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Biomedical subjects

S Sullivan

Publications and source records attributed to S Sullivan.

At least 37 records · Page 2Linked to original sources
PubMed1994

Cellular accumulation of p53 protein: an independent prognostic factor in stage II breast cancer.

The p53 gene product is a tumour suppressor protein, and alterations of the protein are common in human cancer. Previous studies have focused on nuclear accumulation of p53. To investigate if cytoplasmic accumulation of p53 strengthens the relationships to different pathobiological variables and distant recurrence-free survival in breast cancer, tumours from 164 stage II patients were examined with the monoclonal antibody PAb1801. Nine per cent of the tumours were nuclear positive and 21% were cytoplasmic positive. Cellular p53 accumulation, related to the nucleus or the cytoplasm or both, showed stronger associations with pathobiological variables than nuclear accumulation alone. Accumulation of p53 was significantly correlated to tumour size over 20 mm, negative oestrogen receptor (ER) status, DNA aneuploidy, high S-phase fraction and positive erbB-2 status. Cytoplasmic p53 was significantly correlated to distance recurrence-free survival in patients negative for nuclear p53 (P < 0.0001). Cellular p53 accumulation was an independent prognostic factor, in addition to lymph node status and ER content. We conclude that consideration of cytoplasmic staining enhances the clinical importance of p53.

Breast Neoplasms↗
PubMed1994

S-phase fraction and survival benefit from adjuvant chemotherapy or radiotherapy of breast cancer.

Cancer chemotherapy interacts with cell proliferation, but data on the relationship between cancer cell replication and the effect of adjuvant chemotherapy are scarce. We have investigated the S-phase fractions of the primary tumour from premenopausal breast cancer patients who participated in a randomised trial comparing 12 cycles of polychemotherapy (CMF) with post-operative radiotherapy. DNA flow cytometry was performed on frozen tissues from 208 primary breast carcinomas, of which the S-phase fraction was estimated in 176 cases. There was a significantly higher benefit from CMF among patients with a high S-phase fraction (P = 0.0033). The relative risk of distant recurrence or death in the chemotherapy group as compared with the radiotherapy group was 0.19 for patients whose tumours had an S-phase fraction of 10% or over (95% CI 0.07-0.51) and 1.55 (0.88-2.73) for patients whose tumours showed lower S-phase levels. The interaction was still significant in multivariate analysis (P = 0.0057), including lymph node metastases, tumour size and oestrogen receptor content. We conclude that the benefit from adjuvant chemotherapy compared with radiotherapy is largely confined to patients with highly proliferative tumours.

Breast Neoplasms↗
PubMed1994

Eosinophil peroxidase differs from neutrophil myeloperoxidase in its ability to bind antineutrophil cytoplasmic antibodies reactive with myeloperoxidase.

The majority of antineutrophil cytoplasmic antibodies (ANCA) in patients with systemic vasculitis (a subset of whom exhibit eosinophilia associated with systemic vasculitis) recognize two neutrophil primary cytoplasmic granule constituents, namely myeloperoxidase (MPO) and proteinase-3. As eosinophil peroxidase (EPO) shares 68% amino acid identity with neutrophil MPO, we have investigated whether serum ANCA reactive with MPO (P-ANCA) also reacts with EPO. In this study we demonstrate that P-ANCA-reactive serum binds to ethanol-fixed neutrophils but not to eosinophils in a perinuclear pattern as assessed by indirect immunofluorescence. In addition, P-ANCA reactive serum did not bind to purified EPO or alter purified EPO function as assessed in a guaiacol assay of EPO activity. These studies suggest that the antigenic epitope recognized by P-ANCA-reactive serum is not determined by the homologous 68% peroxidase sequence shared by neutrophil MPO and EPO.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1993

Molecular cloning and characterization of p64, a chloride channel protein from kidney microsomes.

Chloride channels were previously purified from bovine kidney cortex membranes using a drug affinity column. Reconstitution of the purified proteins into artificial liposomes and planar bilayers yielded chloride channels. A 64-kDa protein, p64, identified as a component of this chloride channel was used to generate antibodies which depleted solubilized kidney membranes of all chloride channel activity. This antibody has now been used to identify a clone, H2B, from a kidney cDNA library. Antibodies, affinity-purified against the fusion protein of H2B also depleted solubilized kidney cortex from all chloride channel activity. The predicted amino acid sequence of p64 shows that it contains two and possibly four putative transmembrane domains and potential phosphorylation sites by protein kinase A, protein kinase C, and casein kinase II. There was no significant homology to other protein (or DNA) sequences in the data base. The protein is expressed in all cells tested. Expression of its mRNA in Xenopus laevis oocytes led to the insertion of a protein with the appropriate molecular mass in microsomes but not in the plasma membrane. It is likely that p64 represents the chloride channel of intracellular organelles.

Amino Acid Sequence↗
PubMed1993

Effects of pancreaticobiliary diversion and gastric fundectomy on azaserine-induced pancreatic carcinogenesis in the rat.

The effects of pancreaticobiliary diversion (PBD) and gastric fundectomy on the pancreas in azaserine-treated rats were studied over 14 months. Sham-operated azaserine-treated animals served as controls. A significant increase in pancreatic weight and total DNA and protein content was found in PBD-operated and fundectomized animals. DNA flow cytometry showed a significantly increased ratio of tetraploid to diploid cells in pancreatic tissue in both experimental groups. Mean values of all these variables were significantly higher after PBD than after fundectomy. Acidophilic atypical acinar cell foci of the pancreas were observed in all of the experimental and 75% of the control animals. The volume density of these foci was significantly higher in each experimental group than in the controls. The volume density, radioactive thymidine labeling index, and mitotic index of the foci were significantly higher after PBD than after fundectomy. Changes consistent with pancreatic adenoma were diagnosed in the PBD group only. It is concluded that not only PBD with endogenous hypercholecystokininemia, but also fundectomy with endogenous hypergastrinemia lasting about half of the life span in rats, induces pancreatic hypertrophy and enhances the development of precancerous pancreatic changes after azaserine treatment. In comparison with PBD, fundectomy caused less pronounced changes and no observable neoplasia.

Animals↗
PubMed1993

Pancreatic hypertrophy with acinar cell nodules after longterm fundectomy in the rat.

The effect of gastric fundectomy with hypergastrinaemia on the pancreas in rats was studied for 14 months. Rats with hypercholecystokininaemia that had had a pancreaticobiliary diversion (PBD) operation and sham operated rats served as controls. Fundectomised rats showed a significant increase in pancreatic weight and total DNA and protein content compared with sham operated rats. DNA flow cytometry showed a significantly higher ratio of tetraploid to diploid nuclei in pancreatic tissue after fundectomy than after sham operation. Mean values of all these variables were significantly lower after fundectomy than after PBD. Acidophilic atypical acinar cell foci of the pancreas were diagnosed in both fundectomised and PBD operated rats, but not in sham operated controls. The volume density and 3H-thymidine labelling index of the acidophilic atypical acinar cell foci were significantly lower after fundectomy than after PBD. Changes consistent with pancreatic adenoma were diagnosed in the PBD group only. In conclusion, fundectomy lasting about half of the life span in rats causes pancreatic hyperplasia and hypertrophy, as well as development of acidophilic atypical acinar cell foci. Although hypergastrinaemia is a prominent feature, it may not be the only factor responsible for this pancreaticotrophical effect of fundectomy.

Animals↗
PubMed1993

Anxiety and depression in patients with abdominal bloating.

Eighteen patients with a syndrome of abdominal bloating and discomfort were examined to explore the relationship between their symptoms and their emotional problems. They were compared with 33 patients with Crohn's disease and 38 normal, healthy volunteers. Using the Hospital Anxiety and Depression Scale, patients with bloating were found to resemble patients with Crohn's disease. Both groups showed increased anxiety and depression. After controlling for age, sex, education, occupation, personality variables and childhood experience, there was a trend towards more anxiety in the bloating group compared with normal subjects and a significant difference for depression. These characteristics appear to be related to the effects of the illness or to selection, but not to personality or childhood experience. Although psychiatric problems are common among patients with abdominal bloating and pain who stay in touch with a clinic, they are not the primary cause of the disorder.

Abdominal Pain↗
PubMed1993

S-phase fraction is a prognostic factor in stage I breast carcinoma.

PURPOSE AND METHODS: The prognostic significance of cell proliferation, estimated as cytometric S-phase fraction (SPF), was investigated in node-negative breast cancer patients with small tumors (T1, NO). The 219 stage I patients originated from two series and were diagnosed either from 1978 to 1981 or from 1981 to 1985. The tumors were analyzed for estrogen receptors (ERs) by isoelectric focusing and for cellular DNA content by static cytofluorometry or flow cytometry. RESULTS: A high SPF correlated with the absence of ERs and abnormal DNA content, and was less often found in tumors smaller than 11 mm compared with those with a diameter between 11 and 20 mm. Among the variables age, tumor size, DNA ploidy, ER status, and SPF, only SPF showed a significant association with distant recurrence and breast cancer survival in systemically untreated patients. The relative recurrence rate for patients with an SPF of 10% or greater was three times that for patients with lower SPFs. Estimated 8-year breast cancer survival rates for the same groups were 72% and 91%, respectively. CONCLUSION: This study suggests that cytometric SPF has prognostic significance in stage I breast carcinoma.

Analysis of Variance↗
PubMed1993

Gastrocolic fistula. A review of 15 cases and an update of the literature.

Gastrocolic fistulas are not common. We review the 10-year experience in our center of 15 cases that emphasize the changing pattern of this disease. The female-to-male ratio was 2:1, with a mean age of 55. Even though we are affiliated with the regional cancer center, the commonest cause of a fistula was benign gastric ulceration. Sixty percent of those with peptic ulcer and a fistula had not had previous gastric surgery. Barium enema was the most accurate investigation, showing the fistula in 10 of 10. Barium meal showed it in seven of eight, and the fistula was seen in seven of 10 patients who had endoscopy. Eleven patients were operated on, and only one was treated "medically." Three deaths occurred, two from advanced carcinoma and one from myocardial infarction.

Adult↗
PubMed1992

Trace quantitation of 4-hydroxy-2-nonenal in biological samples as its oxime-bis-tert.-butyldimethylsilyl derivative using 3-hydroxynonanal as an internal standard.

A gas chromatographic-mass spectrometric method for the determination of the lipid aldehyde 4-hydroxy-2-nonenal (4HNE) in trace quantities is described. The method utilizes the reaction of aldehydes with hydroxylamine leading to the formation of the oxime derivative. The aldehydes are recovered by octadecylsilyl solid-phase extraction and converted to the bis-tert.-butyldimethylsilyl derivatives for analysis using electron ionization. A novel 4HNE analogue, 3-hydroxynonanal, has been synthesized and is used as an internal standard. A limit of detection of approximately 1 pmol of 4 HNE in preparations of approximately 2.10(6) cells or 0.5 ml of whole blood, plasma or serum was observed. Standard addition analysis indicates that the method is accurate at these levels. Replicate analysis of the National Institutes of Standards and Technology Standard Reference Material SRM 909 indicates an average in-run precision of 8.1% and a between-run precision of 13.5% at an average concentration of 82.1 pmol/ml of reconstituted material.

Aldehydes↗
PubMed1992

Ribozymes as anti-HIV-1 therapeutic agents: principles, applications, and problems.

An emerging strategy in the treatment of viral infections is the use of antisense DNA or RNA to pair with, and block expression of viral transcripts. RNA, in addition to being an informational molecule, can also possess enzymatic activity. Thus, by combining anti-sense and enzymatic functions into a single transcript, it is now possible to design catalytic RNAs, or ribozymes, which can specifically pair with virtually any viral RNA, and cleave the phosphodiester backbone at a specified location, thereby functionally inactivating the viral RNA. In carrying out this cleavage, the ribozyme is not itself altered, and is thus capable of recycling and cleaving other molecules, making it a true enzyme. There are several different catalytic motifs which possess enzymatic activity, and each one of these can be incorporated into an enzymatic antisense with site-specific cleavage capabilities. By focusing on one type of catalytic motif, the hammerhead, we describe the principles behind the development of ribozymes as transacting, site-specific ribonucleases, several applications of ribozymes in functional destruction of target RNAs, as well as several of the problems confronting their use. We also describe a liposome delivery system which facilitates intracellular inclusion of ribozymes, and may provide a means for therapeutic delivery of ribozymes to HIV-1 infected cells.

Animals↗
PubMed1991

A manual sequencing method for identification of phosphorylated amino acids in phosphopeptides.

We describe a simple and inexpensive method for determining the location of phosphoamino acids in an isolated phosphopeptide. Phosphopeptides are immobilized on arylamine membrane discs using water-soluble carbodiimide, and the immobilized peptides are subjected to manual Edman degradation. The use of a membrane disc resulted in excellent recovery (65 to 80%) of radiolabeled phosphate following Edman degradation. Furthermore, interference from carryover and peptide washout is reduced to a minimum. The methodology should therefore be able to generate reliable results when used to analyze phosphopeptides that contain multiple phosphorylation sites. In addition to its advantage in sensitivity, the manual sequencing method is easy to perform and does not entail any sophisticated instrumentation.

Amino Acid Sequence↗
PubMed1991

Exploring the use of antisense, enzymatic RNA molecules (ribozymes) as therapeutic agents.

Antisense catalytic RNAs that specifically base-pair with and cleave target RNA sequences have potential for use as therapeutic agents against viral as well as endogenous gene expression. With the ultimate goal of developing anti-human immunodeficiency virus type 1 (HIV-1) ribozymes for therapeutic use, we have been exploring ways to improve upon the functional activity of ribozymes in living cells. This is being done by the systematic exploration of parameters that affect antisense, and hence ribozyme, function. These include target accessibility, stability of the catalyst, methods for delivery, and intracellular localization of the ribozyme. In addition, we have been examining the kinetic consequences of having extra, nontargeted sequences appended to the ribozyme flanking sequences. Perhaps the single most important consideration for ribozyme effectiveness in an intracellular environment is the accessibility of the target RNA for cleavage. By exploiting the mechanisms by which naturally occurring antisense RNAs interact with their target sequences, we hope to be able to address this problem of targeting and fully capitalize upon the potential of ribozymes as therapeutic agents.

Antiviral Agents↗
PubMed1990

Cytometric and histopathologic features of tumors detected in a randomized mammography screening program: correlation and relative prognostic influence.

Cytometric determination of S-phase fraction and ploidy type was performed on 430 tumors detected within a randomized trial of mammographic screening. The results were compared to several histopathologic features. A high S-phase fraction was estimated in tumors with a high grade of malignancy and other histopathologic findings related to rapid tumor progression, including lack of tubule formation, a high mitotic index, marked nuclear pleomorphism, multifocal cancer growth, tumor emboli in lymphatic and blood vessels, tumor necrosis, and inflammatory reaction. DNA aneuploidy was correlated with a high malignancy grade, frequent mitoses, a high degree of nuclear pleomorphism, vascular invasion, necrosis, and the presence of noninvasive ductal carcinoma. Both cytometric variables were inversely related to the degree of elastosis. Positive nodes, large tumor size, DNA aneuploidy, a high S-phase fraction, high grade of malignancy, lack of tubule formation, as well as high mitotic index and pleomorphism, presence of multifocal cancer, and vascular invasion, predicted a significantly shorter distant recurrence-free interval after a median follow-up time of 46.6 months. Elastosis and the presence of estrogen and progesterone receptors indicated favorable prognosis. In the multivariate analysis, only lymph node status, tumor size, S-phase fraction, and multifocal growth pattern had independent prognostic value.

Adult↗
PubMed1990

Conditioned flavor preferences in young children.

In this experiment 11 children participated in a series of 8 pairs of conditioning trials in order to investigate the hypothesis that children could form conditioned flavor preferences based on caloric density. Unfamiliar drink flavors were used in these trials, and the drinks were either high in caloric density (155 kcal/150 ml) or low (less than 5 kcal/150 ml). Caloric density was altered by the addition of low glucose maltodextrin. Each child always had the same caloric density/flavor pairing throughout the conditioning trials. Each trial pair included one high and one low density preload, followed by ad lib consumption. These conditioning trials substituted for the children's regularly scheduled morning snack four days per week, one trial per day. Conditioning trials were given as a series of two-part snacks, consisting of fixed volumes of initially unfamiliar drinks, followed by the opportunity to eat a variety of foods ad lib. Two measures, obtained before and after conditioning, provided evidence for the formation of conditioned flavor preferences: 1) preference assessments, and 2) two-flavor choice tests. In addition, the ad lib consumption data indicated that the children were responsive to the caloric density manipulation, by consistently eating more following the low than the high density drink. The potential contribution of such acquired flavor preferences to the reduction of neophobia is discussed.

Child Development↗
PubMed1990

Analysis of dose response of trinitrochlorobenzene contact hypersensitivity induction in mice: pretreatment with cyclophosphamide reveals an optimal sensitizing dose.

A detailed dose-response curve has been established for induction of contact hypersensitivity (CH) in mice with trinitrochlorobenzene (TNCB). It was determined that in BALB/c, CBA/J, and C57BL/6 mice, the dose required to sensitize via epicutaneous application was between 1 and 10 micrograms TNCB. When doses of hapten of 200 micrograms or greater were painted on abdominal skin, CH responses were induced which were only marginally greater than responses induced by sensitizing doses of hapten in the 10-50-micrograms range, implying that no further dose-response relationship exists beyond 50 micrograms of hapten. However, in companion experiments, in which panels of mice were pretreated with cyclophosphamide, it was determined that sensitizing doses of hapten in excess of 50 micrograms induced both CH and concomitant induction of down-regulation of CH. Thus, at 200 micrograms or higher doses of TNCB, CH responses of cyclophosphamide pretreated mice were invariably more intense than in their untreated, hapten-painted cohorts. In the animals pretreated with cyclophosphamide, it was possible to see that a dose-response relationship continued to exist between the amount of epicutaneously applied hapten over a 200 micrograms to 14 mg range and the intensity of the CH induced. We conclude that the optimal dose for immunizing mice epicutaneously with TNCB is between 10 and 50 micrograms. This is considered optimal since animals sensitized in this manner display no evidence of concomitant down-regulation of their CH responses.

Animals↗
PubMed1989

Cytometric characterization and clinical course of breast cancer diagnosed in a population-based screening program.

A randomized controlled trial evaluating mammographic screening was started in two Swedish counties in 1977. In one of these, Ostergötland county, the authors performed static cytofluorometry on 161 cancers detected at the second and third screening rounds, 50 interval cancers, and 219 cancers appearing in the nonscreened control group during the same time period. The median follow-up time was 42 months. No difference in mean S-phase was found between screening and control group cancers, but interval cancers, appearing between two screenings, had increased mean S-phase levels (P = 0.01) compared to both of the other groups. A high S-phase fraction was associated with distant recurrence in both node-negative and node-positive tumors. Aneuploid tumors were more often found in the control group (67%) and among interval cancers (72%) than among screening detected cancers (55%, P = 0.02). In Cox's multivariate analysis, including all patients, the lymph node status, tumor size, estrogen receptor content, and S-phase all contributed independent prognostic information about the clinical course. DNA ploidy predicted the outcome in simple but not in multivariate Cox's analysis. When analyzing screening-detected cancers separately, only the S-phase significantly predicted distant recurrence in multivariate analysis. In tumors with local recurrence, a high S-phase implicated an increased, although not statistically significant, risk for distant recurrence. Survival with metastatic disease was significantly influenced by the S-phase level (P = 0.002). The authors conclude that S-phase fraction provides valuable kinetic information related to the clinical outcome for all stages of the disease and serves as a prognostic factor in screened populations, which have tumors predominantly in early stages.

Adult↗