995 resultados para B.A.P. Unanue


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A genomewide linkage scan was carried out in eight clinical samples of informative schizophrenia families. After all quality control checks, the analysis of 707 European-ancestry families included 1615 affected and 1602 unaffected genotyped individuals, and the analysis of all 807 families included 1900 affected and 1839 unaffected individuals. Multipoint linkage analysis with correction for marker-marker linkage disequilibrium was carried out with 5861 single nucleotide polymorphisms (SNPs; Illumina version 4.0 linkage map). Suggestive evidence for linkage ( European families) was observed on chromosomes 8p21, 8q24.1, 9q34 and 12q24.1 in nonparametric and/or parametric analyses. In a logistic regression allele-sharing analysis of linkage allowing for intersite heterogeneity, genomewide significant evidence for linkage was observed on chromosome 10p12. Significant heterogeneity was also observed on chromosome 22q11.1. Evidence for linkage across family sets and analyses was most consistent on chromosome 8p21, with a one-LOD support interval that does not include the candidate gene NRG1, suggesting that one or more other susceptibility loci might exist in the region. In this era of genomewide association and deep resequencing studies, consensus linkage regions deserve continued attention, given that linkage signals can be produced by many types of genomic variation, including any combination of multiple common or rare SNPs or copy number variants in a region. Molecular Psychiatry (2009) 14, 786-795; doi:10.1038/mp.2009.11; published online 17 February 2009

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Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P(combined) = 4.09 × 10(-9); odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P(combined) = 2.74 × 10(-10); OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

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5-Fluorouracil (5-FU) is routinely used in the treatment of gastrointestinal, breast and head and neck cancers. A major limitation to the use of this drug is acquired or inherent resistance.

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Three hundred and seventy-six patients attending their general practitioner with cutaneous warts at five health centres in Northern Ireland were screened for human papilloma virus (HPV) types 1 and 2 IgM antibody using an indirect immunofluorescence test. Eight-eight (23.4%) patients were positive for HPV type 1 IgM and 156 (41.5%) for HPV type 2 IgM. HPV 1 IgM antibody was significantly more likely to be associated with plantar warts than warts elsewhere (P less than 0.0001). HPV 2 IgM was present in 45 (34.1%) patients with plantar warts and 99 (45.6%) patients with warts at other sites (P = 0.1). Evidence of multiple infection by HPV types 1 and 2 was demonstrated by the finding of HPV 1 and 2 IgM antibodies in the sera of 16 (4.3%). HPV 4 was found in only 1 out of 30 biopsies and HPV 4 IgM was undetectable in 50 randomly chosen sera.

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Aberrant expression of the MAD2 protein has been linked to chromosomal instability, malignant transformation and chemoresistance. Although reduced MAD2 expression is well recognised in human cancer cell lines, the mechanism(s) underlying its downregulation remain elusive. The objective of this study was to establish the impact of hypoxia on MAD2 expression and to investigate the potential role of aberrant promoter methylation as a possible mechanism of MAD2 downregulation. For this purpose, three ovarian cancer cell lines, displaying differing levels of MAD2, were treated with chromatin modifying drugs, pre and post-hypoxia exposure and a DHPLC analysis of DNA promoter methylation carried out. We show that hypoxia induces downregulation of MAD2 expression, independently of MAD2 promoter methylation. We also show no evidence of MAD2 promoter methylation in breast and prostate cancer cells or in breast cancer clinical material. While our findings provide no evidence for MAD2 promoter methylation, we show a concomitant upregulation of p21 with downregulation of MAD2 in hypoxia. Our in vitro results were also confirmed in an ovarian cancer tissue microarray (TMA), where a reciprocal staining of MAD2 and CAIX was found in 21/60 (35%) of tumours. In summary, MAD2 downregulation may be a crucial mechanism by which hypoxic cells become chemorefractory. This stems from our previous work where we demonstrated that MAD2 downregulation induces cellular senescence, a viable cellular fate, with resultant cellular resistance to paclitaxel. Moreover, MAD2 downregulation could play a central role in the induction of chemoresistance in hypoxia, a key tumour microenvironment associated with chemoresistance.

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Several studies with erythropoiesis-stimulating agents claim that maintenance therapy of renal anaemia may be possible at extended dosing intervals; however, few studies were randomized, results varied, and comparisons between agents were absent. We report results of a multi-national, randomized, prospective trial comparing haemoglobin maintenance with methoxy polyethylene glycol-epoetin beta and darbepoetin alfa administered once monthly.

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Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.

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Alzheimer's disease (AD) and age-related macular degeneration (AMD) are both neurodegenerative disorders which share common pathological and biochemical features of the complement pathway. The aim of this study was to investigate whether there is an association between well replicated AMD genetic risk factors and AD. A large cohort of AD (n = 3898) patients and controls were genotyped for single nucleotide polymorphisms (SNPs) in the complement factor H (CFH), the Age-related maculopathy susceptibility protein 2 (ARMS2) the complement component 2 (C2), the complement factor B (CFB), and the complement component 3 (C3) genes. While significant but modest associations were identified between the complement factor H, the age-related maculopathy susceptibility protein 2, and the complement component 3 single nucleotide polymorphisms and AD, these were different in direction or genetic model to that observed in AMD. In addition the multilocus genetic model that predicts around a half of the sibling risk for AMD does not predict risk for AD. Our study provides further support to the hypothesis that while activation of the alternative complement pathway is central to AMD pathogenesis, it is less involved in AD.

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Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil.

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BRCA1 encodes a tumour suppressor protein that plays pivotal roles in homologous recombination (HR) DNA repair, cell-cycle checkpoints, and transcriptional regulation. BRCA1 germline mutations confer a high risk of early-onset breast and ovarian cancer. In more than 80% of cases, tumours arising in BRCA1 germline mutation carriers are oestrogen receptor (ER)-negative; however, up to 15% are ER-positive. It has been suggested that BRCA1 ER-positive breast cancers constitute sporadic cancers arising in the context of a BRCA1 germline mutation rather than being causally related to BRCA1 loss-of-function. Whole-genome massively parallel sequencing of ER-positive and ER-negative BRCA1 breast cancers, and their respective germline DNAs, was used to characterize the genetic landscape of BRCA1 cancers at base-pair resolution. Only BRCA1 germline mutations, somatic loss of the wild-type allele, and TP53 somatic mutations were recurrently found in the index cases. BRCA1 breast cancers displayed a mutational signature consistent with that caused by lack of HR DNA repair in both ER-positive and ER-negative cases. Sequencing analysis of independent cohorts of hereditary BRCA1 and sporadic non-BRCA1 breast cancers for the presence of recurrent pathogenic mutations and/or homozygous deletions found in the index cases revealed that DAPK3, TMEM135, KIAA1797, PDE4D, and GATA4 are potential additional drivers of breast cancers. This study demonstrates that BRCA1 pathogenic germline mutations coupled with somatic loss of the wild-type allele are not sufficient for hereditary breast cancers to display an ER-negative phenotype, and has led to the identification of three potential novel breast cancer genes (ie DAPK3, TMEM135, and GATA4).