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51.
Heterozygous carriers of mutations in the BRCA2 gene have a high risk of developing breast and other cancers. In these individuals, BRCA2 appears to act as a tumour suppressor gene, in that loss of the wild type allele is frequently observed within tumours, leading to loss of BRCA2 function. Because BRCA2 functions in DNA repair via homologous recombination, this leads to genomic instability. However, it is unclear whether loss of the wild type allele is stochastic or if heterozygosity for BRCA2 mutation carries a phenotype that contributes to tumorigenic progression. Here we demonstrate that, in a specific vertebrate cell type, the chicken B cell line DT40, heterozygosity for a BRCA2 mutation has a distinct phenotype. This is characterized by a reduced growth rate, increased cell death, heightened sensitivity to specific DNA damaging agents and reduced RAD51 focus formation after irradiation. Thus in certain cell types, genome instability might be driven directly by heterozygosity for BRCA2 mutation. 相似文献
52.
Localization of a gene for otosclerosis to chromosome 15q25-q26 总被引:5,自引:0,他引:5
Tomek MS; Brown MR; Mani SR; Ramesh A; Srisailapathy CR; Coucke P; Zbar RI; Bell AM; McGuirt WT; Fukushima K; Willems PJ; Van Camp G; Smith RJ 《Human molecular genetics》1998,7(2):285-290
Among white adults otosclerosis is the single most common cause of hearing
impairment. Although the genetics of this disease are controversial, the
majority of studies indicate autosomal dominant inheritance with reduced
penetrance. We studied a large multi- generational family in which
otosclerosis has been inherited in an autosomal dominant pattern. Five of16
affected persons have surgically confirmed otosclerosis; the remaining nine
have a conductive hearing loss but have not undergone corrective surgery.
To locate the disease- causing gene we completed genetic linkage analysis
using short tandem repeat polymorphisms (STRPs) distributed over the entire
genome. Multipoint linkage analysis showed that only one genomic region, on
chromosome 15q, generated a lod score >2.0. Additional STRPs were typed
in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and
D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis
gene.
相似文献
53.
Skill NJ Griffin M El Nahas AM Sanai T Haylor JL Fisher M Jamie MF Mould NN Johnson TS 《Laboratory investigation; a journal of technical methods and pathology》2001,81(5):705-716
Diabetic nephropathy (DN) is characterized by an early, progressive expansion and sclerosis of the glomerular mesangium leading to glomerulosclerosis. This is associated with parallel fibrosis of the renal interstitium. In experimental renal scarring, the protein cross-linking enzyme, tissue transglutaminase (tTg), is up-regulated and externalized causing an increase in its crosslink product, epsilon-(gamma-glutamyl)-lysine, in the extracellular space. This potentially contributes to the extracellular matrix (ECM) accumulation central to tissue fibrosis by increasing deposition and inhibiting breakdown. We investigated if a similar mechanism may contribute to the ECM expansion characteristic of DN using the rat streptozotocin model over 120 days. Whole kidney epsilon-(gamma-glutamyl)-lysine (HPLC analysis) was significantly increased from Day 90 (+337%) and peaked at Day 120 (+650%) (p < 0.05). Immunofluorescence showed this increase to be predominantly extracellular in the peritubular interstitial space, but also in individual glomeruli. Total kidney transglutaminase (Tg) was not elevated. However, using a Tg in situ activity assay, increased Tg was detected in both the extracellular interstitial space and glomeruli by Day 60, with a maximal 53% increase at Day 120 (p < 0.05). Using a specific anti-tTg antibody, immunohistochemistry showed a similar increase in extracellular enzyme in the interstitium and glomeruli. To biochemically characterize glomerular changes, glomeruli were isolated by selective sieving. In line with whole kidney measurement, there was an increase in glomerular epsilon-(gamma-glutamyl) lysine (+361%); however, in the glomeruli this was associated with increases in Tg activity (+228%) and tTg antigen by Western blotting (+215%). Importantly, the ratio of glomerular epsilon-(gamma-glutamyl) lysine to hydroxyproline increased by 2.2-fold. In DN, changes in the kidney result in increased translocation of tTg to the extracellular environment where high Ca(2+) and low GTP levels allow its activation. In the tubulointerstitium this is independent of increased tTg production, but dependent in the glomerulus. This leads to excessive ECM cross-linking, contributing to the renal fibrosis characteristic of progressive DN. 相似文献
54.
N R Griffin M R Howard P Quirke C J O''Brien J A Child C C Bird 《Journal of clinical pathology》1988,41(8):866-870
The prognostic importance of ploidy and proliferative index (%S + G2) assessed by flow cytometry, mitotic and centroblast counts, and histological growth pattern were evaluated in biopsy specimens taken before treatment from 60 cases of centroblastic-centrocytic non-Hodgkin's lymphoma. Cases with a high proliferative index (greater than or equal to 18%) or DNA aneuploidy showed significantly poorer survival than those with a low proliferative index (less than 18%). A high mitotic count was also associated with a poor prognosis. On multiple regression analysis the flow cytometric assessments and mitotic counts were significant predictors of survival. Assessments of proliferative activity clearly have prognostic potential in centroblastic-centrocytic lymphoma and may permit more accurate characterisation of individual tumours. 相似文献
55.
Peritoneal fluid concentrations of interleukin-8 in women with endometriosis: relationship to stage of disease 总被引:7,自引:10,他引:7
Gazvani MR; Christmas S; Quenby S; Kirwan J; Johnson PM; Kingsland CR 《Human reproduction (Oxford, England)》1998,13(7):1957-1961
There is increasing evidence that immunological mechanisms play a role in
the pathogenesis and pathophysiology of endometriosis. It was therefore of
interest to study interleukin-8 (IL-8), a chemokine, in the peritoneal
fluid and peripheral blood of women undergoing laparoscopic procedures. The
presence and concentrations of IL-8 in relation to endometriosis,
infertility and abdominal pain were evaluated. Samples of peritoneal fluid
(n = 49) and peripheral blood (n = 50) were obtained from 50 consecutive
patients undergoing laparoscopic surgery for various gynaecological
indications (abdominal pain, infertility, sterilization). IL-8 was present
in the peritoneal fluid of most women (87%). The concentration of IL-8 in
the peritoneal fluid was higher in women with endometriosis compared to
women without (P = 0.02). This difference was more pronounced in early
(stage 1) endometriosis (P = 0.001). IL-8 concentrations in the peritoneal
fluid were also higher in women with early endometriosis compared to women
with later stages of the disease (P = 0.003). Peripheral blood
concentrations did not correlate with peritoneal fluid concentrations of
IL-8 and/or the presence of endometriosis. We conclude that IL-8 is an
important factor that may contribute to the pathogenesis of endometriosis
possibly by promoting neovascularization. This information can be a guide
in the development of new therapeutic approaches for the treatment of
endometriosis.
相似文献
56.
Fluorescence in situ hybridization to determine engraftment status after murine bone marrow transplant. 总被引:3,自引:0,他引:3
A L Hawkins R J Jones B A Zehnbauer M S Zicha M J Collector S J Sharkis C A Griffin 《Cancer Genetics and Cytogenetics》1992,64(2):145-148
The mouse Y-specific DNA sequence pY2 was used as a probe for fluorescence in situ hybridization (FISH) to evaluate murine hematopoietic tissues after sex-mismatched bone marrow transplant (BMT). The pY2 probe was localized to the long arm of the Y chromosome on BM metaphases. Hybridization of pY2 in FISH of interphase cells from BM, spleen, and thymus after BMT was compared with Southern blot analysis; both methods gave comparable results. Only FISH was able to analyze post-BMT peripheral blood (PB) samples successfully, and provides a useful method for following engraftment status in the mouse on an ongoing basis. 相似文献
57.
Weiss RD Kolodziej M Griffin ML Najavits LM Jacobson LM Greenfield SF 《Journal of affective disorders》2004,79(1-3):279-283
BACKGROUND: Bipolar disorder (BPD) is the Axis I disorder with the highest risk for coexisting substance use disorder. One explanation for this phenomenon is the 'self-medication hypothesis', which states that some patients experience improvement in psychiatric symptoms as a result of substance use. We thus investigated reasons for substance use and perceived substance-induced improvement in BPD symptoms among patients with current BPD and substance dependence. METHODS: A total of 45 patients received six monthly assessments; 21 also received integrated group therapy (IGT), focusing simultaneously on BPD and substance dependence, while 24 did not receive IGT. Patients reported at intake their current reasons for initiating substance use (including BPD symptoms) and the effects of substance use on those symptoms. RESULTS: Nearly all patients initiated substance use because of at least one BPD symptom, especially depression (77.8%) and racing thoughts (57.8%); most (66.7%) reported improvement in at least one BPD symptom as a result of substance use. Among patients reporting substance-induced improvement in BPD symptoms, those receiving IGT reported fewer days of drug use over the 6-month study period than those not receiving IGT; this difference was not significant among patients without substance-induced improvement in BPD symptoms. LIMITATIONS: The study is limited by its small sample size and by the potential inaccuracy of self-reports regarding the effects of substance use on mood. CONCLUSIONS: Substance dependent patients who report that substance use improves their BPD symptoms may benefit from treatment that focuses simultaneously on both disorders. 相似文献
58.
59.
C A Griffin B A Zehnbauer W E Beschorner R Ambinder R Mann 《Genes, chromosomes & cancer》1992,4(2):153-157
We have identified two cases of previously untreated, small lymphocytic lymphoma with extranodal involvement, which had a reciprocal translocation, t(11;18)(q21;q21), as the sole cytogenetic abnormality. These two cases are remarkably similar to two previously reported cases carrying this translocation with regard to clinical features, cytogenetic abnormality, histologic subtype, and immunophenotype. Molecular genetic analysis of these two cases revealed clonal gene rearrangement of the IGH locus but only germline configuration of the BCL2 oncogene at 18q21 when probes and conditions that usually identify BCL2 rearrangement in lymphomas were used. Lymphomas bearing an (11;18) rearrangement appear to make up a phenotypically identifiable subgroup. Identification of the genes at the translocation breakpoints will be important. 相似文献
60.
Use of in vivo-induced antigen technology for identification of Escherichia coli O157:H7 proteins expressed during human infection
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John M Kudva IT Griffin RW Dodson AW McManus B Krastins B Sarracino D Progulske-Fox A Hillman JD Handfield M Tarr PI Calderwood SB 《Infection and immunity》2005,73(5):2665-2679
Using in vivo-induced antigen technology (IVIAT), a modified immunoscreening technique that circumvents the need for animal models, we directly identified immunogenic Escherichia coli O157:H7 (O157) proteins expressed either specifically during human infection but not during growth under standard laboratory conditions or at significantly higher levels in vivo than in vitro. IVIAT identified 223 O157 proteins expressed during human infection, several of which were unique to this study. These in vivo-induced (ivi) proteins, encoded by ivi genes, mapped to the backbone, O islands (OIs), and pO157. Lack of in vitro expression of O157-specific ivi proteins was confirmed by proteomic analysis of a mid-exponential-phase culture of E. coli O157 grown in LB broth. Because ivi proteins are expressed in response to specific cues during infection and might help pathogens adapt to and counter hostile in vivo environments, those identified in this study are potential targets for drug and vaccine development. Also, such proteins may be exploited as markers of O157 infection in stool specimens. 相似文献