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  • 1
    Article
    Article
    2005
    ISSN: 0028-4793 
    Language: English
    In: The New England journal of medicine, 01 September 2005, Vol.353(9), pp.949-50
    Description: Most targeted therapies for cancer are designed to bind a specific protein expressed by cancer cells. Two recent studies indicate that a new approach may work: attacking a tumor at its weak spot. Most targeted therapies for cancer are designed to bind a specific protein expressed by cancer cells. Two recent studies indicate that a new approach may work: attacking a tumor at its weak spot. When it comes to antitumor drugs, both the physicians who prescribe them and the patients who receive them would agree that better chemotherapeutic agents are needed. Drugs in common use were designed to take advantage of general characteristics of tumor cells such as hormone responsiveness or high rates of cell division. Unfortunately, these properties are also found in some healthy cells. This general lack of specificity has led to the use of drug doses that straddle a knife edge between efficacy and toxicity. Two recent studies, one by Bryant et al....
    Subject(s): DNA Repair ; Genes, Brca1 ; Genes, Brca2 ; Poly(Adp-Ribose) Polymerase Inhibitors ; Neoplasms -- Genetics
    ISSN: 0028-4793
    E-ISSN: 1533-4406
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  • 2
    Language: English
    In: JAMA : the journal of the American Medical Association, 25 December 2018, Vol.320(24), pp.2600-2601
    Description: Kaufman et al comment on the study by Wong et al discussing the issues that may arise when participants in biomedical research are provided with their individual research results, such as whether and how to return personal research data (including incidental findings) to participants. As the authors pointed out, studies that are returning individual results can provide structured environments to test various approaches, which will inform the development and adaptation of return policies in the future. Kaufman et al note the research funded by the National Human Genome Research Institute (NHGRI) and other institutes of the National Institutes of Health (NIH) over the last decade to establish conceptual, normative, and legal frameworks to inform how research results are returned. There has also been considerable investment in empirical research evaluating the processes and outcomes of studies returning genomic data directly to research participants.
    Subject(s): Medicine
    ISSN: 0098-7484
    E-ISSN: 1538-3598
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  • 3
    Language: English
    In: The Journal of biological chemistry, 09 November 2018, Vol.293(45), pp.17606-17621
    Description: In humans, transport of food-derived cobalamin (vitamin B) from the digestive system into the bloodstream involves three paralogous proteins: transcobalamin (TC), haptocorrin (HC), and intrinsic factor (IF). Each of these proteins contains two domains, an α-domain and a β-domain, which together form a cleft in which cobalamin binds. Zebrafish () are thought to possess only a single cobalamin transport protein, referred to as Tcn2, which is a transcobalamin homolog. Here, we used CRISPR/Cas9 mutagenesis to create null alleles of in zebrafish. Fish homozygous for -null alleles were viable and exhibited no obvious developmentally or behaviorally abnormal phenotypes. For this reason, we hypothesized that previously unidentified cobalamin-carrier proteins encoded in the zebrafish genome may provide an additional pathway for cobalamin transport. We identified genes predicted to code for two such proteins, Tcn-beta-a (Tcnba) and Tcn-beta-b (Tcnbb), which differ from all previously characterized...
    Subject(s): Affinity ; Cobalamin ; One-Carbon Metabolism ; Phylogenetics ; Protein Evolution ; Transcobalamin ; Transport ; Vitamin B12 ; Zebrafish ; Transcobalamins ; Zebrafish
    ISSN: 0021-9258
    E-ISSN: 1083-351X
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  • 4
    Language: English
    In: The New England journal of medicine, 09 September 2010, Vol.363(11), pp.997-9
    Description: On April 13, 2010, the legislative council for Division I of the National Collegiate Athletic Association (NCAA) approved mandatory testing for sickle cell carrier status (sickle cell trait) for all student athletes participating in Division I sports. Students are to begin being tested for the first season during which they are eligible to compete, and the new rule takes effect this academic year (2010–2011). 1 NCAA data for the 2008–2009 academic year suggest that the requirement will ultimately affect more than 166,900 student athletes. The NCAA program is the most extensive and high-profile sickle cell screening program instituted in the past . . .
    Subject(s): Athletes ; Mandatory Testing ; Universities ; Sickle Cell Trait -- Diagnosis
    ISSN: 0028-4793
    E-ISSN: 1533-4406
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  • 5
    In: The Journal of Nutrition, 2017, Vol. 147(7), pp.1290-1295
    Description: Background: Moderate hyperhomocysteinemia is an attractive target for intervention because it is present in 5–7% of the population and can be reversed by diet. This approach presupposes that hyperhomocysteinemia is directly involved in the disease process. Epidemiologic studies have indicated that moderately elevated homocysteine may contribute to thoracic aortic aneurysm (TAA) dilatation and dissection in humans. In vitro, elevated homocysteine disrupts the structure and function of extracellular matrix components, suggesting that moderate hyperhomocysteinemia may contribute to the development and/or progression of TAA. Objective: We investigated moderately elevated homocysteine in the development and progression of TAA in a mouse model of Marfan syndrome (MFS) and in isogenic wild-type mice. The MFS mouse is a well-described model of a systemic connective tissue disorder characterized by thoracic aortic dilatation, dissection, and rupture. We used this model as a sensitized indicator system to examine the impact of homocysteine on the progression of TAA. Methods: Murine fibrillin 1 gene ( Fbn1 ) C1039G/+ MFS and C57BL/6J wild-type mice were fed a cobalamin-restricted diet to induce moderate hyperhomocysteinemia from weaning until the age of 32 wk. Homocysteine and methylmalonic acid were measured and aortic root diameter assessed with the use of echocardiography in mice aged 3, 7, 15, and 32 wk. Results: Cobalamin-restricted mice exhibited significantly higher homocysteine ( P 〈 0.0001) and methylmalonic acid ( P 〈 0.0001) in the blood. For both strains, no significant difference in thoracic aortic diameter was observed in mice on the cobalamin-restricted diet compared with those on the control diet. Conclusions: Fbn1 C1039G/+ mice are a well-characterized model of progressive aortic root dilation. Hyperhomocysteinemia in the physiologic range did not induce abnormal aortic growth in wild-type mice and did not accelerate or otherwise influence aortic root growth and pathologic progression in mice with an underlying predisposition for aortic dilatation.
    Subject(s): Thoracic Aortic Aneurysm ; Homocysteine ; Methylmalonic Acid ; Marfan Syndrome ; Vitamin B - 12 ; Cobalamin ; Mouse Model
    ISSN: 0022-3166
    E-ISSN: 1541-6100
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  • 6
    Language: English
    In: PLoS ONE, 2012, Vol.7(3), p.e32941
    Description: Despite improved outcomes in the past 30 years, less than half of all women diagnosed with epithelial ovarian cancer live five years beyond their diagnosis. Although typically treated as a single disease, epithelial ovarian cancer includes several distinct histological subtypes, such as papillary serous and endometrioid carcinomas. To address whether the morphological differences seen in these carcinomas represent distinct characteristics at the molecular level we analyzed DNA methylation patterns in 11 papillary serous tumors, 9 endometrioid ovarian tumors, 4 normal fallopian tube samples and 6 normal endometrial tissues, plus 8 normal fallopian tube and 4 serous samples from TCGA. For comparison within the endometrioid subtype we added 6 primary uterine endometrioid tumors and 5 endometrioid metastases from uterus to ovary. Data was obtained from 27,578 CpG dinucleotides occurring in or near promoter regions of 14,495 genes. We identified 36 locations with significant increases or decreases in methylation in comparisons of serous tumors and normal fallopian tube samples. Moreover, unsupervised clustering techniques applied to all samples showed three major profiles comprising mostly normal samples, serous tumors, and endometrioid tumors including ovarian, uterine and metastatic origins. The clustering analysis identified 60 differentially methylated sites between the serous group and the normal group. An unrelated set of 25 serous tumors validated the reproducibility of the methylation patterns. In contrast, 〉1,000 genes were differentially methylated between endometrioid tumors and normal samples. This finding is consistent with a generalized regulatory disruption caused by a methylator phenotype. Through DNA methylation analyses we have identified genes with known roles in ovarian carcinoma etiology, whereas pathway analyses provided biological insight to the role of novel genes. Our finding of differences between serous and endometrioid ovarian tumors indicates that intervention strategies could be developed to specifically address subtypes of epithelial ovarian cancer.
    Subject(s): Research Article ; Biology ; Medicine ; Molecular Biology ; Computational Biology ; Oncology
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: The American journal of clinical nutrition, August 2011, Vol.94(2), pp.495-500
    Description: In elderly individuals with low serum vitamin B-12, those who have high serum folate have been reported to have greater abnormalities in the following biomarkers for vitamin B-12 deficiency: low hemoglobin and elevated total homocysteine (tHcy) and methylmalonic acid (MMA). This suggests that folate exacerbates vitamin B-12-related metabolic abnormalities. We determined whether high serum folate in individuals with low serum vitamin B-12 increases the deleterious effects of low vitamin B-12 on biomarkers of vitamin B-12 cellular function. In this cross-sectional study, 2507 university students provided data on medical history and exposure to folic acid and vitamin B-12 supplements. Blood was collected to measure serum and red blood cell folate (RCF), hemoglobin, plasma tHcy, and MMA, holotranscobalamin, and ferritin in serum. In subjects with low vitamin B-12 concentrations (30 nmol/L; group 1) did not show greater abnormalities in vitamin B-12 cellular function in any area than did those with lower folate concentrations (≤30 nmol/L; group 2). Group 1 had significantly higher holotranscobalamin and RCF, significantly lower tHcy, and nonsignificantly lower (P = 0.057) MMA concentrations than did group 2. The groups did not differ significantly in hemoglobin or ferritin. Compared with group 2, group 1 had significantly higher mean intakes of folic acid and vitamin B-12 from supplements and fortified food. In this young adult population, high folate concentrations did not exacerbate the biochemical abnormalities related to vitamin B-12 deficiency. These results provide reassurance that folic acid in fortified foods and supplements does not interfere with vitamin B-12 metabolism at the cellular level in a healthy population.
    Subject(s): Folic Acid -- Blood ; Vitamin B 12 Deficiency -- Metabolism
    ISSN: 0002-9165
    E-ISSN: 1938-3207
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  • 8
    In: The American Journal of Clinical Nutrition, 2018, Vol. 107(3), pp.345-354
    Description: Background: Formate is an important metabolite that serves as a donor of one-carbon groups to the intracellular tetrahydrofolate pool. However, little is known of its circulating concentrations or of their determinants. Objective: This study aimed to define formate concentrations and their determinants in a healthy young population. Design: Serum formate was measured in 1701 participants from the Trinity Student Study. The participants were men and women, aged 18 to 28 y, enrolled at Trinity College, Dublin. Formate concentrations were compared with other one-carbon metabolites, vitamin status, potential formate precursors, genetic polymorphisms, and lifestyle factors. Results: Serum formate concentrations ranged from 8.7 to 96.5 ([micro]M, with a mean of 25.9 [micro]M. Formate concentrations were significantly higher in women than in men; oral contraceptive use did not further affect them. There was no effect of smoking or of alcohol ingestion, but the TT genotype of the methylenetetrahydrofolate reductase (MTHFR)677C[right arrow]T (rs1801133) polymorphism was associated with a significantly decreased formate concentration. Formate was positively associated with potential metabolic precursors (serine, methionine, tryptophan, choline) but not with glycine. Formate concentrations were positively related to serum folate and negatively related to serum vitamin B-12. Conclusions: Formate concentrations were sensitive to the concentrations of metabolic precursors. In view of the increased susceptibility of women with the TT genotype of MTHFR to give birth to infants with neural tube defects as well as the effectiveness of formate supplementation in decreasing the incidence of folate-resistant neural tube defects in susceptible mice, it will be important to understand how this genotype decreases the serum formate concentration. This trial was registered at www.clinicaltrials.gov as NCT03305900. Keywords: folate, vitamin B-12, methylenetetrahydrofolate reductase, one-carbon metabolism. Trinity Student Study doi: https://doi.org/10.1093/ajcn/nqx065.
    Subject(s): Folate ; Vitamin B - 12 ; Methylenetetrahydrofolate Reductase ; One - Carbon Metabolism ; Trinity Student Study
    ISSN: 0002-9165
    E-ISSN: 1938-3207
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  • 9
    In: The American Journal of Clinical Nutrition, 2018, Vol. 108(6), pp.1334-1341
    Description: Genetic polymorphisms can explain some of the population- and individual-based variations in nutritional status biomarkers. We sought to screen the entire human genome for common genetic polymorphisms that influence folate-status biomarkers in healthy individuals. We carried out candidate gene analyses and genome-wide association scans in 2232 young, healthy Irish subjects to evaluate which common genetic polymorphisms influence red blood cell folate, serum folate, and plasma total homocysteine. The 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T (rs1801133) variant was the major genetic modifier of all 3 folate-related biomarkers in this Irish population and reached genome-wide significance for red blood cell folate (P = 1.37 × 10-17), serum folate (P = 2.82 × 10-11), and plasma total homocysteine (P = 1.26 × 10-19) concentrations. A second polymorphism in the MTHFR gene (rs3753584, P = 1.09 × 10-11) was the only additional MTHFR variant to exhibit any significant independent effect on red blood cell folate. Other MTHFR variants, including the 1298A→C variant (rs1801131), appeared to reach genome-wide significance, but these variants shared linkage disequilibrium with MTHFR 677C→T and were not significant when analyzed in MTHFR 677CC homozygotes. No additional non-MTHFR modifiers of red blood cell or plasma folate were detected. Two additional genome-wide significant modifiers of plasma homocysteine were found in the region of the dipeptidase 1 (DPEP1) gene on chromosome...
    Subject(s): Biomarkers ; Folate ; Homocysteine ; Vitamin B - 12 ; Methylenetetrahydrofolate Reductase ; 1 - Carbon Metabolism ; Trinity Student Study
    ISSN: 0002-9165
    E-ISSN: 1938-3207
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  • 10
    Language: English
    In: Blood, 01 September 2011, Vol.118(9), pp.2430-42
    Description: Biallelic mutations in the human breast cancer susceptibility gene, BRCA2, are associated with Fanconi anemia, implying that some persons who inherit 2 deleterious variants of BRCA2 are able to survive even though it is well established that BRCA2 is indispensable for viability in mice. One such variant, IVS7 + 2T 〉 G, results in premature protein truncation because of skipping of exon 7. Surprisingly, the persons who are either IVS7 + 2T 〉 G homozygous or compound heterozygous are born alive but die of malignancy associated with Fanconi anemia. Using a mouse embryonic stem cell-based functional assay, we found that the IVS7 + 2T 〉 G allele produces an alternatively spliced transcript lacking exons 4-7, encoding an in-frame BRCA2 protein with an internal deletion of 105 amino acids (BRCA2(Δ105)). We demonstrate that BRCA2(Δ105) is proficient in homologous recombination-mediated DNA repair as measured by different functional assays. Evaluation of this transcript in normal and leukemia cells...
    Subject(s): Genes, Brca2 ; Genetic Complementation Test ; Fanconi Anemia -- Genetics
    ISSN: 0006-4971
    E-ISSN: 1528-0020
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