RESUMO
AIMS/HYPOTHESIS: This study explored the hypothesis that significant abnormalities in the metabolism of intestinally derived lipoproteins are present in individuals with type 2 diabetes on statin therapy. These abnormalities may contribute to residual CVD risk. METHODS: To investigate the kinetics of ApoB-48- and ApoB-100-containing lipoproteins, we performed a secondary analysis of 11 overweight/obese individuals with type 2 diabetes who were treated with lifestyle counselling and on a stable dose of metformin who were from an earlier clinical study, and compared these with 11 control participants frequency-matched for age, BMI and sex. Participants in both groups were on a similar statin regimen during the study. Stable isotope tracers were used to determine the kinetics of the following in response to a standard fat-rich meal: (1) apolipoprotein (Apo)B-48 in chylomicrons and VLDL; (2) ApoB-100 in VLDL, intermediate-density lipoprotein (IDL) and LDL; and (3) triglyceride (TG) in VLDL. RESULTS: The fasting lipid profile did not differ significantly between the two groups. Compared with control participants, in individuals with type 2 diabetes, chylomicron TG and ApoB-48 levels exhibited an approximately twofold higher response to the fat-rich meal, and a twofold higher increment was observed in ApoB-48 particles in the VLDL1 and VLDL2 density ranges (all p < 0.05). Again comparing control participants with individuals with type 2 diabetes, in the latter, total ApoB-48 production was 25% higher (556 ± 57 vs 446 ± 57 mg/day; p < 0.001), conversion (fractional transfer rate) of chylomicrons to VLDL was around 40% lower (35 ± 25 vs 82 ± 58 pools/day; p=0.034) and direct clearance of chylomicrons was 5.6-fold higher (5.6 ± 2.2 vs 1.0 ± 1.8 pools/day; p < 0.001). During the postprandial period, ApoB-48 particles accounted for a higher proportion of total VLDL in individuals with type 2 diabetes (44%) compared with control participants (25%), and these ApoB-48 VLDL particles exhibited a fivefold longer residence time in the circulation (p < 0.01). No between-group differences were seen in the kinetics of ApoB-100 and TG in VLDL, or in LDL ApoB-100 production, pool size and clearance rate. As compared with control participants, the IDL ApoB-100 pool in individuals with type 2 diabetes was higher due to increased conversion from VLDL2. CONCLUSIONS/INTERPRETATION: Abnormalities in the metabolism of intestinally derived ApoB-48-containing lipoproteins in individuals with type 2 diabetes on statins may help to explain the residual risk of CVD and may be suitable targets for interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02948777.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Apolipoproteína B-100/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Apolipoproteína B-48 , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/complicações , Lipoproteínas VLDL/metabolismo , Apolipoproteínas B/metabolismo , Apolipoproteínas B/uso terapêutico , Lipoproteínas , Triglicerídeos , Lipoproteínas IDL , QuilomícronsRESUMO
OBJECTIVE: The aim of the study was to assess long-term morbidity in children operated for choledochal malformation (CM) by relating clinical complications to liver histopathology, follow-up imaging, liver stiffness, and biochemistry. METHODS: A single-center retrospective follow-up study including all CM patients (nâ=â55, 71% girls) treated during 1976 to 2018 was performed. Mann-Whitney U test and Spearman rank correlation were used for statistical analyses. RESULTS: During median follow-up of 5.8 (interquartile range, 2.5-12) years, 1 patient was lost to follow-up whereas all survived. Intraoperative liver biopsies showed fibrosis in 32%, and patients with Metavir stage ≥2 were younger at surgery (0.36 [0.11-1.9] vs 3.8 [0.72-10.5] years, Pâ=â0.024) than those without fibrosis. Overall, 21% had long-term complications including cholangitis in 9 (>2 episodes in 5) patients, anastomotic stricture in 2 referred patients and adhesive volvulus or hepatocellular carcinoma in 1 each. Anastomotic strictures were successfully managed nonoperatively and hepatocellular carcinoma with thermoablation. In postoperative magnetic resonance cholangiography (MRCP) performed 6.4 (3.6-16) years after hepaticojejunostomy, diameters of both main intrahepatic ducts had decreased significantly to 3.0 (2.5-3.5) mm (Pâ=â0.0001) but a distal cyst stump was remaining in 30% with a length of 6.0 (4.0-20) mm that associated with operation age (râ=â0.71, Pâ=â0.015) and fusiform CM type. Follow-up ultrasound revealed mild dilation of intrahepatic bile ducts in 6.3% and mildly to moderately elevated liver biochemistry in 23%, and liver stiffness (>7âkPa) in 22%. CONCLUSIONS: Whilst cholangitis was the most common postoperative problem, individual patients experienced other more significant complications and one quarter of patients showed evidence of underlying liver dysfunction.
Assuntos
Cisto do Colédoco , Ductos Biliares Intra-Hepáticos , Criança , Cisto do Colédoco/diagnóstico por imagem , Cisto do Colédoco/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Morbidade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Neoadjuvant therapy for pancreatic cancer remains controversial. Our aim was to assess differences in survival, disease recurrence and histopathological tumor characteristics between patients treated with neoadjuvant therapy followed by subsequent surgery and patients undergoing upfront surgery. MATERIAL AND METHODS: Out of 399 consecutive pancreatic ductal adenocarcinoma (PDAC) patients operated at Helsinki University Hospital in 2000-2015, 75 borderline resectable patients were treated with neoadjuvant therapy. Resectable propensity scored patients (n = 150) underwent upfront surgery. Neoadjuvant therapy consisted of folfirinox, single gemcitabine or combined with cisplatin, nab-paclitaxel or capecitabine with or without radiation. Survival was calculated with Kaplan-Meier and compared with the Breslow test. Survival was determined from the start of treatment, being the first day of treatment for patients treated with neoadjuvant therapy and the date of surgery for others. RESULTS: Between 2000 and 2015 median disease-specific survival (DSS) [34 vs. 26 months, p = .016] and disease-free survival (DFS) [22 vs. 13 months, p = .001] were longer in patients treated with neoadjuvant therapy than in those undergoing upfront surgery. Survival differences were not significant in the 2000s but were, in turn, among patients treated in the 2010s with better survival for patients treated with neoadjuvant therapy [DSS 35 vs. 26 months, p = .008 and DFS 25 vs. 13 months, p = .001]. Especially patients with poorly differentiated G3 tumors [DSS 30 vs. 11 months, p = .004 and DFS 21 vs. 7 months, p = .001] and higher stage IIB-III [DSS 34 vs. 20 months, p = .006 and DFS 21 vs. 10 months, p = .001] had longer survival when treated with neoadjuvant therapy. CONCLUSIONS: PDAC patients treated with neoadjuvant therapy had longer DSS and DFS than those undergoing upfront surgery. Neoadjuvant therapy benefits especially borderline resectable patients with higher stage and poorly differentiated tumors.
Assuntos
Carcinoma Ductal Pancreático/terapia , Terapia Neoadjuvante/métodos , Neoplasias Pancreáticas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Radioterapia Adjuvante/métodosRESUMO
AIMS: To identify individuals with incidental fatty liver disease (FLD), and to evaluate its prevalence, metabolic co-morbidities and impact on follow-up. METHODS: We leveraged the data-lake of Helsinki Uusimaa Hospital district (Finland) with a population of 1.7 million (specialist and primary care). A phrase recognition script on abdominal imaging reports (2008-2020) identified/excluded FLD or cirrhosis; we extracted ICD-codes, laboratory and BMI data. RESULTS: Excluding those with other liver diseases, the prevalence of FLD was 29% (steatosis yes/no, N=61,271/155,521; cirrhosis, N=3502). The false positive and negative rates were 5-6%. Only 1.6% of the FLD cases had the ICD code recorded and 32% had undergone full clinical evaluation for associated co-morbidities. Of the 35-65-year-old individuals with FLD, 20% had diabetes, 42% prediabetes and 28% a high liver fibrosis index. FLD was independently predicted by diabetes (OR 1.56, CI 1.46-1.66, p = 2.3 * 10^-41), BMI (1.46, 1.42-1.50, p = 1.7 * 10^-154) and plasma triglyceride level (1.5, 1.43-1.57, p = 3.5 * 10^-68). Alanine aminotransferase level mildly increased (1.12, 1.08-1.16, p = 2.2 * 10^-9) and high age decreased the risk (0.92, 0.89-0.94, p = 4.65*10^-09). Half of the cases had normal ALT. CONCLUSIONS: The incidental radiological finding of FLD is reliable and associated with metabolic risks but largely ignored, although it should lead to metabolic and hepatic follow-up.
Assuntos
Diabetes Mellitus , Hepatopatia Gordurosa não Alcoólica , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Estudos de Coortes , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Comorbidade , Cirrose Hepática/epidemiologia , Diabetes Mellitus/epidemiologiaRESUMO
OBJECTIVE: Pancreatic neuroendocrine tumors (panNETs) are the leading cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). The role of somatostatin receptor positron emission tomography/computed tomography (SSTR PET/CT) in MEN1 has not been established. The aim was to assess pancreatic imaging in MEN1 in a real-life setting. DESIGN: Fifty-eight patients with MEN1 [median age 40 (range 16-72) years] underwent SSTR PET/CT imaging; either as a screening tool regardless of disease stage (n = 47) or to further characterize known panNETs (n = 11). SSTR PET/CT and matched conventional imaging were blindly analyzed. We assessed the findings and the impact of SSTR PET/CT during a median follow-up of 47 months. RESULTS: SSTR PET/CT detected three times as many panNETs as conventional imaging (P < .001). SSTR PET/CT altered the management of 27 patients (47%). Seven patients (12%) were referred for surgery, and five (9%) received systemic treatment. In 15/25 (60%) patients with no previous panNET (n = 22) or in remission after surgery (n = 3), SSTR PET/CT identified a panNET (n = 14) or recurrence (n = 1). In eight patients, SSTR PET/CT revealed a panNET not immediately visible on conventional imaging. During a median follow-up of 47 months, three became visible on conventional imaging, but none required intervention. When SSTR PET/CT was negative, no panNETs were identified on conventional imaging during 38 months of follow-up. CONCLUSIONS: SSTR PET/CT demonstrates high accuracy in the detection of panNETs and alters the clinical management in nearly half of the MEN1-patients. SSTR PET/CT enables timely diagnosis and staging of MEN1-related panNETs.
Assuntos
Neoplasia Endócrina Múltipla Tipo 1 , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Receptores de Somatostatina , Neoplasias Pancreáticas/diagnóstico , Pâncreas/patologia , Tumores Neuroendócrinos/patologiaRESUMO
Cine-MRI for adhesion detection is a promising novel modality that can help the large group of patients developing pain after abdominal surgery. Few studies into its diagnostic accuracy are available, and none address observer variability. This retrospective study explores the inter- and intra-observer variability, diagnostic accuracy, and the effect of experience. A total of 15 observers with a variety of experience reviewed 61 sagittal cine-MRI slices, placing box annotations with a confidence score at locations suspect for adhesions. Five observers reviewed the slices again one year later. Inter- and intra-observer variability are quantified using Fleiss' (inter) and Cohen's (intra) κ and percentage agreement. Diagnostic accuracy is quantified with receiver operating characteristic (ROC) analysis based on a consensus standard. Inter-observer Fleiss' κ values range from 0.04 to 0.34, showing poor to fair agreement. High general and cine-MRI experience led to significantly (p < 0.001) better agreement among observers. The intra-observer results show Cohen's κ values between 0.37 and 0.53 for all observers, except one with a low κ of -0.11. Group AUC scores lie between 0.66 and 0.72, with individual observers reaching 0.78. This study confirms that cine-MRI can diagnose adhesions, with respect to a radiologist consensus panel and shows that experience improves reading cine-MRI. Observers without specific experience adapt to this modality quickly after a short online tutorial. Observer agreement is fair at best and area under the receiver operating characteristic curve (AUC) scores leave room for improvement. Consistently interpreting this novel modality needs further research, for instance, by developing reporting guidelines or artificial intelligence-based methods.
Assuntos
Radioisótopos de Gálio , Neoplasia Endócrina Múltipla Tipo 1 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico por imagem , Doenças das Paratireoides/diagnóstico por imagem , Neoplasias das Paratireoides/diagnóstico por imagemRESUMO
BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine carcinoma with poor 5-year survival rates of < 40%. According to the literature, ACC is rarely an incidental imaging finding. However, presentation, treatment and outcome may differ in modern series. DESIGN AND METHODS: We studied all patients (n = 47, four children) from a single centre during years 2002-2018. We re-evaluated radiologic and histopathological findings and assessed treatments and outcome. We searched for possible TP53 gene defects and assessed nationwide incidence of ACC. RESULTS: In adults, incidental radiologic finding led to diagnosis in 79% at median age of 61 years. ENSAT stage I, II, III and IV was 19%, 40%, 19% and 21%, respectively. Nonenhanced CT demonstrated > 20 Hounsfield Units (HU) for all tumours (median 34 (21-45)), median size 92 mm (20-196), Ki67 17% (1-40%), Weiss score 7 (4-9) and Helsinki score 24 (4-48). ACC was more often found in the left than the right adrenal (p < 0.05). One child had Beckwith-Wiedemann and one a TP53 mutation. In adults, the primary tumour was resected in 88 and 79% received adjuvant mitotane therapy. Median hospital stay was significantly shorter in the laparoscopic vs. open surgery group (4 (3-7) vs. 8 (5-38) days, respectively; p < 0.001). In 3/4 patients, prolonged remission of > 5 to > 10 years was achieved after repeated surgery of metastases. Overall 5-year survival was 67%, and 96% vs. 26% for ENSAT stage I-II vs. III-IV (p < 0.0001). ENSAT stage and Ki67 predicted survival, type of surgery did not. Mitotane associated with better survival. CONCLUSIONS: Contemporary ACC predominantly presents as an incidental imaging finding, characterised by HU > 20 on nonenhanced CT but variable tumour size (20-196 mm). Malignancy cannot be ruled out by small tumour size only. The 5-year survival of 96% in ENSAT stage I-III compares favourably to previous studies.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/epidemiologia , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/terapia , Adrenalectomia , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/epidemiologia , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/terapia , Adulto , Antineoplásicos Hormonais/uso terapêutico , Criança , Pré-Escolar , Estudos de Coortes , Terapia Combinada , Análise Mutacional de DNA , Feminino , Seguimentos , Genes p53/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Of the six GATA transcription factors, GATA-4 and GATA-6 are expressed in the mouse and human adrenal with distinct developmental profiles. GATA-4 is confined to the fetal cortex, i.e. to the less differentiated proliferating cells, while GATA-6 is expressed both in the fetal and adult adrenal. In vitro, GATA-4 regulates inhibin-alpha and steroidogenic factor-1 implicated in normal adrenal function. GATA-6 probably has roles in the development and differentiation of adrenocortical cells, and in the regulation of steroidogenesis. GATA-4 expression is dramatically upregulated and GATA-6 downregulated in gonadotropin dependent mouse adrenocortical tumors. This is accompanied by the appearance of luteinizing hormone receptor (LHR). In vitro, GATA-4 transactivates LHR promoter, and gonadotropins upregulate GATA-4 levels. Human adrenal tumors occasionally express GATA-4, whereas GATA-6 levels are usually lower than normal.
Assuntos
Neoplasias do Córtex Suprarrenal/genética , Glândulas Suprarrenais/embriologia , Carcinoma Adrenocortical/genética , Fatores de Transcrição GATA/metabolismo , Glândulas Suprarrenais/metabolismo , Animais , Fatores de Transcrição GATA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Fator Esteroidogênico 1RESUMO
Context: The clinical spectrum of organogenetic anomalies associated with HNF1B mutations is heterogeneous. Besides cystic kidney disease, diabetes, and various other manifestations, odd cases of mainly neonatal and posttransplantation cholestasis have been described. The biliary phenotype is incompletely defined. Objective: To systematically characterize HNF1B-related anomalies in the bile ducts by imaging with magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography (MRCP). Setting and Patients: Fourteen patients with HNF1B mutations in the catchment area of the Helsinki University Hospital were evaluated with upper abdominal MRI and MRCP. Blood samples and clinical history provided supplemental data on the individual phenotype. Main Outcome Measure(s): Structural anomalies in the biliary system, medical history of cholestasis, other findings in abdominal organs, diabetes and antihyperglycemic treatment, hypomagnesemia, and hyperuricemia. Results: Structural anomalies of the bile ducts were found in seven of 14 patients (50%). Six patients had choledochal cysts, which are generally considered premalignant. Conclusions: Structural anomalies of the biliary system were common in HNF1B mutation carriers. The malignant potential of HNF1B-associated choledochal cysts warrants further studies.
Assuntos
Cisto do Colédoco/genética , Diabetes Mellitus Tipo 2/genética , Fator 1-beta Nuclear de Hepatócito/genética , Doenças Renais Císticas/genética , Pâncreas/anormalidades , Pancreatopatias/congênito , Anormalidades Urogenitais/genética , Adolescente , Adulto , Idoso , Sistema Biliar/anormalidades , Sistema Biliar/diagnóstico por imagem , Criança , Colangiopancreatografia por Ressonância Magnética , Cisto do Colédoco/diagnóstico por imagem , Feminino , Finlândia , Humanos , Doenças Renais Císticas/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Pâncreas/diagnóstico por imagem , Pancreatopatias/diagnóstico por imagem , Pancreatopatias/genética , Fenótipo , Anormalidades Urogenitais/diagnóstico por imagem , Útero/anormalidades , Útero/diagnóstico por imagem , Adulto JovemRESUMO
In response to prepubertal gonadectomy certain inbred mouse strains, including DBA/2J, develop sex steroid-producing adrenocortical neoplasms. This phenomenon has been attributed to a lack of gonadal hormones or a compensatory increase in gonadotropins. To assess the relative importance of these mechanisms, we created a new inbred model of adrenocortical neoplasia using female NU/J nude mice. These mice developed adrenocortical neoplasms in response to either gonadectomy or gonadotropin elevation from xenografts of human chorionic gonadotropin (hCG)-secreting Chinese hamster ovary cells. In each instance the adrenal tumors resembled the neoplasms found in gonadectomized DBA/2J mice and were composed of spindle-shaped A cells and lipid-laden B cells. Both cell populations were defined by ectopic expression of GATA-4 and an absence of the adrenocortical markers melanocortin-2-receptor and steroid 21-hydroxylase, but only B cells expressed the gonadal steroidogenic markers inhibin-alpha, LH receptor, P450c17, and P450c19. Expression of sex steroidogenic markers was attenuated in the neoplastic adrenal cortex of hCG-treated vs. gonadectomized mice. Whereas neoplastic adrenals were an obvious source of estradiol in gonadectomized mice, ovaries appeared to be the major source of this hormone in hCG-treated mice. Gonadectomy and hCG treatment elicited comparable increases in serum estradiol, but testosterone levels increased significantly only in hCG-treated mice. We conclude that chronic gonadotropin elevation, caused by either gonadectomy or hCG administration, signals a population of cells in the adrenal subcapsular region of permissive mice to undergo differentiation along a gonadal rather than an adrenal lineage. Thus, NU/J nude mice can be used as a model to study both neoplasia and adrenogonadal lineage specification.
Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/fisiopatologia , Modelos Animais de Doenças , Gonadotropinas/sangue , Camundongos Nus , Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/patologia , Animais , Gonadotropina Coriônica/sangue , Gonadotropina Coriônica/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos , Ovariectomia , RNA Mensageiro/análise , Receptor Tipo 2 de Melanocortina/genética , Receptor Tipo 2 de Melanocortina/metabolismo , Esteroide 21-Hidroxilase/genética , Esteroide 21-Hidroxilase/metabolismoRESUMO
Certain inbred strains of mice, including DBA/2J, develop adrenocortical tumors in response to gonadectomy. Spindle-shaped cells with limited steroidogenic capacity, termed A cells, appear in the subcapsular region of the adrenal gland, followed by sex steroid-producing cells known as B cells. These changes result from unopposed gonadotropin production by the pituitary, but the adrenocortical factors involved in tumorigenesis have not been characterized. GATA-4, a transcription factor normally expressed in fetal, but not adult, adrenocortical cells, was found in neoplastic cells that proliferate in the adrenal cortex of gonadectomized DBA/2J mice. GATA-4 mRNA was detected in the adrenal glands of female mice 0.5 months after ovariectomy and reached a maximum by 4 months. Castrated male mice developed adrenocortical tumors more slowly than gonadectomized females, and the onset of GATA-4 expression in the adrenal was delayed. In situ hybridization and immunohistochemistry revealed GATA-4 mRNA and protein in A and B cells, but not in normal adrenocortical cells. mRNA encoding another factor associated with adrenocortical tumorigenesis, LH receptor (LHR), was detected in A and B cells. In addition, transcripts for P450 17 alpha-hydroxylase/C17-C20 lyase, an enzyme essential for the production of sex steroids, and inhibin-alpha were found in B cells. Unilateral ovarian regeneration, a phenomenon known to occur in gonadectomized mice, was observed in a subset of DBA/2J mice undergoing complete ovariectomy. In these animals, adrenocortical tumor progression was arrested; A cells and GATA-4 expression were evident, but there was no expression of LHR or P450 17 alpha-hydroxylase/C17-C20 lyase. Strain susceptibility to adrenocortical tumorigenesis (DBA/2J >> FVB/N) correlated with the expression of GATA-4 and LHR, implicating these factors in the process of adrenocortical neoplasia in response to continuous gonadotropin stimulation.
Assuntos
Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/fisiopatologia , Proteínas de Ligação a DNA/genética , Ovariectomia , Receptores do LH/genética , Fatores de Transcrição/genética , Córtex Suprarrenal/patologia , Córtex Suprarrenal/fisiopatologia , Neoplasias do Córtex Suprarrenal/patologia , Animais , Biomarcadores Tumorais , Suscetibilidade a Doenças , Feminino , Fator de Transcrição GATA4 , Regulação Neoplásica da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Orquiectomia , Ovário/fisiologia , Ovário/cirurgia , RNA Mensageiro/análise , Regeneração , Especificidade da Espécie , Esteroide 17-alfa-Hidroxilase/genéticaRESUMO
Factors controlling benign and malignant adrenocortical tumorigenesis are largely unknown, but several mouse models suggest an important role for inhibin-alpha (INHA). To show that findings in the mouse are relevant to human tumors and clinical outcome, we investigated the expression of signaling proteins and transcription factors involved in the regulation of INHA in human tumor samplesâ Thirty-one adrenocortical tumor samples, including 13 adrenocortical carcinomas (ACCs), were categorized according to Weiss score, hormonal profile, and patient survival data and analyzed using immunohistochemistry and RT-PCR. Expression of the TGF-ß signaling mediator SMAD3 varied inversely with Weiss score, so that SMAD3 expression was lowest in the most malignant tumors. By contrast, SMAD2 expression was upregulated in most malignant tumors. Wnt pathway co-receptors LRP5 and LRP6 were predominantly expressed in benign adrenocortical tumors. In ACCs, expression of transcription factors GATA-6 and SF-1 correlated with that of their target gene INHA. Moreover, the diminished expression of GATA-6 and SF-1 in ACCs correlated with poor outcome. We conclude that the factors driving INHA expression are reduced in ACCs with poor outcome, implicating a role for INHA as a tumor suppressor in humans.
Assuntos
Neoplasias do Córtex Suprarrenal/química , Carcinoma Adrenocortical/química , Biomarcadores Tumorais/análise , Fatores de Transcrição/análise , Fator de Crescimento Transformador beta/análise , Proteínas Wnt/análise , Via de Sinalização Wnt , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/patologia , Adulto , Idoso , Biomarcadores Tumorais/genética , Criança , Feminino , Fator de Transcrição GATA6/análise , Humanos , Imuno-Histoquímica , Lactente , Inibinas/análise , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/análise , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/análise , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Sistema de Registros , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Smad2/análise , Proteína Smad3/análise , Fator Esteroidogênico 1/análise , Análise de Sobrevida , Fatores de Transcrição/genética , Proteínas Wnt/genética , Via de Sinalização Wnt/genética , Adulto Jovem , beta Catenina/análiseRESUMO
In response to gonadectomy certain inbred mouse strains develop sex steroidogenic adrenocortical neoplasms. One of the hallmarks of neoplastic transformation is expression of GATA4, a transcription factor normally present in gonadal but not adrenal steroidogenic cells of the adult mouse. To show that GATA4 directly modulates adrenocortical tumorigenesis and is not merely a marker of gonadal-like differentiation in the neoplasms, we studied mice with germline or conditional loss-of-function mutations in the Gata4 gene. Germline Gata4 haploinsufficiency was associated with attenuated tumor growth and reduced expression of sex steroidogenic genes in the adrenal glands of ovariectomized B6D2F1 and B6AF1 mice. At 12 months after ovariectomy, wild-type B6D2F1 mice had biochemical and histological evidence of adrenocortical estrogen production, whereas Gata4(+/-) B6D2F1 mice did not. Germline Gata4 haploinsufficiency exacerbated the secondary phenotype of postovariectomy obesity in B6D2F1 mice, presumably by limiting ectopic estrogen production in the adrenal glands. Amhr2-cre-mediated deletion of floxed Gata4 (Gata4(F)) in nascent adrenocortical neoplasms of ovariectomized B6.129 mice reduced tumor growth and the expression of gonadal-like markers in a Gata4(F) dose-dependent manner. We conclude that GATA4 is a key modifier of gonadectomy-induced adrenocortical neoplasia, postovariectomy obesity, and sex steroidogenic cell differentiation.
Assuntos
Neoplasias do Córtex Suprarrenal/genética , Córtex Suprarrenal/metabolismo , Transformação Celular Neoplásica/genética , Fator de Transcrição GATA4/genética , Ovariectomia , Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Animais , Estrogênios/metabolismo , Feminino , Fator de Transcrição GATA4/metabolismo , Regulação Neoplásica da Expressão Gênica , Mutação em Linhagem Germinativa , Haploinsuficiência , Imuno-Histoquímica , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de TempoRESUMO
WNT4 plays an important role in female sexual development and ovarian function. WNT4-deficiency leads disturbed development of the internal genitalia in mouse and human, and to a dramatic reduction of mouse oocytes. However, the expression and role of WNT4 in human ovaries is yet unknown. The expression of WNT4 mRNA and protein was studied in human adult and fetal ovaries (gestational ages 12-41 weeks), and the role of WNT4 in oocyte apoptosis was investigated in WNT4-deficient mice. WNT4 mRNA and protein were present in human ovaries throughout fetal development and in different follicular stages in adult ovaries. Compared with wild-type mice, WNT4-deficient mice had a markedly enhanced rate of oocyte apoptosis, with the highest values at gestational ages of 14.5 and 16.5 days post-coitum. The current results support a view that WNT4 may have a role in oocyte selection and follicle formation and maturation in human ovaries.
Assuntos
Feto/embriologia , Ovário/citologia , Ovário/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , Adulto , Animais , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Sobrevivência Celular , Feminino , Feto/citologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Imuno-Histoquímica , Camundongos , Pessoa de Meia-Idade , Oócitos/citologia , Oócitos/metabolismo , Folículo Ovariano/citologia , Folículo Ovariano/metabolismo , Ovário/embriologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Wnt/deficiência , Proteínas Wnt/genética , Proteína Wnt4 , Adulto JovemRESUMO
Transcription factor GATA-4 is a key participant in cytodifferentiation of the mouse hindstomach. Here we show that GATA-4 cooperates with a Friend-of-GATA (FOG) cofactor to direct gene expression in this segment of gut. Immunohistochemical staining revealed that GATA-4 and FOG-1 are co-expressed in hindstomach epithelial cells from embryonic days (E) 11.5 to 18.5. The other member of the mammalian FOG family, FOG-2, was not detected in gastric epithelium. To show that GATA-4:FOG interactions influence stomach development, we analyzed Gata4(ki/ki) mice, which express a mutant GATA-4 that cannot bind FOG cofactors. Sonic Hedgehog, an endoderm-derived signaling molecule normally down-regulated in the distal stomach, was over-expressed in hindstomach epithelium of E11.5 Gata4(ki/ki) mice, and there was a concomitant decrease in fibroblast growth factor-10 in adjacent mesenchyme. We conclude that functional interaction between GATA-4 and a member of the FOG family, presumably FOG-1, is required for proper epithelial-mesenchymal signaling in the developing stomach.
Assuntos
Epitélio/embriologia , Fator de Transcrição GATA4/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Mesoderma/metabolismo , Proteínas Nucleares/fisiologia , Estômago/embriologia , Fatores de Transcrição/fisiologia , Animais , Regulação para Baixo , Endotélio/metabolismo , Endotélio Vascular/metabolismo , Epitélio/metabolismo , Fator 10 de Crescimento de Fibroblastos/genética , Fator 10 de Crescimento de Fibroblastos/fisiologia , Fator de Transcrição GATA4/metabolismo , Proteínas Hedgehog , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Camundongos Transgênicos , Mutação , Proteínas Nucleares/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Fatores de Tempo , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , Ativação TranscricionalRESUMO
Transcription factor GATA-4 has been suggested to have a role in mammalian gonadogenesis, e.g., through activation of the Müllerian-inhibiting substance (MIS) gene expression. Although the expression of GATA-4 during gonadogenesis has been elucidated in detail, very little is known about FOG-2, an essential cofactor for GATA-4, in ovarian development. We explored in detail the expression of FOG-2 and GATA-4 in the fetal and postnatal mouse ovary and in the fetal testis using Northern blotting, RNA in situ hybridization, and immunohistochemistry. GATA-4 and FOG-2 are evident in the bipotential urogenital ridge, and their expression persists in the fetal mouse ovary; this result is different from earlier reports of GATA-4 downregulation in the fetal ovary. In contrast to ovary, FOG-2 expression is lost in the fetal Sertoli cells along with the formation of the testicular cords, leading to the hypothesis that FOG-2 has a specific role in the fetal ovaries counteracting the transactivation of the MIS gene by GATA-4. In vitro transfection assays verified that FOG-2 is able to repress the effect of GATA-4 on MIS transactivation in granulosa cells. In postnatal ovary, granulosa cells of growing follicles express FOG-2, partially overlapping with the expression of MIS. These data suggest an important role for FOG-2 and the GATA transcription factors in the developing ovary.