/patologíaRESUMEN
The endothelial differentiation factor-1 (EDF-1) is a calmodulin binding protein that regulates calmodulin-dependent enzymes. In endothelial cells, this factor can form a protein complex with calmodulin. We analyzed the relationship between this factor and the members of calmodulin/calcineurin/nuclear factor of activated T-cells (NFAT) signaling pathway during adipogenesis of 3T3-F442A cells. We found that the expression of edf1 is upregulated during early adipogenesis, whereas that of calcineurin gene is lowered, suggesting that this pathway should be downregulated to allow for adipogenesis to occur. We also found that EDF-1 associates with calmodulin and calcineurin, most likely inactivating calcineurin. Our results showed that EDF-1 inactivates the calmodulin/calcineurin/NFAT pathway via sequestration of calmodulin, during early adipogenesis, and we propose a mechanism that negatively regulates the activation of calcineurin through a complex formation between EDF-1 and calmodulin. This finding raises the possibility that modulating this pathway might offer some alternatives to regulate adipose biology.
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Adipogénesis/fisiología , Calcineurina/metabolismo , Proteínas de Unión a Calmodulina/metabolismo , Calmodulina/metabolismo , Factores de Transcripción NFATC/metabolismo , Adipogénesis/genética , Animales , Calcineurina/genética , Inhibidores de la Calcineurina , Calmodulina/genética , Proteínas de Unión a Calmodulina/genética , Línea Celular , Regulación hacia Abajo , Ratones , Factores de Transcripción NFATC/genética , Transducción de SeñalRESUMEN
INTRODUCTION: Hypertension is a multifactorial disease influenced by genetic and environmental components, with its prevalence varying across ethnic groups. Manifold studies on blood pressure regulatory system genes have been carried out -such as the renin-angiotensin-aldosterone system, the sympathetic nervous system, endothelial factor, and sodium balance-, but the results yielded were inconsistent among populations. OBJECTIVES: To evaluate the effect of both variants in genes AGT, AGTR1, ACE, ADRB2, DRD1, ADD1, ADD2, ATP2B1, TBXA2R PTGS2, and the result of the individual ancestry component on hypertension and blood pressure levels among population in Antioquia. METHODS AND MATERIALS: 107 cases and 253 controls were genotyped for 12 variants on genes AGT, AGTR1, ACE, ADRB2, DRD1, ADD1, ADD2, ATP2B1, TBXA2R y PTGS2, and for 20 ancestry informative markers. The association of polymorphisms and their interactions, and the association of ancestral genetic composition with hypertension and blood pressure levels were examined. RESULTS: Genes ADD2, rs4852706 (OR=3.0; p=0.023); DRD1, rs686 (OR=0.38; p=0.012) and ADRB2, rs1042718 (OR=10.0; p=0.008); as well as genotypic combinations of DRD1 and AGTR1; AGT and ADD1; and ADD1 to ATP2B1 and PTGS2 were associated to hypertension. The Amerindian ancestry component was associated to some decrease in diastolic blood pressure. CONCLUSION: Variants on genes ADD2, DRD1, ADRB2, AGTR1, AGT, ADD1, ATP2B1 and PTGS2 individually or interacting, are associated to hypertension. The Amerindian ancestry component has an effect on blood pressure.
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Hipertensión/genética , Adulto , Angiotensinógeno/genética , Presión Sanguínea/genética , Proteínas de Unión a Calmodulina/genética , Colombia , Ciclooxigenasa 2/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Peptidil-Dipeptidasa A/genética , ATPasas Transportadoras de Calcio de la Membrana Plasmática/genética , Receptor de Angiotensina Tipo 1/genética , Receptores Adrenérgicos beta 2/genética , Receptores de Dopamina D1/genética , Receptores de Tromboxano A2 y Prostaglandina H2/genética , Factores de RiesgoRESUMEN
Calmodulin (CaM) is the primary sensor for calcium in the cell. It modulates various functions by activating CaM-binding proteins (CaMBPs). This study examined the calcium/CaM-dependent system in the ancient eukaryote Giardia intestinalis. A specific antibody against the parasite's CaM was developed; this protein's expression and location during different stages of the parasite's life cycle were analyzed. The results showed that it is a housekeeping protein which is possibly involved in the parasite's motility. No CaMBP has been identified in G. intestinalis to date. Pull-down assays were used for isolating proteins which specifically bind to CaM in a calcium-dependent way. Three of them were identified through mass spectrometry; they were GASP180, α-tubulin, and pyruvate phosphate dikinase (PPDK).The first two are cytoskeleton proteins, and the last one is an essential enzyme for glycolysis. The presence of binding sites was analyzed through bioinformatics in each protein sequence. This is the first report of a CaMBP in this organism; it is considered to be a very interesting differentiation model, indicating that CaM is involved at least in two vital processes: G. intestinalis motility and energetic metabolism.
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Proteínas de Unión a Calmodulina/metabolismo , Calmodulina/metabolismo , Giardia lamblia/crecimiento & desarrollo , Proteínas Protozoarias/metabolismo , Trofozoítos/metabolismo , Calcio/metabolismo , Calmodulina/genética , Técnicas de Cultivo de Célula , Diferenciación Celular , Movimiento Celular , Biología Computacional , Giardia lamblia/metabolismo , Filogenia , Procesamiento Proteico-Postraduccional , Piruvato Ortofosfato Diquinasa/metabolismo , Tubulina (Proteína)RESUMEN
Angiomatoid "malignant" fibrous histiocytoma is a rare sarcoma of low malignant potential that occurs most commonly in the extremities of children and young adults. Herein, we present a case of angiomatoid malignant fibrous histiocytoma with unusual histologic features arising in the mediastinum of an 80-year-old man. The tumor exhibited a reticular growth pattern and myxoid stroma. The tumor cells expressed epithelial membrane antigen and desmin. Cytogenetic analysis revealed the translocation t(2;22)(q33;q12). Molecular genetic analysis confirmed the rearrangement of the EWSR1 locus and the presence of the EWSR1/CREB1 fusion. This report expands the clinicopathologic spectrum of angiomatoid malignant fibrous histiocytoma and underscores the value of integrating morphologic, immunophenotypic, and molecular findings in the identification of its unusual morphologic variants.
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Histiocitoma Fibroso Maligno/patología , Neoplasias del Mediastino/patología , Anciano de 80 o más Años , Proteínas de Unión a Calmodulina/genética , Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 22/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Análisis Citogenético , Histiocitoma Fibroso Maligno/genética , Humanos , Masculino , Neoplasias del Mediastino/genética , Proteínas de Fusión Oncogénica/genética , Proteína EWS de Unión a ARN , Proteínas de Unión al ARN/genética , Translocación GenéticaRESUMEN
The Ca(2+)/calmodulin complex interacts with and regulates various enzymes and target proteins known as calmodulin-binding proteins (CaMBPs). This group of proteins includes molecular motors such as myosins. In this study, we show that non-muscle myosin-IIB is overexpressed in the brains of diabetic rats. We isolated CaMBPs from the brains of non-diabetic rats and rats with streptozotocin-induced diabetes and purified them by immobilized-calmodulin affinity chromatography. The proteins were eluted with EGTA and urea, separated by SDS-PAGE, digested and submitted to peptide mass fingerprinting analysis. Thirteen intense bands were found in both types of brains, two were found exclusively in non-diabetic brains and four were found exclusively in diabetic brains. A large fraction of the eluted proteins contained putative IQ motifs or calmodulin-binding sites. The results of the myosin-IIB affinity chromatography elution, western blot and RT-PCR analyses suggest that myosin-IIB protein and mRNA are expressed at high levels in diabetic brains. This is the first study that has demonstrated differential expression of CaMBPs in diabetic and non-diabetic brain tissue through a comparative proteomic analysis, and it opens up a new approach to studying the relationship between the expression of myosins in the brain, hyperglycemia and intracellular calcium regulation.
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Química Encefálica/fisiología , Diabetes Mellitus Experimental/metabolismo , Miosina Tipo IIB no Muscular/biosíntesis , Secuencia de Aminoácidos , Animales , Western Blotting , Proteínas de Unión a Calmodulina/metabolismo , Cromatografía de Afinidad , ADN Complementario/biosíntesis , ADN Complementario/genética , Electroforesis en Gel de Poliacrilamida , Inmunohistoquímica , Masculino , Datos de Secuencia Molecular , Biblioteca de Péptidos , Péptidos/química , ARN/biosíntesis , ARN/aislamiento & purificación , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Tripsina/químicaRESUMEN
OBJECTIVE: Follicular dendritic cells (FDCs) and interdigitating dendritic cells (IDCs) are dendritic cells found in lymphoid follicles, reactive follicles and in lymphomas. The goal of this study was to evaluate the presence and distribution of FDCs and IDCs in oral lymphomas. MATERIAL AND METHODS: Immunohistochemistry reactions were applied to 50 oral lymphomas using the antibodies anti-CD21, anti-CD35 and anti-caldesmon to FDCs, and anti-S100 protein to IDCs. Caldesmon+/FDCs and S100+/IDCs were quantified in Imagelab® software. RESULTS: FDCs revealed by CD21 and CD35 were positively stained in two cases of diffuse large B-cell lymphoma, one MALT lymphoma, and in one case of mantle cell lymphoma. FDCs were immunopositive to caldesmon in all cases, as well as IDCs to S100 protein. Burkitt lymphoma presented a lower amount of caldesmon+/FDCs and S100+/IDCs than diffuse large B-cell lymphoma and plasmablastic lymphoma of the oral mucosa type. CONCLUSIONS: The microenvironment determined by neoplastic lymphoid cells in oral lymphomas is responsible by the development and expression of dendritic cells types.
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Humanos , Células Dendríticas Foliculares/química , Células Dendríticas/química , Linfoma no Hodgkin/química , Neoplasias de la Boca/química , Proteínas de Unión a Calmodulina/análisis , Inmunohistoquímica , Linfoma de Células B de la Zona Marginal/química , Linfoma de Células B de la Zona Marginal/patología , Linfoma de Células B Grandes Difuso/química , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células del Manto/química , Linfoma de Células del Manto/patología , Linfoma no Hodgkin/patología , Neoplasias de la Boca/patología , /análisis , /análisis , /análisisRESUMEN
OBJECTIVE: Follicular dendritic cells (FDCs) and interdigitating dendritic cells (IDCs) are dendritic cells found in lymphoid follicles, reactive follicles and in lymphomas. The goal of this study was to evaluate the presence and distribution of FDCs and IDCs in oral lymphomas. MATERIAL AND METHODS: Immunohistochemistry reactions were applied to 50 oral lymphomas using the antibodies anti-CD21, anti-CD35 and anti-caldesmon to FDCs, and anti-S100 protein to IDCs. Caldesmon+/FDCs and S100+/IDCs were quantified in Imagelab software. RESULTS: FDCs revealed by CD21 and CD35 were positively stained in two cases of diffuse large B-cell lymphoma, one MALT lymphoma, and in one case of mantle cell lymphoma. FDCs were immunopositive to caldesmon in all cases, as well as IDCs to S100 protein. Burkitt lymphoma presented a lower amount of caldesmon+/FDCs and S100+/IDCs than diffuse large B-cell lymphoma and plasmablastic lymphoma of the oral mucosa type. CONCLUSIONS: The microenvironment determined by neoplastic lymphoid cells in oral lymphomas is responsible by the development and expression of dendritic cells types.
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Células Dendríticas Foliculares/química , Células Dendríticas/química , Linfoma no Hodgkin/química , Neoplasias de la Boca/química , Proteínas de Unión a Calmodulina/análisis , Humanos , Inmunohistoquímica , Linfoma de Células B de la Zona Marginal/química , Linfoma de Células B de la Zona Marginal/patología , Linfoma de Células B Grandes Difuso/química , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células del Manto/química , Linfoma de Células del Manto/patología , Linfoma no Hodgkin/patología , Neoplasias de la Boca/patología , Receptores de Complemento 3b/análisis , Receptores de Complemento 3d/análisis , Proteínas S100/análisisRESUMEN
Calmodulin is a Ca(+2)-binding protein important in a variety of cell functions. The Ca(+2)/calmodulin complex interacts with and regulates various enzymes and target proteins, known as calmodulin-binding proteins (CaMBPs). In this study, we revealed a comparative identification of the CaMBPs composition in the worker honeybee (Apis mellifera) brain, considering two different honeybee behaviors in the colony. To this end, the CaMBPs of forager and nurse workers were purified by affinity chromatography, separated in 1D gel, digested and submitted to peptide mass fingerprinting (PMF). In the PMF analysis, 15 different proteins, considered behavior-specific proteins, were identified, one of them exclusively in forager workers and 10 in nurses. All the proteins were classified in terms of their function and cell localization, revealing a greater expression of metabolism-related CaMBPs in both worker subcastes. Protein sequences were then analyzed for the presence of the calmodulin-binding sites. Therefore, the honeybee brain CaMBPs profiles presented differences between worker subcastes. This is the first identification of calmodulin-binding proteins in the brain of A. mellifera upon nursing and foraging behaviors in the colony and this diversity of target proteins for Ca(+2)/CaM may be involved in terms of the function of these proteins in the nervous system.
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Abejas/metabolismo , Encéfalo/metabolismo , Proteínas de Unión a Calmodulina/metabolismo , Secuencias de Aminoácidos , Animales , Encéfalo/citología , Proteínas de Unión a Calmodulina/química , Proteínas de Unión a Calmodulina/clasificación , Vesículas Citoplasmáticas/metabolismo , Citoesqueleto/metabolismoRESUMEN
Androgens play an important role in growth and maintenance of prostate cells. The actions of androgens are mediated by the androgen receptor (AR), a transcription factor member of the super-family of nuclear hormone receptors. Androgen regulated genes (ARGs) are potential markers for early diagnosis and treatment of prostate cancer patients. In the present study, we used DDRT-PCR (differential display reverse transcriptase polymerase chain reaction) technique in order to investigate differentially expressed genes in the prostate cancer cell line LNCaP after treatment with dihydrotestosterone and bicalutamide for 6, 24, and 48 hours. Fifty-five differentially expressed fragments were isolated, cloned, and sequenced. Sequencing analysis of these fragments revealed 56 different transcripts that showed homology to transcription factors, cell cycle regulators, metabolic enzymes, and hypothetical proteins. Among the differentially expressed genes, SPA17 and DDEF2 were further validated using quantitative real time RT-PCR (qPCR) in a series of 25 prostate tumor samples. The DDEF2 gene is involved in adhesion and cell migration of monocytes, and the SPA17 gene might be involved in cellular signal transduction. The transcripts of both, SPA17 and DDEF2 genes, showed altered pattern of expression in the group of prostate tumors analyzed by qPCR. The differentially expressed genes identified in this study might provide new insights into the androgen signaling pathways in prostate cells.