See also Monahan PE. The expanding menagerie: animal models of hemophilia A. This issue, pp 2469-71.Summary. Background: We recently described an inherited coagulopathy arising in an inbred colony of WAG/RijYcb rats. The bleeding phenotype, demonstrated by both male and female rats, included periarticular hemorrhage, spontaneous bruising, prolonged bleeding from minor wounds and maternal peripartum deaths. Coagulation testing of affected rats revealed normal prothrombin time but prolongation of activated partial thromboplastin time to twice that of controls. Objective: To determine the specific coagulation factor and the underlying genetic defect responsible for the inherited coagulopathy in the WAG/RijYcb rats. Results: Evaluation of individual clotting factor activities revealed that the affected animals had a specific deficiency of factor (F) VIII (FVIII). The FVIII gene (F8) has an autosomal location on chromosome 18 in rats, in contrast to its location on the X chromosome in mice and humans. Sequencing of F8 cDNA led to the identification of a point mutation resulting in a substitution, Leu176Pro, in the A1 domain, that is predicted to disrupt the tertiary structure of the FVIII molecule. Administration of human plasma or human recombinant FVIII corrects the coagulation abnormality in the affected animals. Conclusions: We have now identified the genetic basis of the hemostatic defect in the WAG/RijYcb rat colony. The larger size of rats relative to mice and the presence of this coagulation defect in both sexes provide a unique model, well-suited to the development of novel therapies for acquired and hereditary FVIII deficiencies.
IntroductionThe assessment of risk of recurrence and progression of bladder cancer (BC) is still rather difficult. We decided to check the rates of the changes mentioned above in the group of the Polish patients after a year–long observation and next to compare them with the results calculated in the European Organisation of Research and Treatment of Cancer (EORTC) risk tables.MethodsThe tested group consisted of 91 patients who underwent transurethral resection of bladder tumour (TURBT). When being diagnosed, 60 cases were in the pTa clinical stage, whereas 30 cases were in T1. The coexisting carcinoma in situ (CIS) was observed in four cases. On the basis of the scores obtained from the EORTC tables, the patients were divided into the groups of low, intermediate or high risk of disease recurrence and progression.ResultsRecurrence was noticed in 23 patients (25%), while progression was observed in 11 patients (12.1%). The rate of the observed recurrences proved to be lower than it had been predicted in all the groups, except for one of the intermediate–risk group (score 1– 4). Moreover, the rate of the progressions predicted according to the EORTC risk tables was higher in all the risk groups.ConclusionsIt can be noticed that the rate of real recurrences is lower than expected, whereas the rate of the observed progressions is overestimated. Partly, it could be the result of using a relatively small group of patients for observation and applying a different method of treatment.
IntroductionUrinary bladder carcinoma ranks the fourth position in malignancy incidence rates in men (6.1%) and the 17th position in women (1.6%). In general, neoplastic diseases should be approached from two perspectives: prevention with implementation of prophylactic measures and early diagnostics. Prophylactics is possible in the preclinical phase of neoplasm, being both justified and plausible in patients from high–risk groups. Thus, it is particularly important to select such groups, not only by referring to environmental carcinogenic factors (occupational and extra–occupational) but also from genetic predisposition, which may be conductive for neoplasm formation. The mutations / polymorphisms of CHEK2 and CYP1B1 genes predispose to neoplasm via multiorgan mechanisms, while the human papilloma virus (HPV) may participate in the neoplastic transformation as an environmental factor.Material and methods131 patients with diagnosed urinary bladder cancer were qualified to the study. Mutations/polymorphisms of CHEK2 (IVS2 + 1G > A gene, 1100delC, del5395, I157T) and CYP1B1– 355T/T were identified by the PCR in DNA isolated directly from the tumor and from peripheral blood. The ELISA test was used for the studies of 37 HPV genotypes in DNA, isolated tumour tissue.Results11 mutations of CHEK2 gene were found, 355T/T polymorphism if CYP1B1 gene occurred in 18 patients (12.9%). Oncogenic HPV was found in 36 (29.3%), out of 123 examined patients.ConclusionsThe concomitance of CHEK2 gene mutations or 355T/T polymorphism of CYP1B1 gene and the presence of oncogenic HPV types statistically significantly correlates with histological malignancy grades of urinary bladder carcinoma.
IntroductionLoss of heterozygosity (LOH) is frequently observed in urinary bladder neoplasms. In the reported study, an attempt was undertaken to determine the loss of heterozygosity of TP53(17p13), RB1(13q14), CDKN2A/ ARF(9p21) genes in DNA from neoplastic tissue, collected from patients with diagnosed urinary bladder carcinoma, and to compare the results with those of LOH evaluation in DNA isolated from urine sediment cells.Material and methodsAfter isolation, DNA was amplified (PCR) by means of primers to five polymorphic microsatellite markers, the products being then separated on agarose gel. Following the method, a total of 125 DNA samples were obtained, isolated from neoplastic cells, together with 125 corresponding DNA samples, isolated from urine sediment cells.ResultsThe loss of heterozygosity in at least one marker was identified in 39.2%. (49/125) of DNA from studied tumors and in 34.3% (43/125) of DNA samples, isolated from urine sediment cells. An analysis of LOH from the DNA, isolated from urine sediment cells, allowed for identification of 81.8% of neoplastic tumors with 99.7% specificity.ConclusionsOur observations have demonstrated that LOH within 13q14, 17p13 and 9p21 loci is more often observed in clinically more advanced neoplasms. LOH in 17p13 locus is more frequently found in tumors at high histopathological stage, while in low-stage neoplasms, LOH is most often observed on chromosome 9. The high sensitivity (81.8%) and specificity (99.7%) of LOH studies in DNA, isolated from urine sediment cells, make this technique an advantageous, non-invasive method for detection and screening of bladder cancer.
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