Search PubMed⌕ Search

Biomedical subjects

M Levine

Publications and source records attributed to M Levine.

At least 217 records · Page 12Linked to original sources
PubMed1995

The somatic-visceral subdivision of the embryonic mesoderm is initiated by dorsal gradient thresholds in Drosophila.

The maternal dorsal regulatory gradient initiates the differentiation of the mesoderm, neuroectoderm and dorsal ectoderm in the early Drosophila embryo. Two primary dorsal target genes, snail (sna) and decapentaplegic (dpp), define the limits of the presumptive mesoderm and dorsal ectoderm, respectively. Normally, the sna expression pattern encompasses 18-20 cells in ventral and ventrolateral regions. Here we show that narrowing the sna pattern results in fewer invaginated cells. As a result, the mesoderm fails to extend into lateral regions so that fewer cells come into contact with dpp-expressing regions of the dorsal ectoderm. This leads to a substantial reduction in visceral and cardiac tissues, consistent with recent studies suggesting that dpp induces lateral mesoderm. These results also suggest that the dorsal regulatory gradient defines the limits of inductive interactions between germ layers after gastrulation. We discuss the parallels between the subdivision of the mesoderm and dorsal ectoderm.

Animals↗
PubMed1995

Effect of cimetidine on hepatic cytochrome P450: evidence for formation of a metabolite-intermediate complex.

Cimetidine is an inhibitor of hepatic cytochrome P450 (CYP) in vivo and in vitro in both rats and humans. However, the concentrations of cimetidine required to inhibit drug metabolism in hepatic microsomes in vitro are 100-1000-fold higher than those associated with a similar degree of inhibition in vivo. Recently, we provided evidence indicating that cimetidine selectively inhibits CYP2C11 in the rat and that it acts by forming a metabolite-intermediate (MI) complex. To investigate this further, optical-difference spectroscopy was performed with the use of microsomes from uninduced and phenobarbital-induced male rats treated with cimetidine in vivo or, after a preincubation step, in vitro. In microsomes from uninduced rats treated with cimetidine in vivo or in vitro, a spectral peak at 428-430 nm was observed that was not dissociated by the addition of potassium ferricyanide. The spectral peak obtained with cimetidine in vitro was dependent on the presence of NADPH and on the concentration of cimetidine in the reaction mixture, indicating the presence of an MI complex. The magnitude of this complex was reduced in microsomes from phenobarbital induced rats that were administered cimetidine either in vivo or in vitro. The formation of the complex was also inhibited by preincubation of the microsomes with anti-rat CYP2C11 immunoglobulin. These results are consistent with the hypothesis that cimetidine inhibits CYP in vivo in the rat by forming an MI complex, largely with CYP2C11, and that this complex can be generated in vitro by incubating microsomes with cimetidine in the presence of NADPH.

Animals↗
PubMed1995

Clinical trial design in metastatic breast cancer: a commentary.

Trial designs traditionally used in the development of new anti-cancer agents are usually categorized as phase I, phase II, phase III and phase IV. Such trials are often performed in patients with metastatic cancer. Phase I trials are conducted in small numbers of patients to determine a drug's maximally tolerated dose (MTD) and toxicity profile. In phase II studies, the anti-tumor activity of the new agent is tested in different tumor types. If a drug is found to be promising in phase II studies, it is then compared to standard therapy through a randomized trial design in phase III studies. In phase IV studies, the efficacy and safety profile of the drug are evaluated in a standard clinical setting. In the field of oncology, studies have been conducted in which agents already approved by the regulatory agency are combined with other anti-cancer drugs and evaluated for anti-tumor efficacy. These have also been termed phase II studies.

Antineoplastic Agents↗
PubMed1994

Uncoupling gastrulation and mesoderm differentiation in the Drosophila embryo.

In Drosophila, ventral furrow formation and mesoderm differentiation are initiated by two regulatory genes, twist (twi) and snail (sna). Both genes are evolutionarily conserved and have also been implicated in vertebrate gastrulation. Evidence is presented that sna is sufficient to initiate the invagination of the ventral-most embryonic cells in the absence of twi+ gene activity. The invaginated cells fail to express mesoderm regulatory genes, suggesting that ventral furrow formation can be uncoupled from mesoderm differentiation. Despite the previous demonstration that sna functions as a sequence-specific transcriptional repressor, low levels of sna that fail to repress neuroectoderm determinants in the presumptive mesoderm are nonetheless able to promote invagination. Cells that possess an ambiguous developmental identity can initiate the invagination process, providing further evidence that ventral furrow formation need not be linked to mesoderm differentiation.

Animals↗
PubMed1994

Ipsilateral breast tumor recurrence postlumpectomy is predictive of subsequent mortality: results from a randomized trial. Investigators of the Ontario Clinical Oncology Group.

PURPOSE: To determine whether ipsilateral breast tumor recurrence (IBTR) postlumpectomy was independently predictive of distant relapse and mortality in women with node negative breast cancer. METHODS AND MATERIALS: A randomized trial was conducted in Ontario between 1984 and 1989, in which 837 women with node negative disease who had undergone lumpectomy and axillary dissection were randomized to either postoperative radiation (40 Gy in 16 fractions to the whole breast, followed by a boost of 12.5 Gy in five fractions to the primary site), or no further treatment. A Cox proportional hazards regression analysis was performed for the endpoints mortality and distant relapse using the fixed covariates, treatment, age, tumor size, estrogen receptor status, progesterone receptor status, and nuclear grade; and the time dependent variable IBTR. RESULTS: The analysis was based on 799 patients for which all fixed covariate data was available. Median follow-up was 66 months. The cumulative rate of IBTR at 5 years was significantly greater for the no treatment group compared to the radiation group; 30% vs. 8% respectively (p < 0.0001). No difference was detected in overall survival between the treatment groups (p = 0.45). Significant independent predictors for mortality were nuclear grade, high vs. medium or low (relative risk (RR) = 2.28, p = 0.0001); and tumor size > or = 2 cm. vs. < 2 cm. (RR = 1.64, p = 0.01). In addition, IBTR predicted increased mortality (RR = 2.18, p < 0.0006). Similar results were observed for distant relapse. An IBTR within 1 year of surgery was associated with a higher risk of distant relapse and mortality. CONCLUSION: Local breast recurrence following lumpectomy is associated with an increased risk of distant relapse and death.

Breast Neoplasms↗
PubMed1994

Short-range repression permits multiple enhancers to function autonomously within a complex promoter.

Transcriptional repressors play a key role in establishing localized patterns of gene expression in the early Drosophila embryo. Several different modes of repression have been implicated in previous studies, including competition and direct interference with the transcription complex. Here, we present evidence for "quenching," whereby activators and repressors co-occupy neighboring sites in a target promoter, but the repressor blocks the ability of the activator to contact the transcription complex. This study centers on a zinc finger repressor, snail (sna), which represses the expression of neuroectodermal regulatory genes in the presumptive mesoderm. We show that sna can mediate efficient repression when bound 50-100 bp from upstream activator sites. Repression does not depend on proximity of sna-binding sites to the transcription initiation site. sna is not a dedicated repressor but, instead, appears to block disparate activators. We discuss the importance of quenching as a means of permitting separate enhancers to function autonomously within a complex promoter.

Animals↗
PubMed1994

Regulation of the dorsal morphogen by the Toll and torso signaling pathways: a receptor tyrosine kinase selectively masks transcriptional repression.

The dorsal (dl) nuclear gradient initiates the differentiation of the mesoderm, neuroectoderm, and dorsal ectoderm by activating and repressing gene expression in the early Drosophila embryo. This gradient is organized by a Toll signaling pathway that shares many common features with the mammalian IL-1 cytokine pathway. Here we present evidence that a second signaling pathway, controlled by the torso (tor) receptor tyrosine kinase, also modulates dl activity. Evidence is presented that the tor pathway selectively masks the ability of dl to repress gene expression but has only a slight effect on activation. Intracellular kinases that are thought to function downstream of tor, such as D-raf and the rolled MAP kinase, mediate this selective block in repression. Normally, the Toll and tor pathways are both active only at the embryonic poles, and consequently, target genes (zen and dpp) that are repressed in middle body regions are expressed at these sites. Constitutive activation of the tor pathway causes severe embryonic defects, including disruptions in gastrulation and mesoderm differentiation, as a result of misregulation of dl target genes. These results suggest that RTK signaling pathways can control gene expression by antirepression, and that multiple pathways can fine-tune the activities of a single transcription factor.

Animals↗
PubMed1994

Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer.

Patients receiving chemotherapy for metastatic breast cancer are at high risk of thromboembolic disease. Long-term oral anticoagulant therapy is needed but increases the risk of haemorrhagic complications. We have assessed the safety and efficacy of warfarin in very low doses as prophylaxis. Women receiving chemotherapy for metastatic breast cancer were randomly assigned either very-low-dose warfarin (152 patients) or placebo (159). The warfarin dose was 1 mg daily for 6 weeks and was then adjusted to maintain the prothrombin time at an international normalised ratio (INR) of 1.3 to 1.9. Study treatment continued until 1 week after the end of chemotherapy. The average daily dose from initiation of titration was 2.6 (SD 1.2) mg for the warfarin group and the mean INR was 1.52. The mean time at risk of thrombosis was 199 (126) days for warfarin-treated patients and 188 (137) days for placebo recipients (p = 0.45). There were 7 thromboembolic events (6 deep-vein thrombosis, 1 pulmonary embolism) in the placebo group and 1 (pulmonary embolism) in the warfarin group, a relative risk reduction of about 85% (p = 0.031). Major bleeding occurred in 2 placebo recipients and 1 warfarin-treated patient. There was no detectable difference in survival between the treatment groups. Very-low-dose warfarin is a safe and effective method for prevention of thromboembolism in patients with metastatic breast cancer who are receiving chemotherapy.

Antineoplastic Agents↗
PubMed1994

Related target enhancers for dorsal and NF-kappa B signaling pathways.

Drosophila dorsoventral (DV) patterning and mammalian hematopoiesis are regulated by related signaling pathways (Toll, interleukin-1) and transcription factors (dorsal, nuclear factor-kappa B). These factors interact with related enhancers, such as the rhomboid NEE and kappa light chain enhancer, that contain similar arrangements of activator and repressor binding sites. It is shown that the kappa enhancer can generate lateral stripes of gene expression in transgenic Drosophila embryos in a pattern similar to that directed by the rhomboid NEE. Drosophila DV determinants direct these stripes through the corresponding mammalian cis regulatory elements in the kappa enhancer, including the kappa B site and kappa E boxes. These results suggest that enhancers can couple conserved signaling pathways to divergent gene functions.

Animals↗
PubMed1994

Summary of the round table discussion on strategies for cancer prevention: diet, food, additives, supplements, and drugs.

A Round Table Discussion was held at the Fourth International Conference on Anticarcinogenesis and Radiation Protection. Scientists from government and academia were brought together to discuss the evidence for the preventive effect of foods, specific nutrients and drugs against cancer, and the most appropriate methods of initiating nutritional cancer prevention activities to improve the health of the public. The panel reviewed the epidemiological evidence of the role of diet and specific micronutrients for the prevention of cancer, the doses of specific micronutrients required for preventive effects and their safety, the evidence for aspirin as a chemopreventive agent, the issue of foods versus specific micronutrients in the prevention of cancer, food safety, and approaches to prevention such as food fortification or dietary supplements. The remarks of the panel members are summarized.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1994

Ascorbic acid and insulin secretion in pancreatic islets.

The effect of ascorbic acid on glucose-induced insulin release from single pancreatic islets was measured using a new, ultra-sensitive enzyme-linked immunosorbent insulin assay. Within 20 s ascorbic acid inhibited insulin secretion; inhibition was dose dependent and completely reversible. There was a 50% inhibition of the secretory response with 200 microM ascorbic acid and 90% inhibition with 400 microM ascorbic acid. The decrease in insulin secretion was recorded as a reduction of the amplitudes of the fast insulin transients, which give rise to the oscillatory nature of insulin secretion. The inhibition of glucose-induced insulin release by ascorbic acid was associated with hyperpolarization of the pancreatic beta-cell. Suppression of glucose-induced membrane depolarization was evident after 20 s, was dose dependent, and was completely reversible. The data here may provide the first explanation of why plasma ascorbate concentrations are tightly controlled.

Animals↗
PubMed1994

Immunocytochemical assay for androgen receptors in prostate cancer: a prospective study of 63 cases with long-term follow-up.

BACKGROUND: Numerous problems are associated with biochemical androgen receptor (AR) assay performance and interpretation in prostatic cancer. The purpose of this study was to determine if a novel immunocytochemical AR assay performed on intact tissue sections would prove useful in prognosticating endocrine response and survival. METHODS: A prospective study was done on 63 prostatic carcinomas maintained in liquid nitrogen for over a decade. The study used the peroxidase-antiperoxidase system and a polyclonal anti-AR antibody. RESULTS: Marked tissue and cellular heterogeneity of nuclear AR was apparent. A cut-off of 10% AR-positive cells maximized assay prognostic efficiency. Frequency of positivity was 48% and correlated significantly with endocrine response (p = 0.03), time to progression (p = 0.0016), and survival (p = 0.02), but not with grade, stage, or ethnicity. CONCLUSIONS: This AR assay could be prognostically useful in the clinical management of prostate cancer and is suitable for use in the community hospital laboratory.

Aged↗
PubMed1994

The Vancouver sedative recovery scale for children: validation and reliability of scoring based on videotaped instruction.

We originally developed and tested the Vancouver Sedative Recovery Scale (VSRS) to measure recovery from sedation following paediatric open heart surgery and reported excellent clinical inter-observer reliability. We now report a new study using videotape instruction of novice raters and videotaped case examples to determine whether the instruction produces adequate skill with the VSRS. Inter-rater reliability was assessed using videotapes of 16 children across a range of ages (six months to six years), and all levels of sedation (unresponsive to fully awake). Variably randomized subsets of six of the 16 test cases were randomly assigned to be rated by each of 16 video-instructed ICU staff volunteers, according to a balanced incomplete block design, such that every pair of raters assessed two children in common. The validity of the ratings from the video-instructed raters was assessed by comparison with "gold standard" scores from two experts who rated all 16 children clinically as the test cases were videotaped. The experts were in agreement themselves (intraclass correlation of 0.976). The correlation between the novice scores (average of six ratings per video) and the live clinical scores (average of two expert ratings) was 0.977 over the 16 test cases. On average, the mean expert rating was slightly higher, but the difference was negligible. (The differences between the mean ratings of the experts and novices for 13 of the 16 videos are very close to zero, while the other three differences, from technically less good videos, are two standard deviations away from zero). The VSRS, video instruction method and incomplete block design may be of use to other clinicians and investigators.

Anesthesia Recovery Period↗
PubMed1994

Molecular genetics of Drosophila immunity.

Insects resist bacterial infections through the induction of both cellular and humoral immune responses. The cellular response involves the mobilization of hemocytes, whereas the humoral response utilizes antibacterial peptides that are synthesized in the fat bodies and secreted into the circulating hemolymph. Recent studies suggest that the induction of the humoral response involves Rel-containing regulatory proteins, Dif and dorsal, which are related to mammalian NF-kappa B. These regulatory proteins function as sequence-specific transcription factors that induce the expression of immunity genes, including cecropin and diptericin. In mammals, NF-kappa B has been implicated in both lymphocyte differentiation and the acute-phase response. The finding that insect and mammalian immunity involve related transcription factors offers the promise that genetic studies in Drosophila might lead to the identification of novel components mediating mammalian immunity.

Animals↗
PubMed1994

Role of Mg-ATP in norepinephrine biosynthesis in intact chromaffin granules.

Dopamine beta-monooxygenase converts dopamine to norepinephrine in intact chromaffin granules using intragranular ascorbic acid as a cosubstrate. Mg-ATP with external ascorbic acid is required for maximal norepinephrine biosynthesis. Mechanisms to explain these requirements were investigated specifically using intact granules. The effect of Mg-ATP was independent of membrane potential (delta psi) because norepinephrine biosynthesis was unchanged whether delta psi was positive or collapsed. Furthermore, the effect of Mg-ATP was independent of absolute intragranular and extragranular pH as well as the pH difference across the chromaffin granule membrane (delta pH). Nevertheless, norepinephrine biosynthesis was inhibited by N-ethylmaleimide, 4-chloro-7-nitrobenzofurazane, and N,N-dicyclohexylcarbodiimide, specific inhibitors of the secretory vesicle ATPase that may directly affect proton pumping. Biosynthesis occurred normally with other ATPase inhibitors that do not inhibit the ATPase in secretory vesicles. The data indicate that the effect of Mg-ATP with ascorbic acid is mediated by the granule membrane ATPase but independent of maintaining delta psi and delta pH. An explanation of these findings is that Mg-ATP, via the granule ATPase, may change the rate at which protons or dopamine are made available to dopamine beta-monooxygenase.

Adenosine Triphosphatases↗
PubMed1994

Saliva versus blood sampling for therapeutic drug monitoring in children: patient and parental preferences and an economic analysis.

The objective of this study was to conduct an assessment of patient and parental preferences and an economic analysis of hospital costs in sampling blood and saliva for therapeutic drug monitoring (TDM). Costs and preferences were evaluated in the course of a study, which compared anticonvulsant concentrations in blood routinely drawn for therapeutic monitoring and in saliva in infants and children attending a pediatric neurology clinic. Parents of 84.8% of children, and half of the children, indicated a preference for saliva sampling over venous blood drawing. Children who had been on medications that required therapeutic monitoring for < 2 years were more likely to prefer saliva sampling as compared to those who were under treatment for > or = 2 years. Computation, based upon a basic assumption that a registered nurse obtained blood and a medical technician or a registered nurse assistant sampled saliva, indicated that for every 1,000 cases of changing from blood to saliva sampling, total cost savings would amount to $1,930 for cooperative children and $1,660 for infants and uncooperative children. This saving is equivalent to approximately 100 h of a registered nurse's initial salary. The important contributions to the differential cost were derived from the requirements for more highly trained individuals to take the blood sample and from the doubling time required for the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗