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Biomedical subjects

M J Moore

Publications and source records attributed to M J Moore.

At least 55 records · Page 3Linked to original sources
PubMed2000

Determination of lovastatin in human plasma using reverse-phase high-performance liquid chromatography with UV detection.

The authors have developed a simple, rapid HPLC assay with ultraviolet (UV) detection for the analytical determination of lovastatin and its acid in human plasma for a concentration range of 100-5,000 ng/mL. Sample clean-up involved the use of C10 solid-phase extraction cartridges. Our limit of quantitation was 100 ng/mL. Standard curves were linear from 100 to 5,000 ng/mL, with a correlation coefficient (r2) of 0.999 +/- 0.0002. Stored samples were stable at -70 degrees C for up to 4 months prior to reversed-phase HPLC analysis. This assay was able to measure steady-state lovastatin concentration (Css) at the initial dose level in a phase I trial of lovastatin as a modulator of apoptosis.

Anticholesteremic Agents↗
PubMed2000

Utilizing the SIECUS Guidelines to assess sexuality education in one state: content scope and importance.

Comprehensive sexuality education programs, advocated as the most effective means of promoting sexual health for youth, include a broad range of sexuality topics taught throughout the school years as a part of comprehensive health education. Programs must include not only the negative consequences of sexual behavior, but content that cultivates a positive view of sexuality as well. This study assessed the scope of sexuality education topics taught, using the SIECUS Guidelines for Comprehensive Sexuality Education: Kindergarten--12th Grade, and rated importance of these topics, by public high school teachers within a state that mandates sexuality education. The majority of the 261 teachers responding to the survey reported they taught most of the topics recommended by the Guidelines. They also rated most Guidelines' topics as "important" to teach. However, numerous teachers omitted topics crucial to comprehensive sexuality education. The relationship between teacher ratings of importance and what was taught, and implications for future research are discussed.

Adolescent↗
PubMed2000

Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study.

PURPOSE: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were compared in patients with locally advanced or metastatic transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with stage IV TCC and no prior systemic chemotherapy were randomized to GC (gemcitabine 1,000 mg/m2 days 1, 8 and 15; cisplatin 70 mg/m2 day 2) or standard MVAC every 28 days for a maximum of six cycles. RESULTS: Four hundred five patients were randomized (GC, n = 203; MVAC, n = 202). The groups were well-balanced with respect to prognostic factors. Overall survival was similar on both arms (hazards ratio [HR], 1.04; 95% confidence interval [CI], 0.82 to 1.32; P = .75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI 0.72 to 1.10), and response rate (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments. The toxic death rate was 1% on the GC arm and 3% on the MVAC arm. More GC than MVAC patients had grade 3/4 anemia (27% v 18%, respectively), and thrombocytopenia (57% v 21%, respectively). On both arms, the RBC transfusion rate was 13 of 100 cycles and grade 3/4 hemorrhage or hematuria was 2%; the platelet transfusion rate was four patients per 100 cycles and two patients per 100 cycles on GC and MVAC, respectively. More MVAC patients, compared with GC patients, had grade 3/4 neutropenia (82% v 71%, respectively), neutropenic fever (14% v 2%, respectively), neutropenic sepsis (12% v 1%, respectively), and grade 3/4 mucositis (22% v 1%, respectively) and alopecia (55% v 11%, respectively). Quality of life was maintained during treatment on both arms; however, more patients on GC fared better regarding weight, performance status, and fatigue. CONCLUSION: GC provides a similar survival advantage to MVAC with a better safety profile and tolerability. This better-risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC.

Anti-Infective Agents↗
PubMed2000

Prostate specific antigen response to mitoxantrone and prednisone in patients with refractory prostate cancer: prognostic factors and generalizability of a multicenter trial to clinical practice.

PURPOSE: We determine prostate specific antigen (PSA) response and durability, and prognostic factors associated with response and survival in patients with symptomatic hormone refractory prostate cancer treated with mitoxantrone and prednisone at a single institution. We then compare the results with those of a randomized phase III clinical trial. MATERIALS AND METHODS: A retrospective review of all 133 patients treated with mitoxantrone and prednisone at Princess Margaret Hospital since 1994 was performed. PSA response and duration, and overall survival were determined as well as the influence of baseline factors on these outcome parameters. Results were compared to those for patients randomized to receive mitoxantrone and prednisone in the Canadian clinical trial which demonstrated palliative benefit of this regimen. RESULTS: Patients treated after trial closure had shorter survival (p = 0.003) but represented a poorer prognosis cohort. PSA response of the trial and post-trial cases was 34% and 28%, respectively (p = 0.36), and median duration of response was 118 and 175 days or greater, respectively. Factors predictive of PSA response in the non-trial cohort were longer time from diagnosis of prostate cancer (p = 0. 027) and higher baseline PSA (p = 0.013). Factors predictive of increased survival in both groups were younger age (p <0.04), better baseline Eastern Cooperative Oncology Group performance status (p <0. 02), and higher hemoglobin (p </=0.05) and PSA response (p <0.0001). Gleason score was not predictive of response or survival. CONCLUSIONS: Although patients treated outside of the trial had poorer prognostic features, rates of PSA response to mitoxantrone and prednisone were comparable. Factors predictive of survival were similar in the 2 cohorts. Results of the randomized trial are generalizable to clinical practice.

Adenocarcinoma↗
PubMed1999

Prostate cancer: 9. Treatment of advanced disease.

A 70-year-old man is referred to a urologist for recommendations on the management of metastatic prostate cancer. His cancer was diagnosed 5 years ago, and he underwent radical prostatectomy at that time. The tumour was confined to the prostate gland (Gleason score 7), and during surgery the lymph nodes were assessed as being clear of cancer. Before the surgery, the patient's prostate-specific antigen (PSA) level had been 8 ng/mL. After the prostatectomy, PSA was at first undetectable, but recently the PSA level rose to 2 ng/mL and then, at the most recent test, to 16 ng/mL. A bone scan was ordered to investigate back discomfort, which has been persistent but easily controlled with acetaminophen. Unfortunately, the bone scan shows several sites of metastatic disease. The man's medical history includes type 2 diabetes, which has developed during the past 3 years and which is controlled by diet, as well as asymptomatic hypertension, which is managed by means of a thiazide diuretic. The patient asks what treatments are available, what impact they are likely to have on his disease and what risks are associated with the therapies.

Aged↗
PubMed1999

The effects of short-term variation in abortion funding on pregnancy outcomes.

The appropriations for North Carolina's abortion fund have proven inadequate during five of the years between 1980 and 1994. This on-again, off-again funding pattern provides a natural experiment for estimating the short-run effect of changes in the cost of abortions on the number of abortions to indigent women. Using an unusually detailed dataset, we estimate the effects of funding termination on the monthly abortion and birth rates. Overall, approximately one-third of pregnancies that would have resulted in an abortion, had state funds been available, are instead carried to term.

Abortion, Legal↗
PubMed1999

The C-terminal region of hPrp8 interacts with the conserved GU dinucleotide at the 5' splice site.

A U5 snRNP protein, hPrp8, forms a UV-induced crosslink with the 5' splice site (5'SS) RNA within splicing complex B assembled in trans- as well as in cis-splicing reactions. Both yeast and human Prp8 interact with the 5'SS, branch site, polypyrimidine tract, and 3'SS during splicing. To begin to define functional domains in Prp8 we have mapped the site of the 5'SS crosslink within the hPrp8 protein. Immunoprecipitation analysis limited the site of crosslink to the C-terminal 5060-kDa segment of hPrp8. In addition, size comparison of the crosslink-containing peptides generated with different proteolytic reagents with the pattern of fragments predicted from the hPrp8 sequence allowed for mapping of the crosslink to a stretch of five amino acids in the C-terminal portion of hPrp8 (positions 1894-1898). The site of the 5'SS:hPrp8 crosslink falls within a segment spanning the previously defined polypyrimidine tract recognition domain in yPrp8, suggesting that an overlapping region of Prp8 may be involved both in the 5'SS and polypyrimidine tract recognition events. In the context of other known interactions of Prp8, these results suggest that this protein may participate in formation of the catalytic center of the spliceosome.

Amino Acid Sequence↗
PubMed1999

The human Prp8 protein is a component of both U2- and U12-dependent spliceosomes.

This study reports the cloning, sequencing, and development of antisera against the human U5 snRNP 220-kDa protein or hPrp8p. Prp8p is the most highly conserved large nuclear protein known to date, but it is not related to any other protein. Southern, Northern, and expressed sequence tag analyses indicate that hPrp8p is encoded by a single gene. Prp8p is a core component of U5 snRNP and the U4/U6.U5 tri-snRNP, and antibodies raised against it immunoprecipitate both the major, U2-dependent and minor, U12-dependent spliceosomes. These spliceosomes, which excise different classes of introns, contain distinct sets of snRNAs overlapping only with U5 snRNA. Other than the core Sm proteins, hPrp8p is the first splicing factor shown to be common to both spliceosomes.

Amino Acid Sequence↗
PubMed1999

A functional, discontinuous HIV-1 gp120 C3/C4 domain-derived, branched, synthetic peptide that binds to CD4 and inhibits MIP-1alpha chemokine binding.

This paper describes a branched synthetic peptide [3.7] that incorporates sequence discontinuous residues of HIV-1 gp120 constant regions. The approach was to bring together residues of gp120 known to interact with human cell membranes such that the peptide could fold to mimic the native molecule. The peptide incorporates elements of both the conserved CD4 and CCR5 binding sites. The 3.7 peptide, which cannot be produced by conventional genetic engineering methods, is recognized by antiserum raised to native gp120. The peptide also binds to CD4 and competitively inhibits binding of QS4120 an antibody directed against the CDR2 region of CD4. When preincubated with the CD4+ve MM6 macrophage cell line, which expresses mRNA for the CCR3 and CCR5 chemokine receptors, both 3.7 and gp120 inhibit binding of the chemokine MIP-1alpha. The peptide also inhibits infection of primary macrophages by M-tropic HIV-1. Thus, 3.7 is a prototype candidate peptide for a vaccine against HIV-1 and represents a novel approach to the rational design of peptides that can mimic complex sequence discontinuous ligand binding sites of clinically relevant proteins.

Amino Acid Sequence↗
PubMed1999

99Tcm-sestamibi imaging of inhibition of the multidrug resistance transporter in a mouse xenograft model of human breast cancer.

Sestamibi is known to be a substrate for P-glycoprotein, the membrane transporter which confers multidrug resistance by pumping certain chemotherapeutic agents out of tumour cells. In this study, the utility of sestamibi imaging for detecting inhibition of P-glycoprotein (Pgp) function by two potent, second-generation chemosensitizers, PSC833 and GG918, was assessed in a mouse xenograft model of multidrug-resistant human breast cancer, MCF7-AdrR. Preliminary in vitro studies confirmed that MCF7-AdrR cells accumulate only low levels of sestamibi and that both sensitizers inhibit transporter function to a similar extent, resulting in 20-fold higher accumulation of sestamibi. MCF7-AdrR cells were grown as a xenograft in SCID mice and sestamibi kinetics in the tumour were analysed by dynamic imaging (30 frames at a rate of one frame per minute). Administration of either chemosensitizer produced a dose-dependent slowing of the efflux rate of sestamibi compared to untreated tumours. The same effect was evident in two additional parameters: percent activity remaining at 30 min determined by imaging and sestamibi levels measured in excised tissues. These results show that sestamibi imaging can detect inhibition of Pgp function and suggest that this approach could be used clinically to document effective delivery of chemosensitizers.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To evaluate the efficacy and toxicity of gemcitabine (2', 2'-difluorodeoxycytidine) plus cisplatin in previously untreated patients with advanced transitional-cell carcinoma. PATIENTS AND METHODS: Thirty-one patients with measurable advanced transitional-cell carcinoma who had received no prior chemotherapy for metastatic disease were scheduled to receive gemcitabine 1,000 mg/m(2) intravenously over 30 minutes on days 1, 8, and 15 and cisplatin 70 mg/m(2) over 1 hour on day 2 of a 28-day cycle. Prior adjuvant or neoadjuvant therapy for locally advanced disease was allowed if this was completed more than 1 year before study entry. RESULTS: There were six complete responses and 10 partial responses in 28 assessable patients, for an overall response rate of 16 of 28 (57%). The response rate on an intent-to-treat basis was 16 of 31 patients (52%). The median survival is 13.2 months, with 18 patients still alive at this time. Toxicity was primarily hematologic, with 12 of 31 patients (39%) having > or = grade 3 granulocytopenia and 17 of 31 (55%) having > or = grade 3 thrombocytopenia. Two patients had febrile neutropenia. All patients required a dose modification of gemcitabine at some point in their therapy; the primary reason was thrombocytopenia and/or neutropenia. CONCLUSION: Gemcitabine plus cisplatin is an active regimen for the treatment of urothelial cancer.

Adult↗
PubMed1999

Succinimide and saccharin-based enzyme-activated inhibitors of serine proteases.

The inhibition of human leukocyte elastase (HLE), and other serine proteases, by succinimide and saccharin-based compounds is reviewed. The succinimide compounds are unique in that the inactivating species is generated within the enzyme active site via a molecular rearrangement. The related saccharin derivatives also inactivate serine proteases by an enzyme-activated mechanism. Those factors effecting the potency, selectivity and stability of these important classes of inhibitor are discussed.

Binding Sites↗
PubMed1998

Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. Canadian Urologic Oncology Group.

BACKGROUND: Most trials of immunomodulators in metastatic renal-cell carcinoma have been uncontrolled and subject to selection bias. The objective of this blinded, placebo-controlled study was to compare overall response rates, time to disease progression, and survival of patients with metastatic renal-cell carcinoma treated with recombinant human interferon gamma-1b or placebo. METHODS: Patients with biopsy-proved metastatic renal-cell carcinoma were randomly assigned to receive interferon gamma-1b (60 microg per square meter of body-surface area subcutaneously once weekly) or placebo. The primary tumor had been treated by nephrectomy or angioinfarction at least three weeks previously. Patients were evaluated for radiologic evidence of progression, and all responses were independently reviewed by a committee that was unaware of the treatment. RESULTS: A total of 197 patients with metastatic renal-cell carcinoma were enrolled at 17 centers in Canada. One hundred eighty-one patients could be evaluated; of these, 91 were assigned to receive interferon gamma-1b and 90 were given placebo. The groups were well balanced in terms of prognostic factors. Two thirds of all patients had Karnofsky scores of 90 or 100, and more than half had two or more metastatic sites. Grade I and II toxicity, mostly chills, fever, asthenia, or headaches, was reported in 91 percent and 61 percent, respectively, of the patients in the interferon group, as compared with 76 percent and 63 percent in the placebo group. Life-threatening drug-related events were rare, occurring in 1 percent of patients in the interferon group. No significant differences between groups were observed in overall response rates, time to disease progression, or survival. The overall response rate was 4.4 percent (3.3 percent complete response and 1.1 percent partial response) in the interferon group and 6.6 percent (3.3 percent complete response and 3.3 percent partial response) in the placebo group (P=0.54), with a rate of durable complete response of 1 percent in both groups. The median time to disease progression was 1.9 months in both groups (P=0.49), and there was no significant difference in median survival (12.2 months with interferon vs. 15.7 months with placebo, P=0.52). CONCLUSIONS: No difference in outcome was observed in patients with metastatic renal-cell carcinoma who were treated with interferon gamma-1b as compared with placebo. These results emphasize the necessity of testing the efficacy of immunomodulators in randomized studies.

Adjuvants, Immunologic↗
PubMed1998

Role of glutathione S-transferases in the resistance of human colon cancer cell lines to doxorubicin.

The anthracycline doxorubicin has little activity against colorectal cancers. It is hypothesized that this is attributable to a multifactorial resistance mechanism in which the glutathione S-transferases (GST) may play a role. We studied the relationship between GST expression and doxorubicin resistance in four human colon adenocarcinoma cell lines (HT-29, LoVo, SW620, and Caco-2), with the goal of modulating GST activity to overcome resistance. Caco-2 cells were the most resistant to doxorubicin, showing an IC50 value approximately 80- to 90-fold higher than HT-29 or LoVo and 600-fold higher than SW620. Total GST catalytic activity was significantly higher in Caco-2 cells compared with the other lines. All four cell lines expressed GST-pi at the catalytic activity, protein, and mRNA levels; however, no significant differences were observed among the cell lines. GST-mu expression was not detectable at the protein and mRNA levels, and the four cell lines displayed very low catalytic activity toward a GST-mu-selective substrate. Caco-2 cells showed a unique, highly expressed GST-alpha-immunoreactive band that was not detected in the other lines; however, the glutathione peroxidase activity of Caco-2 cells was the lowest among the four cell lines. Neither ethacrynic acid nor glutathione analogues that function as GST class-selective inhibitors were able to potentiate the cytotoxic effects of doxorubicin in these colon cancer cell lines, as demonstrated in both microplate colorimetric and clonogenic assays. The multidrug resistance-associated protein and P-glycoprotein were either not detectable or expressed at such low levels that they are not likely to contribute to the differences in doxorubicin sensitivity observed among these cell lines.

Antibiotics, Antineoplastic↗