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Biomedical subjects

D Moore

Publications and source records attributed to D Moore.

At least 19 recordsLinked to original sources
PubMed1992

Phase I trial of Taxotere: five-day schedule.

BACKGROUND: Taxotere, a semisynthetic compound structurally related to taxol, has a broad spectrum of activity in murine transplantable tumors; in the B16 melanoma model, it caused a total log cell kill 2.5 times greater than that caused by taxol at equitoxic doses. PURPOSE: We conducted a phase I study of Taxotere (a) to determine its qualitative and quantitative toxic effects and a starting dose for phase II trials, (b) to investigate its clinical pharmacology, and (c) to document its antitumor activity. METHODS: Taxotere was given as a 1-hour infusion at a starting dose of 1 mg/m2 per day for 5 consecutive days. The 5-day course of therapy was repeated every 21 days. Thirty-nine cancer patients with advanced disease were entered in the study; at least three patients were entered at each dose level. Initial dose escalations were planned at 100% increments until biologic activity was observed; subsequent escalations were planned at 50% increments until grade 2 toxicity (the National Cancer Institute's Common Toxicity Criteria) occurred and then at 25% increments until the maximum tolerated dose was established. RESULTS: Thirty-nine patients were entered in the study. Successive dose levels used were 1, 4, 8, 16, 12, and 14 mg/m2 per day. The dose-limiting toxic effects were granulocytopenia and concurrent mucositis. Grade 4 granulocytopenia associated with grade 3 mucositis developed in six of 12 patients treated at a dose of 16 mg/m2 per day, two of 10 treated at 12 mg/m2 per day, and two of eight treated at 14 mg/m2 per day. Because these toxic effects occurred concurrently, all patients so affected developed neutropenic fevers and required hospitalization. Neither cardiac nor neurologic toxic effects were noted. Anti-tumor activity was observed in six patients with ovarian cancer and in one with breast carcinoma. Although pharmacokinetic parameters were consistent between day 1 and day 5 for individual patients, considerable variation existed among those treated at the same dose level. A relationship was observed between the area under the curve for plasma concentration of drug x time (AUC) on day 1 and the percentage decrease in absolute granulocyte counts. CONCLUSION: Granulocytopenia associated with oral mucositis is the dose-limiting toxicity of this schedule. We recommended a starting dose of 14 mg/m2 per day for phase II studies of this 5-day schedule. Dose modifications on days 2-5 based on the day-1 AUC may allow individualized dosing.

Adult↗
PubMed1992

Heterogeneity for allelic loss in human breast cancer.

BACKGROUND: Loss of heterozygosity (LOH) at specific chromosomal regions in the tumor cells implicates the presence of tumor suppressor genes. However, it is also possible for an LOH to be randomly acquired and irrelevant to tumor development. PURPOSE: To determine whether a particular LOH in human breast carcinomas represents a loss of tumor suppressor gene or merely a random loss, we analyzed untreated primary breast cancers for LOH. METHODS: Ninety-eight primary human breast cancers from previously untreated patients were analyzed for LOH at 12 chromosomal regions including five randomly selected regions and seven regions previously reported in other cancer types and/or breast cancers. RESULTS: The baseline incidence of LOH was five out of 124 tests (4%) using randomly selected probes on chromosomes 1p, 2p, 4p, 11q, and Xq. Incidences of LOH significantly greater than background were seen in the following chromosomal regions: 22q (10 of 26 cases, 38%); 18p (five of 24 cases, 21%); 17p (30 of 59 cases, 51%); 13q (five of 14 cases, 36%); 3p (13 of 28 cases, 46%); and 1q (18 of 70 cases, 26%). In contrast to previous reports, the incidence of LOH was not significantly different from background for 11p15. In all cases, results were the same for metastatic lymph nodes and primary tumors, suggesting that the losses occurred early in the malignant progression. In cases with LOH at more than one locus, the same DNA sample often varied in degree of signal reduction for the missing alleles. CONCLUSION: These observations indicate the presence of both intertumor and intratumor heterogeneity for LOH.

Adult↗
PubMed1992

The complete nucleotide sequence of pepper mottle virus genomic RNA: comparison of the encoded polyprotein with those of other sequenced potyviruses.

The complete nucleotide sequence of a pepper mottle virus isolate from California (PepMoV C) has been determined from cloned viral cDNAs. The PepMoV C genomic RNA is 9640 nucleotides excluding the poly(A) tail and contains a long open reading frame starting at nucleotide 168 and potentially encoding a polyprotein of 3068 amino acids. Comparison of the PepMoV C presumptive polyprotein with those of other sequenced members of the potyvirus group, including tobacco etch virus (TEV), tobacco vein mottling virus (TVMV), plum pox virus (PPV), and potato virus Y (PVY), allowed localization of putative protein cleavage sites. A similar analysis was used to determine the position of conserved viral protein-coding regions along the viral genomic RNA. These analyses confirm previous work indicating that genome organization is conserved among members of the genus Potyvirus. The localization of one PepMoV C gene product, the nuclear inclusion body protein a (NIa protein), was analyzed by expressing PepMoV cDNA deletion clones in bacteria and assaying for appearance of mature-sized coat protein, a cleavage product of the NIa protease. Comparative sequence analyses of the putative PepMoV polyprotein with those of TEV, TVMV, PPV, and PVY served to identify regions of the potyviral polyproteins which have diverged within the genus, as well as highly conserved protein features which may play an important functional role in the potyviral life cycle.

Amino Acid Sequence↗
PubMed1992

Modulation of T-cell reactivity to synthetic peptide analogues of foot-and-mouth disease virus in sheep by amino acid substitutions.

The ability of synthetic peptide analogues of foot-and-mouth disease virus VP1 capsid protein to induce T-cell proliferation in vitro following immunization of sheep with the uncoupled peptides was assessed. Elevated T-cell responses were obtained to a 21-residue peptide containing VP1 residues 141-158, and a 40-residue peptide containing residues 200-213 and 141-158 linked via a diproline-serine spacer. In contrast, no significant T-cell response was obtained with a 19-residue peptide containing residues 200-213 alone. In an attempt to engineer T-cell reactivity to this peptide, a sequence motif found in many peptides recognized by human or mouse T-cells was introduced by amino acid substitution. Substitution of a glycine or an aspartic acid for an alanine at position 207 in the 19-residue peptide resulted in the introduction of two such motifs running consecutively. Immunization of sheep with these peptides resulted in significant T-cell proliferative responses and elevated antibody responses. Analysis of further sequence variants showed that T-cell responsiveness was maintained with peptides containing single amino acid changes within these motifs, provided position 207 was glycine. The results thus suggest that increased T-cell reactivity, might be engineered via sequence manipulation of the 200-213 component of the 40-residue synthetic peptide. Such an additional T-cell epitope in the 40-residue peptide could potentially result in superior neutralizing antibody responses directed against the major epitope in residues 141-160 of VP1.

Amino Acid Sequence↗
PubMed1992

Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility.

A cDNA encoding a unique hyaluronan receptor has been molecularly cloned from a lambda GT11 3T3 cDNA expression library. Immunoblot analyses of cell lysates, using antibodies to peptides encoded in the cDNA, specifically react with a 58-kD protein. This protein is regulated by the mutant H-ras gene in cells containing a metallothionein promoter H-ras hybrid gene. Further, antibodies to peptide sequences encoded in the cDNA block the increase in locomotion resulting from induction of the mutant H-ras gene in this cell line. In a transblot assay, the bacterially expressed protein binds to biotinylated hyaluronan. Antibodies to peptides encoded in the cDNA react in immunoblot assays with the 58- and 52-kD proteins of a novel hyaluronan receptor complex previously implicated in cell locomotion. Furthermore, antibodies specific to the 58- and 52-kD proteins, which block ras-induced locomotion, also cross-react with the expressed, encoded protein. The gene product described here appears to be a new type of hyaluronan receptor that is involved in cell locomotion. It is named RHAMM, an acronym for receptor for hyaluronan-mediated motility.

3T3 Cells↗
PubMed1992

Lipoprotein [Lp(a)] and peripheral vascular disease.

Lipoprotein(a) [Lp(a)], which combines structural elements of the lipid and fibrinolytic systems, is a major independent risk factor for the development of coronary heart disease. Eighty-four consecutive patients with peripheral vascular disease (of whom 42 had concomitant ischaemic heart disease) and 43 healthy controls were enrolled in a case-control study. We found that the mean Lp(a) concentration in male patients with peripheral vascular disease (PVD) was almost threefold higher than that of controls, while in female patients the Lp(a) concentration was more than twice that of controls. This marked difference was borne out in patients with and without concomitant ischaemic heart disease (IHD). A multivariate logistic regression analysis indicated that Lp(a) is independently associated with PVD when adjusted for age and sex (odds ratio per 100 mg l-1 increase in Lp(a) = 1.35; P < 0.01). A similar association is observed for patients with concomitant IHD (odds ratio per 100 mg l-1 increase in Lp(a) = 1.65; P < 0.01).

Aged↗
PubMed1992

Prevention and treatment of osteoporosis. One of the most frequent disorders in American women: a review.

This review summarizes basic pathophysiology, epidemiology, classification and theories on the etiology of osteoporoses. Diagnostic, preventative and therapeutic aspects are discussed including the use of hormones and hormone analogues (estrogen, progestins, calcitonins, anabolic steroids), calcium, fluoride, bisphosphonates, vitamins D and their metabolites and the recently proposed "coherence therapy". Reference is made to new compounds under study including imidazoquinazolinones, methylxanthines and benzothiophenes.

Calcitonin↗
PubMed1992

Sclerosing encapsulating peritonitis: differential diagnosis to peritoneal encapsulation and abdominal cocoon--a case report.

A 59 year old man presented with symptoms of partial bowel obstruction. Small bowel x-ray studies did not allow to identify the nature of the intestinal process in the upper ileum. At laparotomy small bowel encapsulation with a whitish membrane was encountered. Despite partial removal of this membrane small bowel obstruction persisted and two weeks postoperatively the patient died of peritonitis and cardiac insufficiency. Autopsy findings revealed massive fibrous adhesions in the abdomen with granulomatous inflammation. The presence of foreign body giant cells and bifringent crystals were characteristic for talcum powder. The latter suggested a causal role of an appendectomy 45 years earlier. The diagnosis of sclerosing encapsulating peritonitis as established in our patient needs to be separated from peritoneal encapsulation, a congenital malformation, and abdominal cocoon, which contains histological elements of inflammation. This case report should draw attention to these entities in the differential diagnosis and surgical management of small bowel obstruction.

Appendectomy↗
PubMed1992

Functional ovarian cysts in relation to the use of monophasic and triphasic oral contraceptives.

This population-based case-control study assessed the effect of current use of monophasic or triphasic oral contraceptives (OCs) on the risk of functional ovarian cyst development. The cases were all 15-39-year-old enrollees in the Group Health Cooperative of Puget Sound who had either an inpatient primary diagnosis of functional ovarian cyst in 1988 or 1989 (N = 67) or an outpatient primary diagnosis of functional ovarian cyst from March 1988 through August 1989 at one of five Group Health Cooperative primary care clinics (N = 39). Controls were randomly selected enrollees matched to the cases for age, primary care clinic, and enrollment date (N = 255). Subjects with previous hysterectomy or oophorectomy were excluded from this analysis. Pharmacy and medical record review showed that 16% of cases and 19% of controls were currently using monophasic OCs, whereas 11% of cases and 9% of controls were using triphasic OCs. Compared with women not using hormonal contraception, the relative risks of a diagnosed functional ovarian cyst among women currently using OCs were 0.8 (95% confidence interval [CI] 0.4-1.8) for users of monophasic OCs and 1.3 (95% CI 0.5-3.3) for users of triphasic OCs. In contrast to previous studies of monophasic OCs containing higher steroid dosages, the results of this study suggest that current use of low-dose monophasic OCs does not substantially decrease a woman's risk of functional ovarian cyst formation. In addition, our results do not support recent speculation that current use of triphasic OCs appreciably increases the risk of functional ovarian cysts.

Adult↗
PubMed1991

Loss of heterozygosity on the short arm of chromosome 17 is associated with high proliferative capacity and DNA aneuploidy in primary human breast cancer.

Loss of heterozygosity (LOH) on the short arm of chromosome 17 (17p) was found in 27 of 52 (52%) previously untreated primary breast cancers. There was a significant correlation between this 17p allelic loss and two parameters associated with aggressive tumor behavior: high cellular proliferative fraction and DNA aneuploidy. These correlations with high cellular proliferative fraction and DNA aneuploidy were not found in tumors with LOH at nine other chromosome locations. The p53 gene, a putative tumor suppressor gene located at 17p13, was examined for aberrations to determine whether it is the target for the 17p LOH in breast cancer. Unlike other types of human cancer, there were no homozygous deletions or rearrangements of the p53 gene, and only 2 of 13 (15%) were mutated in the conserved region where mutational "hot spots" have been previously located. Therefore, we hypothesize that, in breast cancer, either loss or inactivation of gene(s) on chromosome 17p other than the p53 gene or a different mechanism of p53 gene inactivation may be responsible for the observed high labeling index and DNA aneuploidy associated with LOH at 17p.

Base Sequence↗
PubMed1991

Reduction of atherogenic risk factors by short-term weight reduction. Evidence of the efficacy of National Cholesterol Education Program guidelines for the obese.

Five hundred and ninety-nine overweight patients participated for at least 4 weeks in the weight reducing and physical activity promoting Diet and Fitness Center program at Duke University. Twenty-three percent were diabetic and 49% hypertensive. With only modest weight loss (11.8 kg in males and 8.2 kg in females) abnormal levels of blood pressure, fasting blood sugar, total cholesterol, LDL-cholesterol and triglycerides normalized. It was very rewarding to see these results achieved in a very limited period of time. Improvements in the lipid profile were consistent with the predicted outcome of obesity treatment stated by the National Cholesterol Education Program guidelines.

Adult↗
PubMed1991

Stress response protein (srp-27) determination in primary human breast carcinomas: clinical, histologic, and prognostic correlations.

Expression of an estrogen-regulated protein known as the 27,000-d heat-shock or stress-response protein (srp-27) was evaluated in human breast carcinomas and established breast cancer cell lines. Results obtained by Northern and Western blot analyses and immunohistochemical methods were concordant. Immunohistochemical assessment of srp-27 expression in 300 breast carcinomas (with median patient follow-up of 8 years) was performed. Twenty-six percent of lymph node-negative and 45% of lymph node-positive tumors were overexpressors. Univariate analysis demonstrated significant correlations between srp-27 overexpression and estrogen receptor (ER) content, pS2 protein expression, nodal metastases, advanced T stage, lymphatic/vascular invasion, and a shorter disease-free survival period (but not a shorter overall survival) for the study population as a whole. Regression tree analysis showed that srp-27 expression was an independent prognostic indicator for disease-free survival only in patients with one to three positive lymph nodes. The Cox proportional hazards model confirmed the independent prognostic significance of nodal involvement, T stage, and ER content but failed to recognize srp-27 overexpression as a significant independent parameter predictive of patient outcome in the patient population as a whole. The observed associations between srp-27 overexpression and more aggressive tumors suggest a biologic role for srp-27 in human breast carcinomas.

Blotting, Western↗
PubMed1991

Evaluation of BA1112 rhabdomyosarcoma oxygenation with microelectrodes, optical spectrophotometry, radiosensitivity, and magnetic resonance spectroscopy.

We studied tumor tissue oxygenation in the BA1112 rhabdomyosarcoma using micro-electrode pO2 measurements, optical spectrophotometry, analyses of cell survival after irradiation, and 31P magnetic resonance spectroscopy (MRS). Studies were carried out in WAG/Rij/Y rats breathing normoxic, hypoxic, and hyperoxic gas mixtures with and without iv administration of perfluorochemical. Significant changes in tissue oxygenation and metabolic status were found when pO2 values, optical measurements of hemoglobin saturation and cytochrome a, a3 reduction-oxidation, radiation cell survival determinations, and MRS measurements of phosphometabolite ratios were obtained in rats breathing different gas mixtures. Inhalation of 100% O2 caused increases in tumor pO2, hemoglobin saturation, cytochrome a, a3 oxidation, tumor radiosensitivity, and PCr/Pi, NTP/Pi, and PDE/Pi ratios. Such changes were augmented by pretreatment with iv perfluorochemicals. Inhalation of hypoxic gas mixtures resulted in reductions in the above parameters. These results indicate that tissue oxygenation can be manipulated reproducibly in the BA1112 rhabdomyosarcoma and suggest that 31P MRS can be used to monitor changes in tumor oxygenation in this model system.

Animals↗
PubMed1991

Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial.

The Eastern Cooperative Oncology Group (ECOG) conducted a study in which patients with advanced chronic lymphocytic leukemia (CLL) were randomized between a regimen consisting of chlorambucil (30 mg/m2 orally day 1) and prednisone (80 mg orally days 1 to 5) (C + P) administered every 2 weeks and a more intensive regimen of cyclosphosphamide (300 mg/m2 orally days 1 to 5), vincristine (1.4 mg/m2 intravenously [IV] day 1), and prednisone (100 mg/m2 orally days 1 to 5) (CVP) given every 3 weeks. Treatment was continued for up to 18 months to maximal response. Of the 122 eligible patients, 60 received C + P, while 62 received CVP. With a median follow-up of 7 years, there were no significant differences in survival (4.8 v 3.9 years, P = .12), complete remission (CR) rate (25% v 23%; P = .83), or duration of response (2.0 v 1.9 years; P = .78) between C + P and CVP. Toxicity was modest despite the prolonged treatment. The long median survival of 4.1 years for stage III and IV patients is superior to that usually reported. This could stem from continuing treatment to maximal response rather than an increase in intensity of therapy. These results are comparable to those reported with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy by other investigators. The data suggest that intermittent C + P administered to maximal response continues to be the standard treatment approach for advanced CLL.

Adult↗
PubMed1991

A percutaneous liver biopsy technique in ducks (Anas platyrhynchos) experimentally infected with duck hepatitis B virus.

Aylesbury ducks (Anas platyrhynchos) chronically infected with the duck hepatitis B virus provide a useful model for studying hepadna-virus infection, replication and the effects of antiviral therapy. In these studies, it is necessary to have an effective method for obtaining repeat liver specimens for histological and molecular analyses. We have therefore developed a percutaneous liver biopsy technique which has a low rate of complications, can be performed at repeated intervals, and provides sufficient quantities of liver tissue for histological and nucleic acid hybridization analysis.

Animals↗