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  • DKFZ Publication Database  (4,305)
  • Germany  (4,305)
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  • 1
    Keywords: Germany ; RISK ; COLORECTAL-CANCER ; VALIDITY ; PREDICTORS ; INEQUALITIES ; PROGRAM ; ENGLAND ; CANCER SCREENING PARTICIPATION
    Abstract: We aimed to describe the utilization of colonoscopy and its association with sociodemographic characteristics within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort study. We included 15 014 study participants (43% men) of the EPIC-Heidelberg cohort recruited between 1994 and 1998. At baseline recruitment, as well as in the 3-yearly follow-up surveys, study participants completed questionnaires on lifestyle, socioeconomic background variables, health status, and use of medications and medical services, including colonoscopy examinations. The present analyses focused on participants who completed the question on colonoscopy examination in all follow-up rounds. Our results show that by the end of the fourth follow-up round, more than half of all participants of the EPIC-Heidelberg cohort had had a colonoscopy. Colonoscopy was associated with some socioeconomic and demographic characteristics: a positive association with vocational training level as well as overall socioeconomic status level [International Standard Classification of Education (ISCED) classification]. A negative association was found for household size and employment status. Colonoscopy usage increased steeply within the subgroup of participants older than 55 years of age and decreased again within the subgroup of participants older than 75 years of age. Organized colorectal cancer screening should include a written invitation system, to overcome the problem of sociodemographic-related differential awareness of and attendance at colonoscopy examinations. Also, the high proportion of prescreened individuals should be taken into account to avoid unnecessary re-examinations.
    Type of Publication: Journal article published
    PubMed ID: 25244156
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  • 2
    Keywords: Germany ; TOOL ; TRIAL ; education ; ADULTS ; ERRORS ; COMMUNICATION ; ADHERENCE ; knowledge
    Abstract: We investigated the prevalence and quality of medication schedules of elderly ambulatory patients and assessed factors associated with the availability of a medication schedule. In particular, we evaluated whether sending out a blank medication schedule template would increase the chances to use such a document. Data originate from the ESTHER study, a cohort study conducted in Saarland, Germany, in which trained study physicians performed home visits. They scanned all medication schedules, recorded the participants' medication, and performed thorough geriatric assessments. As part of the intervention, a blank medication schedule template along with a brochure was mailed to half of the participants (intervention group) 4 weeks prior to the home visits. In total, 553 of 2470 participants (22.4 %) had a medication schedule. Almost two thirds of the schedules were issued by health care professionals (n = 353, 63.8 %). These schedules offered a higher quality, although important information such as over-the-counter (OTC) medication was regularly missing. Self-reported adherence was higher in participants who used self-issued medication schedules; however, self-reported medication adherence in patients with any medication schedule was poorer compared to those patients not using a schedule. Factors associated with the availability of a medication schedule were male sex, a higher number of medicines to take, and a more complex drug regimen. The intervention did not increase the number of patients having a medication schedule. Only a minority of elderly ambulatory patients had a medication schedule at home. Sending out a brochure along with a blank medication schedule template did not increase the prevalence of medication schedules.
    Type of Publication: Journal article published
    PubMed ID: 26105963
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  • 3
    Keywords: Germany ; DISEASE ; BLOOD-PRESSURE ; TRENDS ; MANAGEMENT ; CARDIOVASCULAR RISK-FACTORS ; EUROPEAN COUNTRIES ; UNITED-STATES ADULTS ; MONICA PROJECT ; AWARENESS
    Abstract: Hypertension is a leading cause of cardiovascular disease. There are very few studies dealing with the incidence of hypertension and changes in blood pressure (BP) over time. We aimed to evaluate the prevalence and incidence of hypertension within an adult population-based cohort.The sample included 967 men and 812 women aged 45 to 83 years at baseline, 1436 subjects completed follow-up1 after 4 years and 1079 completed follow-up2 after 9 years. BP was measured according to a standardized protocol with oscillometric devices and hypertension was defined as mean systolic BP (SBP) 〉/=140 mmHg and/or diastolic BP (DBP) 〉/=90 mmHg and/or use of antihypertensive medication if hypertension was known. We examined prevalence and incidence of hypertension, by age and sex.The age-standardized prevalence of hypertension at baseline was 74.3% for men and 70.2% for women. The age-standardized annual incidence rate of hypertension for men was 8.6 (95% confidence interval [95% CI] 4.3-12.9) for follow-up period1 and 5.4 (95% CI 2.8-10.6) for follow-up period2 and for women 8.2 (95% CI 3.6-12.8) for follow-up1 and 5.6 (95%CI 2.7-11.4) for follow-up2. A clear decrease in SBP and DBP between baseline and follow-up1 and follow-up2 was seen, accompanied by an increase in anti-hypertensive medication consumption and a higher awareness of the condition.Hypertension prevalence and incidence in the CARLA Study appear to be elevated compared with other studies. The decrease of BP over time seems to be caused by improved hypertension control due to interventional effects of our observational study and improved health care.
    Type of Publication: Journal article published
    PubMed ID: 26039136
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  • 4
    Keywords: Germany ; signal transduction ; HUMANS ; gene amplification ; ADULT ; DISEASE PROGRESSION ; female ; Male ; Aged ; Middle Aged ; Time Factors ; Proportional Hazards Models ; treatment outcome ; Gene Dosage ; Disease-Free Survival ; Adenocarcinoma/*drug therapy/enzymology/genetics/mortality/pathology ; Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use ; Deoxycytidine/administration & dosage/analogs & derivatives ; Drug Administration Schedule ; Esophageal Neoplasms/*drug therapy/enzymology/mortality/pathology ; Fluorouracil/administration & dosage/analogs & derivatives ; Kaplan-Meier Estimate ; Protein Kinase Inhibitors/administration & dosage/adverse effects/*therapeutic ; use ; Quinazolines/administration & dosage/adverse effects/*therapeutic use ; Receptor, ErbB-2/*antagonists & inhibitors/genetics/metabolism ; Stomach Neoplasms/*drug therapy/enzymology/genetics/mortality/pathology
    Abstract: INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) amplification is present in a subgroup of gastroo-esophageal cancers (GCs). HER2 inhibition with trastuzumab has shown to improve outcomes in advanced disease. Lapatinib ditosylate (LAP), a dual anti-epidermal growth factor receptor (EGFR) and anti-HER2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in HER2-positive breast cancer. We aimed to study the activity of LAP in HER2-amplified GC. MATERIALS AND METHODS: Patients (pts) with HER2-positive (gene amplification or increased copy numbers based on predefined criteria) advanced GC were randomly allocated 1:1 to receive LAP 1250mg per day 1-21 plus capecitabine (CAP) 2000mg/m(2) on days 1-14 of a 21-day cycle or LAP 1500mg monotherapy day 1-21 after having failed on a platinum-based first-line therapy. HER2 status was assessed centrally. The primary end-point was the objective response rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). We aimed to include 38 pts per arm to show an interesting response rate of 20% in either of the two arms. RESULTS: 37 pts were enrolled (18 to LAP+CAP, 19 to LAP). Pts had received a median of three prior treatment lines. 12 pts in the LAP+CAP group (67%) and 12 pts in the LAP group (63%) had received prior trastuzumab. Only two pts (11.1%; 95% confidence interval (CI): 1.37-34.7), both in the LAP+CAP arm, achieved an objective response. The study was closed prematurely for futility. Median time to progression was 42 (95% CI: 38-61) days in the LAP group and 83 (95% CI: 42-86) days in the LAP+CAP group. Other secondary efficacy end-points (progression-free and overall survival) were comparable in the two treatment groups. Rates of diarrhoea were higher with LAP+CAP (61%; 95% CI: 35-83) compared to 26% (95% CI 9-51) with LAP mono, whereas other adverse events were mostly similar between the groups (18 [100%] versus 17 [90%]). DISCUSSION: Lapatinib showed insufficient activity in HER2-amplified pretreated advanced GC. The safety profile of LAP or LAP+CAP was as expected with some more toxicity in the combination arm. (ClinicalTrials.gov Identifier, NCT01145404).
    Type of Publication: Journal article published
    PubMed ID: 25694417
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  • 5
    Keywords: Germany ; EPIDEMIOLOGY ; EXPOSURE ; smoking ; ALCOHOL ; RISK-FACTOR
    Abstract: Prior studies suggest that history of allergy and infections early in life might be inversely associated with cancer. We explored the association between allergies, recent influenza infections and laryngeal cancer risk. We used data from a case-control study which included 229 cases of laryngeal cancer and 769 population controls matched for age and sex. History of a physician-diagnosed allergy, influenza-like infections in the past 5 years, smoking, alcohol consumption and occupational exposure to carcinogens were self-reported. Allergies were classified into two groups (Type I and Type IV), according to the underlying immunologic mechanism. Conditional logistic regression models were fitted using laryngeal cancer as the outcome, adjusting for smoking, alcohol consumption and occupational exposure and stratified for age and sex. Having any allergy was not associated significantly with laryngeal cancer. Although Type I and Type IV allergies were non-significantly associated with laryngeal cancer, Type IV allergies showed a strong inverse association after adjusting for smoking and alcohol (OR 0.50, 95 % CI 0.22-1.2). Participants who reported at least one influenza-like infection during the past 5 years were significantly less likely to have laryngeal cancer (OR 0.57, 95 % CI 0.39-0.81). After considering fever (〉/=38.5 degrees C) as a criterion for influenza infection, the association between influenza infection and laryngeal cancer was even stronger (OR 0.29, 95 % CI 0.13-0.63). We found no significant association between any allergy and laryngeal cancer, some indication of an inverse association between Type IV allergy and laryngeal cancer, whereas recent influenza infections were inversely associated with laryngeal cancer risk.
    Type of Publication: Journal article published
    PubMed ID: 25634066
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  • 6
    Keywords: RECEPTOR ; CANCER ; SURVIVAL ; Germany ; DEATH ; RISK ; breast cancer ; WOMEN ; chemotherapy ; LONG-TERM SURVIVAL ; UNITED-STATES ; PERIOD ANALYSIS ; RELATIVE SURVIVAL ; EMPIRICAL-EVALUATION ; UP-TO-DATE ; CLINICAL-PRACTICE GUIDELINES ; AUSTRALIA WESTERN-AUSTRALIA ; CANADA BRITISH-COLUMBIA ; Clinical Practice Guidelines ; Evaluation of cancer care ; Population-based cancer registry ; TRIALS IMPROVE SURVIVAL
    Abstract: Background: Studies on the implementation of Clinical Practice Guidelines (CPG) and particularly its effect on breast cancer (BRC) survival on a population-level are scant. This population-based high resolution study from Germany aims at providing data on the usage of BRC treatment, the extent of adherence to CPG and, as a novelty, survival of BRC patients according to major recommended treatment options. Methods: Data from the Saarland Cancer Registry including women diagnosed with invasive BRC without distant metastasis and followed up between 2000 and 2009 were used. Provision of cancer care according to major treatment options is presented by age, clinical subtypes of BRC, and over time. Conventional and modeled period analysis was used to derive estimates of most up-to-date 5-year relative survival (RS) and the effect of non-adherence to CPG on relative excess risk of death (RER). Results: The study revealed increasing guideline adherence, with high levels already seen for local treatment (e.g. 67% of the BRC patients in 2008/09 received breast conserving surgery), and substantial progress since the millennium change with regard to sentinel node dissection (SND) and adjuvant systemic treatments (e. g. SND and chemotherapy provided to 62% of all patients and 79% of the patients with nodal positive or hormone receptor negative BRC in 2008/09, respectively). It further demonstrated increased cancer related mortality among patients without guideline compliant cancer treatment (e. g. patients with nodal positive and hormone receptor negative BRC who were not treated with chemotherapy had a 5-year RS of 29% (RER: 2.89, 95% CI: 1.46-5.71) compared to 54% for patients obtaining chemotherapy). Conclusions: This study provides data on the implementation of CPG in a highly developed European country and extends available population-based survival data of BRC patients and may provide evidence of increased cancer related excess mortality, if BRC patients do not receive guideline compatible treatment
    Type of Publication: Journal article published
    PubMed ID: 25304931
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  • 7
    Keywords: Germany ; DISEASE ; POPULATION ; WOMEN ; MEN ; RATES ; TRENDS ; ISCHEMIC-STROKE ; PHYSICAL-ACTIVITY ; 30-DAY CASE-FATALITY
    Abstract: BACKGROUND AND PURPOSE: Because primary prevention of stroke is a priority, our aim was to assess the primary preventive potential of major lifestyle risk factors for stroke in middle-aged women and men. METHODS: Among 23 927 persons, 551 (195 women and 356 men) had a first diagnosis of stroke during an average follow-up of 12.7 years. Using Cox proportional hazards models, we estimated the associations of adiposity, smoking, physical activity, alcohol consumption, and diet with risk of developing stroke. A competing risk model built from cause-specific proportional hazards models accounting for concurrent risk of death was used to calculate relative and absolute reductions in stroke occurrences that could have been achieved by maintaining a healthy lifestyle pattern. RESULTS: Obesity, smoking, alcohol consumption, diet, and physical inactivity were each identified as modifiable lifestyle risk factors for stroke. About 38% of stroke cases were estimated as preventable through adherence to a healthy lifestyle profile (never smoking, maintaining optimal body mass index and waist circumference, performing physical exercise, consuming a moderate quantity of alcohol, and following a healthy dietary pattern). Age-specific estimates of 5-year incidence rates for stroke in the actual cohort and in a hypothetical, comparable cohort of individuals following a healthy lifestyle would be reduced from 153 to 94 per 100 000 women and from 261 to 161 per 100 000 men for the age group 60 to 65 years. CONCLUSIONS: Our analysis confirms the strong primary prevention potential for stroke based on avoidance of excess body weight, smoking, heavy alcohol consumption, unhealthy diet, and physical inactivity.
    Type of Publication: Journal article published
    PubMed ID: 24876086
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  • 8
    Keywords: SURVIVAL ; Germany ; RISK ; ASSOCIATION ; GENE POLYMORPHISMS
    Abstract: Several studies have suggested that the anti-cancerogenous effects of vitamin D might be modulated by genetic variants in the vitamin D receptor (VDR) gene. The association of VDR polymorphisms with breast cancer-specific and all-cause mortality after a breast cancer diagnosis remains, however, largely unexplored. We assessed the association of genetic variants in VDR (rs731236, rs1989969, rs2228570, 11568820) with breast cancer survival in a sample of 498 breast cancer patients with a mean age at diagnosis of 61 years from Saarland, Germany, who were followed for up to 5 years with respect to total and breast cancer-specific mortality (56 and 48 events, respectively). Adjusted hazard ratios with 95% confidence intervals (CI) were estimated by Cox regression models. We found that breast cancer patients homozygous for the rare allele of rs731236 (15% of the women in our cohort) had a tendency toward an increased risk for breast cancer-specific mortality. The hazard ratio (95% CI) adjusted for age and breast cancer stage was 2.8 (1.1-7.2) for breast cancer-specific mortality and 2.1 (0.9-4.9) for total mortality. Additional adjustment for family history of breast cancer, radical mastectomy, and body mass index changed only marginally the estimates. No association was found for rs1989969, rs2228570, and rs11568820. Our analysis suggests that VDR polymorphism rs731236 might be associated with breast cancer-specific mortality and if our findings are confirmed in future and bigger studies rs731236 might deserve consideration as a prognostic factor in clinical care of breast cancer patients.
    Type of Publication: Journal article published
    PubMed ID: 23300018
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  • 9
    Keywords: Germany ; AGE ; RATES ; LONG-TERM SURVIVAL ; UNITED-STATES ; PATIENT SURVIVAL ; EMPIRICAL-EVALUATION ; 21ST-CENTURY ; REGISTRY DATA
    Abstract: Background:Period analysis is increasingly used to compute long-term cancer survival, as it provides better prediction of survival of newly diagnosed patients than traditional cohort analysis. However, the patient population to which period survival estimates best pertain to and which should be described in a study is less obvious.Methods:Using Finnish Cancer Registry data on 23 common cancer sites, age-standardized period estimates of 5-, 10-, 15-, and 20-year relative survival were computed for each 2-, 5-, and 10-year calendar period in 1954-2003 and compared with survival estimates for two cohorts by means of mean, mean absolute and mean squared differences: a full cohort of all patients potentially contributing some data to the survival analysis and a restricted cohort of patients diagnosed in the period of interest.Results:In most computations, survival estimates for the full cohorts were on average closer to the period estimates for the majority of cancer sites. For 10-year survival, results were less obvious with respect to the mean difference. However, mean squared and mean absolute differences were smaller for the majority of cancers when using the full cohort.Conclusion:Our results suggest that the full cohort should be described in reports of period survival analysis.
    Type of Publication: Journal article published
    PubMed ID: 23361050
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  • 10
    Keywords: Germany ; RISK-FACTORS ; OBSTRUCTIVE PULMONARY-DISEASE ; TRENDS ; NATRIURETIC PEPTIDE ; SOCIETY-OF-CARDIOLOGY ; DIASTOLIC DYSFUNCTION ; VENTRICULAR SYSTOLIC DYSFUNCTION ; EUROPEAN-SOCIETY ; CHAMBER QUANTIFICATION
    Abstract: BACKGROUNDOBJECTIVES: Chronic heart failure (CHF) is one of the most important public health concerns in the industrialized world having increasing incidence and prevalence. Although there are several studies describing the prevalence of heart failure with reduced ejection fraction (HFREF) and heart failure with normal ejection fraction (HFNEF) in selected populations, there are few data regarding the prevalence and the determinants of symptomatic heart failure in the general population. METHODS: Cross-sectional data of a population-based German sample (1,779 subjects aged 45-83 years) were analyzed to determine the prevalence and determinants of chronic SHF and HFNEF defined according to the European Society of Cardiology using symptoms, echocardiography and serum NT-proBNP. Prevalence was age-standardized to the German population as of December 31st, 2005. RESULTS: The overall age-standardized prevalence of symptomatic CHF was 7.7% (95%CI 6.0-9.8) for men and 9.0% (95%CI 7.0-11.5) for women. The prevalence of CHF strongly increased with age from 3.0% among 45-54- year-old subjects to 22.0% among 75-83- year-old subjects. Symptomatic HFREF could be shown in 48% (n = 78), symptomatic HFNEF in 52% (n = 85) of subjects with CHF. The age-standardized prevalence of HFREF was 3.8 % (95%CI 2.4-5.8) for women and 4.6 % (95%CI 3.6-6.3) for men. The age-standardized prevalence of HFNEF for women and men was 5.1 % (95%CI 3.8-7.0) and 3.0 % (95%CI 2.1-4.5), respectively. Persons with CHF were more likely to have hypertension (PR = 3.4; 95%CI 1.6-7.3) or to have had a previous myocardial infarction (PR = 2.5, 95%CI 1.8-3.5). CONCLUSION: The prevalence of symptomatic CHF appears high in this population compared with other studies. While more women were affected by HFNEF than men, more male subjects suffered from HFREF. The high prevalence of symptomatic CHF seems likely to be mainly due to the high prevalence of cardiovascular risk factors in this population.
    Type of Publication: Journal article published
    PubMed ID: 23555000
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  • 11
    Keywords: Germany ; MODELS ; INFORMATION ; QUANTIFICATION ; QUALITY ; QUANTITATION ; MAGNETIC-RESONANCE ; SPECTROSCOPY ; LOCALIZATION ; RECONSTRUCTION ; BRAIN-TUMORS ; MRSI ; spatial prior knowledge ; spectral fitting
    Abstract: We propose a Bayesian smoothness prior in the spectral fitting of MRS images which can be used in addition to commonly employed prior knowledge. By combining a frequency-domain model for the free induction decay with a Gaussian Markov random field prior, a new optimization objective is derived that encourages smooth parameter maps. Using a particular parameterization of the prior, smooth damping, frequency and phase maps can be obtained whilst preserving sharp spatial features in the amplitude map. A Monte Carlo study based on two sets of simulated data demonstrates that the variance of the estimated parameter maps can be reduced considerably, even below the Cramer-Rao lower bound, when using spatial prior knowledge. Long-TE (1) H MRSI at 1.5 T of a patient with a brain tumor shows that the use of the spatial prior resolves the overlapping peaks of choline and creatine when a single voxel method fails to do so. Improved and detailed metabolic maps can be derived from high-spatial-resolution, short-TE (1) H MRSI at 3 T. Finally, the evaluation of four series of long-TE brain MRSI data with various signal-to-noise ratios shows the general benefit of the proposed approach.
    Type of Publication: Journal article published
    PubMed ID: 21538636
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  • 12
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; IN-VIVO ; DIFFERENTIATION ; MICE ; BONE-MARROW ; MOUSE ; NATURAL-KILLER-CELLS ; HEMATOPOIETIC PROGENITOR CELLS ; LYMPHOID ORGANS ; dendritic cell ; HOMEOSTASIS ; STEADY-STATE ; FLT3 LIGAND
    Abstract: Bone marrow-derived dendritic cell (DC) precursors seed peripheral organs, where they encounter diverse cellular environments during their final differentiation into DCs. Flt3 ligand (Flt3-L) is critical for instructing DC generation throughout different organs. However, it remains unknown which cells produce Flt3-L and, importantly, which cellular source drives DC development in such a variety of organs. Using a novel BAC transgenic Flt3-L reporter mouse strain coexpressing enhanced GFP and luciferase, we show ubiquitous Flt3-L expression in organs and cell types. These results were further confirmed at the protein level. Although Flt3-L was produced by immune and nonimmune cells, the source required for development of the DC compartment clearly differed among organs. In lymphoid organs such as the spleen and bone marrow, Flt3-L production by hemopoietic cells was critical for generation of normal DC numbers. This was unexpected for the spleen because both immune and nonimmune cells equally contributed to the Flt3-L content in that organ. Thus, localized production rather than the total tissue content of Flt3-L in spleen dictated normal splenic DC development. No differences were observed in the number of DC precursors, suggesting that the immune source of Flt3-L promoted pre-cDC differentiation in spleen. In contrast, DC generation in the lung, kidney, and pancreas was mostly driven by nonhematopoietic cells producing Flt3-L, with little contribution by immune cells. These findings demonstrate a high degree of flexibility in Flt3-L-dependent DC generation to adapt this process to organ-specific cellular environments encountered by DC precursors during their final differentiation.
    Type of Publication: Journal article published
    PubMed ID: 22198954
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  • 13
    Keywords: CANCER ; EXPRESSION ; carcinoma ; Germany ; TUMORS ; N-nitrosomorpholine ; PYRUVATE-KINASE ; CELLULAR PHENOTYPE ; FRIEDREICH ATAXIA ; GLYCOGEN-SYNTHASE ; HEPATOCELLULAR GLYCOGENOSIS ; PROTEIN-KINASE AMPK ; RAT HEPATIC PRENEOPLASIA ; STOP EXPERIMENTS ; TIME-DEPENDENCE
    Abstract: Friedreich's ataxia is an inherited neurodegenerative disease caused by the reduced expression of the mitochondrially active protein frataxin. We have previously shown that mice with a hepatocyte-specific frataxin knockout (AlbFxn(-/-)) develop multiple hepatic tumors in later life. In the present study, hepatic carbohydrate metabolism in AlbFxn(-/-) mice at an early and late life stage was analyzed. In young (5-week-old) AlbFxn(-/-) mice hepatic ATP, glucose-6-phosphate and glycogen levels were found to be reduced by approximately 74, 80 and 88%, respectively, when compared with control animals. This pronounced ATP, G6P and glycogen depletion in the livers of young mice reverted in older animals: while half of the mice die before 30 weeks of age, the other half reaches 17 months of age and exhibits glycogen, G6P and ATP levels similar to those in age-matched controls. A key event in this respect seems to be the up-regulation of GLUT1, the predominant glucose transporter in fetal liver parenchyma, which became evident in AlbFxn(-/-) mice being 5-12 weeks of age. The most significant histological findings in animals being 17 or 22 months of age were the appearance of multiple clear cell, mixed cell and basophilic foci throughout the liver parenchyma as well as the development of hepatocellular adenomas and carcinomas. The hepatocarcinogenic process in AlbFxn(-/-) mice shows remarkable differences regarding carbohydrate metabolism alterations when compared with all other chemically and virally driven liver cancer models described up to now.
    Type of Publication: Journal article published
    PubMed ID: 22052287
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  • 14
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; DISTINCT ; CUTTING EDGE ; INFECTION ; ANTIGEN ; DENDRITIC CELLS ; T cells ; T-CELLS ; cytokines ; TRANSCRIPTION FACTORS ; CROSS-PRESENTATION ; GENE INDUCTION ; dendritic cell ; CELL BIOLOGY ; sepsis ; IFN-ALPHA/BETA ; RECEPTOR 4 ; splenic macrophages ; type I IFN
    Abstract: Early during Gram-negative sepsis, excessive release of pro-inflammatory cytokines can cause septic shock that is often followed by a state of immune paralysis characterized by the failure to mount adaptive immunity towards secondary microbial infections. Especially, the early mechanisms responsible for such immune hypo-responsiveness are unclear. Here, we show that TLR4 is the key immune sensing receptor to initiate paralysis of T-cell immunity after bacterial sepsis. Downstream of TLR4, signalling through TRIF but not MyD88 impaired the development of specific T-cell immunity against secondary infections. We identified type I interferon (IFN) released from splenic macrophages as the critical factor causing T-cell immune paralysis. Early during sepsis, type I IFN acted selectively on dendritic cells (DCs) by impairing antigen presentation and secretion of pro-inflammatory cytokines. Our results reveal a novel immune regulatory role for type I IFN in the initiation of septic immune paralysis, which is distinct from its well-known immune stimulatory effects. Moreover, we identify potential molecular targets for therapeutic intervention to overcome impairment of T-cell immunity after sepsis.
    Type of Publication: Journal article published
    PubMed ID: 22036947
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  • 15
    Keywords: CANCER ; Germany ; IN-VIVO ; VIVO ; PROTEIN ; METABOLISM ; TUMORS ; MECHANISM ; mechanisms ; colorectal cancer ; metastases ; chemotherapy ; adenocarcinoma ; PET ; neoadjuvant treatment ; K-RAS MUTATIONS ; cetuximab ; ESOPHAGOGASTRIC JUNCTION ; metabolic imaging ; F-18-FDG PET CT
    Abstract: BACKGROUND: The epidermal growth factor receptor monoclonal antibody cetuximab has proven activity in metastatic colorectal cancer. To date, the mechanisms of action are not completely understood. Especially the impact on tumor glucose metabolism, or tumor vascularization remains largely unclear. The understanding of mechanisms such as early changes in tumor metabolism is of clinical importance since there may be a substantial influence on choice and sequence of drug combinations. Early signals of response to cetuximab may prove useful to identify patients having a relevant clinical treatment benefit. The objective of this trial is to evaluate the predictive relevance of the relative change in 18 F-Fluorodeoxyglucose tumor uptake for early clinical response during short-term single agent treatment with cetuximab. Early clinical response will be routinely measured according to the response evaluation criteria in solid tumors. Accompanying research includes cytokine immune monitoring and analysis of tumor proteins and tumor genes. Methods/design The REMOTUX trial is an investigator-initiated, prospective, open-label, single-arm, single-center early exploratory predictive study. The first 18 F-FDG PET-CT is conducted at baseline followed by the run-in phase with cetuximab at days 1 and 8. At day 14, the second 18 F-FDG PET-CT is performed. Subsequently, patients are treated according to the Folfiri-cetuximab regimen as an active and approved first-line regimen for metastatic colorectal carcinoma. At day 56, clinical response is evaluated with a CT-scan compared to the baseline analysis. Tracer uptake is assessed using standardized uptake values (SUVs). The main hypothesis to be tested in the primary analysis is whether or not the relative change in the SUV from baseline to day 14 has any predictive relevance for early clinical response determined at day 56. Patients are followed until death from any cause or until 24 months after the last patient has ended trial treatment. DISCUSSION: The aim of this trial is to evaluate metabolic changes in metastatic colorectal cancer during short-term single agent treatment with cetuximab and to analyse their potential of predicting early clinical response. This could be helpful to answer the question if early identification of patients not responding to cetuximab is possible. Trial registration ClinicalTrials.gov NCT200811021020; EudraCT 200901327923.
    Type of Publication: Journal article published
    PubMed ID: 22439666
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  • 16
    Keywords: Germany ; DIAGNOSIS ; MORTALITY ; RISK ; FAILURE ; PREVALENCE ; QUESTIONNAIRE ; DISABILITY ; PEOPLE ; OLDER-ADULTS
    Abstract: Objectives To develop and evaluate a modification of the Fried frailty assessment using population-independent cutpoints and to determine frailty prevalence of community-dwelling elderly people in a German population. Design Cross-sectional analysis of 8-year follow-up data of a large German cohort study. Setting Saarland, Germany. Participants Three thousand one hundred twelve community-dwelling adults aged 59 and older. Measurements Frailty was operationalized using modified Fried frailty criteria. Criteria were categorized according to quintiles (lowest-quintile approach) or using population-independent cutpoints derived from the literature (population-independent approach). Agreement and construct validity of frailty classification according to both approaches were evaluated according to weighted kappa (kappa) and Spearman rank correlation (r(Sp)). Associations between frailty and covariates were assessed using multiple logistic regression models. Results Although more participants were identified as frail according to the population-independent index (8.9%) than the lowest-quintile index (6.5%), agreement and correlation of frailty classification using both approaches was high (kappa = 0.75 and r(Sp) = 0.84). Sex differences in frailty prevalence were more pronounced when the population-independent approach was used (women 11.4%; men 6.1%). Similarly strong significant associations with sociodemographic, lifestyle, and medical factors such as older age, female sex, smoking, and obesity were seen for both approaches. Conclusion The modified Fried index using literature-derived cutpoints independent from the frailty criteria distributions in the underlying study population showed good correlation with the lowest-quintile approach and enables prevalence estimates that are directly comparable between different populations.
    Type of Publication: Journal article published
    PubMed ID: 23043490
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  • 17
    Keywords: CANCER ; SURVIVAL ; Germany ; BREAST-CANCER ; COLORECTAL-CANCER ; UNITED-STATES ; GASTRIC-CANCER ; TRENDS ; PATIENT SURVIVAL ; PERIOD ANALYSIS ; HELICOBACTER-PYLORI INFECTION ; cancer survival ; UP-TO-DATE ; SOCIOECONOMIC INEQUALITIES
    Abstract: BACKGROUND: Until recently, population-based data of cancer survival in Germany mostly relied on one registry covering -1 million people (1.3% of the German population). Here, we provide up-to-date cancer survival estimates for Germany based on data from 11 population-based cancer registries, covering 33 million people and compare them to survival estimates from the United States. PATIENTS AND METHODS: Cancer patients diagnosed in 1997-2006 were included. Period analysis was employed to calculate 5-year relative survival for 38 cancers for 2002-2006. German and USA survival rates were compared utilizing the Surveillance, Epidemiology and End Results 13 database. RESULTS: Five-year relative survival 〉80% was observed for testicular cancer (93.5%), skin melanoma (89.4%), cancers of the prostate (89.1%) and thyroid (87.8%), Hodgkin's lymphoma (84.5%) and cancers of the breast (83.7%) and endometrium (81.0%), which together account for almost 40% of cases. For the majority of cancers, German survival estimates were close to or below those in the United States. Exceptions with higher survival in Germany were cancers of the stomach, pancreas and kidney and Hodgkin's lymphoma. CONCLUSIONS: German cancer survival estimates are mostly higher than the 2000-2002 pan-European estimates. Further research is needed to investigate causes responsible for differences between German and USA cancer survival rates.
    Type of Publication: Journal article published
    PubMed ID: 21597096
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  • 18
    Keywords: RECEPTOR ; APOPTOSIS ; ENDOTHELIAL-CELLS ; Germany ; IN-VIVO ; THERAPY ; ACTIVATION ; LIGAND ; T-CELLS ; MOUSE ; transactivation ; SMOOTH-MUSCLE-CELLS ; hematology ; ACUTE KIDNEY INJURY ; PAR1 ; REDUCED ANTICOAGULANT ACTIVITY ; THROMBIN
    Abstract: The cytoprotective effects of activated protein C (aPC) are well established. In contrast, the receptors and signaling mechanism through which aPC conveys cytoprotection in various cell types remain incompletely defined. Thus, within the renal glomeruli, aPC preserves endothelial cells via a protease-activated receptor-1 (PAR-1) and endothelial protein C receptor-dependent mechanism. Conversely, the signaling mechanism through which aPC protects podocytes remains unknown. While exploring the latter, we identified a novel aPC/PAR-dependent cytoprotective signaling mechanism. In podocytes, aPC inhibits apoptosis through proteolytic activation of PAR-3 independent of endothelial protein C receptor. PAR-3 is not signaling competent itself as it requires aPC-induced heterodimerization with PAR-2 (human podocytes) or PAR-1 (mouse podocytes). This cytoprotective signaling mechanism depends on caveolin-1 dephosphorylation. In vivo aPC protects against lipopolysaccharide-induced podocyte injury and proteinuria. Genetic deletion of PAR-3 impairs the nephroprotective effect of aPC, demonstrating the crucial role of PAR-3 for aPC-dependent podocyte protection. This novel, aPC-mediated interaction of PARs demonstrates the plasticity and cell-specificity of cytoprotective aPC signaling. The evidence of specific, dynamic signaling complexes underlying aPC-mediated cytoprotection may allow the design of cell type specific targeted therapies.
    Type of Publication: Journal article published
    PubMed ID: 22117049
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  • 19
    Keywords: IN-VITRO ; Germany ; PERMEABILITY BARRIER ; SUBSTRATE-SPECIFICITY ; CANDIDA-ALBICANS ; STRATUM-CORNEUM ; CATHEPSIN-D ; ATOPIC-DERMATITIS ; (DIHYDRO)CERAMIDE SYNTHASE ; NEONATAL SKIN ; OMEGA-HYDROXYCERAMIDES
    Abstract: The stratum corneum as the outermost epidermal layer protects against exsiccation and infection. Both the underlying cornified envelope (CE) and the intercellular lipid matrix contribute essentially to these two main protective barriers. Epidermis-unique ceramides with ultra-long-chain acyl moities (ULC-Cers) are key components of extracellular lipid lamellae (ELL) and are bound to CE proteins, thereby contributing to the cornified lipid envelope (CLE). Here, we identified human and mouse ceramide synthase 3 (CerS3), among CerS1-6, to be exclusively required for the ULC-Cer synthesis in vitro and of mouse CerS3 in vivo. Deficiency of CerS3 in mice results in complete loss of ULC-Cers (〉= C26), lack of continuous ELL and a non-functional CLE. Consequently, newborn mutant mice die shortly after birth from transepidermal water loss. Mutant skin is prone to Candida albicans infection highlighting ULC-Cers to be pivotal for both barrier functions. Persistent periderm, hyperkeratosis and deficient cornification are hallmarks of mutant skin demonstrating loss of Cers to trigger a keratinocyte maturation arrest at an embryonic pre-barrier stage
    Type of Publication: Journal article published
    PubMed ID: 22038835
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  • 20
    Keywords: SURVIVAL ; Germany ; THERAPY ; CLASSIFICATION ; ACTIVATION ; IMPACT ; cytogenetics ; ABERRATIONS ; IN-SITU HYBRIDIZATION ; KAPPA-B ; hematology ; unfolded protein response ; Lenalidomide ; INTERNATIONAL STAGING SYSTEM ; PROTEASOME INHIBITORS INDUCE
    Abstract: In patients with Multiple Myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. Here we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the two-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem-cell transplantation (arm B) in comparison to standard treatment without bortezomib (arm A). For all analyzed chromosomal aberrations, progression free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib-arm as compared to the standard arm. Strikingly, patients with del(17p13) benefitted most from the bortezomib-containing treatment (median PFS time: A: 12.0 months, B: 26.2 months, p=0.024; 3yr-OS rates: A: 17%, B: 69%, p=0.028). After multivariate analysis, del(17p13) was an independent predictor for PFS (p〈0.0001) and OS (p〈0.0001) in arm A, whereas no statistical significant effect on PFS (p=0.28) and OS (p=0.12) was seen in arm B. In conclusion, the adverse impact of del(17p13) on PFS and OS could be significantly reduced by the bortezomib-based treatment, suggesting that long-term administration of bortezomib should be recommended for patients carrying del(17p13). This trial is registered at ISRCTN as ISRCTN64455289
    Type of Publication: Journal article published
    PubMed ID: 22160383
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  • 21
    Keywords: SURVIVAL ; Germany ; DIAGNOSIS ; POPULATION ; statistics ; EUROPE ; PERIOD ANALYSIS ; PROGRESS ; EUROCARE-4 ; 21ST-CENTURY
    Abstract: INTRODUCTION: Evaluation of oncological outcome and prognostic factors of patients with primary breast cancer treated at a certified academic breast unit. PATIENTS AND METHODS: We prospectively collected data of 3338 patients, diagnosed with primary breast cancer between 01.01.2003 and 31.12.2010 and treated at the Breast Unit Heidelberg, Germany, in order to analyze outcome in clinical practice. We evaluated local control rate (LCR), disease-free survival (DFS), distant disease-free survival (DDFS), observed overall survival (OS) and age-adjusted relative overall survival (ROS). In addition, the impact of known prognostic factors on these outcome variables was examined in univariate and multivariate analyses. RESULTS: Of all patients, 368 (11.0%) had carcinoma in situ (CIS) and 197 (5.9%) had bilateral cancers. For the 2970 patients with invasive cancer, of which 49 patients (1.7%) had metastastic disease at time of diagnosis, DFS, LCR, DDFS, OS and ROS at 5 years were 79.8%, 84.7%, 81.2%, 86.3%, and 89.8%, respectively. In multivariate analysis age, pT category, nodal status, hormone receptor status and grading were identified as independent prognostic factors for OS. CONCLUSION: Compared with recent population-based reports from Germany, more favourable patient characteristics and nominally higher survival was found among this large cohort of patients with primary breast cancer treated at a single certified breast unit.
    Type of Publication: Journal article published
    PubMed ID: 22310244
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  • 22
    Keywords: CANCER ; radiotherapy ; Germany ; IMPACT ; QUALITY ; MALIGNANCIES ; CONFORMAL RADIOTHERAPY ; RADIATION-THERAPY ; HEAD ; SKULL BASE ; IMRT ; CONE-BEAM CT ; Image-guided radiotherapy ; Mega-voltage cone beam CT ; Radiation Dosage calculation ; Radiotherapy,intensity-modulated
    Abstract: PURPOSE: The goal of this work was to compare different methods of incorporating the additional dose of mega-voltage cone-beam CT (MV-CBCT) for image-guided intensity modulated radiotherapy (IMRT) of different tumor entities. MATERIAL AND METHODS: The absolute dose delivered by the MV-CBCT was calculated and considered by creating a scaled IMRT plan (scIMRT) by renormalizing the clinically approved plan (orgIMRT) so that the sum with the MV-CBCT dose yields the same prescribed dose. In the other case, a newly optimized plan (optIMRT) was generated by including the dose distribution of the MV-CBCT as pre-irradiation. Both plans were compared with the orgIMRT plan and a plan where the last fraction was skipped. RESULTS: No significant changes were observed regarding the 95% conformity index of the target volume. The mean dose of the organs at risk (OAR) increased by approx. 7% for the scIMRT plan and 5% for the optIMRT plan. A significant increase of the mean dose to the outline contour was observed, ranging from 3.1 +/- 1.3% (optIMRT) to 13.0 +/- 6.1% (scIMRT) for both methods over all entities. If the dose of daily MV-CBCT would have been ignored, the additional dose accumulated to nearly a whole treatment fraction with a general increase of approx. 10% to the OARs and approx. 4% to the target volume. CONCLUSION: Both methods of incorporating the additional MV-CBCT dose into the treatment plan are suitable for clinical practice. The dose distribution of the target volume could be achieved as conformal as with the orgIMRT plan, while only a moderate increase of mean dose to OAR was observed.
    Type of Publication: Journal article published
    PubMed ID: 22215128
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  • 23
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; EXPRESSION ; IN-VITRO ; TUMOR-CELLS ; carcinoma ; Germany ; PATHWAY ; THERAPY ; DEATH ; GENE ; GENE-EXPRESSION ; TUMORS ; LINES ; NF-KAPPA-B ; LIGAND ; breast cancer ; BREAST-CANCER ; TARGET ; p53 ; MEDIATED APOPTOSIS ; ENDOPLASMIC-RETICULUM STRESS ; T-cell leukemia
    Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that kills various tumor cells without damaging normal tissues. However, many cancers remain resistant to TRAIL. To overcome TRAIL resistance, combination therapies using sensitizers of the TRAIL pathway would be an efficacious approach. To investigate potential sensitizers of TRAIL-induced apoptosis, we used TRAIL-resistant human T cell leukemia virus type 1 (HTLV-1)-associated adult T cell leukemia/lymphoma (ATL) cells as a model system. So far, HTLV-1-associated ATL is incurable by presently known therapies. Here, we show that wogonin and the structurally related natural flavones apigenin and chrysin break TRAIL resistance in HTLV-1-associated ATL by transcriptional down-regulation of c-FLIP, a key inhibitor of death receptor signaling, and by up-regulation of TRAIL receptor 2 (TRAIL-R2). This effect is mediated through transcriptional inhibition of the p53 antagonist murine double minute 2 (Mdm2), leading to an increase in p53 levels and, consequently, to up-regulation of the p53 target gene TRAIL-R2. We also show that these flavones can sensitize to TNFalpha- and CD95-mediated cell death. Furthermore, we show that wogonin, apigenin, and chrysin also enhance TRAIL-mediated apoptosis in other human cancer cell lines including breast cancer cell line MDA-MB-231, colon cancer cell line HT-29, hepatocellular carcinoma cell line HepG2, melanoma cell line SK-MEL-37, and pancreatic carcinoma cell line Capan-1 by the same mechanism. Thus, our study suggests the potential use of these flavones as an adjuvant for TRAIL-mediated anticancer therapy.
    Type of Publication: Journal article published
    PubMed ID: 22086925
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  • 24
    Keywords: CANCER ; SURVIVAL ; Germany ; STAGE ; LONG-TERM SURVIVAL ; PROGNOSTIC-SIGNIFICANCE ; ENDOMETRIAL CANCER ; POSTMENOPAUSAL WOMEN ; cancer registries ; PERIOD ANALYSIS ; EMPIRICAL-EVALUATION ; ENDOGENOUS HORMONES ; UP-TO-DATE ; ESTROGEN-RECEPTOR-ALPHA ; ER-ALPHA ; SOCIETY GUIDELINES ; Population based ; UTERINE SARCOMAS
    Abstract: Background: Population-based studies on endometrial cancer providing survival estimates by age, histology, and stage have been sparse. We aimed to derive most up-to-date and detailed survival estimates for endometrial cancer patients in Germany. Methods: We used a pooled German national dataset including data from 11 cancer registries covering a population of 33 million people. 30,906 patients diagnosed with endometrial cancer in 1997-2006 were included. Period analysis was performed to calculate 5-year relative survival (RS) in 2002-2006. Trends in survival between 2002 and 2006 were examined using model-based period analysis. Age-adjustment was performed using five age groups (15-44, 45-54, 55-64, 65-74, and 75+ years). Results: Overall, age-adjusted 5-year relative survival in 2002-2006 was 81%. A moderate age gradient was observed, with 5-year RS decreasing from 90% in the age group 15-49 years to 75% in the age group 70+ years. Furthermore prognosis varied strongly by histologic subtypes and stage, with age-adjusted 5-year RS ranging from 43% (for sarcoma) to 94% (for squamous metaplasia), and reaching 91% for localized, 51% for regional, and 20% for distant stage. Except for age group 65-74 years, no significant improvement in survival was seen during the recent 5-year period under investigation. Conclusion: In this comprehensive population-based survival analysis of patients with endometrial cancer from Germany, prognosis of endometrial cancer moderately varied by age, and strongly varied by histology and stage. While prognosis is rather good overall, further improvement in 5-year relative survival of endometrial cancer patients has been stagnating in the early 21st century
    Type of Publication: Journal article published
    PubMed ID: 22459016
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  • 25
    Keywords: CANCER ; Germany ; RISK ; EXPERIENCE ; OBESITY ; TISSUE FACTOR ; RETROSPECTIVE COHORT ; REPRODUCTIVE HISTORY ; ISCHEMIC-HEART-DISEASE ; FETAL INJURY ; HYPERTENSIVE DISORDERS ; LINK ; STILLBIRTH
    Abstract: Objectives To examine whether pregnancy loss (miscarriage, abortion or stillbirth) is associated with a higher risk of myocardial infarction (MI) and stroke. Design Population-based prospective cohort study. Setting The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort in Heidelberg, Germany (mean follow-up 10.8 years). Participants All 11 518 women who had ever been pregnant (aged 35-66). Results Out of the participants, 2876 (25%) had at least one miscarriage, 2053 (18%) had at least one abortion and 209 (2%) had at least one stillbirth. During the follow-up, 82 cases of MI and 112 of stroke (confirmed by medical records) occurred in these women. Each stillbirth increased the risk of MI 2.65 times (95% CI for age-adjusted HR 1.37 to 5.12; HR adjusted for age, smoking, alcohol consumption, body mass index, waist to hip ratio, physical activity, education, number of pregnancies, hypertension, hyperlipidaemia and diabetes mellitus: HR 2.32 95% CI 1.19 to 4.50, 95% CI). Recurrent miscarriage (〉3) was associated with about nine times higher risk of MI (age-adjusted HR=8.90, 95% CI 3.18 to 24.90; fully adjusted HR 5.06, 95% CI 1.26 to 20.29). No significant association was found between abortion and MI or between any type of pregnancy loss and stroke. Conclusions These results suggest that women who experience spontaneous pregnancy loss are at a substantially higher risk of MI later in life. Recurrent miscarriage and stillbirth are strong sex-specific predictors for MI and thus should be considered as important indicators for cardiovascular risk factors monitoring and preventive measures. Further research is suggested to elucidate underlying risk factors of pregnancy loss that at the same time strongly predispose to cardiovascular disease
    Type of Publication: Journal article published
    PubMed ID: 21123827
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  • 26
    Keywords: Germany ; SUPPORT ; VOLUME ; MRI ; CEREBELLUM ; WHITE-MATTER ; LIGHT ; METAANALYSIS ; STRUCTURAL BRAIN ABNORMALITIES ; VOXEL-BASED MORPHOMETRY ; 1ST-EPISODE SCHIZOPHRENIA ; CHILDHOOD-ONSET SCHIZOPHRENIA ; Early-onset schizophrenia ; GREY-MATTER ; VBM ; vermis ; visual system
    Abstract: ABSTRACT BACKGROUND AND PURPOSE Imaging studies of patients with schizophrenia have described a variety of cerebral alterations. However, long-term medication and the chronicity of the disorder may have contributed substantially to these alterations. Studies examining patients in the early stages of the disorder reduce the possibility of such confounding factors but are rare. In light of this, the aim of the present study was to examine adolescents in the early stages of the disorder to observe primary structural brain abnormalities. METHODS Gray and white matter were measured in 13 adolescents with schizophrenia and 13 healthy controls matched for age, gender, handedness, and school type using voxel-based morphometry. RESULTS Subjects with schizophrenia displayed decreased gray matter in the cerebellar vermis, and alterations in the left putamen and in several parts of the visual system. CONCLUSIONS These findings support cerebellar involvement in the pathogenesis of schizophrenia, and the alterations observed in several parts of the visual system may provide insights into the nature of hallucinations and delusional interpretations.
    Type of Publication: Journal article published
    PubMed ID: 20572905
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  • 27
    Keywords: Germany ; DIFFERENTIATION ; ABSENCE ; embryonal tumors
    Type of Publication: Journal article published
    PubMed ID: 21086133
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  • 28
    Keywords: Germany ; IN-VIVO ; FOLLOW-UP ; IMPLANTATION ; human brain ; ARTICULAR-CARTILAGE ; 3.0-TESLA MRI ; AUTOLOGOUS CHONDROCYTE TRANSPLANTATION ; KNEE CARTILAGE ; PATELLAR CARTILAGE ; REPAIR TISSUE
    Abstract: Purpose: To compare a glycosaminoglycan chemical exchange saturation transfer (gagCEST) imaging method, which enables sampling of the water signal as a function of the presaturation offset (z-spectrum) at 13 points in clinically feasible imaging times, with sodium 23 ((23)Na) magnetic resonance (MR) imaging in patients after cartilage repair surgery (matrix-associated autologous chondrocyte transplantation and microfracture therapy). Materials and Methods: One female patient (67.3 years), and 11 male patients (median age, 28.8 years; interquartile range [IQR], 24.6-32.3 years) were examined with a 7-T whole-body system, with approval of the local ethics committee after written informed consent was obtained. A modified three-dimensional gradient-echo sequence and a 28-channel knee coil were used for gagCEST imaging. (23)Na imaging was performed with a circularly polarized knee coil by using a modified gradient-echo sequence. Statistical analysis of differences and Spearman correlation were applied. Results: The median of asymmetries in gagCEST z-spectra summed over all offsets from 0 to 1.3 ppm was 7.99% (IQR, 6.33%-8.79%) in native cartilage and 5.13% (IQR, 2.64%-6.34%) in repair tissue. A strong correlation (r = 0.701; 95% confidence interval: 0.21, 0.91) was found between ratios of signal intensity from native cartilage to signal intensity from repair tissue obtained with gagCEST or (23)Na imaging. The median of dimensionless ratios between native cartilage and repair tissue was 1.28 (IQR, 1.20-1.58) for gagCEST and 1.26 (IQR, 1.21-1.48) for (23)Na MR imaging. Conclusion: The high correlation between the introduced gagCEST method and (23)Na imaging implies that gagCEST is a potentially useful biomarker for glycosaminoglycans.
    Type of Publication: Journal article published
    PubMed ID: 21460030
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  • 29
    Keywords: CELLS ; IN-VITRO ; Germany ; SEQUENCE ; virus ; HODGKINS-DISEASE ; MESSENGER-RNAS ; BLOOD MONONUCLEAR-CELLS ; BONE-MARROW-CELLS ; ACUTE RESPIRATORY-DISEASES ; DNA VIRUS ; INTRAGENOMIC REARRANGEMENT ; PORCINE CIRCOVIRUS ; TORQUETENOVIRUS ; TT-VIRUS
    Abstract: The family Anelloviridae comprises torque teno viruses (TTVs) diverse in genome structure and organization. The isolation of a large number of TTV genomes (TTV Heidelberg [TTV-HD]) of 26 TTV types is reported. Several isolates from the same type indicate sequence variation within open reading frame 1 (ORF1), resulting in considerably modified open reading frames. We demonstrate in vitro replication of 12 full-length genomes of TTV-HD in 293TT cells. Propagation of virus was achieved by several rounds of infections using supernatant and frozen whole cells of initially infected cells. Replication of virus was measured by PCR amplification and transcription analyses. Subgenomic molecules (mu TTV), arising early during propagation and ranging in size from 401 to 913 bases, were cloned and characterized. Propagation of these mu TTV in in vitro cultures was demonstrated in the absence of full-length genomes
    Type of Publication: Journal article published
    PubMed ID: 21593173
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  • 30
    Keywords: carcinoma ; Germany ; INHIBITION ; PROTEIN ; ACTIVATION ; antibody ; immunohistochemistry ; MUTATION ; MELANOMA ; SIGNALING PATHWAY ; THYROID-CARCINOMA ; SARCOMA ; B-RAF ; BRAF ; HIGH-FREQUENCY ; KRAS MUTATIONS ; biomarker ; monoclonal antibody ; NRAS ; IDH1 ANTIBODY ; Papillary thyroid carcinoma ; V600E
    Abstract: Activating mutations of the serine threonine kinase v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) are frequent in benign and malignant human tumors and are emerging as an important biomarker. Over 95% of BRAF mutations are of the V600E type and specific small molecular inhibitors are currently under preclinical or clinical investigation. BRAF mutation status is determined by DNA-based methods, most commonly by sequencing. Here we describe the development of a monoclonal BRAF V600E mutation-specific antibody that can differentiate BRAF V600E and wild type protein in routinely processed formalin-fixed and paraffin-embedded tissue. A total of 47 intracerebral melanoma metastases and 21 primary papillary thyroid carcinomas were evaluated by direct sequencing of BRAF and by immunohistochemistry using the BRAF V600E mutation-specific antibody clone VE1. Correlation of VE1 immunohistochemistry and BRAF sequencing revealed a perfect match for both papillary thyroid carcinomas and melanoma metastases. The staining intensity in BRAF V600E mutated tumor samples ranged from weak to strong. The generally homogenous VE1 staining patterns argue against a clonal heterogeneity of the tumors investigated. Caution is essential when only poorly preserved tissue is available for VE1 immunohistochemical analysis or when tissues with only little total BRAF protein are analyzed. Immunohistochemistry using antibody VE1 may substantially facilitate molecular analysis of BRAF V600E status for diagnostic, prognostic, and predictive purposes
    Type of Publication: Journal article published
    PubMed ID: 21638088
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  • 31
    Keywords: Germany ; EPIDEMIOLOGY ; smoking ; ethanol ; VALIDITY ; STOMACH-CANCER ; DRINKING ; N-NITROSO COMPOUNDS ; BEVERAGES ; NITROSAMINES
    Abstract: Background: Gastric cancer (GC) is the second leading cause of cancer death worldwide. The association between alcohol consumption and GC has been investigated in numerous epidemiologic studies with inconsistent results. Objective: We evaluated the association between alcohol consumption and GC risk. Design: We conducted a prospective analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which included 444 cases of first primary gastric adenocarcinoma. HRs and 95% CIs for GC were estimated by using multivariable Cox proportional hazards regression for consumption of pure ethanol in grams per day, with stratification by smoking status, anatomic subsite (cardia, noncardia), and histologic subtype (diffuse, intestinal). In a subset of participants, results were further adjusted for baseline Helicobacter pylori serostatus. Results: Heavy (compared with very light) alcohol consumption (〉= 60 compared with 0.1-4.9 g/d) at baseline was positively associated with GC risk (HR: 1.65; 95% CI: 1.06, 2.58), whereas lower consumption amounts (〈60 g/d) were not. When we analyzed GC risk by type of alcoholic beverage, there was a positive association for beer (〉= 30 g/d; HR: 1.75; 95% CI: 1.13, 2.73) but not for wine or liquor. Associations were primarily observed at the highest amounts of drinking in men and limited to noncardia subsite and intestinal histology; no statistically significant linear dose-response trends with GC risk were observed. Conclusion: Heavy (but not light or moderate) consumption of alcohol at baseline (mainly from beer) is associated with intestinal-type noncardia GC risk in men from the EPIC cohort.
    Type of Publication: Journal article published
    PubMed ID: 21993435
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  • 32
    Keywords: CANCER ; Germany ; DIAGNOSIS ; MORTALITY ; COMPONENTS ; COLORECTAL-CANCER ; INSULIN-RESISTANCE SYNDROME
    Abstract: Metabolic syndrome (MetS) is purportedly related to risk of developing colorectal cancer; however, the association of MetS, as defined according to recent international criteria, and colorectal cancer has not been yet evaluated. In particular, it remains unclear to what extent the MetS components individually account for such an association. We addressed these issues in a nested case-control study that included 1,093 incident cases matched (1: 1) to controls by using incidence density sampling. Conditional logistic regression was used to estimate relative risks (RR) and 95% CIs. MetS was defined according to the criteria of the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII), the International Diabetes Federation (IDF), and the 2009 harmonized definition. Among individual components, abdominal obesity (RR = 1.51; 95% CI: 1.16-1.96) was associated with colon cancer, whereas abnormal glucose metabolism was associated with both colon (RR = 2.05; 95% CI: 1.57-2.68) and rectal cancer (RR = 2.07; 95% CI: 1.45-2.96). MetS, as defined by each of the definitions, was similarly associated with colon cancer (e. g., RR = 1.91; 95% CI: 1.47-2.42 for MetS by NCEP/ATPIII), whereas MetS by NCEP/ATPIII, but not IDF or harmonized definition, was associated with rectal cancer (RR = 1.45; 95% CI: 1.02-2.06). Overall, these associations were stronger in women than in men. However, the association between MetS and colorectal cancer was accounted for by abdominal obesity and abnormal glucose metabolism such that MetS did not provide risk information beyond these components (likelihood ratio test P = 0.10 for MetS by NCEP/ATPIII). These data suggest that simple assessment of abnormal glucose metabolism and/or abdominal obesity to identify individuals at colorectal cancer risk may have higher clinical utility than applying more complex MetS definitions.
    Type of Publication: Journal article published
    PubMed ID: 21697276
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  • 33
    Keywords: IRRADIATION ; radiotherapy ; Germany ; VOLUME ; CELL-LINES ; RADIATION-THERAPY ; DOSE-RESPONSE ; HEAD ; RBE ; RELATIVE BIOLOGICAL EFFECTIVENESS ; proton therapy ; CAPACITY ; BEAMS ; Biological optimization ; Plan comparison
    Abstract: Purpose: To investigate in a simulation study whether using a variable relative biological effectiveness (RBE) in calculation and optimization of intensity-modulated proton therapy (IMPT) instead of using an RBE of 1.1 would result in significant changes in the RBE-weighted dose (RWD) distributions. Methods and Materials: For 4 patients with head-and-neck tumors, three IMPT plans were prepared respectively. The first plan was physically optimized (IMPT-PO plan), and the RWD was calculated with a constant RBE of 1.1. Then the plan's RWD was recalculated (IMPT-R plan) using a variable RBE model taking into account the linear energy transfer (LET) and tissue-specific radiobiological parameters. The third IMPT plan was optimized using a biological optimization routine (IMPT-BO plan). Results: Comparing the IMPT-PO and IMPT-R plans, we observed that the RWD in radioresistant tissues was more sensitive to the LET than in radiosensitive tissues. The IMPT-R plans were in general more inhomogeneous than the IMPT-PO plans. The differences of RWD distributions for all volumes between IMPT-PO and IMPT-BO plans complied with predefined dose volume constraints. The average LET was significantly lower in IMPT-BO plans than in IMPT-R plans. Conclusion: In radioresistant normal tissues caution has to be used regarding the LET distribution because these are most sensitive to changes in the LET. Biological optimization of IMPT plans based on the organ-specific biological parameters and LET distributions is feasible.
    Type of Publication: Journal article published
    PubMed ID: 20382482
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  • 34
    Keywords: Germany ; DIAGNOSIS ; TOOL ; PROTEIN ; DIFFERENTIATION ; antibody ; GLIOMAS ; oligodendroglioma ; 19Q ; IMMUNOREACTIVITY ; IDH1 ; CODON 132 MUTATION ; ISOCITRATE DEHYDROGENASE ; R132H ; CHROMOSOMES 1P ; Clear cell ; EXTRAVENTRICULAR NEUROCYTOMA ; NEUROEPITHELIAL TUMORS ; PEDIATRIC OLIGODENDROGLIOMAS
    Abstract: Isocitrate dehydrogenase 1 (IDH1) mutations are frequent in astrocytomas, oligoastrocytomas and oligodendrogliomas. We previously reported the generation of a mutation-specific antibody that specifically detects R132H mutated IDH1 protein (clone H09). Here, we investigate the feasibility of H09 immunohistochemistry to differentiate between oligodendrogliomas/oligoastrocytomas and other tumors with similar morphology. A total of 274 brain tumors presenting with focal or extensive clear cell morphology were investigated. High numbers of H09-positive cases were observed in adult grade II oligodendrogliomas (67 of 74, 91%), grade III oligodendrogliomas (65 of 69, 94%), grade II oligoastrocytomas (11 of 14, 79%) and grade III oligoastrocytomas (10 of 11, 91%). All cases of pediatric oligodendrogliomas (n = 7), neurocytomas (n = 41, 35 central, 4 extraventricular, 2 cerebellar liponeurocytomas), dysembryoplastic neuroepithelial tumors (n = 21), clear cell ependymomas (n = 8), clear cell meningiomas (n = 9) as well as 12 primary glioblastomas with oligodendroglial differentiation and 5 pilocytic astrocytomas with oligodendroglial-like differentiation were negative for H09 immunohistochemistry. Three oligodendrogliomas with neurocytic differentiation had evidence of IDH1/IDH2 mutations either by H09 immunohistochemistry or direct sequencing. We conclude that in tumors with an oligodendroglioma-like morphology, binding of H09 is highly specific for oligodendrogliomas or oligoastrocytomas and substantially helps in the discrimination from other clear cell tumors. Negative H09 immunohistochemistry of an adult oligodendroglioma or oligoastrocytoma should prompt the consideration of other clear cell neoplasms. Further, our observations firmly assign oligodendrogliomas with neurocytic differentiation to the group of oligodendrogliomas and demonstrate that H09 is especially helpful for the difficult discrimination of such lesions from extraventricular neurocytomas.
    Type of Publication: Journal article published
    PubMed ID: 21069360
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    Keywords: Germany ; EXPERIENCE ; LOW-GRADE ASTROCYTOMAS ; METHYLATION ; BRAF ; GLIOMA ; ACUTE MYELOID-LEUKEMIA ; DNA-REPAIR PROTEIN ; MGMT ; PHASE-II TRIAL ; biomarker ; PROMOTER METHYLATION ; IDH1 ; NADP(+)-DEPENDENT ISOCITRATE DEHYDROGENASE ; CODON 132 MUTATION ; NEWLY-DIAGNOSED GLIOBLASTOMA ; GENE O-6-METHYLGUANINE-DNA METHYLTRANSFERASE ; MAPK PATHWAY ACTIVATION
    Abstract: For some, glioma biomarkers have been expected to solve common diagnostic problems in routine neuropathology service caused by insufficient material, technical shortcomings or lack of experience. Further, biomarkers should predict patient outcome and direct optimal therapy for the individual patient. Unfortunately, current biomarkers still fall somewhat short of these grand expectations. While there has been some progress, it has generally been slow and in small steps. In this review, the newest set of glioma biomarkers: O6-methylguanine-DNA methyltransferase (MGMT) methylation, BRAF fusion and IDH1 mutation are discussed. MGMT methylation is well established as a prognostic/predictive marker for glioblastoma; however, technical questions regarding testing remain, it is not currently utilized widely in guiding patient management, and it has proven to be of no assistance in diagnostics. In contrast, BRAF fusion and IDH1 mutation analyses promise to be very helpful for classifying and grading gliomas, while their potential predictive value has yet to be established
    Type of Publication: Journal article published
    PubMed ID: 21129061
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    Keywords: SURVIVAL ; carcinoma ; Germany ; antibody ; leukemia ; COLORECTAL CANCERS ; SARCOMA ; GLIOMAS ; HUMAN BREAST ; BRAIN-TUMORS ; IDH1 ; GLIOBLASTOMAS ; L-2-HYDROXYGLUTARIC ACIDURIA ; ISOCITRATE-DEHYDROGENASE 1 ; haematopoietic tumors ; IDH1 CODON 132
    Abstract: Aims: Mutations in the isocitrate dehydrogenase 1 gene have been identified recently to play a key role in diffuse astrocytoma and oligodendroglioma as well as in acute myeloid leukaemia. In glioma, IDH1R132H is the most common mutation type, which is associated with younger patient age and longer patient survival compared to wild-type status. Sequencing analyses of carcinomas and lymphomas have detected IDH1 mutations in only a small fraction of cases. In those studies, IDH1R132H was also the most frequent mutation. The aim of the present study was to analyse a comprehensive series of human tumours for IDH1R132H mutation. Methods and results: A total of 1844 formalin-fixed paraffin-embedded tumours, including carcinomas, sarcomas and haematopoietic tumours were investigated immunohistochemically using a mutationspecific antibody for IDH1 R132H. Our positive control series consisted of a collection of diffuse astrocytomas and oligodendrogliomas. No IDH1R132H mutation was found in this series. Conclusions: IDH1R132H mutations occur almost exclusively in glioma and acute myeloid leukaemia
    Type of Publication: Journal article published
    PubMed ID: 21707716
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    Keywords: SURVIVAL ; COMBINATION ; Germany ; lung cancer ; radiation ; TRIAL ; IMRT ; SOUTHWEST-ONCOLOGY-GROUP ; PHASE-III ; overall survival ; RADIATION-THERAPY IMRT ; elderly ; NSCLC ; LEUKEMIA GROUP-B ; RADIOIMMUNOTHERAPY ; cetuximab ; CHEMORADIOTHERAPY ; CONFORMAL RADIATION ; INDUCTION-CHEMOTHERAPY ; NODAL IRRADIATION
    Abstract: BACKGROUND: The aim of this study was to evaluate efficacy and toxicity of radioimmunotherapy with intensity-modulated radiation (IMRT) and cetuximab in stage III nonsmall cell lung cancer (NSCLC). METHODS: NEAR was a prospective, monocentric phase II trial including patients unfit for chemoradiation regimen; treatment consisted of IMRT and weekly cetuximab followed by a 13-week maintenance period. Primary endpoints were toxicity and feasibility; secondary endpoints were remission rates at completion of the planned treatment according to Response Evaluation Criteria In Solid Tumor (RECIST), local/distant progression-free survival, and overall survival. RESULTS: Thirty patients (median age, 71 years) were treated within the protocol. Overall response rate was 63% (partial remission: 19 of 30) patients. Median locoregional, distant, overall progression-free survival was 20.5, 10.9, and 8.5 months. Median overall survival was 19.5 months, with an estimated 1- and 2-year survival of 66.7% and 34.9% respectively. Stage (IIIA vs IIIB) and histologic subtype did not have a significant impact on survival rates in our patients. Treatment was tolerated well with only mild toxicity (grade three 3 pneumonitis: 3.3%, any grade three 3 acute toxicity: 36.7%). CONCLUSIONS: Combined radioimmunotherapy with cetuximab was safe and feasible, especially in elderly patients with multiple comorbidities. A more intensified regimen warranted investigation.
    Type of Publication: Journal article published
    PubMed ID: 21264838
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    Keywords: Germany ; DISEASE ; RNA ; transcription ; DNA ; CELL-DEATH ; UP-REGULATION ; p53 ; TIF-IA ; RIBOSOMAL-RNA SYNTHESIS ; MTOR PATHWAY ; PROTECTS MICE
    Abstract: The nucleolus represents an essential stress sensor for the cell. However, the molecular consequences of nucleolar damage and their possible link with neurodegenerative diseases remain to be elucidated. Here, we show that nucleolar damage is present in both genders in Parkinson's disease (PD) and in the pharmacological PD model induced by the neurotoxin 1,2,3,6-tetrahydro-1-methyl-4-phenylpyridine hydrochloride (MPTP). Mouse mutants with nucleolar disruption restricted to dopaminergic (DA) neurons show phenotypic alterations that resemble PD, such as progressive and differential loss of DA neurons and locomotor abnormalities. At the molecular level, nucleolar disruption results in increased p53 levels and downregulation of mammalian target of rapamycin (mTOR) activity, leading to mitochondrial dysfunction and increased oxidative stress, similar to PD. In turn, increased oxidative stress induced by MPTP causes mTOR and ribosomal RNA synthesis inhibition. Collectively, these observations suggest that the interplay between nucleolar dysfunction and increased oxidative stress, involving p53 and mTOR signaling, may constitute a destructive axis in experimental and sporadic PD.
    Type of Publication: Journal article published
    PubMed ID: 21228155
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    Keywords: PEPTIDE ; CELLS ; EXPRESSION ; Germany ; MODEL ; NETWORK ; GENE ; PROTEIN ; transcription ; MACROPHAGES ; PHOSPHORYLATION ; VARIANTS ; FORM ; ASSAY ; LOCALIZATION ; LECTIN ; STRUCTURAL-CHANGES ; ENDOGENOUS LECTINS ; LIGAND-BINDING ; EPITHELIUM ; PROMOTER REGION ; Phylogeny ; READING FRAMES ; GALACTOSIDE-BINDING LECTIN ; CELL-TYPE ; FUNCTIONAL GLYCOMICS ; N-GLYCANS
    Abstract: Characterization of all members of a gene family established by gene divergence is essential to delineate distinct or overlapping expression profiles and functionalities. Their activity as potent modulators of diverse physiological processes directs interest to galectins (endogenous lectins with beta-sandwich fold binding beta-galactosides and peptide motifs), warranting their study with the long-term aim of a comprehensive analysis. The comparatively low level of complexity of the galectin network in chicken with five members explains the choice of this organism as model. Previously, the three proto-type chicken galectins CG-1A, CG-1B, and CG-2 as well as the tandem-repeat-type CG-8 had been analyzed. Our study fills the remaining gap to determine gene structure, protein characteristics and expression profile of the fifth protein, that is, chimera-type chicken galectin-3 (CG-3). Its gene has a unique potential to generate variants: mRNA production stems from two promoters, alternative splicing of the form from the second transcription start point (tsp) can generate three mRNAs. The protein with functional phosphorylation sites in the N-terminus generated by transcription from the first tsp (tsp1CG-3) is the predominant CG-3 type present in adult tissues. Binding assays with neoglycoproteins and cultured cells disclose marked similarity to properties of human galectin-3. The expression and localization profiles as well as proximal promoter regions have characteristic features distinct from the other four CGs. This information on CG-3 completes the description of the panel of CGs, hereby setting the stage for detailed comparative analysis of the entire CG family, e.g., in embryogenesis.
    Type of Publication: Journal article published
    PubMed ID: 21290613
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    Keywords: CANCER CELLS ; Germany ; INHIBITION ; DISEASE ; ACTIVATED PROTEIN-KINASE ; MATURATION ; STRESS ; FUSION ; ISOLATED RAT HEPATOCYTES ; mTOR ; 3-METHYLADENINE ; MONITOR AUTOPHAGY
    Abstract: Background: Autophagy mediates lysosomal degradation of cytosolic components. Recent work has associated autophagic dysfunction with pathologies, including cancer and cardiovascular disease. To date, the identification of clinically-applicable drugs that modulate autophagy has been hampered by the lack of standardized assays capable of precisely reporting autophagic activity. Results: We developed and implemented a high-content, flow-cytometry-based screening approach for rapid, precise, and quantitative measurements of pharmaceutical control over autophagy. Our assay allowed for time-resolved individual measurements of autolysosome formation and degradation, and endolysosomal activities under both basal and activated autophagy conditions. As proof of concept, we analyzed conventional autophagy regulators, including cardioprotective compounds aminoimidazole carboxamide ribonucleotide (AICAR), rapamycin, and resveratrol, and revealed striking conditional dependencies of rapamycin and autophagy inhibitor 3 methyladenine (3-MA). To identify novel autophagy modulators with translational potential, we screened the Prestwick Chemical Library of 1,120 US Food and Drug Administration (FDA)-approved compounds for impact on autolysosome formation. In all, 38 compounds were identified as potential activators, and 36 as potential inhibitors of autophagy. Notably, amongst the autophagy enhancers were cardiac glycosides, from which we selected digoxin, strophanthidin, and digoxigenin for validation by standard biochemical and imaging techniques. We report the induction of autophagic flux by these cardiac glycosides, and the concentrations allowing for specific enhancement of autophagic activities without impact on endolysosomal activities. Conclusions: Our systematic analysis of autophagic and endolysosomal activities outperformed conventional autophagy assays and highlights the complexity of drug influence on autophagy. We demonstrate conditional dependencies of established regulators. Moreover, we identified new autophagy regulators and characterized cardiac glycosides as novel potent inducers of autophagic flux
    Type of Publication: Journal article published
    PubMed ID: 21635740
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    Cancer Biology and Therapy 8 (19), 1869-1870 
    Keywords: APOPTOSIS ; CANCER ; TUMOR-CELLS ; Germany ; THERAPY ; TARGET ; resistance ; chemotherapy ; traditional Chinese medicine ; ONCOLOGY ; pharmacogenomics ; DRUGS ; natural products ; nuclear factor kappaB
    Type of Publication: Journal article published
    PubMed ID: 19713746
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    Keywords: EXPRESSION ; Germany ; PATHWAY ; FOLLOW-UP ; RISK ; GENE ; polymorphism ; PLASMA ; BLOOD-PRESSURE ; POLYUNSATURATED FATTY-ACIDS ; BIRTH COHORT ; HELICOBACTER-PYLORI INFECTION ; ALLERGIC DISEASE ; EARLY-CHILDHOOD
    Abstract: Background: Breastfeeding is considered an optimal nutritional source of n-6 (omega-6) and n-3 (omega-3) fatty acids (FAs) for the proper visual and cognitive development of newborn children. In addition to maternal nutrition as an important regulator of FA concentrations, first results exist on an association of breast-milk FAs with single nucleotide polymorphisms (SNPs) in the FADS gene cluster, which encodes the rate-limiting enzymes in the elongation-desaturation pathway of long-chain polyunsaturated fatty acids (LC-PUFAs). Objective: We analyzed the influence of FADS SNPs on breast-milk FA concentrations and their time course during lactation in the Ulm Birth Cohort study, which comprised 772 nursing mothers at 1.5 mo after giving birth, and in a subset of 463 mothers who were still breastfeeding at 6 mo postpartum. Design: We conducted linear regression analysis of 8 FADS SNPs with FA concentrations at both time points separately and assessed the genotype effect over time in a longitudinal analysis by using a generalized estimating equation regression model. Results: We observed significant associations of FADS genotypes with arachidonic acid (AA) concentrations and the 20:4n-6/20:3n-6 ratio at both time points but no association of FADS SNPs with the time course of AA concentrations. A longitudinal analysis of FAs other than LC-PUFAs by genotype over time showed associations for dodecanoic acid, cis-15-tetracosenoic acid, and trans-9-octadecenoic acid. Conclusions: Maternal FADS genotypes are associated with breast-milk AA concentrations and might therefore influence the supply of this FA for children. Furthermore, our data indicate an interrelation between the LC-PUFA pathway and saturated and monounsaturated FAs.
    Type of Publication: Journal article published
    PubMed ID: 21147856
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