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1.
Int J Cancer ; 150(1): 56-66, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34469588

RESUMO

Lynch syndrome (LS), Lynch-like syndrome (LLS) and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer (CRC). The aim of this prospective study was to characterise and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. Our study may support the development of risk-adapted surveillance policies in LS, LLS and FCCX.


Assuntos
Adenoma/patologia , Biomarcadores Tumorais/genética , Neoplasias Colorretais Hereditárias sem Polipose/classificação , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais/patologia , Adenoma/etiologia , Adenoma/metabolismo , Adulto , Idoso , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Mutação , Prognóstico , Estudos Prospectivos , Fatores de Risco
2.
Sci Rep ; 11(1): 16728, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408227

RESUMO

The main types of thyroid neoplasms, follicular adenoma (FA), follicular thyroid carcinoma (FTC), classical and follicular variants of papillary carcinoma (clPTC and fvPTC), and anaplastic thyroid carcinoma (ATC), differ in prognosis, progression rate and metastatic behaviour. Specific patterns of lncRNAs involved in the development of clinical and morphological features can be presumed. LncRNA landscapes within distinct benign and malignant histological variants of thyroid neoplasms were not investigated. The aim of the study was to discover long noncoding RNA landscapes common and specific to major benign and malignant histological subtypes of thyroid neoplasms. LncRNA expression in FA, FTC, fvPTC, clPTC and ATC was analysed with comprehensive microarray and RNA-Seq datasets. Putative biological functions were evaluated via enrichment analysis of coexpressed coding genes. In the results, lncRNAs common and specific to FTC, clPTC, fvPTC, and ATC were identified. The discovered lncRNAs are putatively involved in L1CAM interactions, namely, pre-mRNA processing (lncRNAs specific to FTC); PCP/CE and WNT pathways (lncRNAs specific to fvPTC); extracellular matrix organization (lncRNAs specific to clPTC); and the cell cycle (lncRNAs specific to ATC). Known oncogenic and suppressor lncRNAs (RMST, CRNDE, SLC26A4-AS1, NR2F1-AS1, and LINC00511) were aberrantly expressed in thyroid carcinomas. These findings enhance the understanding of lncRNAs in the development of subtype-specific features in thyroid cancer.


Assuntos
Adenocarcinoma Folicular , Adenoma , RNA Longo não Codificante , RNA Neoplásico , Câncer Papilífero da Tireoide , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/metabolismo , Adenoma/genética , Adenoma/metabolismo , Humanos , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo
3.
Sci Rep ; 11(1): 16530, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400688

RESUMO

We aimed to identify somatic genetic alterations in pure growth hormone (GH)-secreting pituitary adenomas without GNAS variants. Patients with GH-secreting pituitary adenoma who underwent transsphenoidal adenomectomy at Severance Hospital, Yonsei University College of Medicine were recruited. Somatic genetic alterations were profiled by whole-exome sequencing (WES) and targeted resequencing. WES was performed using DNA from nine GH-secreting pituitary tumors and corresponding blood samples. Absence of GNAS variant was confirmed by Sanger sequencing. For targeted resequencing of 140 fixed tissues, 48 WES-derived candidate genes and 7 GH-secreting pituitary adenoma-associated genes were included. Forty-eight genes with 59 somatic variants were identified by WES. In targeted resequencing, variants in 26 recurrent genes, including MAST4, PRIM2, TNN, STARD9, DNAH11, DOCK4, GPR98, BCHE, DARS, CUBN, NGDN, PLXND1, UNC5B, and COL22A1, were identified, but variants in previously reported genes were not detected. BCHE, DARS, NGDN, and UNC5B variants were associated with increased GH-secreting pituitary tumor biochemical activity, which was confirmed in vitro. Although recurrent point variants were rare, several somatic variants were identified in sporadic pure GH-secreting pituitary adenomas. Several somatic variants may affect pathways involved in the tumorigenesis and biochemical activities of GH-secreting pituitary adenomas.


Assuntos
Adenoma/genética , Genes Neoplásicos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Neoplasias Hipofisárias/genética , Adenoma/metabolismo , Adulto , Idoso , Animais , Biomarcadores Tumorais/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Cromograninas , DNA de Neoplasias/genética , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP , Ontologia Genética , Estudos de Associação Genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Hormônio do Crescimento Humano/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/metabolismo , Ratos , Análise de Sequência de DNA , Transfecção , Sequenciamento Completo do Exoma , Adulto Jovem
4.
Sci Rep ; 11(1): 14730, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34282192

RESUMO

Although 18-fluoro-2-deoxy-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is useful for detecting synchronous colorectal cancer (CRC) in stenotic CRC, long-term outcomes of patients without synchronous FDG-avid lesions are not well reported. We investigated postoperative colonoscopy results in patients with left-sided stenosing CRC without synchronous FDG-avid lesions. In this retrospective review, 754 patients with left-sided CRC without synchronous FDG-avid lesions on preoperative 18F-FDG PET/CT were divided into two groups based on the completeness of preoperative colonoscopy. Propensity score matching was performed to balance baseline characteristics. Results of postoperative colonoscopy were compared in both the unmatched and matched cohorts. At 1 and 5 years after surgery, the cumulative risk of advanced adenoma (AA) or carcinoma (CA) in all patients, risk of CA, and additional surgical risk were 1.8% and 10.1%, 0.1% and 0.4%, and 0% and 0.5%, respectively. In both cohorts, the AA risk was significantly higher in the incomplete colonoscopy group. However, the risk of CA showed no between-group difference in the matched cohort. Additional surgical risk did not differ between the two groups. Thus, the finding of negative FDG-avid lesions in the proximal colon in addition to the target CRC ensures the absence of additional lesions warranting surgical plan changes.


Assuntos
Adenoma/diagnóstico , Neoplasias Colorretais/diagnóstico , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adenoma/metabolismo , Adenoma/patologia , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Colo/diagnóstico por imagem , Colo/metabolismo , Colo/patologia , Colonoscopia/métodos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Constrição Patológica/diagnóstico , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , República da Coreia , Estudos Retrospectivos
5.
Biochim Biophys Acta Proteins Proteom ; 1869(11): 140700, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34303023

RESUMO

Pituitary adenoma is considered as one of the most frequent intracranial tumors having salient impact on human health such as mass effects, hypopituitarism and visual defects etc. During the past few decades, there has been enormous advancement in mass spectrometry (MS)-based proteomics. However, very little is known about the molecular pathogenesis of pituitary adenomas in the context of proteomics. In this review article, we have focused on the provenance of pituitary tumors and their pathogenesis with the help of MS-based proteomics approaches. Recent advancements in quantitative proteomic approaches are outlined here that would be useful in the near pituitary adenoma proteomics research. This review discusses the enormous potential of pituitary adenomas research through proteomics with a common aim of deciphering disease pathobiology and identifying the work done in studying pituitary tumors during past decade.


Assuntos
Adenoma/metabolismo , Neoplasias Hipofisárias/metabolismo , Proteômica/métodos , Biomarcadores Tumorais/química , Biomarcadores Tumorais/metabolismo , Humanos , Espectrometria de Massas/métodos
6.
J Clin Endocrinol Metab ; 106(9): e3346-e3363, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34061962

RESUMO

CONTEXT: Mechanisms underlying pituitary corticotroph adenoma adrenocorticotropin (ACTH) production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes. OBJECTIVE: We characterized the 5' ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production. METHODS: We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent corticotroph adenomas (SCAs) that immunostain for but do not secrete ACTH. RESULTS: We identified a novel regulatory region located near the intron 2/exon 3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCAs, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the ubiquitin-specific protease 8 (USP8) mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing disease. CONCLUSION: We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.


Assuntos
Hipersecreção Hipofisária de ACTH/genética , Pró-Opiomelanocortina/genética , Regiões Promotoras Genéticas/genética , Adenoma Hipofisário Secretor de ACT/sangue , Adenoma/metabolismo , Adolescente , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/genética , Adulto , Idoso , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/sangue , Éxons , Feminino , Regulação da Expressão Gênica , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Neoplasias Hipofisárias/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Resultado do Tratamento , Adulto Jovem
7.
World Neurosurg ; 153: e20-e27, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34087455

RESUMO

OBJECTIVE: To investigate the role of transforming growth factor ß1 (TGF-ß1), Smad3, and phospho-Smad3 (p-Smad3) in the invasion of somatotropinomas. METHODS: In total, 45 somatotropinomas were obtained from patients who underwent surgery for the first time between 2011 and 2015 at Beijing Tiantan Hospital. The expression of TGF-ß1, Smad3, and p-Smad3 was examined by western blot, quantitative reverse transcription polymerase chain reaction, and immunohistochemistry in somatotropinomas, and factors correlated with tumor invasion were analyzed. RESULTS: A total of 13 invasive somatotropinomas and 32 noninvasive somatotropinomas were enrolled in the study. TGF-ß1 protein (P < 0.01) and mRNA (P < 0.01) levels were significantly less in the invasive somatotropinomas than noninvasive somatotropinomas. There was no significant difference in Smad3 protein level or Smad3 mRNA level between invasive somatotropinomas and noninvasive somatotropinomas. However, the p-Smad3 protein level was significantly less in the invasive somatotropinomas than noninvasive somatotropinomas (P < 0.01). Univariate analysis demonstrated that TGF-ß1 (P < 0.01) and p-Smad3 scores (P < 0.01) were associated with invasion. In multivariate analysis, p-Smad3 scores remained a significantly independent predictor of invasion (odds ratio 0.897, 95% confidence interval 0.834-0.964, P < 0.05). CONCLUSIONS: Low expression of p-Smad3 is correlated with invasion of somatotropinomas.


Assuntos
Adenoma/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta1/genética , Adenoma/metabolismo , Adenoma/patologia , Adenoma/cirurgia , Adulto , Western Blotting , Feminino , Expressão Gênica , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Fosforilação , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Carga Tumoral , Adulto Jovem
8.
Nature ; 594(7863): 436-441, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34079128

RESUMO

A delicate equilibrium of WNT agonists and antagonists in the intestinal stem cell (ISC) niche is critical to maintaining the ISC compartment, as it accommodates the rapid renewal of the gut lining. Disruption of this balance by mutations in the tumour suppressor gene APC, which are found in approximately 80% of all human colon cancers, leads to unrestrained activation of the WNT pathway1,2. It has previously been established that Apc-mutant cells have a competitive advantage over wild-type ISCs3. Consequently, Apc-mutant ISCs frequently outcompete all wild-type stem cells within a crypt, thereby reaching clonal fixation in the tissue and initiating cancer formation. However, whether the increased relative fitness of Apc-mutant ISCs involves only cell-intrinsic features or whether Apc mutants are actively involved in the elimination of their wild-type neighbours remains unresolved. Here we show that Apc-mutant ISCs function as bona fide supercompetitors by secreting WNT antagonists, thereby inducing differentiation of neighbouring wild-type ISCs. Lithium chloride prevented the expansion of Apc-mutant clones and the formation of adenomas by rendering wild-type ISCs insensitive to WNT antagonists through downstream activation of WNT by inhibition of GSK3ß. Our work suggests that boosting the fitness of healthy cells to limit the expansion of pre-malignant clones may be a powerful strategy to limit the formation of cancers in high-risk individuals.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Competição entre as Células , Genes APC , Neoplasias Intestinais/genética , Neoplasias Intestinais/patologia , Mutação , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Proteína da Polipose Adenomatosa do Colo/deficiência , Animais , Diferenciação Celular/genética , Feminino , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Humanos , Neoplasias Intestinais/metabolismo , Cloreto de Lítio/farmacologia , Masculino , Camundongos , Organoides/citologia , Organoides/metabolismo , Organoides/patologia , Proteínas Wnt/antagonistas & inibidores , Proteínas Wnt/metabolismo
9.
Clin Nucl Med ; 46(7): e381-e383, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34081055

RESUMO

ABSTRACT: A 67-year-old man was referred to our department to undergo a 68Ga-DOTATOC PET/CT during the systematic follow-up of a small intestine neuroendocrine tumor. PET revealed an incidental focal increased uptake of 68Ga-DOTATOC matching with a left intraparotid lesion on the combined contrast-enhanced CT, suggestive of a benign salivary tumor. An MRI was performed to characterize this lesion, and finally, the patient underwent surgery. Histological analysis confirmed the presence of a basal cell adenoma.


Assuntos
Adenoma/diagnóstico por imagem , Adenoma/metabolismo , Achados Incidentais , Compostos Organometálicos/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias das Glândulas Salivares/diagnóstico por imagem , Neoplasias das Glândulas Salivares/metabolismo , Idoso , Transporte Biológico , Humanos , Imageamento por Ressonância Magnética , Masculino , Traçadores Radioativos
10.
J Steroid Biochem Mol Biol ; 212: 105924, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34089832

RESUMO

Endogenous Cushing syndrome (CS) is an endocrine disorder marked by excess cortisol production rendering patients susceptible to visceral obesity, dyslipidemia, hypertension, osteoporosis and diabetes mellitus. Adrenal CS is characterized by autonomous production of cortisol from cortisol-producing adenomas (CPA) via adrenocorticotropic hormone-independent mechanisms. A limited number of studies have quantified the steroid profiles in sera from patients with CS. To understand the intratumoral steroid biosynthesis, we quantified 19 steroids by mass spectrometry in optimal cutting temperature compound (OCT)-embedded 24 CPA tissue from patients with overt CS (OCS, n = 10) and mild autonomous cortisol excess (MACE, n = 14). Where available, normal CPA-adjacent adrenal tissue (AdjN) was also collected and used for comparison (n = 8). Immunohistochemistry (IHC) for CYP17A1 and HSD3B2, two steroidogenic enzymes required for cortisol synthesis, was performed on OCT sections to confirm the presence of tumor tissue and guided subsequent steroid extraction from the tumor. LC-MS/MS was used to quantify steroids extracted from CPA and AdjN. Our data indicated that CPA demonstrated increased concentrations of cortisol, cortisone, 11-deoxycortisol, corticosterone, progesterone, 17OH-progesterone and 16OH-progesterone as compared to AdjN (p < 0.05). Compared to OCS, MACE patient CPA tissue displayed higher concentrations of corticosterone, 18OH-corticosterone, 21-deoxycortisol, progesterone, and 17OH-progesterone (p < 0.05). These findings also demonstrate that OCT-embedded tissue can be used to define intra-tissue steroid profiles, which will have application for steroid-producing and steroid-responsive tumors.


Assuntos
Adenoma/metabolismo , Neoplasias do Córtex Suprarrenal/metabolismo , Síndrome de Cushing/metabolismo , Esteroides/metabolismo , Adenoma/sangue , Neoplasias do Córtex Suprarrenal/sangue , Adulto , Cromatografia Líquida , Síndrome de Cushing/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Progesterona Redutase/metabolismo , Esteroide 17-alfa-Hidroxilase/metabolismo , Esteroides/sangue , Espectrometria de Massas em Tandem
11.
Cell Death Dis ; 12(6): 580, 2021 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-34091587

RESUMO

Long noncoding RNAs (lncRNAs) and their crosstalks with other RNAs have been revealed to be closely related to tumorigenesis and development, but their role in invasive pituitary adenoma (IPA) remains largely unclear. In our study, LINC00473 was identified as the most upregulated lncRNA in IPA by whole transcriptome RNA sequencing (RNA-Seq). Further, its related signaling pathway LINC00473/miR-502-3p/KMT5A was obtained by constructing a competing endogenous RNA (ceRNA) regulatory network. Their expression in IPA and non-invasive pituitary adenoma (NIPA) tissues was verified by qRT-PCR. Then the effects and mechanisms of LINC00473 and its ceRNA network on the proliferation of pituitary adenoma (PA) cells were confirmed by gene overexpression or silencing techniques combined with CCK-8 assay, EdU staining, flow cytometry assay, and double luciferase reporter gene assay in PA cell lines AtT-20 and GT1-1 in vitro and in a xenograft model in vivo. LINC00473 is overexpressed in IPA and can promote PA cells proliferation. Mechanistically, overexpression of LINC00473 restricts miR-502-3p through the ceRNA mechanism, upregulates KMT5A expression, and promotes the expression of cyclin D1 and CDK2, which is conducive to the cell cycle process, thereby promoting the proliferation of PA cells, involving IPA progression.


Assuntos
Adenoma/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , MicroRNAs/metabolismo , Neoplasias Hipofisárias/metabolismo , RNA Longo não Codificante/metabolismo , Adenoma/genética , Adulto , Animais , Progressão da Doença , Feminino , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias Hipofisárias/genética , RNA Longo não Codificante/genética , Regulação para Cima
12.
J Cancer Res Clin Oncol ; 147(8): 2199-2207, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34115239

RESUMO

Colorectal cancer is an important public health concern leading to significant cancer associate mortality. A vast majority of colon cancer arises from polyp which later follows adenoma, adenocarcinoma, and carcinoma sequence. This whole process takes several years to complete and recent genomic and proteomic technologies are identifying several targets involved in each step of polyp to carcinoma transformation in a large number of studies. Current text presents interaction network of targets involved in polyp to carcinoma transformation. In addition, important targets involved in each step according to network biological parameters are also presented. The functional overrepresentation analysis of each step targets and common top biological processes and pathways involved in carcinoma indicate several insights about this whole mechanism. Interaction networks indicate TP53, AKT1, GAPDH, INS, EGFR, and ALB as the most important targets commonly involved in polyp to carcinoma sequence. Though several important pathways are known to be involved in CRC, the central common involvement of PI3K-AKT indicates its potential for devising CRC management strategies. The common and central targets and pathways involved in polyp to carcinoma progression can shed light on its mechanism and potential management strategies. The data-driven approach aims to add valuable inputs to the mechanism of the years-long polyp-carcinoma sequence.


Assuntos
Carcinoma/prevenção & controle , Transformação Celular Neoplásica , Neoplasias do Colo/prevenção & controle , Pólipos do Colo/terapia , Terapia de Alvo Molecular/métodos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Adenoma/prevenção & controle , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patologia , Pólipos Adenomatosos/prevenção & controle , Antineoplásicos/uso terapêutico , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Pólipos do Colo/genética , Pólipos do Colo/metabolismo , Pólipos do Colo/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/fisiologia , Genes de Troca/efeitos dos fármacos , Humanos , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , Proteômica , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
13.
Eur J Endocrinol ; 185(2): R65-R74, 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34132199

RESUMO

Background and aims: Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare entity, occurring in one per million people. We performed a systematic review of 535 adult cases summarizing the clinical, biochemical, hormonal and radiological characteristics of TSHoma. Furthermore, we discussed the current guidelines for diagnosis and treatment. Methods: A structured research was conducted using Pubmed and Web of Science with the following MeSH terms: 'thyrotropin secreting pituitary adenoma' OR 'TSHoma' OR 'thyrotropinoma.' Results: Our analysis included 535 cases originating from 18 case series, 5 cohort studies and 91 case reports. The mean age at diagnosis was 46 years. At presentation, 75% had symptoms of hyperthyroidism, 55.5% presented with a goitre and 24.9% had visual field defects. The median TSH at diagnosis was 5.16 (3.20-7.43) mU/L with a mean FT4 of 41.5 ± 15.3 pmol/L. The majority (76.9%) of the TSHomas were macroadenoma. Plurihormonality was seen in 37.4% of the adenoma with a higher incidence in macroadenoma. Surgical resection of the adenoma was performed in 87.7% of patients of which 33.5% had residual pituitary adenoma. Post-operative treatment with a somatostatin analogue (SSA) led to a stable disease in 81.3% of the cases with residual tumour. We noticed a significant correlation between the diameter of the adenoma and residual pituitary adenoma (r = 0.490, P < 0.001). However, in patients preoperatively treated with an SSA, this correlation was absent. Conclusion: TSHomas are a rare cause of hyperthyroidism and are frequently misdiagnosed. Based on our structured analysis of case series, cohort studies and case reports, we conclude that the majority of TSHomas are macroadenoma being diagnosed in the fifth to sixth decade of life and presenting with symptoms of hyperthyroidism. Plurihormonalitiy is observed in one-third of TSHomas. Treatment consists of neurosurgical resection and SSA in case of surgical failure.


Assuntos
Adenoma/metabolismo , Hipertireoidismo/metabolismo , Neoplasias Hipofisárias/metabolismo , Tireotropina/metabolismo , Tiroxina/metabolismo , Adenoma/patologia , Adenoma/fisiopatologia , Adenoma/terapia , Fibrilação Atrial/fisiopatologia , Quimioterapia Adjuvante , Bócio/fisiopatologia , Gonadotropinas Hipofisárias/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Insuficiência Cardíaca/fisiopatologia , Hormônios/uso terapêutico , Humanos , Hipertireoidismo/fisiopatologia , Neoplasia Residual , Procedimentos Neurocirúrgicos , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/fisiopatologia , Neoplasias Hipofisárias/terapia , Prolactinoma/metabolismo , Radioterapia Adjuvante , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Carga Tumoral , Transtornos da Visão/fisiopatologia
14.
Endocrinology ; 162(8)2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34111287

RESUMO

The world of long non-coding RNAs (lncRNAs) has opened up massive new prospects in understanding the regulation of gene expression. Not only are there seemingly almost infinite numbers of lncRNAs in the mammalian cell, but they have highly diverse mechanisms of action. In the nucleus, some are chromatin-associated, transcribed from transcriptional enhancers (eRNAs) and/or direct changes in the epigenetic landscape with profound effects on gene expression. The pituitary gonadotrope is responsible for activation of reproduction through production and secretion of appropriate levels of the gonadotropic hormones. As such, it exemplifies a cell whose function is defined through changes in developmental and temporal patterns of gene expression, including those that are hormonally induced. Roles for diverse distal regulatory elements and eRNAs in gonadotrope biology have only just begun to emerge. Here, we will present an overview of the different kinds of lncRNAs that alter gene expression, and what is known about their roles in regulating some of the key gonadotrope genes. We will also review various screens that have detected differentially expressed pituitary lncRNAs associated with changes in reproductive state and those whose expression is found to play a role in gonadotrope-derived nonfunctioning pituitary adenomas. We hope to shed light on this exciting new field, emphasize the open questions, and encourage research to illuminate the roles of lncRNAs in various endocrine systems.


Assuntos
Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Gonadotrofos/metabolismo , RNA Longo não Codificante/metabolismo , Adenoma/metabolismo , Animais , Humanos , Neoplasias Hipofisárias/metabolismo , Maturidade Sexual
15.
Cell Death Dis ; 12(6): 524, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34021124

RESUMO

The molecule mechanisms of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in human diseases have been broadly studied recently, therefore, our research aimed to assess the effect of lncRNA taurine upregulated gene 1 (TUG1)/miR-187-3p/tescalcin (TESC) axis in pituitary adenoma (PA) by regulating the nuclear factor-kappa B (NF-κB) signaling pathway. We observed that TUG1 was upregulated in PA tissues and was associated with invasion, knosp grade and tumor size. TUG1 particularly bound to miR-187-3p. TUG1 knockdown inhibited cell proliferation, invasion, migration, and epithelial-mesenchymal transition, promoted apoptosis, and regulated the expression of NF-κB p65 and inhibitor of κB (IκB)-α in PA cells lines in vitro, and also inhibited tumor growth in vivo, and these effects were reversed by miR-187-3p reduction. Similarly, miR-187-3p elevation inhibited PA cell malignant behaviors and modulated the expression of NF-κB p65 and IκB-α in PA cells, and reduced in vivo tumor growth as well. TUG1 inhibition downregulated TESC, which was targeted by miR-187-3p. In conclusion, this study suggests that TUG1 sponges miR-187-3p to affect PA development by elevating TESC and regulating the NF-κB signaling pathway.


Assuntos
Adenoma/patologia , Proteínas de Ligação ao Cálcio/fisiologia , MicroRNAs/fisiologia , Neoplasias Hipofisárias/patologia , RNA Longo não Codificante/fisiologia , Adenoma/genética , Adenoma/metabolismo , Adolescente , Adulto , Idoso , Animais , Estudos de Casos e Controles , Proliferação de Células/genética , Células Cultivadas , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Transdução de Sinais/genética , Adulto Jovem
16.
Virchows Arch ; 479(4): 687-695, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34043063

RESUMO

Sporadic foveolar-type gastric adenoma (FGA) has been described as an extremely rare polyp that is whitish and flatly elevated. However, we recently found that sporadic FGA with a raspberry-like appearance (FGA-RA) is not rare in Helicobacter pylori (H. pylori)-naïve gastric mucosa. We endoscopically or surgically treated 647 patients with gastric epithelial neoplasms in the last 5 years, with 7.7% (50/647) being H. pylori-naïve. Among these, 43 FGA-RAs were diagnosed based on histologic and endoscopic features in 34 patients, who were all enrolled in this retrospective study. All lesions were observed by white-light endoscopy (WLE) and narrow-band imaging with magnification endoscopy (NBIME). We subsequently analyzed their endoscopic and microscopic features and patient characteristics. The patients were 22 males and 12 females aged 57±23 years (mean±2SD). WLE showed raspberry-like small polyps mimicking gastric hyperplastic polyps in the oxyntic gastric compartment (body/fundus). Multiple growths were confirmed in 20.6% (7/34) of the patients. NBIME revealed irregularly shaped papillary/gyrus-like microstructures with abnormal capillaries. Histologically, all lesions were intraepithelial neoplasms, and most of lesions (62.8%, 27/43) exhibited low-grade dysplasia. Immunohistochemically, neoplastic cells featured strong and diffuse MUC5AC expression, negative or very low MUC6 expression, and negative MUC2/CD10 expression. They also showed Ki-67 hyperexpression with a mean labeling index of 59.4±48.7%. The coexistence of fundic gland polyps in the background mucosa was significantly higher in multiple FGA-RA cases than in solitary cases (100% vs. 55.5%, P< 0.05). FGA-RA is a newly suggested histologic variant of sporadic FGA whose occurrence is not rare in daily endoscopic practice.


Assuntos
Adenoma/metabolismo , Mucosa Gástrica/patologia , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/patologia , Adenoma/diagnóstico , Adenoma/fisiopatologia , Pólipos Adenomatosos/patologia , Adulto , Idoso , Feminino , Fundo Gástrico/patologia , Infecções por Helicobacter , Helicobacter pylori , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Pólipos/patologia , Estudos Retrospectivos , Estômago/patologia , Neoplasias Gástricas/patologia
17.
Sci Rep ; 11(1): 10562, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006971

RESUMO

Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism (PA) and are characterized by constitutively producing aldosterone, which leads to hypertension. Several mutations have been identified in ion channels or ion channel-associated genes that result in APAs. To date, no studies have used a genome-wide association study (GWAS) approach to search for predisposing loci for APAs. Thus, we investigated Scandinavian APA cases (n = 35) and Swedish controls (n = 60) in a GWAS and discovered a susceptibility locus on chromosome Xq13.3 (rs2224095, OR = 7.9, 95% CI = 2.8-22.4, P = 1 × 10-7) in a 4-Mb region that was significantly associated with APA. Direct genotyping of sentinel SNP rs2224095 in a replication cohort of APAs (n = 83) and a control group (n = 740) revealed persistently strong significance (OR = 6.1, 95% CI = 3.5-10.6, p < 0.0005). We sequenced an adjacent gene, MAGEE1, of the sentinel SNP and identified a rare variant in one APA, p.Gly327Glu, which is complementary to other mutations in our primary cohort. Expression quantitative trait loci (eQTL) were investigated on the X-chromosome, and 24 trans-eQTL were identified. Some of the genes identified by trans-eQTL point towards a novel mechanistic explanation for the association of the SNPs with APAs. In conclusion, our study provides further insights into the genetic basis of APAs.


Assuntos
Adenoma/genética , Adenoma/metabolismo , Aldosterona/biossíntese , Cromossomos Humanos X , Proteínas de Transporte/genética , Estudos de Casos e Controles , Estudos de Coortes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
18.
Eur J Dermatol ; 31(2): 170-175, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-34001468

RESUMO

BACKGROUND: Sebaceous neoplasms (SNs) and carcinomas (SCs) represent rare skin adnexal tumours. OBJECTIVES: To establish the prevalence of HPV in SNs, assess the relationship between HPV, p16 and p53 expression, and further elucidate the carcinogenetic course of SCs. MATERIALS & METHODS: A total of 113 resected SNs (five sebaceous adenomas, 10 sebaceomas and 98 SCs) from the Near-East were reviewed. Clinical information (age, gender, size and anatomical location), microscopic variables, and expression of several immunohistochemical markers (EMA, CK5/6, p63, p40, AR, p16 and p53) were documented. Cases were evaluated by fluorescently labelled PCR for HPV detection, followed by DNA microarray hybridization for subtype detection. RESULTS: HPV infection was detected in 9.4% of SNs: 28.6% sebaceous adenomas (HPV-16 and HPV-66), 9.1% sebaceomas (HPV-18) and 8.1% SCs. High-risk HPV types (HPV-16, -18, -52 and -66) constituted 90.9% of HPV infections. Histologically, HPV-positive SCs showed significantly milder cytologic atypia and patchy cellular necrosis. p16 was expressed in SNs irrespective of HPV status (20.0%, 33.3% and 65.5% of HPV-negative sebaceous adenomas, sebaceomas, and SCs, respectively), and p53 was abnormally expressed in 95.5% of HPV-negative SCs and all HPV-positive SCs. CONCLUSION: HPV infection is significantly present in benign and malignant SNs. HPV-positive SCs exhibit less cytologic atypia and necrosis than HPV-negative cases. p16 is not a surrogate marker of HPV infection in the SN setting. Further elucidation of various carcinogenic mechanisms in SCs will allow clinicians to single out the various populations at risk, optimize possible preventive strategies and develop targeted therapies.


Assuntos
Adenoma/virologia , Carcinoma/patologia , Carcinoma/virologia , Infecções por Papillomavirus/diagnóstico , Neoplasias das Glândulas Sebáceas/patologia , Neoplasias das Glândulas Sebáceas/virologia , Adenoma/metabolismo , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Estudos Retrospectivos , Neoplasias das Glândulas Sebáceas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto Jovem
19.
Best Pract Res Clin Endocrinol Metab ; 35(1): 101513, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-34045044

RESUMO

The management of endogenous Cushing's syndrome (CS) typically involves two key steps: (i) confirmation of autonomous hypercortisolism and (ii) localization of the cause to guide treatment. Adrenocorticotropic hormone (ACTH)-dependent CS is most commonly due to a pituitary corticotrope tumor which may be so small as to evade detection on conventional magnetic resonance imaging (MRI). Although biochemical testing (e.g., corticotropin stimulation; dexamethasone suppression) can provide an indication of the likely origin of ACTH excess, bilateral inferior petrosal sinus catheterization offers greater accuracy to distinguish pituitary-driven CS [Cushing's Disease (CD)] from the ectopic ACTH syndrome [EAS, e.g., due to a bronchial or pancreatic neuroendocrine tumor (NET)]. In patients with CD, 40-50% may not have a pituitary adenoma (PA) readily visualized on standard clinical MRI. In these subjects, alternative MR sequences (e.g., dynamic, volumetric, fluid attenuation inversion recovery) and higher magnetic field strength (7T > 3T > 1.5T) may aid tumor localization but carry a risk of identifying coincidental (non-causative) pituitary lesions. Molecular imaging is therefore increasingly being deployed to detect small ACTH-secreting PA, with hybrid imaging [e.g., positron emission tomography (PET) combined with MRI] allowing precise anatomical localization of sites of radiotracer (e.g., 11C-methionine) uptake. Similarly, small ACTH-secreting NETs, missed on initial cross-sectional imaging, may be detected using PET tracers targeting abnormal glucose metabolism (e.g., 18F-fluorodeoxyglucose), somatostatin receptor (SSTR) expression (e.g., 68Ga-DOTATATE), amine precursor (e.g., 18F-DOPA) or amino acid (e.g., 11C-methionine) uptake. Therefore, modern management of ACTH-dependent CS should ideally be undertaken in specialist centers which have an array of cross-sectional and functional imaging techniques at their disposal.


Assuntos
Síndrome de ACTH Ectópico/diagnóstico , Síndrome de Cushing/diagnóstico , Diagnóstico por Imagem/tendências , Hipersecreção Hipofisária de ACTH/diagnóstico , Síndrome de ACTH Ectópico/complicações , Síndrome de ACTH Ectópico/metabolismo , Adenoma Hipofisário Secretor de ACT/complicações , Adenoma Hipofisário Secretor de ACT/diagnóstico , Adenoma Hipofisário Secretor de ACT/metabolismo , Adenoma/complicações , Adenoma/diagnóstico , Adenoma/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Síndrome de Cushing/etiologia , Síndrome de Cushing/metabolismo , Diagnóstico Diferencial , Diagnóstico por Imagem/classificação , Diagnóstico por Imagem/métodos , Técnicas de Diagnóstico Endócrino/classificação , Técnicas de Diagnóstico Endócrino/tendências , Humanos , Invenções , Imageamento por Ressonância Magnética , Hipersecreção Hipofisária de ACTH/metabolismo , Hipófise/diagnóstico por imagem , Hipófise/metabolismo , Tomografia por Emissão de Pósitrons
20.
Sci Rep ; 11(1): 8667, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33883665

RESUMO

Ultraconserved regions (UCRs) are 481 genomic sequences with 100% identity across humans, rats, and mice. Increasing evidence suggests that non-coding RNAs transcribed from UCRs are involved in various diseases, especially cancers. The human transformer 2ß gene (TRA2B) encodes a UCR (uc.138) that spans exon 2 and its neighboring introns. TRA2B4 RNA is the only transcript that contains the whole exon 2 among five spliced TRA2B RNA variants (TRA2B1-5). TRA2B4 is upregulated in colon cancer cell lines, although it is not translated to Tra2ß protein because of its nuclear retention. Nevertheless, the clinical significance and biological functions of uc.138 in colon cancer cells remain unclear. In this study, RNA in situ hybridization showed that TRA2B4 was predominantly overexpressed in the nucleus of colon adenocarcinoma and adenoma. Overexpression of TRA2B4 in colon cancer HCT116 cells promoted cell proliferation by changing the expression of G2/M-related cell cycle regulators. Moreover, TRA2B4 increased migration and cell viability in a uc.138 sequence-dependent manner. TRA2B4 significantly enhanced tumorigenesis in vivo. Taken together, uc.138 encoded in TRA2B4 plays an oncogenic role in tumor progression and may become a potential biomarker and therapeutic target in colon cancer.


Assuntos
Neoplasias do Colo/genética , Sequência Conservada/genética , Regulação Neoplásica da Expressão Gênica , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Animais , Western Blotting , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Humanos , Hibridização In Situ , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Reação em Cadeia da Polimerase
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