974 resultados para CLASSICAL PHENOTYPE


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Objective: We describe a 4-generation family with familial medullary thyroid carcinoma (FMTC) - a variant of multiple endocrine neoplasia type 2 (MEN 2) without extra-thyroid features. RET mutation analysis confirmed an E768D mutation in exon 13 in 8 family members, 3 affected with medullary thyroid cancer alone while the other 5 were detected to be mutation carriers. This mutation has been described in very few families worldwide and the spectrum of disease and natural history is unclear. Results: Three affected members had medullary thyroid cancer (MTC) confirmed histologically at ages 25, 50 and 56 years, respectively. The E768D mutation appears to have a less aggressive clinical course compared to other high risk RET mutations with no evidence of clinical recurrence up to I I years after initial therapy. Of five gene carriers identified, two are asymptomatic at the age of 70 and 61, and three had raised calcitonin levels at 46, 39, and 45 years. Following total thyroidectomy, one gene carrier had a histologically normal thyroid at age 46, following a mildly elevated calcitonin, one had C-cell hyperplasia at the age of 39, and one had a frank focus of carcinoma in the left thyroid lobe at the age of 45. No members had evidence of phaeochromocytoma or parathyroid disease on screening. Conclusion: The RET E768D mutation is associated with MTC with a later age at presentation, incomplete penetrance and less aggressive course compared with other high risk RET mutations. To date in this family the E768D mutation has not been associated with either phaeochromocytoma or hyperparathyroidism. The appropriate screening strategy for and management of E768D carriers is difficult reflecting the phenotypic heterogeneity.

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We present a review of critical concepts and produce recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms, including monitoring, response definition, first-and second-line therapy, and therapy for special issues. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk if age is greater than 60 years or there is a history of previous thrombosis. Risk stratification in primary myelofibrosis (PMF) should start with the International Prognostic Scoring System (IPSS) for newly diagnosed patients and dynamic IPSS for patients being seen during their disease course, with the addition of cytogenetics evaluation and transfusion status. High-risk patients with PV should be managed with phlebotomy, low-dose aspirin, and cytoreduction, with either hydroxyurea or interferon at any age. High-risk patients with ET should be managed with cytoreduction, using hydroxyurea at any age. Monitoring response in PV and ET should use the ELN clinicohematologic criteria. Corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly. Indications for splenectomy include symptomatic portal hypertension, drug-refractory painful splenomegaly, and frequent RBC transfusions. The risk of allogeneic stem-cell transplantation-related complications is justified in transplantation-eligible patients whose median survival time is expected to be less than 5 years.

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Expression profiling of BRCA1-deficient tumours has identified a pattern of gene expression similar to basal-like breast tumours. In this study, we examine whether a BRCA1-dependent transcriptional mechanism may underpin the link between BRCA1 and basal-like phenotype. In methods section, the mRNA and protein were harvested from a number of BRCA1 mutant and wild-type breast cancer cell lines and from matched isogenic controls. Microarray-based expression profiling was used to identify potential BRCA1-regulated transcripts. These gene targets were then validated (by in silico analysis of tumour samples) by real-time PCR and Western blot analysis. Chromatin immunoprecipitation (ChIP) assays were used to confirm recruitment of BRCA1 to specific promoters. In results, we demonstrate that functional BRCA1 represses the expression of cytokeratins 5(KRT5) and 17(KRT17) and p-Cadherin (CDH3) in HCC1937 and T47D breast cancer cell lines at both mRNA and protein level. ChIP assays demonstrate that BRCA1 is recruited to the promoters of KRT5, KRT17 and CDH3, and re-ChIP assays confirm that BRCA1 is recruited independently to form c-Myc and Sp1 complexes on the CDH3 promoter. We show that siRNA-mediated inhibition of endogenous c-Myc (and not Sp1) results in a marked increase in CDH3 expression analogous to that observed following the inhibition of endogenous BRCA1. The data provided suggest a model whereby BRCA1 and c-Myc form a repressor complex on the promoters of specific basal genes and represent a potential mechanism to explain the observed overexpression of key basal markers in BRCA1-deficient tumours.

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Objective: This study investigated the schizophrenia phenotype in 24 subjects with 22q11 deletion syndrome (22qDS) and schizophrenia (22qDS-schizophrenia), a rare but relatively homogenous genetic subtype of schizophrenia associated with a microdeletion on chromosome 22. Individuals with 22qDS are at genetically high risk for schizophrenia.

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In this paper, gain-bandwidth (GB) trade-off associated with analog device/circuit design due to conflicting requirements for enhancing gain and cutoff frequency is examined. It is demonstrated that the use of a nonclassical source/drain (S/D) profile (also known as underlap channel) can alleviate the GB trade-off associated with analog design. Operational transconductance amplifier (OTA) with 60 nm underlap S/D MOSFETs achieve 15 dB higher open loop voltage gain along with three times higher cutoff frequency as compared to OTA with classical nonunderlap S/D regions. Underlap design provides a methodology for scaling analog devices into the sub-100 nm regime and is advantageous for high temperature applications with OTA, preserving functionality up to 540 K. Advantages of underlap architecture over graded channel (GC) or laterally asymmetric channel (LAC) design in terms of GB behavior are demonstrated. Impact of transistor structural parameters on the performance of OTA is also analyzed. Results show that underlap OTAs designed with spacer-to-straggle ratio of 3.2 and operated below a bias current of 80 microamps demonstrate optimum performance. The present work provides new opportunities for realizing future ultra wide band OTA design with underlap DG MOSFETs in silicon-on-insulator (SOI) technology. Index Terms—Analog/RF, double gate, gain-bandwidth product, .

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The effect of fluctuations in the classical control parameters on the Berry phase of a spin 1/2 interacting with an adiabatically cyclically varying magnetic field is analyzed. It is explicitly shown that in the adiabatic limit dephasing is due to fluctuations of the dynamical phase.

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Background Ten to twenty per cent of breast tumours exhibit a basallike genetic profile and these tumours carry a poor prognosis. Breast tumours which contain germline mutations for BRCA1 commonly exhibit a molecular profile similar to basal breast tumours. BRCA1 is a tumour suppressor gene which is mutated in up to 5–10% of breast cancer cases and is involved in multiple cellular processes including DNA damage control, cell cycle checkpoint control, apoptosis, ubiquitination and transcriptional regulation.

Methods Microarray-based profiling was carried out using the HCC1937EV and HCC1937BR breast cancer cell lines. Basal gene and protein expression levels were analysed by qRT-PCR and western blotting. ChIP analyses were performed and demonstrated that BRCA1 regulates basal gene expression through a transcriptional mechanism involving c-myc.

Results We have previously carried out microarray-based expression profiling to examine differences in gene expression when BRCA1 is reconstituted in BRCA1 mutated HCC1937 breast cancer cells. We observed that p-cadherin and the cytokeratin 5 and cytokeratin 17 genes, which are strongly correlated with the basal phenotype, are differentially expressed when BRCA1 is reconstituted. In addition, qRT-PCR and ChIP analysis of BRCA1 reconstituted cells show that BRCA1 represses the expression of these basal genes by a transcriptional mechanism. Furthermore, abrogation of endogenous BRCA1 protein in the T47D cell line using siRNA results in reexpression of these basal genes, suggesting that BRCA1 expression levels may be important in basal gene expression. We have also demonstrated that BRCA1 is physically associated with the promoter regions of basal genes through an association with c-myc. Consequently, we have confirmed that siRNA inhibition of c-myc in T47D cells results in re-expression of these genes.

Conclusions Our results suggest that BRCA1 is involved in the transcriptional regulation of genes associated with the basal phenotype and that BRCA1 controls basal gene expression through a transcriptional mechanism involving c-myc. Further work is now concentrating on defining the relationship between BRCA1 and basal gene expression and how this may affect clinical responses to breast cancer chemotherapy.

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This paper explores relationships between classical and parametric measures of graph (or network) complexity. Classical measures are based on vertex decompositions induced by equivalence relations. Parametric measures, on the other hand, are constructed by using information functions to assign probabilities to the vertices. The inequalities established in this paper relating classical and parametric measures lay a foundation for systematic classification of entropy-based measures of graph complexity.

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Objective: To describe the ocular phenotype in patients with ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome (MIM#604292) and to determine the pathogenic basis of visual morbidity. Design: Retrospective case series. Participants: Nineteen families (23 patients) affected by EEC syndrome from the United Kingdom, Ireland, and Italy. Methods: General medical examination to fulfill the diagnostic criteria for EEC syndrome and determine the phenotypic severity. Mutational analysis of p63 was performed by polymerase chain reaction-based bidirectional Sanger sequencing. All patients with EEC syndrome underwent a complete ophthalmic examination and ocular surface assessment. Limbal stem cell deficiency (LSCD) was diagnosed clinically on the basis of corneal conjunctivalization and anatomy of the limbal palisades of Vogt. Impression cytology using immunofluorescent antibodies was performed in 1 individual. Histologic and immunohistochemical analyses were performed on a corneal button and corneal pannus from 2 EEC patients. Main Outcome Measures: The EEC syndrome phenotypic severity (EEC score), best-corrected Snellen visual acuity (decimal fraction), slit-lamp biomicroscopy, tear function index, tear breakup time, LSCD, p63 DNA sequence variants, impression cytology, and corneal histopathology. Results: Eleven heterozygous missense mutations in the DNA binding domain of p63 were identified in all patients with EEC syndrome. All patients had ocular involvement and the commonest was an anomaly of the meibomian glands and lacrimal drainage system defects. The major cause of visual morbidity was progressive LSCD, which was detected in 61% (14/23). Limbal stem cell deficiency was related to advancing age and caused a progressive keratopathy, resulting in a dense vascularized corneal pannus, and eventually leading to visual impairment. Histologic analysis and impression cytology confirmed LSCD. Conclusions: Heterozygous p63 mutations cause the EEC syndrome and result in visual impairment owing to progressive LSCD. There was no relationship of limbal stem cell failure with the severity of EEC syndrome, as classified by the EEC score, or the underlying molecular defect in p63. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. © 2012 American Academy of Ophthalmology.