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1.
Curr Med Res Opin ; : 1-8, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31394049

RESUMO

Objectives: Potential opportunities and challenges of predictive genetic risk classification of healthy persons are currently discussed. However, the budgetary impact of rising demand is uncertain. This project aims to evaluate budgetary consequences of predictive genetic risk classification for statutory health insurance in Germany. Methods: A Markov model was developed in the form of a cohort simulation. It analyzes a population of female relatives of hereditary breast cancer patients. Mutation carriers are offered intensified screening, women with a BRCA1 or BRCA2 mutation can decide on prophylactic mastectomy and/or ovarectomy. The model considers the following scenarios: (a) steady demand for predictive genetic testing, and (b) rising demand. Most input parameters are based on data of the German Consortium for Hereditary Breast and Ovarian Cancer. The model contains 49 health states, starts in 2015, and runs for 10 years. Prices were evaluated from the perspective of statutory health insurance. Results: Steady demand leads to an expenditure of €49.8 million during the 10-year period. Rising demands lead to additional expenses of €125.5 million. The model reveals the genetic analysis to be the main cost driver while cost savings in treatment costs of breast and ovarian cancer are indicated. Conclusions: The results contribute to close the knowledge gap concerning the budgetary consequences due to genetic risk classification. A rising demand leads to additional costs especially due to costs for genetic analysis. The model indicates budget shifts with cost savings due to breast and ovarian cancer treatment in the scenario of rising demands.

2.
BMC Cancer ; 19(1): 787, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31395037

RESUMO

BACKGROUND: Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon. METHODS: We used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways. RESULTS: Patients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00-27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6%; 95%-CI 24.7 - 47.7%) compared to 16 women of controls (26.7%; 95%-CI 16.1 to 39.7%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95%-CI 0.92 to 11.5; p-value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05. CONCLUSIONS: To our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1-positive patients. Larger cohorts are needed to confirm these results.

3.
Genet Med ; 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31337882

RESUMO

PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. METHODS: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. RESULTS: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. CONCLUSION: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

4.
Br J Cancer ; 121(2): 180-192, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31213659

RESUMO

BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

5.
Transl Psychiatry ; 9(1): 160, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175272

RESUMO

Accumulating evidence supports a link between depression and being overweight in women. Given previously reported sex differences in fat accumulation and depression prevalence, as well as the likely role of sex hormones in both overweight and mood disorders, we hypothesised that the depression-overweight association may be mediated by sex hormones. To this end, we investigated the association of being overweight with depression, and then considered the role of sex hormones in relation to being overweight and depression in a large population-based cohort. We included a total of 3124 women, 970 premenopausal and 2154 postmenopausal from the LIFE-Adult cohort study in our analyses. We evaluated associations between being overweight (BMI >25 kg/m2), sex hormone levels, and depressive symptomatology according to Centre for Epidemiologic Studies Depression (CES-D) scores, and explored mediation of depression in a mediation model. Being overweight was significantly associated with depressive symptoms in premenopausal but not postmenopausal women. Both premenopausal and postmenopausal overweight women had higher free testosterone levels compared with normal weight women. Premenopausal women with depressive symptomatology had higher free testosterone levels compared to women without. We found a significant mediation effect of depressive symptomatology in overweight premenopausal women through free testosterone level. These findings highlight the association between being overweight and depressed, and suggest that high free testosterone levels may play a significant role in depression of overweight premenopausal women. Based on this, pharmacological approaches targeting androgen levels in overweight depressed females, in particular when standard anti-depressive treatments fail, could be of specific clinical relevance.

6.
Breast Cancer Res ; 21(1): 55, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036035

RESUMO

BACKGROUND: The role of the BARD1 gene in breast cancer (BC) and ovarian cancer (OC) predisposition remains elusive, as published case-control investigations have revealed controversial results. We aimed to assess the role of deleterious BARD1 germline variants in BC/OC predisposition in a sample of 4920 BRCA1/2-negative female BC/OC index patients of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). METHODS: A total of 4469 female index patients with BC, 451 index patients with OC, and 2767 geographically matched female control individuals were screened for loss-of-function (LoF) mutations and potentially damaging rare missense variants in BARD1. All patients met the inclusion criteria of the GC-HBOC for germline testing and reported at least one relative with BC or OC. Additional control datasets (Exome Aggregation Consortium, ExAC; Fabulous Ladies Over Seventy, FLOSSIES) were included for the calculation of odds ratios (ORs). RESULTS: We identified LoF variants in 23 of 4469 BC index patients (0.51%) and in 36 of 37,265 control individuals (0.10%), resulting in an OR of 5.35 (95% confidence interval [CI] = 3.17-9.04; P < 0.00001). BARD1-mutated BC index patients showed a significantly younger mean age at first diagnosis (AAD; 42.3 years, range 24-60 years) compared with the overall study sample (48.6 years, range 17-92 years; P = 0.00347). In the subgroup of BC index patients with an AAD < 40 years, an OR of 12.04 (95% CI = 5.78-25.08; P < 0.00001) was observed. An OR of 7.43 (95% CI = 4.26-12.98; P < 0.00001) was observed when stratified for an AAD < 50 years. LoF variants in BARD1 were not significantly associated with BC in the subgroup of index patients with an AAD ≥ 50 years (OR = 2.29; 95% CI = 0.82-6.45; P = 0.11217). Overall, rare and predicted damaging BARD1 missense variants were significantly more prevalent in BC index patients compared with control individuals (OR = 2.15; 95% CI = 1.26-3.67; P = 0.00723). Neither LoF variants nor predicted damaging rare missense variants in BARD1 were identified in 451 familial index patients with OC. CONCLUSIONS: Due to the significant association of germline LoF variants in BARD1 with early-onset BC, we suggest that intensified BC surveillance programs should be offered to women carrying pathogenic BARD1 gene variants.

7.
Alzheimers Res Ther ; 11(1): 43, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077241

RESUMO

BACKGROUND: Studies in older adults or those with cognitive impairment have shown associations between cognitive and olfactory performance, but there are few population-based studies especially in younger adults. We therefore cross-sectionally analyzed this association using data from the population-based LIFE-Adult-Study. METHODS: Cognitive assessments comprised tests from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD): verbal fluency (VF), word list learning and recall (WLL, WLR), and the Trail Making Tests (TMT) A and B. The "Sniffin' Sticks Screening 12" test was used to measure olfactory performance. Linear regression analyses were performed to determine associations between the number of correctly identified odors (0 to 12) and the five cognitive test scores, adjusted for sex, age, education, and the presence of depressive symptoms. Receiver operating characteristic (ROC) analysis was carried out to determine the discriminative performance of the number of correctly identified odors regarding identification of cognition impairment. RESULTS: A total of 6783 participants (51.3% female) completed the olfaction test and the VF test and TMT. A subgroup of 2227 participants (46.9% female) also completed the WLL and WLR tests. Based on age-, sex-, and education-specific norms from CERAD, the following numbers of participants were considered cognitively impaired: VF 759 (11.2%), WLL 242 (10.9%), WLR: 132 (5.9%), TMT-A 415 (6.1%), and TMT-B/A ratio 677 (10.0%). On average, score values for VF were higher by 0.42 points (p < 0.001), for WLL higher by 0.32 points (p = 0.001), for WLR higher by 0.31 points (p = 0.002), for TMT-A lower by 0.25 points (p < 0.001), and for TMT-B/A ratio lower by 0.01 points (p < 0.001) per number of correctly identified odors. ROC analysis revealed area under the curve values from 0.55 to 0.62 for the five cognitive tests. CONCLUSIONS: Better olfactory performance was associated with better cognitive performance in all five tests in adults - adjusted for age, sex, education, and the presence of depressive symptoms. However, the ability of the smell test to discriminate between individuals with and without cognitive impairment was limited. The value of olfactory testing in early screening for cognitive impairment should be investigated in longitudinal studies.

8.
Aging Ment Health ; : 1-7, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-31129995

RESUMO

Objectives: Mental demands at the workplace can be preventive against cognitive decline. However, personality shapes the way information is processed and we therefore assume that Neuroticism, Extraversion, Openness, Agreeableness and Conscientiousness, would moderate the beneficial effects of workplace stimulation on cognitive outcomes. Methods: We analyzed data from the population-based LIFE-Adult-Study (n = 6529). Cognitive outcomes were assessed via the Trail-Making Test (TMTA, TMTB) and the Verbal Fluency Test. Personality was assessed via the Personality Adjective List (16 AM). Mental demands were classified with the indices Verbal and Executive based on the O*NET database. Results: Multivariate regression analyses showed only two significant moderation effects of personality, i.e. in individuals with low scores on Conscientiousness/Openness, index Verbal was connected to better TMTB performance, while this effect disappeared for individuals with high values on the personality trait. However, the additional explained variance remained marginal. Conclusion: The findings suggest that personality does not modify associations between high mental demands at work and better cognitive functioning in old age; however, there is a tendency that high levels of Openness and Conscientiousness may offset effects of mental demands.

9.
Int J Cancer ; 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31081934

RESUMO

Comparably little is known about breast cancer (BC) risks in women from families tested negative for BRCA1/2 mutations despite an indicative family history, as opposed to BRCA1/2 mutation carriers. We determined the age-dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers of BRCA1/2 mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n = 4,380; 16,398 person-years [PY], median baseline age: 39 years) and CBC (n = 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8-70.9%) for BRCA1 mutation carriers, 43.2% (95% CI 32.1-56.3%) for BRCA2 mutation carriers and 15.7% (95% CI 11.9-20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9-29.8) for BRCA1 mutation carriers, 13.5 (95% CI 9.2-19.1) for BRCA2 mutation carriers and 4.9 (95% CI 3.8-6.3) for BRCA1/2 noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6-31.9%) for BRCA1 mutation carriers, 6.6% (95% CI 3.4-12.5%) for BRCA2 mutation carriers and 3.6% (95% CI 2.2-5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women from BRCA1/2 negative families with elevated risk.

10.
Sleep Health ; 5(2): 208-215, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30928123

RESUMO

OBJECTIVES: Shorter sleep duration in childhood has already been associated with health-related and psychological factors, such as overweight/obesity or stress. This study investigates associations of sleep duration with overweight/obesity and stress related to academic success in school ("academic stress") in dependence on children's socioeconomic status. DESIGN: Cross-sectional. SETTING: LIFE Child Study, a study investigating child development from pregnancy to adulthood. PARTICIPANTS: A total of 1537 (2325 observations) 1- to 14-year-old children were considered. Analyses on academic stress were performed in a subgroup of 450 school-aged children (631 observations). MEASUREMENTS: Associations between sleep duration and overweight/obesity as well as academic stress were analyzed using linear mixed-effect regression models controlling for multiple visits. Importantly, all associations were checked for interactions with families' socioeconomic status. RESULTS: The analyses revealed negative associations between sleep duration and overweight/obesity as well as academic stress, which, however, were only observable in children from families with a low socioeconomic status. The associations were consistent across all ages. CONCLUSIONS: The findings suggest that children from families with a low socioeconomic status have a higher susceptibility for risk factors promoting sleep deficiency, overweight, or academic stress, for example, unhealthy food intake, high media consumption, or the loss of coping strategies for academic stress at school.


Assuntos
Obesidade Pediátrica/epidemiologia , Sono , Classe Social , Estresse Psicológico/epidemiologia , Estudantes/psicologia , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Feminino , Disparidades nos Níveis de Saúde , Humanos , Lactente , Masculino , Fatores de Risco , Estudantes/estatística & dados numéricos , Fatores de Tempo
11.
Cancer Epidemiol Biomarkers Prev ; 28(6): 1010-1014, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30824524

RESUMO

BACKGROUND: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families. METHODS: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias. RESULTS: Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162-4.328] for the second generation and 2.644 (95% CI, 1.082-6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648-2.619) and HR = 1.074 (95% CI, 0.406-2.842) for second and third generations, respectively]. CONCLUSIONS: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome. IMPACT: This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition.

12.
Gesundheitswesen ; 2019 Mar 15.
Artigo em Alemão | MEDLINE | ID: mdl-30877686

RESUMO

AIM: This study explores gender-specific differences in the utilization of health care services in an urban population sample. METHOD: As part of the LIFE-ADULT-Study, 2244 individuals (19-79 years) filled out a questionnaire about their use of health care services during the past year. Information regarding the frequency of general and specialized practitioners consultation, medical advice from general practitioners and utilization of preventive and health promoting programs were analyzed. RESULTS: Women visited general practitioners or specialists and utilized prevention and health-promotion programs more often than men. No gender differences were found regarding the frequency of receiving medical advice from general practitioners. CONCLUSIONS: The results mainly replicate prior findings showing that women utilize health care services more frequently than men. However, these gender differences vary as a function of the indicator employed and should therefore be discussed differentially.

13.
PLoS One ; 14(2): e0212627, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30818393

RESUMO

BACKGROUND: PR interval prolongation is associated with increased risk for atrial fibrillation (AF). Different biomarkers are used to predict AF incidence and its outcomes. The aim of this study was to investigate the association between echocardiographic parameters and blood biomarkers in PR interval groups and AF. METHODS: The LIFE-Adult-Study is a population-based cohort study of randomly selected participants from Leipzig, Germany. In this cross-sectional analysis, individuals ≥40 years with available echocardiographic (LA diameter, EF) and laboratory data (creatinine, Troponin, NT-proBNP) were included. RESULTS: The study population comprised 1.429 individuals (median age 56 (IQR 48-66) years, 40% males) with complete ECG, echocardiographic and laboratory data. There were 48 (3.4%) individuals with AF, 177 (12.4%) with short, 138 (9.7%) with prolonged and 1.066 (74.5%) with normal PR interval. Individuals with PR interval prolongation had larger LA diameter, higher Troponin and NT-proBNP levels than individuals with normal PR interval, but lower than AF group (p<0.001). In contrast, eGFR was significantly higher in the group with PR interval prolongation than in AF, but lower than in individuals with normal PR interval (p<0.001). In the multivariate analysis, PR interval prolongation and AF shared similar characteristics, the only parameter different between both groups was NT-proBNP. CONCLUSIONS: Individuals with PR interval prolongation and AF showed similarities in echocardiographic parameters, renal function and blood biomarker levels. Longitudinal studies are necessary to prove whether the PR interval prolongation may be considered as preliminary stage for AF.

14.
Breast Cancer Res Treat ; 175(1): 217-228, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30725383

RESUMO

PURPOSE: To report on 10 years of high-risk service screening with annual MRI in the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). METHODS: A cohort of 4,573 high-risk, previously unaffected women (954 BRCA1 carriers, 598 BRCA2 carriers, 3021 BRCA1/2 non-carriers) participating in the GC-HBOC surveillance program was prospectively followed. Screening outcomes for 14,142 screening rounds with MRI between 2006 and 2015 were analyzed and stratified by risk group, type of screening round, and age. RESULTS: A total of 221 primary breast cancers (185 invasive, 36 in situ) were diagnosed within 12 months of an annual screening round with MRI. Of all cancers, 84.5% (174/206, 15 unknown) were stage 0 or I. In BRCA1 carriers, 16.9% (10/59, 5 unknown) of all incident cancers (screen-detected and interval cancers combined) and in BRCA2 carriers 12.5% (3/24, 4 unknown) were stage IIA or higher, compared to only 4.8% (2/42, 2 unknown) in high-risk BRCA1/2 non-carriers. Program sensitivity was 89.6% (95% CI 84.9-93.0) with no significant differences in sensitivity between risk groups or by age. Specificity was significantly lower in the first screening round (84.6%, 95% CI 83.6-85.7) than in subsequent screening rounds (91.1%, 95% CI 90.6-91.7), p < 0.001. Cancer detection rates (CDRs) and as a result positive predictive values were strongly dependent on type of screening round, risk group and patient age. CDRs ranged from 43.5‰ (95% CI 29.8-62.9) for the first screening round in BRCA2 carriers to 2.9‰ (95% CI 1.3-6.3) for subsequent screening rounds in high-risk non-carriers in the age group 30 to 39 years. CONCLUSIONS: High-risk screening with MRI was successfully implemented in the GC-HBOC with high sensitivity and specificity. Risk prediction and inclusion criteria in high-risk non-carriers need to be adjusted to improve CDRs and thus screening efficacy in these patients.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/epidemiologia , Imagem por Ressonância Magnética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Detecção Precoce de Câncer , Feminino , Genes BRCA1 , Genes BRCA2 , Alemanha/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico por imagem , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/patologia , Humanos , Imagem por Ressonância Magnética/métodos , Programas de Rastreamento , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Vigilância em Saúde Pública , Reprodutibilidade dos Testes , Risco , Adulto Jovem
15.
Biochem Soc Trans ; 47(1): 411-423, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30710057

RESUMO

In all domains of life, the regulation of transcription by DNA-dependent RNA polymerases (RNAPs) is achieved at the level of initiation to a large extent. Whereas bacterial promoters are recognized by a σ-factor bound to the RNAP, a complex set of transcription factors that recognize specific promoter elements is employed by archaeal and eukaryotic RNAPs. These initiation factors are of particular interest since the regulation of transcription critically relies on initiation rates and thus formation of pre-initiation complexes. The most conserved initiation factor is the TATA-binding protein (TBP), which is of crucial importance for all archaeal-eukaryotic transcription initiation complexes and the only factor required to achieve full rates of initiation in all three eukaryotic and the archaeal transcription systems. Recent structural, biochemical and genome-wide mapping data that focused on the archaeal and specialized RNAP I and III transcription system showed that the involvement and functional importance of TBP is divergent from the canonical role TBP plays in RNAP II transcription. Here, we review the role of TBP in the different transcription systems including a TBP-centric discussion of archaeal and eukaryotic initiation complexes. We furthermore highlight questions concerning the function of TBP that arise from these findings.


Assuntos
Proteína de Ligação a TATA-Box/química , Proteína de Ligação a TATA-Box/metabolismo , Iniciação da Transcrição Genética , Proteínas Arqueais , RNA Polimerases Dirigidas por DNA/metabolismo , Evolução Molecular , Conformação Proteica
16.
Eur J Health Econ ; 20(5): 739-750, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30790097

RESUMO

BACKGROUND: The 'German Consortium for Hereditary Breast and Ovarian Cancer' (GC-HBOC) offers women with a family history of breast and ovarian cancer genetic counseling. The aim of this modeling study was to evaluate the cost-effectiveness of genetic testing for BRCA 1/2 in women with a high familial risk followed by different preventive interventions (intensified surveillance, risk-reducing bilateral mastectomy, risk-reducing bilateral salpingo-oophorectomy, or both mastectomy and salpingo-oophorectomy) compared to no genetic test. METHODS: A Markov model with a lifelong time horizon was developed for a cohort of 35-year-old women with a BRCA 1/2 mutation probability of ≥ 10%. The perspective of the German statutory health insurance (SHI) was adopted. The model included the health states 'well' (women with increased risk), 'breast cancer without metastases', 'breast cancer with metastases', 'ovarian cancer', 'death', and two post (non-metastatic) breast or ovarian cancer states. Outcomes were costs, quality of life years gained (QALYs) and life years gained (LYG). Important data used for the model were obtained from 4380 women enrolled in the GC-HBOC. RESULTS: Compared with the no test strategy, genetic testing with subsequent surgical and non-surgical treatment options provided to women with deleterious BRCA 1 or 2 mutations resulted in additional costs of €7256 and additional QALYs of 0,43 (incremental cost-effectiveness ratio of €17,027 per QALY; cost per LYG: €22,318). The results were robust in deterministic and probabilistic sensitivity analyses. CONCLUSION: The provision of genetic testing to high-risk women with a BRCA1 and two mutation probability of ≥ 10% based on the individual family cancer history appears to be a cost-effective option for the SHI.

18.
Artigo em Inglês | MEDLINE | ID: mdl-30456541

RESUMO

PURPOSE: The Sniffin' Sticks Screening 12 test is a test of olfactory performance based on pen-like odor dispensing devices. The aims of this study were to analyze the performance of this test in a general population sample and to explore associations between olfactory dysfunction and quality of life. METHODS: A large community sample (n = 7267) completed the Sniffin' Sticks Screening 12 test and several questionnaires measuring quality of life, anxiety, dispositional optimism, social support, and satisfaction with life. RESULTS: According to the criteria recommended by the test manufacturer, 5.1% of the participants were anosmic (score ≤ 6), 52.4% were dysosmic (7 ≤ score ≤ 10), and 42.5% were normosmic (score ≥ 11). While frequencies of correct identification differed between the 12 sticks, all sticks contributed positively to the test results. The associations between olfactory functioning and quality of life variables were negligible. In the multivariate analyses, none of the associations reached the 1% significance level. CONCLUSIONS: While studies with patients in otorhinolaryngological clinics often report substantial detriments to their quality of life in relation to olfactory dysfunction, the present epidemiological study cannot confirm this association for the general population.

19.
J Natl Cancer Inst ; 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30312457

RESUMO

Background: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. Methods: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer. Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

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