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  • 1
    Abstract: Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at-risk primary melanoma patients. In this study, we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. Tumors from 300 patients with stage I/II melanoma were sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression-free and melanoma-specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease-free and melanoma-specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease-free survival was 2.3 (95% CI 1.2-4.4) and for melanoma-specific survival 5.8 (95% CI 1.9-18.3). The effect of the mutations on melanoma-specific survival in noncarriers of variant allele of the polymorphism was significant (HR 4.5, 95% CI 1.4-15.2) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.3, 95% CI 0.1-0.9). The data in this study provide preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter.
    Type of Publication: Journal article published
    PubMed ID: 26875008
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  • 2
    Keywords: p53 ; MUTATIONS ; EUROPEANS ; PIGMENTATION ; BASAL-CELL CARCINOMA ; GENETIC-DETERMINANTS ; COMMON VARIANTS ; SEQUENCE VARIANTS ; LI-FRAUMENI SYNDROME ; ASSOCIATE
    Abstract: To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 x 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 x 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 x 10(-6)), glioma (OR = 2.35, P = 1.0 x 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 x 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
    Type of Publication: Journal article published
    PubMed ID: 21946351
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  • 3
    Keywords: carcinoma ; CELL ; DISEASE ; EPIDEMIOLOGY ; NEW-YORK ; RISK ; GENE ; GENES ; SAMPLE ; TIME ; RISK-FACTORS ; SEQUENCE ; ASSOCIATION ; SIGNAL ; VARIANTS ; NO ; HEALTH ; genetics ; SNP ; risk factors ; MELANOMA ; HUMAN HOMOLOG ; INDIVIDUALS ; EUROPE ; heredity ; SKIN-CANCER ; basal cell carcinoma ; CELL CARCINOMA ; VARIANT ; SNPs ; CANDIDATE GENES ; EUROPEANS ; USA ; PIGMENTATION ; CANDIDATE ; RISK-FACTOR ; SIGNALS ; COMMON VARIANT ; SET ; NOV ; association study ; BASAL-CELL ; GENOME-WIDE ; CITRULLINATION ; GENETIC-DETERMINANTS ; PEPTIDYLARGININE DEIMINASE
    Abstract: To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide SNP association study of 930 Icelanders with BCC and 33,117 controls. After analyzing 304,083 SNPs, we observed signals from loci at 1p36 and 1q42, and replicated these associations in additional sample sets from Iceland and Eastern Europe. Overall, the most significant signals were from rs7538876 on 1p36 (OR = 1.28, P = 4.4 x 10(-12)) and rs801114 on 1q42 (OR = 1.28, P = 5.9 x. 10(-12)). The 1p36 locus contains the candidate genes PADI4, PADI6, RCC2 and ARHGEF10L, and the gene nearest to the 1q42 locus is the ras-homolog RHOU. Neither locus was associated with fair pigmentation traits that are known risk factors for BCC, and no risk was observed for melanoma. Approximately 1.6% of individuals of European ancestry are homozygous for both variants, and their estimated risk of BCC is 2.68 times that of noncarriers
    Type of Publication: Journal article published
    PubMed ID: 18849993
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  • 4
    Keywords: CANCER ; carcinoma ; CELL ; COMMON ; FOLLOW-UP ; RISK ; GENE ; FAMILY ; ASSOCIATION ; SUSCEPTIBILITY ; VARIANTS ; genetics ; SNP ; CDKN2A ; MELANOMA ; squamous cell carcinoma ; EPIDERMOLYSIS-BULLOSA SIMPLEX ; CELL CARCINOMA ; VARIANT ; keratins ; EUROPEANS ; USA ; PIGMENTATION ; SQUAMOUS-CELL ; COMMON VARIANT ; GENOME-WIDE ASSOCIATION ; GENETIC-DETERMINANTS ; Genetic ; COMMON VARIANTS ; Genome-wide association studies ; INK4/ARF
    Abstract: In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC)(1), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 x 10(-9)). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 x 10(-9)), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 x 10(-10)). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma-and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma
    Type of Publication: Journal article published
    PubMed ID: 19578363
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  • 5
    Keywords: SPECTRA ; carcinoma ; CELL ; NEW-YORK ; POPULATION ; RISK ; RISK-FACTORS ; SKIN ; ASSOCIATION ; polymorphism ; SUSCEPTIBILITY ; VARIANTS ; ACID ; genetics ; MELANOMA ; POPULATIONS ; INDIVIDUALS ; heredity ; MELANOCORTIN-1 RECEPTOR MC1R ; basal cell carcinoma ; CELL CARCINOMA ; VARIANT ; INCREASE ; hair ; HAPLOTYPE ; NONMELANOMA SKIN-CANCER ; USA ; PIGMENTATION ; INCREASES ; GENOME-WIDE ASSOCIATION ; association study ; BASAL-CELL ; CONFERS RISK ; AGOUTI ; EYE-COLOR ; GENE VARIANTS ; MC1R
    Abstract: Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) 1.45, P = 1.2 x 10(-9)) and BCC (OR = 1.33, P = 1.2 x 10(-6)). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 x 10(-7)) and BCC (OR = 1.14, P = 6.1 x 10(-4)). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 x 10(-4)). The association of all three variants is robust with respect to adjustment for the effect of pigmentation
    Type of Publication: Journal article published
    PubMed ID: 18488027
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  • 6
    ISSN: 1612-1112
    Keywords: Column liquid chromatography ; Ion-pair and GPC separations ; Amoxicillin oligomers ; β-Lactam ring polymers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Polymeric substances formed from concentrated sodium amoxicillin in an aqueous solution have been separated using two high-performance liquid chromatographic methods. We used a C18 reversed-phase column with tetrabutylammonium chloride as an ion-pairing agent with an acetonitrile gradient and a TSKgel G2500PWxl column with water as the solvent for gel permeation chromatography. The separated materials, ranging in size from the monomer to the tetramer, have been characterized by functional-group chemical analysis, while the identification of the piperazine-2,5-dione was done using a pure standard. A greater number of peaks which were also better defined were obtained using the ion-pair reversed-phase method, and open and closed beta-lactam ring polymer forms could be distinguished. Using the gel permeation method, only a few monomer, piperazine-2,5-dione, dimer, trimer and combined amoxicillin trimer and tetramer peaks were obtained with water, although those obtained were quite well defined. The data on the time-course of formation of the oligomers and the amoxicillin degradation product were virtually identical by both methods.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1573-7284
    Keywords: Clinical manifestations ; Diagnosis ; Epidemiology ; HIV-1 ; HTLV-I ; HTLV-II
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The human T-lymphotropic virus type II (HTLV-II) has recently been associated with the genesis of some subacute neurological syndromes and, rarely, with atypical T-lymphoid malignancies. The virus is endemic in some Amerindian and African tribes, and among intravenous drug users (IDUs) in North America and Europe. Given that HTLV-II is transmitted by the same routes as other human retroviruses, the screening of antibodies to HTLV-II in blood donors has became a matter of controversy in some countries. Herein, we describe the clinical, epidemiological and virological features of 113 individuals with HTLV-II infection identified in Spain up to September 1995. Most of them (94/113; 83%) were male, and all but seven were natives. Four were African immigrants living in Madrid and 3 had been born in other European countries. All but six subjects were IDUs, and sexual transmission of HTLV-II and transfusion were involved in five and one individual, respectively. Eighty-four percent of the IDUs infected with HTLV-II were co-infected by HIV-1 (93/107). Clinical manifestations potentially linked to HTLV-II were absent, although an IDU male co-infected by HIV-1 and HTLV-II developed a severe non-inflammatory proximal myopathy. In conclusion, HTLV-II infection is present in Spain, mainly among IDUs, with a growing incidence and a current overall prevalence of 2.0 percent.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1573-7284
    Keywords: Drug users ; Hepatitis B ; Hepatitis C ; Human immunodeficiency virus (HIV) ; Liver ; Natural history ; Viral hepatitis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The life expectancy of HIV-positive individuals has been prolonged in recent years, as a consequence of the wide use of antiretroviral drugs and primary prophylaxis for the most common opportunistic infections. In HIV-positive persons infected parenterally, chronic viral liver disease (CVLD), mainly that caused by hepatitis C virus (HCV), is frequently seen. Moreover, chronic hepatitis C seems to present a more accelerated course in HIV-infected patients, leading to cirrhosis and liver failure in a shorter period of time. The aim of the present study was to investigate the impact of CVLD on the morbidity and mortality of HIV-positive patients. A retrospective analysis of the causes of hospital admission during a 4.5-year period in a reference centre for AIDS situated in Madrid was performed. Decompensated liver disease (encephalopathy, ascites, jaundice), or complications directly related to it (gastrointestinal bleeding, hepatorenal syndrome, peritonitis) were diagnosed in 143 (8.6%) of 1670 hospital admissions. These episodes of CVLD corresponded to 105 different individuals, a quarter of whom had two or more re- admissions. HCV alone or in combination with other hepatotropic viruses was involved in 93 (88.6%) patients admitted for CVLD. Death directly associated with CVLD occurred in 15 individuals, which represented 4.8% of the total causes of inhospital mortality during the study period, and represented the fifth cause of death in hospital for HIV-infected patients. In conclusion, CVLD represents an important cause of hospital admission and death in HIV-infected drug users.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Introduction The natural history of stings, the clinical reaction of the patient and in vivo and in vitro tests are necessary parameters to assess before initiating Hymenoptera venom immunotherapy. In the decision to initiate immunotherapy with Hymenoptera venom, it is not usual to evaluate the natural history of the disease, which seems to be self-limiting and therefore of variable clinical significance.Objectives Our aim was to determine the natural history of Hymenoptera hypersensitivity over 4 consecutive years in a rural Mediterranean population.Methods An epidemiological study of Hymenoptera sting reactions and possible sensitivity was carried out in 145 randomly selected subjects out of a rural Mediterranean population of 600. Seventy-two subjects, including those with a history of anaphylaxis, completed the 4-year study. The nature of their clinical reactions, age, sex, history of atopy, profession, family history of reactions to Hymenoptera insects, time elapsed since the last sting, number of stings and specific IgE and IgG were determined (the latter, to the three most important insects in the area: Apis mellifera, Polistes dominulus, and Vespula germanica).Results Of the 72 subjects, four subjects had systemic reactions (SR), 23 had large local reaction (LLR) and all the others (117) was minor local reactions. None who had experienced an SR had a repeat SR when re-stung over the 4-year study. Of those with LLR, 12 subjects had the same type of reaction and 11 experienced more mild local reactions when re-stung. In the SR and local reaction groups, IgE to honey bee (Hb) increased significantly during the study period, whereas in those with only LLR, specific IgE to wasp (Polistes) decreased. Specific IgG to Polistes and Vespula (wasps) decreased significantly, whereas there was no change in the specific IgG to Hb in any of the groups. The number of stings per year decreased at the end of the study in all groups, but positive-specific IgG was higher in subjects with the greatest number of stings. On multivariate analysis using logistic regression, the existence of specific IgE to bee venom, male sex, being an agricultural worker, age of over 16 years and more than five stings per year are seen as individual or co-factors for developing SR or LLR.Conclusions The prevalence of SR was 2.8% in our Mediterranean population. The evolution of IgE and IgG throughout the 4-year study differed depending on the Hymenoptera studied. Adult male agricultural workers are at greater risk of having SR or LLR, especially when they have specific IgE to Hb and suffer from more than five stings every 4 years.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1435-4373
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Current tests to confirm human T-cell lymphotropic virus (HTLV) infection in individuals at risk of retroviral infection commonly yield indeterminate results. To assess the significance of HTLV-seroindeterminate reactivities in a high-risk population, 16 at-risk individuals who had this serologic pattern by Western blot were studied using a polymerase chain reaction (PCR) assay. Human T-cell lymphotropic virus type II infection was confirmed by the presence of virus-specific nucleic acid in four patients. However, PCR analysis was negative in the remaining 12 individuals. These results indicate strongly that all specimens from at-risk individuals with nondiagnostic HTLV reactivity by current Western blot assay should continue to be considered inconclusive, requiring further testing by more sensitive tests.
    Type of Medium: Electronic Resource
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