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Biomedical subjects

I Dunn

Publications and source records attributed to I Dunn.

At least 19 recordsLinked to original sources
PubMed2004

HER2/neu gene amplification and protein overexpression in G3 pT2 transitional cell carcinoma of the bladder: a role for anti-HER2 therapy?

HER2/neu is an oncogene encoding a type 1 tyrosine kinase growth factor receptor. Polysomy 17, gene amplification and HER2/neu protein overexpression are associated with a poor prognosis in transitional cell carcinomas (TCC) of the bladder. Due to the application of different laboratory techniques, the exact incidence of HER/neu abnormalities remains uncertain in TCC. Standardised laboratory techniques are therefore important in the determination of the HER2/neu status if an assessment of the potential value of anti-HER2/neu treatments in the clinical management of patients with TCC is to be made. In this study, 75 TCCs with evidence of detrusor muscle invasion at first clinical presentation were included. Gene amplification, polysomy 17 and HER2 copy number were assessed using fluorescence in situ hybridisation (FISH), with separate probes for chromosome 17 and HER2/neu. Protein overexpression was assessed using immunohistochemistry (IHC), with the CB11 antibody and a scoring system evaluating only membranous staining as positive. The mean patient age was 69.5 years (range 42-93 years) and the median survival was 15 months (range 1-156 months). Polysomy 17 occurred in 97%, increased HER/neu copy number in 92% and HER2/neu gene amplification in 7%. Protein overexpression occurred in 57% of cases. Polysomy 17 and HER2/neu protein overexpression are common in G3 pT2 TCCs of the bladder. However, gene amplification is uncommon. Mechanisms other than gene amplification may be responsible for protein overexpression in this tumour type. Evidence from breast cancer suggests that only tumours with HER2/neu gene amplification respond to the anti-HER2/neu therapy trastuzumab (Herceptin). If this were true for bladder cancer, only 4/75 (5%) of G3 pT2 TCCs would be suitable for treatment. The role of trastuzumab in these tumours remains untested at present.

Adult↗
PubMed2003

HER2/neu overexpression in the development of muscle-invasive transitional cell carcinoma of the bladder.

The mortality from transitional cell carcinoma (TCC) of the urinary bladder increases significantly with the progression of superficial or locally invasive disease (pTa/pT1) to detrusor muscle-invasive disease (pT2+). The most common prognostic markers in clinical use are tumour stage and grade, which are subject to considerable intra- and interobserver variation. Polysomy 17 and HER2/neu gene amplification and protein overexpression have been associated with more advanced disease. Standardised techniques of fluorescence in situ hybridisation and immunohistochemistry, which are currently applied to other cancers with a view to offering anti-HER2/neu therapies, were applied to tumour pairs comprising pre- and postinvasive disease from 25 patients undergoing treatment for bladder cancer. In the preinvasive tumours, increased HER2/neu copy number was observed in 76% of cases and increased chromosome 17 copy number in 88% of cases, and in the postinvasive group these values were 92 and 96%, respectively (not significantly different P=0.09 and 0.07, respectively). HER2 gene amplification rates were 8% in both groups. Protein overexpression rates were 76 and 52%, respectively, in the pre- and postinvasive groups (P=0.06). These results suggest that HER2/neu abnormalities occur prior to and persist with the onset of muscle-invasive disease. Gene amplification is uncommon and other molecular mechanisms must account for the high rates of protein overexpression. Anti-HER2/neu therapy might be of use in the treatment of TCC.

Adult↗
PubMed2002

Genetic aberrations of c-myc and CCND1 in the development of invasive bladder cancer.

Detrusor muscle invasive transitional cell carcinoma is associated with poor prognosis and is responsible for the majority of bladder cancer related deaths. Amplifications of c-myc and CCND1 are associated with detrusor-muscle-invasive transitional cell carcinoma, however, their precise role in driving disease progression is unclear. Fluorescence in situ hybridisation on archival tissue from 16 patients with primary diagnosis of > or = pT2 transitional cell carcinoma and 15 cases with primary pTa/pT1 disease subsequently progressing to detrusor-muscle-invasion was performed, in the latter group both pre and post muscle invasive events were studied. No patients presenting with >/=pT2 had amplification of c-myc, two out of 16 (12.5%) had CCND1 amplification. Of patients who developed > or = pT2, two out of 15 (13.3%) had amplification of c-myc, both in > or = pT2, five out of 15 (33.3%) had CCND1 amplification, two in pTa/pT1 tumours, three in > or = pT2 transitional cell carcinomas. In total, two out of 31 (6.5%) of patients' > or = pT2 TCCs were amplified for c-myc and six out of 31 (19%) were amplified for CCND1. Eighty-seven per cent (40 out of 46) of tumours were polysomic for chromosome 8 and 80% (37 out of 46) were polysomic for chromosome 11 and this reflected the high copy numbers of c-myc and CCND1 observed. In almost all cases an increase in c-myc/CCND1 copy number occurred prior to invasion and persisted in advanced disease. Amplification of CCND1 or alterations in c-myc/CCND1 early in bladder cancer may have clinical relevance in promoting and predicting progression to detrusor-muscle-invasive transitional cell carcinoma.

Adult↗
PubMed2000

Differences in gene density on chicken macrochromosomes and microchromosomes.

The chicken karyotype comprises six pairs of large macrochromosomes and 33 pairs of smaller microchromosomes. Cytogenetic evidence suggests that microchromosomes may be more gene-dense than macrochromosomes. In this paper, we compare the gene densities on macrochromosomes and microchromosomes based on sequence sampling of cloned genomic DNA, and from the distribution of genes mapped by genetic linkage and physical mapping. From these different approaches we estimate that microchromosomes are twice as gene-dense as macrochromosomes and show that sequence sampling is an effective means of gene discovery in the chicken. Using this method we have also detected a conserved linkage between the genes for serotonin 1D receptor (HTR1D) and the platelet-activating factor receptor protein gene (PTAFR) on chicken chromosome 5 and human chromosome 1p34.3. Taken together with its advantages as an experimental animal, and public access to genetic and physical mapping resources, the chicken is a useful model genome for studies on the structure, function and evolution of the vertebrate genome.

Animals↗
PubMed1998

Activation of human macrophages by mechanical ventilation in vitro.

Positive-pressure mechanical ventilation supports gas exchange in patients with respiratory failure but is also responsible for significant lung injury. In this study, we have developed an in vitro model in which isolated lung cells can be submitted to a prolonged cyclic pressure-stretching strain resembling that of conventional mechanical ventilation. In this model, cells cultured on a Silastic membrane were elongated up to 7% of their initial diameter, corresponding to a 12% increase in cell surface. The lung macrophage was identified as the main cellular source for critical inflammatory mediators such as tumor necrosis factor-alpha, the chemokines interleukin (IL)-8 and -6, and matrix metalloproteinase-9 in this model system of mechanical ventilation. These mediators were measured in supernatants from ventilated alveolar macrophages, monocyte-derived macrophages, and promonocytic THP-1 cells. Nuclear factor-kappaB was found to be activated in ventilated macrophages. Synergistic proinflammatory effects of mechanical stress and molecules such as bacterial endotoxin were observed, suggesting that mechanical ventilation might be particularly deleterious in preinjured or infected lungs. Dexamethasone prevented IL-8 and tumor necrosis factor-alpha secretion in ventilated macrophages. Mechanical ventilation induced low levels of IL-8 secretion by alveolar type II-like cells. Other lung cell types such as endothelial cells, bronchial cells, and fibroblasts failed to produce IL-8 in response to a prolonged cyclic pressure-stretching load. This model is of particular value for exploring physical stress-induced signaling pathways, as well as for testing the effects of novel ventilatory strategies or adjunctive substances aimed at modulating cell activation induced by mechanical ventilation.

Cytokines↗
PubMed1996

Graded compression stockings for prevention of deep-vein thrombosis after hip and knee replacement.

We performed a prospective, randomised controlled trial in 177 patients who were having either total hip or knee replacement, to evaluate the use of both above- and below-knee graded compression stockings in the prevention of deep-vein thrombosis (DVT). With above-knee stockings, we found no significant reduction of the overall, proximal or major calf (> 5 cm) DVT rates. With below-knee stockings, the overall thrombosis rate was similar to that of the control group but the stockings appeared to have altered the pattern of thrombosis. Patients who had total hip replacement and wore below-knee stockings had a significantly higher rate of proximal or major calf DVT (p = 0.03). This pattern was reversed in patients with total knee replacement who developed a significantly lower rate of proximal or major calf DVT with below-knee stockings (p < 0.05). Our results showed that, with the exception of below-knee stockings in knee replacement patients, graded compression stockings were ineffective in preventing DVT after hip or knee replacement surgery.

Aged↗
PubMed1995

Nature of G1/S cell cycle checkpoint defect in ataxia-telangiectasia.

We have previously demonstrated that cells from patients with ataxia-telangiectasia (A-T) fail to show initial delay at several cell cycle checkpoints post-irradiation. In addition a defect in the induction of p53 by ionizing radiation was evident. We demonstrate here that the radiation signal transduction pathway operating through p53, its target gene WAF1, cyclin-dependent kinases and the retinoblastoma (Rb) protein is defective in A-T cells. The defective p53 induction after ionizing radiation, observed previously in A-T cells, was also reflected at the functional level using p53-DNA binding activity, transactivation and transfection with wild type p53. Correction of the defect at the G1/S checkpoint was observed when wild type p53 was constitutively expressed in A-T cells. Exposure of control cells to radiation gave rise to p53 induction and as a consequence increased expression of WAF1 mRNA and protein, but A-T cells were defective in this response. As expected the WAF1 response in irradiated control cells resulted in an inhibition of cyclin-dependent kinase activity including cyclin E-cdk2, which plays an important role in the transition from G1 to S phase. No inhibition of cyclin-dependent kinase activity was observed in A-T cells correlating with the delayed WAF1 response. On the contrary an enhancement of cyclin-dependent kinase activity was seen in A-T cells post-irradiation. An accumulation of the hypophosphorylated form of Rb protein occurred in irradiated control cells compatible with the G1/S phase delay observed in these cells after exposure to radiation. In unirradiated A-T cells the amount of Rb protein was much higher compared to controls and it was mainly in the hyperphosphorylated (functionally inactive) form. In addition, accumulation of the hypophosphorylated form of Rb in A-T cells post-irradiation was defective, consistent with the lack of cell cycle arrest. Thus the failure of the G1/S checkpoint in A-T cells after exposure to ionizing radiation is consistent with a defective radiation signal transduction pathway operating through p53.

Ataxia Telangiectasia↗
PubMed1994

Seroprevalence of human T-lymphotropic virus in blacks from a selected central Brooklyn population.

Human T-cell leukemia virus type I (HTLV-I) has been causally linked to adult T-cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-I-associated myelopathy. Few seroprevalence studies have been carried out in the United States. Because of the number of reports of adult T-cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-I-associated myelopathy in blacks from central Brooklyn, New York, we decided to initiate a seroprevalence study in this community. Intravenous drug users and male homosexuals were excluded. A total of 480 individuals from medical clinics and health fairs were surveyed via questionnaire, and their sera were assayed for HTLV-I/II antibody by two laboratories. An overall seroprevalence rate was 21/480 (4.4%). This is almost 200 times greater than a study of a national sample of U.S. blood donors. Rates were similar for individuals originating from the United States and the Caribbean. Nine of the 21 seropositive individuals returned for further testing. Polymerase chain reaction assays revealed that 8 were positive for HTLV-I and 1 for HTLV-II. Although this group may not be representative of the "normal" black population of central Brooklyn, the high seroprevalence rate necessitates that the incidence of HTLV-I-associated illnesses be determined in this community.

Adolescent↗
PubMed1986

Clinical, morphological, and biochemical alterations in acute intestinal Yersiniosis.

The aim of this study was to examine the intestinal response to Yersinia enterocolitica (YE) infection. Growing New Zealand white rabbits (450-800 g) were infected with 10(10) organisms of a human pathogenic strain (n = 43) or NaHCO3 for controls (n = 30) and studied 3, 6, 10, and 14 days after infection. In a separate experiment infected (n = 6) and pair-fed controls (n = 6) were studied 6 days after infection. Weight gain, excretion of YE, and diarrhea were examined daily. At sacrifice segments of proximal and mid- and distal small intestine, cecum, and colon were obtained for histologic examination and mucosa of small intestine and colon for enzyme determinations. Infection with YE resulted in weight loss and diarrhea within 48-72 h. Microabscesses were present in all sections of small and large intestine by day 3 but became more severe in the ileocecal region by day 6. In infected animals at day 6 there was crypt hyperplasia throughout the small intestine and villus atrophy in the ileum. Disaccharidases were decreased in all regions by day 3 but returned to normal by day 14 in proximal and mid-, but not distal, small intestine. The pair-fed controls experienced a similar weight loss to infected animals, but showed only minor morphologic changes and no mucosal enzyme abnormalities. Our findings demonstrate that infection of weanling rabbits with YE causes diarrhea and weight loss and that, while the weight loss is largely due to reduced food intake, the morphologic and mucosal enzyme alterations are due to intestinal injury by the organism.

Acute Disease↗
PubMed1983

Familial focal segmental glomerulosclerosis.

We have observed the nephrotic syndrome in more than one sibling in three unrelated hispanic families. The histological lesion in the involved children was either focal segmental glomerulosclerosis or IgM nephropathy evolving into focal sclerosis. Tissue typing revealed the presence of HLA DRw8 in six out of eight patients. The frequency of this antigen in our patients, when compared with its frequency in a group of unrelated normal hispanic children was highly significant (p less than 0.0001). Our study suggests that there may be a genetic predilection towards developing focal segmental glomerulosclerosis.

Adolescent↗
PubMed1983

Endoscopic findings in chronic hemodialysis patients with upper gastrointestinal bleeding.

Over a 7-year period 20 episodes of upper gastrointestinal bleeding in 18 patients on chronic hemodialysis were evaluated endoscopically. The site, type of lesion and outcome were studied. We confirm that 1) mucosal inflammation is more commonly found in these patients than that reported in upper gastrointestinal bleeding in the general population and 2) mortality of gastrointestinal bleeding is not higher in this subset of patients than in the general population. The indications for endoscopy in this population are better defined than in other upper gastrointestinal bleeders.

Adult↗
PubMed1976

Prosthetic arteriovenous fistula for vascular access in hemodialysis.

Vascular access through subcutaneous prosthetic arteriovenous fistulas was studied in eighteen dogs. Dacron velour and woven Dacron grafts (6 mm diameter) were constructed across the lower abdomen between the common femoral artery and the opposite common femoral vein. In heparinized animals 197 percutaneous punctures were made with a "14 guage hemodialysis cannula at weekly intervals. Over a period of one and a half years there was no instance of infection. One of the fourteen Dacron velous and all four woven Dacron fistulas thrombosed. These data suggested the feasibility of achieving repetitive blood access through Dacron velour vascular prostheses. Nineteen Dacron velour fistula bypasses between the brachial artery and median basilic vein were performed in fifteen selected patients for a total dialysis period of ninety-six months. Failed standard subcutaneous fistulas or absence of suitable vessels in the upper extremity were indications for the primary procedure. Of three looped forearm fistulas, two thrombosed at twenty-two and two months. Complications among sixteen straight bypasses in the arm included two graft infections and one cannula tract infection. There were no instances of thrombosis in this group. The advantages of single needle dialysis in these high risk patients have been emphasized. Eleven grafts are presently functioning two to nine months postoperatively. Our preliminary results suggest that a Dacron velour fistula merits consideration as an alternative for vascular access in maintenance hemodialysis.

Adolescent↗