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1.
J Med Genet ; 61(6): 503-519, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38471765

RESUMEN

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.


Asunto(s)
Proteína de Unión a CREB , Proteína p300 Asociada a E1A , Síndrome de Rubinstein-Taybi , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/terapia , Humanos , Proteína de Unión a CREB/genética , Proteína p300 Asociada a E1A/genética , Consenso , Manejo de la Enfermedad , Mutación
2.
J Steroid Biochem Mol Biol ; 174: 183-191, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28890368

RESUMEN

CYP17A1-independent intratumoral steroid hormone synthesis is regarded as one possible explanation for resistance to treatment with the CYP17-inhibitor Abiraterone (Abi). The aim of our study was therefore to investigate the steroid metabolism of prostate cancer cells under serum starvation and the effects of Abi treatment. We assessed steroid metabolism in a panel of prostate cancer cells under serum starvation by radioactivity detector-coupled HPLC and HPLC-ESI-ToF-mass spectrometry after treatment with pregnenolone, progesterone and allopregnanolone. We further evaluated the effects of Abi on steroid metabolism of testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA) by enzyme immunoassays (EIAs). Androgen-responsive cell lines metabolized pregnenolone primarily to mitogenic steroid 5α-pregnan-3ß,6α-diol-20-one under serum starvation. Co-administration of Abi lead to detectable concentrations of the Abi metabolite Δ4-Abi (D4A), known to inhibit enzymes other than CYP17A1 in steroid metabolism. In addition, co-administration of Abi abrogated pregnenolone metabolism and resulted in a CYP17A1-independent significant increase of DHEA (13- to >100-fold) and DHT (2.5-fold) in androgen-responsive cells. Our results demonstrate the CYP17A1-independent formation of 5α-pregnan-3ß,6α-diol-20-one by androgen-responsive prostate cancer cells under serum starvation and its inhibition by Abi. Its metabolism from pregnenolone suggests a major steroidogenesis shift in these cells, hinting at a neuroendocrine transdifferentiation phenomenon. The marked increase of DHEA levels by Abi resembles the steroidogenic pathways in nervous tissue, in a manner that precludes CYP17A1 activity. To which extent these processes are responsible or involved in the development of resistance to Abi, needs to be further elucidated.


Asunto(s)
Pregnanolona/análogos & derivados , Neoplasias de la Próstata/metabolismo , Esteroide 17-alfa-Hidroxilasa/metabolismo , Andrógenos/metabolismo , Androstenos/farmacología , Línea Celular Tumoral , Hormonas Esteroides Gonadales/metabolismo , Humanos , Masculino , Pregnanolona/metabolismo , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores
3.
Ann Diagn Pathol ; 19(4): 221-5, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25990776

RESUMEN

Sclerosing epithelioid fibrosarcoma (SEF) is a rare fibrosarcoma variant with specific histomorphology and consistent translocation (EWSR1-CREB3L1/2). To date, 110 cases have been reported; only 15 originated within the abdomen. With only 2 cases reported parallel to our study and one case briefly mentioned in a previous series, primary renal SEF is exceptionally rare but might be underrecognized. We herein describe 2 cases affecting a 23-year-old woman and a 43-year-old man. Tumor size was 22 and 4.2 cm, respectively. Patient 1 developed skeletal and multiple pulmonary metastases. She died of disease 82 months later, despite aggressive multimodality therapy. Patient 2 has no evidence of recurrence or metastasis (8 months after surgery). Histologic examination showed similar appearance with monotonous bland medium-sized epithelioid cells with rounded slightly vesicular nuclei and clear cytoplasm imparting a carcinoma-like appearance set within a highly sclerotic hyaline fibrous stroma. The tumor cells were arranged in nests, single cell cords, trabeculae, or solid sheets with frequent entrapment of renal tubules and glomeruli. Immunohistochemistry showed strong expression of vimentin, bcl2, CD99, and MUC4, whereas cytokeratin and other markers were negative. Fluorescence in situ hybridization showed a translocation involving the EWSR1 gene locus in case 2. Molecular analysis in case 1 was not successful due to poor signal quality. To our knowledge, this is the second report documenting primary renal SEF. Awareness of this entity would help avoid misinterpretation as clear cell carcinoma, sclerosing perivascular epithelioid cell tumor, Xp.11 translocation carcinoma, and other more frequent neoplasms at this site.


Asunto(s)
Fibrosarcoma/patología , Neoplasias Renales/patología , Neoplasias de los Tejidos Blandos/patología , Adulto , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Diagnóstico Diferencial , Células Epitelioides/metabolismo , Células Epitelioides/patología , Femenino , Fibrosarcoma/diagnóstico , Fibrosarcoma/genética , Fibrosarcoma/metabolismo , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Masculino , Metástasis de la Neoplasia , Enfermedades Raras , Esclerosis/genética , Esclerosis/metabolismo , Esclerosis/patología , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/metabolismo , Adulto Joven
4.
Eur J Cancer ; 49(2): 323-8, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22939115

RESUMEN

The expression of anti-apoptosis gene Bcl-2 associated anthanogen-1 (Bag-1), has been associated with outcome in several cancer types, however its prognostic role in pancreatic cancer is unknown. Aim was therefore to evaluate expression of Bag-1 in two anatomically closely related however prognostically different tumours, pancreatic head- and periampullary cancer and correlate expression with outcome. Bag-1 protein expression was studied by immunohistochemistry on original paraffin embedded tissue from 217 patients with microscopic radical resection (R0) of adenocarcinoma of the pancreatic head or periampullary region. Expression was assessed for associations with recurrence free- (RFS), cancer specific- (CSS), overall survival (OS) and conventional prognostic factors. Nuclear Bag-1 was present in 80% of tumours. In 40% Bag-1 resided in the cytosol, which was almost exclusively associated with nuclear expression. Nuclear Bag-1 protein was identified as an independent factor predicting a favourable outcome following radical resection of pancreatic head cancer. Eighteen percent of patients with nuclear Bag-1 were recurrence free and alive 5 years following surgery compared to none of the patients lacking expression. In periampullary cancer Bag-1 was not associated with outcome. In conclusion, Bag-1 was present in the majority of both pancreatic head- and periampullary cancers. However it was only identified as a discriminator of outcome in pancreatic head cancer.


Asunto(s)
Ampolla Hepatopancreática/metabolismo , Proteínas de Unión al ADN/biosíntesis , Neoplasias Pancreáticas/metabolismo , Factores de Transcripción/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Ampolla Hepatopancreática/patología , Proteínas de Unión al ADN/genética , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Adhesión en Parafina , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Transcripción/genética , Resultado del Tratamiento
5.
Eur J Cancer ; 47(17): 2576-84, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21958461

RESUMEN

Angiogenesis has been associated with disease progression in many solid tumours, however the statement that tumours need angiogenesis to grow, invade and metastasise seems no longer applicable to all tumours or to all tumour subtypes. Prognostic studies in pancreatic cancer are conflicting. In fact, pancreatic cancer has been suggested an example of a tumour in which angiogenesis is less essential for tumour progression. The aim of the present study was therefore to measure angiogenesis in two anatomically closely related however prognostically different types of pancreatic cancer, pancreatic head and periampullary cancer, and investigate its relation with outcome. Vessels were stained by CD31 on original paraffin embedded tissue from 206 patients with microscopic radical resection (R0) of pancreatic head (n=98) or periampullary cancer (n=108). Angiogenesis was quantified by microvessel density (MVD) and measured by computerised image analysis of three randomly selected fields and investigated for associations with recurrence free survival (RFS), cancer specific survival (CSS), overall survival (OS) and conventional prognostic factors. MVD was heterogeneous both between and within tumours. A higher MVD was observed in periampullary cancers compared with pancreatic head cancers (p<.01). Furthermore, MVD was associated with lymph node involvement in pancreatic head (p=.014), but not in periampullary cancer (p=.55). Interestingly, MVD was not associated with RFS, CSS or with OS. In conclusion, angiogenesis is higher in periampullary cancer and although associated with nodal involvement in pancreatic head cancer, pancreatic cancer prognosis seems indeed angiogenesis independent.


Asunto(s)
Ampolla Hepatopancreática/irrigación sanguínea , Neoplasias del Conducto Colédoco/irrigación sanguínea , Neovascularización Patológica/patología , Neoplasias Pancreáticas/irrigación sanguínea , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Neoplasias del Conducto Colédoco/metabolismo , Neoplasias del Conducto Colédoco/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Masculino , Microvasos/patología , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Valor Predictivo de las Pruebas , Estudios Retrospectivos
6.
Eur J Cancer ; 46(18): 3393-9, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20724141

RESUMEN

The high mortality rate and minimal progress made in the treatment of pancreatic cancer over the last few decades, warrant an alternative approach. Treatment protocols should be individualised to the patient guided by prognostic markers. A particularly interesting target would be the architectural transcription factor high mobility group A1 (HMGA1), that is low or undetectable in normal tissue, induced during neoplastic transformation and consequently often exceptionally high in cancer. The aim of the current study was therefore to determine the differential expression of HMGA1 in pancreatic head and periampullary cancer and investigate its relation with outcome. HMGA1 expression was determined by immunohistochemistry on original paraffin embedded tissue from 99 pancreatic head- and 112 periampullary cancers (with R0). Expression was investigated for associations with recurrence free (RFS), cancer specific (CSS) and overall survival (OS) and conventional prognostic factors. HMGA1 was expressed in 47% and 26% of pancreatic head- and periampullary cancer, respectively and associated with poor RFS, CSS and OS in periampullary cancer. CSS 5years following surgery was 25% and 44% for patients with tumours which were positive or negative for HMGA1 protein, respectively. HMGA1 expression was not associated with survival in pancreatic head cancer. In conclusion HMGA1 was identified as an independent prognostic marker predicting poor outcome in periampullary cancer. Although expressed to a higher extent as compared to periampullary cancer, HMGA1 was not associated with survival in pancreatic head cancer.


Asunto(s)
Ampolla Hepatopancreática , Neoplasias del Conducto Colédoco/mortalidad , Proteína HMGA1a/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Conducto Colédoco/metabolismo , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismo , Pronóstico , Estudios Retrospectivos
7.
Gastrointest Cancer Res ; 1(4 Suppl 2): S7-S12, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-19360152

RESUMEN

Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. It is a highly aggressive malignancy for which currently available treatments are of only limited efficacy. For this reason, much research is directed at elucidating fundamental molecular mechanisms underlying the biology of pancreatic cancer. These efforts are generating a rapidly growing body of information. The yet unmet challenge is to translate this information into clinically applicable strategies for early detection, prediction of prognosis, and effective therapies for patients diagnosed with pancreatic cancer.

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