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  • 1
    Keywords: SYSTEM ; RATS ; cytokines ; INVOLVEMENT ; PHARMACOKINETICS ; BEHAVIOR ; ANIMAL-MODEL ; forced swimming test ; CHRONIC HEPATITIS-C ; Anhedonia ; Dexamethasone suppression test ; Forced swim test ; IMMOBILITY
    Abstract: Interferon (IFN) alpha proteins are proinflammatory cytokines having immunomodulating and antiviral properties. States during which cytokine systems are activated (e.g., during viral infection or during treatment of chronic hepatitis C and various malignancies with IFN alpha, etc.) can be associated with depression-like syndromes or even full-blown depressive episodes. Therefore, the role of IFN alpha and other cytokines in the pathogenesis of depressive disorder ("cytokine hypothesis of depression") has been assessed for many years with contradictory results. We have investigated whether intraperitoneal administration of high doses (up to 600microg/kg body weight) of pegylated, recombinant human IFN alpha 2a in mice induces changes known to be associated with depression using three different readouts: behavior in a model of despair (Porsolt swim test), presence of anhedonia (sucrose preference test), and sensitivity of the hypothalamic-pituitary-adrenal system (dexamethasone suppression test). We also assessed potential IFN-induced changes in gene expression in the liver. In none of the performed experiments, depression-associated effects could be found despite very high serum levels of IFN-induced antiviral activity compared to levels measured in hepatitis C virus (HCV) patients treated routinely with pegylated recombinant human IFN alpha 2a. The lack of such expected effects is probably due to the fact that pegylated human recombinant IFN alpha 2a does not activate the murine class I IFN receptor. Our results do not support the hypothesis that administration of recombinant pegylated human IFN alpha to mice produces a robust model of depression.
    Type of Publication: Journal article published
    PubMed ID: 20580843
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  • 2
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; neoplasms ; PATHWAY ; RISK ; GENE ; ASSOCIATION ; SUSCEPTIBILITY ; BREAST ; BREAST-CANCER ; METASTASIS ; POOR-PROGNOSIS ; HIGH-FREQUENCY ; GENETIC SUSCEPTIBILITY ; OVARIAN ; association study ; CORRELATE ; germline variation ; PIK3CA MUTATIONS ; PTEN LOSS
    Abstract: Background:Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer.Methods:A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC).Results:Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 x 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139).Conclusion:Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 22033276
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  • 3
    Keywords: RECEPTOR ; CANCER ; MODEL ; BRCA1 ; OVARIAN-CANCER ; MUTATIONS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; GENOTYPE ; CHEK2-ASTERISK-1100DELC ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; FAMILY REGISTRY
    Abstract: Introduction: Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. Methods: We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects. Results: These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar. Conclusions: The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these
    Type of Publication: Journal article published
    PubMed ID: 21194473
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  • 4
    Keywords: POPULATION ; RISK ; TUMORS ; ASSOCIATION ; VARIANTS ; breast cancer ; SELECTION ; SUBTYPES ; breast cancer risk ; CONSORTIUM ; INVESTIGATORS ; MODIFIERS ; COMMON VARIANTS ; GENETIC-VARIANTS ; SUSCEPTIBILITY ALLELES ; ZNF365
    Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers
    Type of Publication: Journal article published
    PubMed ID: 23544013
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  • 5
    Keywords: CANCER ; EXPRESSION ; RISK ; GENE ; SUSCEPTIBILITY ; breast cancer ; PATTERNS ; risk factors ; ESTROGEN-RECEPTOR ; ALLELES ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS ; PROGESTERONE-RECEPTOR ; BRCA2 MUTATION CARRIERS ; Risk prediction
    Abstract: Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 x 10(-18)), rs3803662 (16q12) (P = 3.7 x 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 x 10(-6) and P = 4.1 x 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P 〈= 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P 〈= 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment
    Type of Publication: Journal article published
    PubMed ID: 21596841
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  • 6
    Keywords: EXPRESSION ; GROWTH ; MODEL ; RISK ; RISK-FACTORS ; POSTMENOPAUSAL WOMEN ; ESTROGEN ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; BIRTH ; HORMONE-RECEPTOR ; susceptibility loci ; REPAIR GENES ; EPITHELIAL OVARIAN-CANCER ; BASAL-LIKE SUBTYPE ; DIFFERENT HISTOPATHOLOGIC TYPES ; PROGESTERONE-RECEPTOR STATUS
    Abstract: Background Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. Methods We pooled tumor marker and epidemiological risk factor data from 35 568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. Results In case-case analyses, of the epidemiological risk factors examined, early age at menarche (〈= 12 years) was less frequent in case patients with PR- than PR+ tumors (P = .001). Nulliparity (P = 3 x 10(-6)) and increasing age at first birth (P = 2 x 10(-9)) were less frequent in ER- than in ER+ tumors. Obesity (body mass index [BMI] 〉= 30 kg/m(2)) in younger women (〈= 50 years) was more frequent in ER /PR than in ER+/PR+ tumors (P = 1 x 10(-7)), whereas obesity in older women (〉50 years) was less frequent in PR- than in PR+ tumors (P = 6 x 10(-4)). The triple-negative (ER-/PR-/HER2-) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/ or epidermal growth factor receptor [EGFR] 1) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER+ or PR+ tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors. Conclusions This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology
    Type of Publication: Journal article published
    PubMed ID: 21191117
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  • 7
    Keywords: SURVIVAL ; RISK ; WOMEN ; ATM GENE ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; LOCUS ; GENOME-WIDE ASSOCIATION ; CONSORTIUM ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS
    Abstract: Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P〈0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.
    Type of Publication: Journal article published
    PubMed ID: 22532573
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