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Biomedical subjects

M J Moore

Publications and source records attributed to M J Moore.

At least 91 records · Page 5Linked to original sources
PubMed1996

Domain analysis of human U5 RNA. Cap trimethylation, protein binding, and spliceosome assembly.

We have analyzed the sequence requirements of the human U5 RNA during small nuclear ribonucleoprotein (snRNP) and spliceosome assembly. A collection of mutant derivatives of the human U5 RNA gene was constructed in a U1 expression vector and transiently transfected in mammalian cells. Using immunoprecipitation and affinity selection assays, the cap trimethylation, the binding of Sm proteins and of the U5 snRNP-specific protein p220, as well as the assembly of the U4/U5/U6 triple snRNP and of spliceosomes were determined. By mutational analysis we were able to assign distinct functions to several structural elements of the human U5 RNA. Efficient binding of the Sm proteins requires the 3' stem-loop. Both the Sm protein-binding site and the 3' stem-loop are necessary for the formation of the trimethyl guanosine cap, consistent with Sm protein binding being a prerequisite for cap trimethylation. Specific elements of the U5 RNA 5' stem-loop contribute to efficient p220 association, in particular stem Ib. Interestingly, the highly conserved loop I appears to be a multifunctional element; in addition to its function in splice-site selection the 5' loop is involved in binding of p220 and in the assembly of the U4/U5/U6 triple snRNP. In sum, this mutational analysis has identified four functional domains of the human U5 RNA.

Animals↗
PubMed1996

Hepatocyte vacuolation and autolytic changes in the liver of pilot whales, Globicephala melas, stranded on Cape Cod, MA, USA.

Most cetacea available for internal sampling in recent times have died through mass or single stranding events. It is important to know how the time elapsed between death and sampling affect quality of tissues. This study evaluated histological quality in the liver of long-finned pilot whales that either died or were euthanased after mass stranding events. Histological detection of significant autolysis was found in animals when 2 or more hours elapsed between death and sampling. In addition, hepatocytes often had marked idiopathic cytoplasmic vacuolation that did not stain with hematoxylin and eosin. The extent of this vacuolation did not show any correlation with time between death and sampling, but did appear more often in animals of greater total length. These observations suggest that when animals die or are euthanased at a single or mass stranding, every effort should be made to obtain samples as soon as possible, although meaningful histological observations can still be made in the presence of significant autolysis. These data also suggest that a multi-disciplinary study should be conducted to determine whether increasing autolysis is associated with changes in the organic chemical residues, molecular biology, histopathology and microbiology of those tissues.

Animals↗
PubMed1996

A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer.

PURPOSE: To assess the effect of gemcitabine in patients with metastatic pancreas cancer that had progressed despite prior treatment with 5-FU. PATIENTS AND METHODS: Seventy-four patients were enrolled in this multicenter trial. Alleviation of cancer-related symptoms was the primary endpoint. Sixty-three patients completed a pain stabilization period and were treated with gemcitabine. Clinical Benefit Response was defined as a > or = 50% reduction in pain intensity, > or = 50% reduction in daily analgesic consumption, or > or = 20 point improvement in KPS that was sustained for > or = 4 consecutive weeks. RESULTS: Seventeen of 63 pts (27.0%) attained a Clinical Benefit Response (95% CI: 16.0%-38.0%). The median duration of Clinical Benefit Response was 14 weeks (range: 4-69 weeks). Median survival for patients treated with gemcitabine was 3.85 months (range: 0.3-18.0+ months). Therapy was generally well-tolerated with a low incidence of grade 3 or 4 toxicities. CONCLUSION: Systematic assessment of subjective outcomes can be used to evaluate the clinical impact of new therapies for pancreas cancer, a highly symptomatic disease. Our findings suggest that gemcitabine is a useful palliative agent in patients with 5-FU-refractory pancreas cancer.

Adenocarcinoma↗
PubMed1996

Supportive care is not the only option in prostate cancer patients resistant to hormone therapy: the argument against.

Hormone-resistant prostate cancer patients are elderly, frail and in pain. They have a median survival of 6 months. There is no convincing evidence from controlled trials that anything we do will increase life expectancy. Any attempt to do so with currently available agents may either kill them earlier or decrease the quality of the short life left to them. The alternatives for management include the simple, non-toxic, supportive measures of better analgesic use, antiandrogen withdrawal, external beam radiation and steroids, which can produce significant symptomatic improvement. There is little evidence that the benefits of more aggressive therapy exceed those achieved with supportive care.

Antineoplastic Agents, Hormonal↗
PubMed1996

Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points.

PURPOSE: To investigate the benefit of chemotherapy in patients with symptomatic hormone-resistant prostate cancer using relevant end points of palliation in a randomized controlled trial. PATIENTS AND METHODS: We randomized 161 hormone-refractory patients with pain to receive mitoxantrone plus prednisone or prednisone alone (10 mg daily). Nonresponding patients on prednisone could receive mitoxantrone subsequently. The primary end point was a palliative response defined as a 2-point decrease in pain as assessed by a 6-point pain scale completed by patients (or complete loss of pain if initially 1 +) without an increase in analgesic medication and maintained for two consecutive evaluations at least 3 weeks apart. Secondary end points were a decrease of > or = 50% in use of analgesic medication without an increase in pain, duration of response, and survival. Health-related quality of life was evaluated with a series of linear analog self-assessment scales (LASA and the Prostate Cancer-Specific Quality-of-Life Instrument [PROSQOLI]), the core questionnaire of the European Organization for Research and Treatment of Cancer (EORTC), and a disease-specific module. RESULTS: Palliative response was observed in 23 of 80 patients (29%; 95% confidence interval, 19% to 40%) who received mitoxantrone plus prednisone, and in 10 of 81 patients (12%; 95% confidence interval, 6% to 22%) who received prednisone alone (P = .01). An additional seven patients in each group reduced analgesic medication > or = 50% without an increase in pain. The duration of palliation was longer in patients who received chemotherapy (median, 43 and 18 weeks; P < .0001, log-rank). Eleven of 50 patients randomized to prednisone treatment responded after addition of mitoxantrone. There was no difference in overall survival. Treatment was well tolerated, except for five episodes of possible cardiac toxicity in 130 patients who received mitoxantrone. Most responding patients had an improvement in quality-of-life scales and a decrease in serum prostate-specific antigen (PSA) level. CONCLUSION: Chemotherapy with mitoxantrone and prednisone provides palliation for some patients with symptomatic hormone-resistant prostate cancer.

Adenocarcinoma↗
PubMed1996

Technetium-99m-tetrofosmin as a substrate for P-glycoprotein: in vitro studies in multidrug-resistant breast tumor cells.

UNLABELLED: The accumulation of 99mTc-tetrofosmin (TFos) was studied in wildtype (WT) and doxorubicin-resistant (AdrR) variants of the rat MatB and human MCF-7 breast tumor cell lines to determine whether TFos, like 99mTc-sestamibi (MIBI), is a substrate for P-glycoprotein (P-gp), a multidrug-resistance transporter. METHODS: The time course of accumulation of TFos and MIBI in WT and AdrR cells over 1 hr was studied using single-cell suspensions at 1 x 10(6) cells/ml incubated at 37 degrees C in the presence or absence of PSC833, a potent modulator of P-gp. Modulator dose-response curves were generated for PSC833, cyclosporin A, and verapamil. RESULTS: In both MatB and MCF-7 cells, TFos and MIBI accumulated extensively in WT cells and accumulation was not affected by PSC833. In contrast, ADrR cell lines accumulated very little of either tracer, but addition of PSC833 or other modulator increased this accumulation in a dose-dependent fashion. TFos and MIBI did not differ significantly in their behavior. CONCLUSION: TFos shares with MIBI the property of being a substrate for P-gp and thus TFos may be useful for functional imaging of tumor P-gp status.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Overview of Canadian trials in hormonally resistant prostate cancer.

There is no consensus about the best systemic treatment for hormonally resistant prostate cancer. Several regimens have been examined; none of them have demonstrated a consistent increase in overall survival. The treatment of hormonally resistant prostate cancer is therefore palliative. Recent studies in Canada have taken the approach that the best way to measure disease palliation is to assess the effects of therapy on disease-related symptoms and quality of life. Studies with mitoxantrone and prednisone confirm that this regimen is well tolerated and leads to symptomatic improvement in approximately 40% of patients, with a median duration of improvement of more than 10 months. This is greater than that achieved with prednisone alone. Treatments that have greater activity against hormonally resistant disease are urgently needed, although improvements probably will be gradual and modest. While it may be appealing to intensity treatments to obtain greater efficacy, there is a real risk that the toxicity will nullify any benefits. This approach of directly measuring the ability of systemic therapies to provide palliation is an appropriate way to assess newer therapies for hormonally resistant prostate cancer.

Antineoplastic Agents↗
PubMed1995

A clinical and pharmacological study of 5-fluorouracil, leucovorin and interferon alfa in advanced colorectal cancer.

Modulation of 5-fluorouracil (FUra) using leucovorin (LV) is a standard treatment approach in patients with metastatic colorectal cancer. Modulation of FUra with interferon alfa has also shown some promise. Laboratory data have demonstrated increased cytotoxicity when FUra is combined with both LV and interferon. The current study examined the effects of double modulation of FUra using LV and interferon. Patients with measurable advanced colorectal cancer received bolus FUra 375 mg/m2 plus LV 20 mg/m2 daily for 5 days, repeated every 28 days. Recombinant human interferon alfa-2a, 3 million IU/m2 subcutaneously, was given daily on the days of chemotherapy then three times weekly. There was one complete response and nine partial responses (10/41) seen for an overall response rate of 24% (95% CI 12.0-40.0%). Overall, 70% of patients experienced one or more episodes of nonhematologic toxicity of grade 3 or more. Weight loss was common, with a mean decrease of 2.9 kg over the first two months (P < 0.0001). Improvements in tumor-related symptoms were balanced by increased fatigue and a deterioration in body weight and performance status. There was no evidence of progressive changes in FUra metabolism from interferon usage.

Adult↗
PubMed1995

Caregiver time use: an outcome measure in clinical trial research on Alzheimer's disease.

OBJECTIVE: To assess whether unpaid caregiver time and paid professional time increase as cognitive impairment associated with Alzheimer's disease increases and to evaluate the utility of caregiver time as an additional outcome measure in clinical trial research of Alzheimer's disease. METHODS: This was a 24-week, double-blind, multicenter, parallel-group, placebo-controlled study conducted at 17 clinical outpatient sites by Hoechst-Roussel Pharmaceuticals Inc. A total of 449 patients older than 40 years with probable Alzheimer's disease of mild to moderate severity (criteria of the National Institute for Neurological and Communicative Disorders and Stroke--Alzheimer's Disease and Related Disorders Association) entered the study, and 284 completed both baseline and week 24 data collection. A total of 160 caregivers completed time allocation surveys at baseline and at 24 weeks. Patients with Alzheimer's disease received 150 mg/day and 225 mg/day Velnacrine maleate (parallel-group treatment) and placebo. Cognitive function was measured with use of cognitive and noncognitive subscales of the Alzheimer's Disease Assessment Scale (ADAS). Unpaid caregiver and paid professional time use were measured with use of the Caregiver Activities Time Survey (CATS). RESULTS: Unpaid caregiver time per day increased significantly with cognitive impairment at baseline as measured by the ADAS cognitive and noncognitive components. Velnacrine therapy significantly improved cognitive function relative to placebo, and this was associated with decreased unpaid caregiving time at trend levels. Specifically, caregivers of patients in the high-dose velnacrine group (225 mg/day) experienced a partial release from their time involvements, especially in the area of patient supervision, by an average of 3.3 hours per day. CONCLUSIONS: To our knowledge, this study represents the first time that the ADAS has been linked to a caregiver outcome. Results suggest that unpaid caregiver time allocation is sensitive to changes in cognitive function and therefore may be useful as an additional outcome measure in clinical trials of pharmaceutical interventions for Alzheimer's disease.

Aged↗
PubMed1995

The learning curve for laparoscopic cholecystectomy. The Southern Surgeons Club.

BACKGROUND: The use of laparoscopic surgical procedures without previous training has grown rapidly. At the same time, there have been allegations of increased complications among less experienced surgeons. METHODS: Using multivariate regression analyses, we evaluated the relationship between bile duct injury rate and experience with laparoscopic cholecystectomy for surgeons in the Southern Surgeons Club. RESULTS: Fifty-five surgeons performed 8,839 procedures. Fifteen bile duct injuries (by 13 surgeons) resulted with 90% of the injuries occurring within the first 30 cases performed by an individual surgeon. Multivariate analyses indicated that the only significant factor associated with an adverse outcome was the surgeon's experience with the procedure. A regression model predicted that a surgeon had a 1.7% chance of a bile duct injury occurring in the first case and a 0.17% chance of a bile duct injury at the 50th case. CONCLUSIONS: While surgeons appear to learn this procedure rapidly, institutions might consider requiring surgeons to move beyond the initial learning curve before awarding privileges.

Bile Ducts↗
PubMed1994

Novel HOX, POU and FKH genes expressed during bFGF-induced mesodermal differentiation in Xenopus.

Cells from the cap of the animal hemisphere of the early Xenopus embryo are determined to form ectodermal lineages. When these cells are explanted and cultured in the presence of various growth factors a change in fate to cells of mesodermal lineage can be observed. Proteins of the fibroblast growth factor (FGF) family belong to this class of fate altering compounds. The ability of FGFs to change animal cap cell fate is in part due to an alteration in the program of genes expressed in these explanted cells. Several genes that are known to be pattern regulating in other systems have been shown to be induced by FGFs in the animal cap assay. We have utilized a PCR-based sib-selection and cloning protocol to identify a large number of cDNAs of the HOX, POU and FKH families that are present in animal caps very early during bFGF-induced mesodermal differentiation. A total of 11 different HOX, 7 POU and 4 FKH cDNAs were identified in an induced animal cap cDNA library. In several cases, pairs of highly related sequence variants were identified that presumably represent expression from the duplicated alleles of the ancestrally tetraploid Xenopus genome. In this report we characterize the temporal and spatial expression of three novel Xenopus genes during early development as well as during bFGF-induced mesodermal differentiation.

Amino Acid Sequence↗
PubMed1994

Branch nucleophile selection in pre-mRNA splicing: evidence for the bulged duplex model.

Selection of the nucleophile for the first step of nuclear pre-mRNA splicing was probed by site-specific incorporation into splicing substrates of nucleotides modified at the 2' position. The differing abilities of ribose, 2'-deoxyribose, and arabinose nucleotides to base-pair within an RNA.RNA duplex and to contribute a nucleophilic 2'-OH group were exploited to analyze the paired/unpaired disposition of the branch site nucleotide. The results provide direct evidence for a bulged duplex model in which either of two adjacent purines within the consensus branch site sequence may shift into a bulged position and contribute the 2'-OH group for the first step of splicing. Furthermore, the presence of a consensus branch site that cannot present a reactive nucleophile suppresses splicing, including the use of cryptic branch sites elsewhere. We conclude that the branch site region base-pairing with U2 snRNA determines the first step nucleophile and persists at the time of the first transesterification reaction.

Arabinose↗
PubMed1994

Variability in the pharmacokinetics of cyclophosphamide, methotrexate and 5-fluorouracil in women receiving adjuvant treatment for breast cancer.

A total of 23 women with stage II breast cancer receiving adjuvant cyclophosphamide, methotrexate and 5-fluorouracil had detailed pharmacokinetic monitoring performed on the first and third courses of therapy. The area under the concentration time curve (AUC) of each of these three drugs varied by a factor of 3-4 among patients. No systematic change in pharmacokinetics between the first and third courses was seen for cyclophosphamide, methotrexate or 5-fluorouracil, and the mean AUC for each of the three drugs did not change. However, significant intrapatient variability in drug pharmacokinetics was observed for all three drugs such that the AUC, clearance and half-life in an individual on the third course could not be reliably predicted from data generated on the first course. On the basis of these results, cyclophosphamide, methotrexate, and 5-fluorouracil pharmacokinetic data from one treatment would not be useful information from which the doses of subsequent courses could be determined.

Adult↗
PubMed1994

The voiding alert system: a new application in the treatment of incontinence.

The voiding alarm system was developed to control nocturnal enuresis in children more than 5 years of age. Its acceptance by American clinicians, including pediatricians, has been modest at best. This article describes a new application of the voiding alarm system in different patient populations. The concept is that of notifying care attendants of voiding by individuals who are unaware or unable to communicate. Five case examples are presented involving individuals in a long-term care facility with neurogenic bladder, spina bifida, traumatic spinal cord injury, stress incontinence, and organic brain syndrome. Benefits were documented with respect to accurate measurements of post-void residual volumes, titering of oxybutynin chloride medication to the minimum effective dose, and the elimination of indwelling urinary catheters in the treatment of incontinence causing perineal skin breakdown. Further developments of the voiding alarm system are postulated for use in multiple clinical environments.

Adult↗