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At least 1,171 records · Page 65Linked to original sources
PubMed2003

Preclinical and clinical evaluation of four gemcitabine plus carboplatin schedules as front-line treatment for stage IV non-small-cell lung cancer.

BACKGROUND: To explore the activity and tolerability of gemcitabine (GEM) and carboplatin (CBDCA) in non-small-cell lung cancer (NSCLC) we tested four administration sequences on H460 NSCLC cells, and at the same time performed a randomized phase II trial using analogous schedules. PATIENTS AND METHODS: GEM was given first in two in vitro sequences, and CBDCA first in the other two; interaction was quantified calculating a combination index. Eighty-eight chemotherapy-naïve, stage IV NSCLC patients were randomly assigned to receive either: GEM (1000 mg/m(2)) on days 1 and 8 and CBDCA (AUC 5 mg.min/ml) on day 1, 4 h before GEM (arm A); same as arm A except CBDCA given 4 h after GEM (arm B); GEM on days 1 and 8 and CBDCA on day 2 (arm C); GEM on days 2 and 9 and CBDCA on day 1 (arm D). Courses were repeated every 21 days. RESULTS: In the preclinical study, CBDCA given before GEM produced a synergistic cytotoxic effect. Two complete and 29 partial responses occurred in 86 of 88 treated patients (intention-to-treat analysis 35%; 95% confidence interval 25.5% to 46.8%). One- and 2-year survivals were 44% and 11%, respectively. Grade 3/4 thrombocytopenia occurred in 11%; grade 3/4 neutropenia in 17%; and non-hematological toxicity was insignificant. Median survival was 11 months (range 7-18+), but better in patients receiving CBDCA first (arms A and D) (13 versus 9 months) than in patients receiving GEM first (arms B and C). The response was greater (50% versus 31%) in arm A than in the other arms. CONCLUSIONS: The CBDCA/GEM combination is safe and active against stage IV NSCLC. Our preclinical and clinical findings suggest that administration of CBDCA before GEM gives the better outcome.

Adult↗
PubMed1990

Dental health of Spanish children: an investigation in primary care.

The oral hygiene of patients between seven and 14 years old from a health centre in Toledo was studied through case-finding from March to December 1987. A total of 304 interviews were held; bad dental care (frequency of teeth brushing with fluoride toothpaste less than once per day and/or daily consumption of chocolate and sweets) was found in 83%, and caries were diagnosed through inspection in 92% of the patients. Seventy three per cent reported washing their teeth only occasionally or never; 40% consumed sweets daily; 53% had never visited the dentist; and 50% had not received preventive care for dental disease. These results contrast with those from the United Kingdom and other developed countries, indicating a precarious state of dental health in Spain, a fact which should be taken into account by the Spanish health organization when comparing the health levels between different countries.

Adolescent↗
PubMed2003

Coupled mutagenesis screens and genetic mapping in zebrafish.

Forward genetic analysis is one of the principal advantages of the zebrafish model system. However, managing zebrafish mutant lines derived from mutagenesis screens and mapping the corresponding mutations and integrating them into the larger collection of mutations remain arduous tasks. To simplify and focus these endeavors, we developed an approach that facilitates the rapid mapping of new zebrafish mutations as they are generated through mutagenesis screens. We selected a minimal panel of 149 simple sequence length polymorphism markers for a first-pass genome scan in crosses involving C32 and SJD inbred lines. We also conducted a small chemical mutagenesis screen that identified several new mutations affecting zebrafish embryonic melanocyte development. Using our first-pass marker panel in bulked-segregant analysis, we were able to identify the genetic map positions of these mutations as they were isolated in our screen. Rapid mapping of the mutations facilitated stock management, helped direct allelism tests, and should accelerate identification of the affected genes. These results demonstrate the efficacy of coupling mutagenesis screens with genetic mapping.

Animals↗
PubMed2000

Restoration of a normal reproductive lifespan after grafting of cryopreserved mouse ovaries.

Fresh and frozen ovaries from 10 day old C57BL/6J-Gpi-1(a) mice were grafted orthotopically into ovariectomized B6CBF1 (homozygous Gpi-1(b)) recipients. The recipients were mated with B6CBF1 males. The birth and size of each litter was recorded. The electrophoretic variant of glucose phosphate isomerase was determined for each neonate. Twelve of 13 recipients of fresh ovary and 10 of 12 recipients of frozen ovary were fertile. Of these, 10 (fresh) and eight (frozen) had litters derived from the ovarian grafts only, or from the graft and native ovary. The breeding characteristics of recipients of fresh and frozen grafts were similar. The reproductive lifespan of the recipients of fresh (6.2 litters) and frozen (8.4 litters) grafts was similar to that of unoperated C57BL/6-Gpi-1(a) control females mated with B6CBF1 males (6.3 litters). Litter size was similar in recipients of grafted ovaries (fresh, 5.4 pups/litter; frozen, 6.3 pups/litter) and C57BL/6-Gpi-1(a) females (6.3 pups/litter). The results suggest that cryopreservation per se does not affect the long-term viability of ovarian tissue and provides an option for storing female germ cells. This is the first unequivocal demonstration that a normal reproductive lifespan can be restored by orthotopic grafting of frozen ovary.

Animals↗
PubMed2003

Cocoa powder increases postprandial insulinemia in lean young adults.

We hypothesized that chocolate products elicit higher insulin responses than matched products with alternate flavoring. To test this, we used a within-subject, repeated-measures comparison of six pairs of foods, one flavored with chocolate (cocoa powder) and the other not. Healthy subjects (n = 10, 4 men, 6 women) tested each pair of foods. Postprandial glucose and insulin levels were determined at intervals over 2 h using standardized glycemic index (GI) methodology. The product categories were chocolate bars, cakes, breakfast cereals, ice creams, flavored milks and puddings. Although the GI did not differ within each pair, the insulin index (II) of the chocolate product was always higher, by a mean of 28%, than the alternate flavored product (P < 0.001). The greatest difference occurred within the flavored milk category in which the chocolate version elicited 45% greater insulinemia than the strawberry flavored milk (P = 0.021). Macronutrient composition (fat, protein, sugar, fiber or energy density) accounted for nearly all of the variation in GI among the foods, but did not explain differences in insulinemia. The presence of cocoa powder in foods leads to greater postprandial insulin secretion than alternate flavorings. Specific insulinogenic amino acids or greater cephalic phase insulin release may explain the findings.

Adult↗
PubMed2007

Trans-10 octadecenoic acid does not reduce milk fat synthesis in dairy cows.

Diet-induced milk fat depression (MFD) involves the interrelation between rumen fermentation and mammary synthesis of milk fat, and the reduction in milk fat coincides with a marked increase in the trans-10 18:1 content of milk fat. Our objective was to directly examine the effect of trans-10 18:1 on milk fat synthesis in dairy cows. Three mid-lactation cows were used in a 3 x 3 Latin square design; treatments were abomasal infusion of: 1) ethanol (control); 2) trans-10 18:1 (t10); and 3) trans-10, cis-12 conjugated linoleic acid (CLA; positive control). The t10 and CLA supplements (>90% purity) were infused for 4 d and provided 42.6 and 4.3 g/d of trans-10 18:1 and trans-10, cis-12 CLA, respectively. Milk yield, feed intake, milk protein, and milk lactose were unaffected by treatment. Compared with the control, the t10 treatment had no effect on milk fat synthesis, whereas the CLA treatment resulted in a 27 and 24% reduction in milk fat content and yield, respectively. The transfer efficiency of the abomasally infused trans-10 18:1 and trans-10, cis-12 CLA into milk fat was 15 +/- 1 and 23 +/- 5% (means +/- SD), respectively. Overall, trans-10 18:1 had no effect on milk fat synthesis when abomasally infused at approximately 43 g/d, although it was taken up by the mammary glands and incorporated into milk fat. Therefore, our results offer no support for the concept that changes in rumen production of trans-10 18:1 within the physiological range play a role in the regulation of fatty acid synthesis during diet-induced MFD.

Animals↗
PubMed1999

Bleomycin genotoxicity alteration by glutathione and cytochrome P-450 cellular content in respiratory proficient and deficient strains of Saccharomyces cerevisiae.

The genotoxic effects of the antiblastic drug bleomycin were studied in the D7 strain of Saccharomyces cerevisiae and on its derivative mitochondrial mutant rho degree at different cellular concentrations of two drug metabolizing systems, glutathione (GSH) and cytochrome P-450. Bleomycin mutagenic activity was evaluated as frequencies of mitotic gene conversion, reversion and total aberrations under different physiological conditions. In the D7 strain, petite mutant induction was also detected. This is important due to the role of the mitochondrial genome in cancer induction, ageing and degenerative diseases. Both strains showed higher convertant than revertant induction. At high cytochrome P-450 levels, bleomycin-induced gene conversion was enhanced in both strains although mitochondrial functionality showed a detoxicant role while cellular GSH content decreased the induction of convertants only in the respiratory proficient strain. Cell metabolic conditions, such as cell cycle, aerobic/hypoxic conditions of the cell and content of drug metabolizing enzymes, appeared to interact with the genotoxic effectiveness of bleomycin. Moreover, the usefulness of S.cerevisiae as a model organism for drug assessment for mutagenicity was emphasized.

Bleomycin↗
PubMed1987

Electrophysiological effects and mechanism of action of oral quinidine in patients with sinus bradycardia and first degree A-V nodal block.

The effects of quinidine on sinus nodal and A-V nodal function were assessed in 20 patients (age: 60 +/- 7 years) with sinus bradycardia and a prolonged A-H interval. Electrophysiological studies were performed twice in each patient. In the first study, the measurements of sinus and A-V node function were evaluated both in the basal state and after autonomic blockade (propranolol 0.2 mg kg-1 and atropine 0.04 mg kg-1). Oral quinidine was administered for 3-4 days (1200 mg day-1) and the study was then repeated using the same methods. Comparison of data obtained in the two studies in the basal state allowed us to evaluate the overall effect of quinidine. Comparing the results obtained following autonomic blockade, the direct action of the drug could be assessed. In the basal state quinidine did not significantly change the function of either node. In contrast, after autonomic blockade, significant changes were noted after quinidine. In 3 patients with sinus rate less than 50 beats min-1 and an abnormal intrinsic heart rate, quinidine induced marked depression of sinus automaticity. These data suggest that: (1) in patients with sinus bradycardia and prolongation of the A-H interval, oral quinidine has a direct depressant effect on sinus and A-V nodal function, but this effect is counteracted by autonomically mediated actions; (2) in patients with moderate or severe bradycardia and an abnormal intrinsic heart rate, the drug can induce marked depression of sinus automaticity.

Aged↗
PubMed1995

Follicular development in cryopreserved marmoset ovarian tissue after transplantation.

Pieces of marmoset ovary were frozen by slow cooling in 1.5 M dimethylsulphoxide. The follicles in fresh and frozen tissue were counted and examined for morphological appearance in stained serial sections. The proportion of normal follicles was similar in fresh tissue and frozen tissue examined immediately after thawing. Follicles at all stages of folliculogenesis up to the small antral stage survived freezing and thawing. Fresh and frozen tissue was transplanted underneath the kidney capsules of ovariectomized immunodeficient mice. The establishment of grafts was similar, and oestrogenic activity (cornification of the vaginal epithelium) was observed in the recipients 20 and 16 days after transplantation of fresh and frozen grafts respectively. The total number of follicles and the proportion of normal follicles were similar in fresh and frozen grafts. Grafts of frozen tissue recovered between 7 and 15 days after transfer contained follicles up to the small antral stage of development. Grafts recovered between 21 and 32 days contained follicles at all stages of folliculogenesis, including large antral follicles (1-2 mm diameter). Our results suggest that freezing and thawing do not substantially damage marmoset ovarian tissue, and the cryopreserved tissue retains its ability to support the development of large antral follicles.

Animals↗
PubMed1994

Cryopreservation of immature mouse oocytes.

Mouse oocytes enclosed in cumulus cells were isolated from antral follicles at the germinal vesicle (GV) stage. They were stored in straws at -196 degrees C by a conventional mouse embryo freezing method using dimethylsulphoxide (1.5 M) as the cryoprotectant. Overall survival assessed after removal of the cumulus cells was 93% (299/320). A significantly greater proportion of fresh oocytes remained arrested at the GV stage during culture (11 versus 1%), but the rate of maturation to metaphase II was not significantly different between frozen and fresh oocytes (83 versus 74%). The rate of fertilization in vitro was similar for frozen and fresh oocytes matured in vitro (70 versus 81%) but significantly less than with mature ovulated oocytes (96%). Fertilization of frozen and fresh oocytes arrested after germinal vesicle breakdown was similar (77 versus 95%). No evidence of parthenogenetic activation was found in the different groups after overnight incubation of metaphase II oocytes. Implantation was similar for embryos derived from fresh and frozen GV-stage oocytes matured in vitro and mature ovulated oocytes, but the loss of embryos after implantation was significantly higher in the in-vitro matured groups (frozen, 40% and fresh, 46% versus 24%). The overall survival of oocytes frozen at the GV stage was 27%. This compares favourably with the estimated overall survival of mature oocytes cryopreserved by a similar procedure. We conclude that the increased post-implantation loss is due to suboptimal conditions for maturation in vitro rather than freezing injury.

Animals↗
PubMed1994

Mitogen-activated protein (MAP) kinase phosphorylation of MAP kinase kinase: determination of phosphorylation sites by mass spectrometry and site-directed mutagenesis.

Mitogen-activated protein kinase kinase (MKK) phosphorylates and activates mitogen-activated protein kinase (MAPK) in response to stimulation of various eukaryotic signaling pathways. Conversely, a recent report showed that MAPK phosphorylates MKK in vitro [Matsuda, S., Gotoh, Y., and Nishida, E. (1993) J. Biol. Chem. 268, 3277-3281]. To gain insight into the function of this feedback phosphorylation, we identified the major sites targeted for phosphorylation by MAPK and examined whether such a modification plays a role in regulating the basal and stimulated MKK activities. Two phosphopeptides generated by tryptic digestion of MAPK-phosphorylated MKK were identified by electrospray ionization mass spectrometry. Cyanogen bromide cleavage also yielded two phosphopeptides whose sequence overlapped with the tryptic phosphopeptides. Both sets of phosphopeptides contained candidate MAPK target sites at Thr292 and Thr386 that fit the consensus sequence ProXThr*Pro. Replacement of either Thr292 or Thr386 with alanine by site-directed mutagenesis reduced the phosphate incorporation respectively to 32 or 75% that of wild type MKK. Replacement of both threonine residues with alanine reduced phosphate incorporation to 2.5% that of wild type enzyme. Comparison of MAPK-phosphorylated vs. unphosphorylated MKK showed no significant differences in basal or Raf-1-stimulated MKK activity. We conclude that the phosphorylation of MKK at Thr292 and Thr386 does not interfere with catalysis in vitro.

Amino Acid Sequence↗
PubMed2003

Effect of cigarette smoking on urinary 3,N4-ethenocytosine levels measured by gas chromatography/mass spectrometry.

Etheno DNA adducts are DNA damages derived from exogenous carcinogens as well as endogenous lipid peroxidation and oxidative stress. Elevated levels of etheno DNA adducts were found in cancer-prone tissues and blood samples, suggesting that these promutagenic lesions correlate with risk of cancers. We previously reported the detection of 3,N4-ethenocytosine (epsilon Cyt) in the urine samples of two smokers using the isotope dilution gas chromatography/negative ion chemical ionization/mass spectrometry (GC/NICI/MS) assay (Chen et al., 2001, Chem. Res. Toxicol. 14, 1612-1619). Since smokers are found to have elevated levels of lipid peroxidation and oxidative stress, we examined the association between urinary epsilon Cyt levels with cigarette smoking. Among the 23 samples analyzed, the average concentration of urinary epsilon Cyt in smokers was significantly higher than that of nonsmokers, 2.65 +/- 4.0 versus 0.61 +/- 0.90 ng/kg/g creatinine (p= 0.03). Albeit the number of subjects is limited, the results indicate that the measurement of epsilon Cyt in human urine may provide a useful noninvasive biomarker for oxidative DNA damage and cancer chemoprevention studies.

Adult↗
PubMed2004

Establishment of a functional genomics platform for Leifsonia xyli subsp. xyli.

Leifsonia xyli subsp. xyli, the causal agent of ratoon stunting disease in sugarcane, is a xylem-limited, nutritionally fastidious, slow growing, gram-positive coryneform bacterium. Because of the difficulties in growing this bacterium in pure culture, little is known about the molecular mechanisms of pathogenesis. Currently, the genome sequence of L. xyli subsp. xyli is being completed by the Agronomical and Environmental Genomes group from the Organization for Nucleotide Sequencing and Analysis in Brazil. To complement this work, we produced 712 Lxx::Tn4431 transposon mutants and sequenced flanking regions from 383 of these, using a rapid polymerase chain reaction-based approach. Tn4431 insertions appeared to be widespread throughout the L. xyli subsp. xyli genome; however, there were regions that had significantly higher concentrations of insertions. The Tn4431 mutant library was screened for individuals unable to colonize sugarcane, and one noncolonizing mutant was found. The mutant contained a transposon insertion disrupting two open reading frames (ORF), one of which had homology to an integral membrane protein from Mycobacterium leprae. Sequencing of the surrounding regions revealed two operons, pro and cyd, both of which are believed to play roles in disease. Complementation studies were carried out using the noncolonizing Lxx::Tn4431 mutant. The noncolonizing mutant was transformed with a cosmid containing 40 kbp of wild-type sequence, which included the two ORF disrupted in the mutant, and several transformants were subsequently able to colonize sugarcane. However, analysis of each of these transformants, before and after colonization, suggests that they have all undergone various recombinant events, obscuring the roles of these ORF in L. xyli subsp. xyli pathogenesis.

Actinomycetales↗