3,524 research outputs found
The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers
No full text<p>Introduction: The androgen receptor (AR) gene exon 1 CAG repeat polymorphism encodes a string of 9–32 glutamines. Women with germline BRCA1 mutations who carry at least one AR allele with 28 or more repeats have been reported to have an earlier age at onset of breast cancer.</p>
<p>Methods: A total of 604 living female Australian and British BRCA1 and/or BRCA2 mutation carriers from 376 families were genotyped for the AR CAG repeat polymorphism. The association between AR genotype and disease risk was assessed using Cox regression. AR genotype was analyzed as a dichotomous covariate using cut-points previously reported to be associated with increased risk among BRCA1 mutation carriers, and as a continuous variable considering smaller allele, larger allele and average allele size.</p>
<p>Results: There was no evidence that the AR CAG repeat polymorphism modified disease risk in the 376 BRCA1 or 219 BRCA2 mutation carriers screened successfully. The rate ratio associated with possession of at least one allele with 28 or more CAG repeats was 0.74 (95% confidence interval 0.42–1.29; P = 0.3) for BRCA1 carriers, and 1.12 (95% confidence interval 0.55–2.25; P = 0.8) for BRCA2 carriers.</p>
<p>Conclusion: The AR exon 1 CAG repeat polymorphism does not appear to have an effect on breast cancer risk in BRCA1 or BRCA2 mutation carriers.</p>
Correlation of inter-locus polyglutamine toxicity with CAG•CTG triplet repeat expandability and flanking genomic DNA GC content
No full textDynamic expansions of toxic polyglutamine (polyQ)-encoding CAG repeats in ubiquitously expressed, but otherwise unrelated, genes cause a number of late-onset progressive neurodegenerative disorders, including Huntington disease and the spinocerebellar ataxias. As polyQ toxicity in these disorders increases with repeat length, the intergenerational expansion of unstable CAG repeats leads to anticipation, an earlier age-at-onset in successive generations. Crucially, disease associated alleles are also somatically unstable and continue to expand throughout the lifetime of the individual. Interestingly, the inherited polyQ length mediating a specific age-at-onset of symptoms varies markedly between disorders. It is widely assumed that these inter-locus differences in polyQ toxicity are mediated by protein context effects. Previously, we demonstrated that the tendency of expanded CAG center dot CTG repeats to undergo further intergenerational expansion (their 'expandability') also differs between disorders and these effects are strongly correlated with the GC content of the genomic flanking DNA. Here we show that the inter-locus toxicity of the expanded polyQ tracts of these disorders also correlates with both the expandability of the underlying CAG repeat and the GC content of the genomic DNA flanking sequences. Inter-locus polyQ toxicity does not correlate with properties of the mRNA or protein sequences, with polyQ location within the gene or protein, or steady state transcript levels in the brain. These data suggest that the observed inter-locus differences in polyQ toxicity are not mediated solely by protein context effects, but that genomic context is also important, an effect that may be mediated by modifying the rate at which somatic expansion of the DNA delivers proteins to their cytotoxic stat
CagI is an essential component of the Helicobacter pylori Cag type IV secretion system and forms a complex with CagL.
No full textHelicobacter pylori, the causative agent of type B gastritis, peptic ulcers, gastric adenocarcinoma and MALT lymphoma, uses the Cag type IV secretion system to induce a strong proinflammatory response in the gastric mucosa and to inject its effector protein CagA into gastric cells. CagA translocation results in altered host cell gene expression profiles and cytoskeletal rearrangements, and it is considered as a major bacterial virulence trait. Recently, it has been shown that binding of the type IV secretion apparatus to integrin receptors on target cells is a crucial step in the translocation process. Several bacterial proteins, including the Cag-specific components CagL and CagI, have been involved in this interaction. Here, we have examined the localization and interactions of CagI in the bacterial cell. Since the cagI gene overlaps and is co-transcribed with the cagL gene, the role of CagI for type IV secretion system function has been difficult to assess, and conflicting results have been reported regarding its involvement in the proinflammatory response. Using a marker-free gene deletion approach and genetic complementation, we show now that CagI is an essential component of the Cag type IV secretion apparatus for both CagA translocation and interleukin-8 induction. CagI is distributed over soluble and membrane-associated pools and seems to be partly surface-exposed. Deletion of several genes encoding essential Cag components has an impact on protein levels of CagI and CagL, suggesting that both proteins require partial assembly of the secretion apparatus. Finally, we show by co-immunoprecipitation that CagI and CagL interact with each other. Taken together, our results indicate that CagI and CagL form a functional complex which is formed at a late stage of secretion apparatus assembly
No Evidence that 2D:4D is Related to the Number of CAG Repeats in the Androgen Receptor Gene
No full textThe length ratio of the second to the fourth digit (2D:4D) is a putative marker of prenatal testosterone (T) effects. The number of CAG repeats (CAGn) in the AR gene is negatively correlated with T sensitivity in vitro. Results regarding the relationship between 2D:4D and CAGn are mixed but have featured prominently in arguments for and against the validity of 2D:4D. Here, I present random-effects meta-analyses on 14 relevant samples with altogether 1,904 subjects. Results were homogeneous across studies. Even liberal estimates (upper limit of the 95% CI) were close to zero and therefore suggested no substantial relationship of CAGn with either right-hand 2D:4D, left-hand 2D:4D, or the difference between the two. However, closer analysis of the effects of CAGn on T dependent gene activation in vitro and of relationships between CAGn and T dependent phenotypic characteristics suggest that normal variability of CAGn has mostly no, very small, or inconsistent effects. Therefore, the lack of a clear association between CAGn and 2D:4D has no negative implications for the latter’s validity as a marker of prenatal T effects
The CAG trinucleotide repeat length in the androgen receptor does not predict the early onset of prostate cancer
No full textObjective To relate the repeat length of the androgen-receptor CAG trinucleotide to the age of onset of prostate cancer, stage and grade of disease. Patients and methods After obtaining ethical approval, 265 patients with locally confined or locally advanced/metastatic prostate cancer were identified and evaluated for age at diagnosis (less than 65 years and greater than 75 years). DNA was extracted from peripheral blood lymphocytes and 1 mug aliquots subjected to polymerase chain reaction using fluorescently labelled primers. Samples were then run on an ABI 377 gene scan analysis gel with an internal molecular weight marker. The length of the CAG repeat was determined by comparing the gene scan product size to samples where the CAG repeat length had been quantified using direct sequencing. The Kruskal-Wallis, Mann-Whitney and Wilcoxon two sample tests were used to analyse the data. Results The mean (range) length of the CAG repeat in the androgen receptor was 22.2 (10-31) in the younger and 22.5 (16-32) in the older group, and was not statistically different. There was no significant association between the CAG repeat length and the age of onset of prostate cancer (P = 0.568) or with stage (P = 0.577) and grade (P = 0.891) of prostate cancer. Conclusion These results suggest that there is no correlation between the androgen receptor CAG repeat length and the age of onset, stage and grade of prostate cancer, confirming recent doubts from other similar studies of a suggested correlation between shorter androgen receptor CAG repeat and early onset and aggressiveness of prostate cancer
Helicobacter pylori cag-Pathogenicity island-dependent early immunological response triggers later precancerous gastric changes in Mongolian gerbils
No full textInfection with Helicobacter pylori, carrying a functional cag type IV secretion system (cag-T4SS) to inject the Cytotoxin associated antigen (CagA) into gastric cells, is associated with an increased risk for severe gastric diseases in humans. Here we studied the pathomechanism of H. pylori and the role of the cag-pathogenicity island (cag-PAI) for the induction of gastric ulcer and precancerous conditions over time (2-64 weeks) using the Mongolian gerbil model. Animals were challenged with H. pylori B128 (WT), or an isogenic B128DeltacagY mutant-strain that produces CagA, but is unable to translocate it into gastric cells. H. pylori colonization density was quantified in antrum and corpus mucosa separately. Paraffin sections were graded for inflammation and histological changes verified by immunohistochemistry. Physiological and inflammatory markers were quantitated by RIA and RT-PCR, respectively. An early cag-T4SS-dependent inflammation of the corpus mucosa (4-8 weeks) occurred only in WT-infected animals, resulting in a severe active and chronic gastritis with a significant increase of proinflammatory cytokines, mucous gland metaplasia, and atrophy of the parietal cells. At late time points only WT-infected animals developed hypochlorhydria and hypergastrinemia in parallel to gastric ulcers, gastritis cystica profunda, and focal dysplasia. The early cag-PAI-dependent immunological response triggers later physiological and histopathological alterations towards gastric malignancies
Variation within the Huntington's disease gene influences normal brain structure.
No full textGenetics of the variability of normal and diseased brain structure largely remains to be elucidated. Expansions of certain trinucleotide repeats cause neurodegenerative disorders of which Huntington's disease constitutes the most common example. Here, we test the hypothesis that variation within the IT15 gene on chromosome 4, whose expansion causes Huntington's disease, influences normal human brain structure. In 278 normal subjects, we determined CAG repeat length within the IT15 gene on chromosome 4 and analyzed high-resolution T1-weighted magnetic resonance images by the use of voxel-based morphometry. We found an increase of GM with increasing long CAG repeat and its interaction with age within the pallidum, which is involved in Huntington's disease. Our study demonstrates that a certain trinucleotide repeat influences normal brain structure in humans. This result may have important implications for the understanding of both the healthy and diseased brain
A Small Trinucleotide Expansion in the TBP Gene Gives Rise to a Sporadic Case of SCA17 with Abnormal Putaminal Findings on MRI
No full textA Japanese woman developed gait disturbances at 25 years of age, and subsequently underwent gradual changes in her personality. By the age of 42, she showed clear signs of dementia and cerebellar ataxia, and displayed behavioral abnormalities, choreic movements and hyperreflexia. The findings of MRI not only showed cerebellar and cerebral atrophy, but also revealed putaminal rim hyperintensity on T2-weighted images. We identified a heterozygously expanded CAG/CAA repeat (45/36) within the TATA-binding protein gene, leading to a diagnosis of SCA17. These results show that a 45 CAG/CAA repeat is pathological, giving rise to early-onset SCA17.</p
Management by geographic area or management specialised by disorder? A mixed-methods evaluation of the effects of an organisational intervention on secondary mental health care for common mental disorder
No full textIn 2010, South London and Maudsley NHS Foundation Trust (SLaM) established a programme replacing the borough directorates responsible for adult mental health services with three Clinical Academic Groups (CAGs), each of which took on a subset of adult services straddling all four boroughs. Care pathways were also introduced. We studied the Mood Anxiety and Personality CAG, which took on assessment and treatment teams and psychotherapy services.\ud
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Objectives\ud
We aimed (1) to understand the CAG programme using realistic evaluation and (2) to assess whether or not it led to changes in activity and health-care quality.\ud
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Methods\ud
Qualitative analysis was based on interviews and project documents. Quantitative analyses were based on electronic patient records and compared care in community mental health teams (CMHTs) and psychotherapy teams before and after CAG implementation. Analyses of activity covered caseload, counts of new episodes, episode length and number of contacts per episode. We also looked at CMHT costs. Analyses of effectiveness covered processes (pharmacological and psychological treatment of depression in CMHTs) and outcomes (effect on the Health of the Nation Outcome Scales total score or the Clinical Outcomes in Routine Evaluation 10-item version total score). Analyses of safety examined the rates of self-harm among current or recent CMHT patients. Patient centredness was represented by waiting time.\ud
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Results\ud
The first core component of SLaM’s CAG programme was the CAG restructuring itself. The second was the promotion of care pathways; interpreted as ‘high level pathways’, these schematised processes of referral, assessment, treatment, reassessment and discharge, but abstracted from the details of treatment. The three mechanisms of the CAG restructuring were increasing oversight, making teams fit the template of team types defined for each CAG (‘CAG compliance’) and changing financial accounts by grouping services in new ways; these mechanisms resulted in further reconfigurations. The use of high-level pathways supported service redesign and performance management. In CMHTs and psychotherapy teams activity tended to decrease, but this was probably not because of the CAG programme. CMHT costs were largely unchanged. There was no evidence that the CAG programme altered effectiveness or safety. Effects on waiting times varied but these were reduced in some cases. Overall, therefore, the CAG programme appeared to have had few effects on quality. We attributed this to the limited effect of the programme on individual treatment.\ud
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Conclusions\ud
SLaM’s CAG programme had clear effects on service reconfiguration at team level, with high-level pathways changing the ways that managers conceptualised their work. However, our quantitative work indicated no clear effects on quality. Thinking about how to use care pathways in ways that complement ‘high-level’ pathways by supporting the delivery of evidence-based treatments is a strategy that could help SLaM and other providers. Future research should look at the genesis of organisational change and how this is altered through implementation; it should also look at the effectiveness of care pathways in mental health services
A Role for the Vacuolating Cytotoxin, VacA, in Colonization and Helicobacter pylori-Induced Metaplasia in the Stomach
No full textCarriage of Helicobacter pylori strains producing more active (s1/i1) forms of VacA is strongly associated with gas-tric adenocarcinoma. To our knowledge, we are the
first to determine effects of different polymorphic forms of VacA on inflammation and metaplasia in the mouse stomach. Bacteria producing the less active s2/i2 form of VacA colonized mice more efficiently than mutants null for VacA or producing more active forms of it, providing the
first evidence of a positive role for the minimally active s2/i2 toxin. Strains producing more active toxin forms induced more severe and extensive metaplasia and in flammation in the mouse stomach than strains producing weakly active (s2/i2) toxin. We also examined the association in humans, controlling for cag PAI status. In human gastric biopsy specimens, the vacA i1 allele was strongly associated with precancerous intestinal metaplasia, with almost complete absence of intestinal metaplasia in subjects infected with i2-type strains, even in a vacA s1, cagA+ background
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