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  • 1
    Abstract: Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015. Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420081 cases (median cases, 2526 per disease) and 1093105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
    Type of Publication: Journal article published
    PubMed ID: 28241208
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  • 2
    Abstract: Tumor immune escape is a critical problem which frequently accounts for the failure of therapeutic tumor vaccines. Among the most potent suppressors of tumor immunity are myeloid derived suppressor cells (MDSCs). MDSCs can be targeted by all-trans-retinoic-acid (atRA), which reduced their numbers and increased response rates in several vaccination studies. However, not much is known about the optimal administration interval between atRA and the vaccine as well as about its mode of action. Here we demonstrate in 2 different murine tumor models that mice unresponsive to a therapeutic vaccine harbored higher MDSC numbers than did responders. Application of atRA overcame MDSC-mediated immunosuppression and restored tumor control. Importantly, atRA was protective only when administered 3 d after vaccination (delayed treatment), whereas simultaneous administration even decreased the anti-tumor immune response and reduced survival. When analyzing the underlying mechanisms, we found that delayed, but not simultaneous atRA treatment with vaccination abrogated the suppressive capacity in monocytic MDSCs and instead caused them to upregulate MHC-class-II. Consistently, MDSCs from patients with colorectal carcinoma also failed to upregulate HLA-DR after ex vivo treatment with TLR-ligation. Overall, we demonstrate that atRA can convert non-responders to responders to vaccination by suppressing MDSCs function and not only by reducing their number. Moreover, we identify a novel, strictly time-dependent mode of action of atRA to be considered during immunotherapeutic protocols in the future.
    Type of Publication: Journal article published
    PubMed ID: 28920004
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Immunogenetics 5 (1977), S. 295-308 
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract We have investigated the effect of immune selection against a single gene product on a cultured mouse Friend leukemia cell line. The clonal cell line used is heterozygous at theH-2 complex and expresses theH-2 d andH-2 b haplotypes. The genes selected against were theH-2K locus alleles. Variants were obtained after a single-step selection using either antiH-2Kb or anti-H-2Kd serum. The phenotypes of the variants obtained showed an interesting asymmetry between the two haplotypes. Selection against theH 2K b allele resulted in the isolation of the two expected types of variant-those that had lost only H-2Kb and those that had lost both H-2Kb and the linked H-2Db. Selection against H-2Kd yielded, exclusively, variants that had lost both the selected antigen and the linked H-2Dd. None of the variants showed an alteration in expression of antigens intrans configuration. Karyotypic analyses of the variants revealed that all the cells had retained both copies of chromosome 17 present in the wild-type cells. The results suggest that the variants did not emerge through chromosome loss.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-5195
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé Les auteurs ont réalisé une lésion traumatique de la zone de croissance iliaque ou pubienne du cartilage en Y chez des rats Wistar afin d'étudier le rôle de cette structure dans le développement des anomalies de la hanche. Les résultats radiologiques, fonctionnels, morphologiques et morphométriques ont été évalués à la douzième semaine d'évolution. Dans les lésions du cartilage de croissance pubien, les constatations les plus remarquables ont été les dysplasies acétabulaires et les luxations. Des modifications de forme de l'acetabulum et de la tête fémorale ont été notées dans les deux groupes. On en conclut que le diagnostic de traumatisme du cartilage en Y peut avoir un grand intérêt dans le pronostic des lésions de la hanche.
    Notes: Summary Experimental traumatic lesions of the iliac and pubic parts of the triradiate cartilage of the acetabulum in young Wistar rats, were created to study the effect on the development of the hip joint. Radiological, functional and morphometric results were evaluated at twelve weeks of evolution, a time when the epiphysis was mature in a control series. Interference with the pubic growth plate caused acetabular dysplasia and dislocation of the hip. Both lesions caused deformities of the acetabulum and the femoral head. It is concluded that varied traumatic lesions of the triradiate cartilage may be of prognostic significance.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-5195
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé L'objet de notre travail est d'analyser le développement des canaux de cartilage du scaphoïde tarsien grâce à 26 spécimens humains d'âge compris entre 12 semaines de gestation et 10 mois après la naissance. Une méthode de transparence et d'histologie sérielle de l'os nous a permis de noter l'apparition des canaux et leur nombre par os. Les résultats obtenus nous montrent que: la formation des canaux dans le scaphoïde tarsien commence dès la 12ème ou 13ème semaine de la gestation; avec la méthode de transparence, les canaux sont évidents après 17 semaines de gestation; le nombre des canaux augmente durant la gestation; ils sont plus nombreux sur la face dorsale des os; et le schéma de distribution des canaux ne se modifie pas au cours de la gestation.
    Notes: Summary We have analysed the development of the cartilage canals in the tarsal navicular in 26 human foetuses and infants, aged between 12 weeks after gestation and 10 months, using a technique of transparentation and serial histological sections of the bone. The formation of cartilage canals starts in the first 12 to 13 weeks of gestation and can be seen by transparentation at 17 weeks after gestation. They increase in number with the age of the foetus or infant and develop a branching pattern almost to the centre of the tarsal navicular. They begin and are more numerous on the dorsal surface of the cartilage structure.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-5195
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé On a luxé expérimentalement l'articulation de la hanche de rats en période de croissance afin d'en déterminer l'influence sur la morphologie du bassin et sur l'orientation du cotyle. En conséquence de la luxation l'os iliaque s'incline latéralement dans le plan frontal, il s'incurve vers l'avant dans le plan sagittal et il tourne du côté opposé dans le plan horizontal. Il ne se produit pas d'antéversion acétabulaire significative.
    Notes: Summary The hip joints of growing rats have been dislocated experimentally to determine how this affects pelvic shape and acetabular orientation. After hip dislocation the innominate bone tilts laterally in the frontal plane. It bends anteriorly in the sagittal plane and rotates contralaterally in the coronal plane. No significant acetabular anteversion develops.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1420-9071
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Mice inoculated withPlasmodium berghei developed a drastic and significant pulmonary edema. Treatment of animals with phenoxybenzamine rendered mice hyporeactive to this physiopathological alteration.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 0022-0248
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Cyclin-dependent kinase, Cdk5, has been identified in neural tissue in connection with neurofilament and τ protein phosphorylation. This report describes the characterization of a 62-kDa protein that copurifies with Cdk5 from rat spinal cord homogenates. Dissociation of the protein from neural Cdk5 is concomitant with a reversible loss in kinase activity. Amino acid sequence information from tryptic peptide fragments was used to clone the complementary DNA from rat brain. A single full-length cDNA was characterized coding for a 67.5-kDa protein (p67). Exogenously expressed p67 stimulated Cdk5 kinase activity in vitro in a dose-dependent manner and when presented as an affinity matrix, selectively adsorbed Cdk5 from a cleared rat brain homogenate. In situ hybridization analysis of E18 rat embryos and adult rat brain demonstrated that p67 transcript expression is restricted to neural tissue. Immunohistochemical staining with an amino-terminal peptide-specific antibody further indicated that p67 is exclusively expressed in neurons. Localization in vivo and in cultured rat hippocampal neurons showed that p67 is highly enriched in axons. We propose that p67, by virtue of its regulation of Cdk5, participates in the dynamics of axonal architecture through the modulation of phosphorylation of cytoskeletal components.
    Type of Medium: Electronic Resource
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