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  • 1
    Keywords: Germany ; TOOL ; PROTEIN ; COMPLEX ; COMPLEXES ; DNA ; INTERVENTION ; PREDICTION ; WEB ; QUESTIONNAIRE ; ANNOTATION ; GENOME DATABASE ; PROTEIN DATA ; RESOURCE ; SEQUENCE DATABASE
    Abstract: The Helmholtz Network for Bioinformatics (HNB) is a joint venture of eleven German bioinformatics research groups that offers convenient access to numerous bioinformatics resources through a single web portal. The 'Guided Solution Finder' which is available through the HNB portal helps users to locate the appropriate resources to answer their queries by employing a detailed, tree-like questionnaire. Furthermore, automated complex tool cascades ('tasks'), involving resources located on different servers, have been implemented, allowing users to perform comprehensive data analyses without the requirement of further manual intervention for data transfer and re-formatting. Currently, automated cascades for the analysis of regulatory DNA segments as well as for the prediction of protein functional properties are provided
    Type of Publication: Journal article published
    PubMed ID: 14734319
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  • 2
    Keywords: CANCER ; SURVIVAL ; carcinoma ; Germany ; LUNG ; TOXICITY ; lung cancer ; LUNG-CANCER ; DISEASE ; TIME ; PATIENT ; primary ; QUALITY ; treatment ; STAGE ; DIFFERENCE ; CLINICAL-TRIALS ; RATES ; chemotherapy ; ELDERLY-PATIENTS ; PHASE-III ; MULTICENTER TRIAL ; PLUS VINORELBINE ; QUALITY-OF-LIFE ; SINGLE-AGENT GEMCITABINE
    Abstract: Purpose To evaluate whether cisplatin-based chemotherapy (gemcitabine, vinorelbine, and cisplatin [GVP]) prolongs overall survival in comparison to cisplatin-free chemotherapy (gemcitabine and vinorelbine [GV]) as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods Between September 1999 and June 2001, 300 patients with NSCLC stage 11113 with malignant pleural effusion or stage IV disease were randomly assigned to receive GV (gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) on days 1 and 8 every 3 weeks) or GVP (gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) on days I and 8 + cisplatin 75 mg/m(2) on day 2 every 3 weeks). Primary end point of the study was overall survival. Results Two hundred eighty-seven patients (GV, 143 patients; GVP, 144 patients) were eligible for analysis. At the time of analysis, April 15, 2002, 209 patients (GV, 103 patients; GVP, 106 patients) of 287 patients had died (73%). No statistically significant difference was observed for overall survival (P =.73; median survival, 35.9 versus 32.4 weeks; 1-year survival rate, 33.6% versus 27.5%) as well as for event-free survival (P =.35; median time-to-event, 19.3 versus 22.3 weeks) between GV and GVP. Two hundred fourteen patients were assessable for best response. The overall response rates were 13.0% for GV versus 28.3% for GVP (P =.004; complete responders, 0% versus 3.8%; partial responders, 13.0% versus 24.5%). Hematologic and nonhematologic toxicity was significantly lower in the GV treatment arm compared with GVP. No statistically significant difference in quality of life was observed. Conclusion In this phase III study, the cisplatin-based GVP regimen showed no survival benefit as first-line chemotherapy in advanced NSCLC when compared with the cisplatin-free GV regimen, which was substantially better tolerated. (C) 2004 by American Society of Clinical Oncology
    Type of Publication: Journal article published
    PubMed ID: 15197195
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  • 3
    Keywords: CANCER ; Germany ; human ; LUNG ; lung cancer ; LUNG-CANCER ; DISEASE ; EXPOSURE ; TISSUE ; MECHANISM ; DATABASE ; CONCURRENT ; CARCINOGEN ; METAANALYSIS ; data analysis ; development ; analysis ; silicosis
    Abstract: The alveolar fraction of quartz has been classified as a human carcinogen by the International Agency for Research on Cancer (IARC). Crystalline-silica-associated lung cancer concurrent with a proven silicosis or silicotuberculosis is an occupational disease (so-called BK 4112) in Germany. The mechanism of interaction between silicosis and the development of lung cancer, however, is still not known. Based on the Wismut database and tissue repository, the hypothesis was tested whether silicosis influences the distribution of the major histopathologic types of lung cancer. The degree of quartz exposure was included in the data analysis
    Type of Publication: Journal article published
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  • 4
    Keywords: APOPTOSIS ; CELLS ; BLOOD ; CELL ; Germany ; IN-VIVO ; KINASE ; PATHWAY ; PATHWAYS ; SYSTEM ; DEATH ; PROTEIN ; PROTEINS ; RNA ; MICE ; NF-KAPPA-B ; ACTIVATION ; MECHANISM ; FAMILY ; primary ; INDUCTION ; T cell ; T cells ; T-CELL ; T-CELLS ; MEMBER ; MEMBERS ; TRANSGENIC MICE ; CD95 ligand ; CELL-DEATH ; INDUCED APOPTOSIS ; LYMPHOCYTES ; B-CELLS ; SIGNALING COMPLEX ; Bcl-2 ; molecular ; MOLECULAR-BASIS ; RE ; FAMILIES ; LIFE ; LEVEL ; cell death ; ANTIGEN RECEPTORS ; progenitor ; SUPPRESSOR ; FAS LIGAND ; AICD ; HEMATOPOIETIC PROGENITOR KINASE-1 ; USA ; B-LYMPHOCYTES ; FATE ; FRAGMENT ; FAMILY-MEMBER BIM ; B-CELL ; KINASE-1 ; EXPANSION ; caspase-3 ; block ; B cells ; BCL-2 FAMILY ; COMPLEMENT ; FULL-LENGTH ; MEDIATED CLEAVAGE ; SMALL INTERFERING RNA
    Abstract: Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-KB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-KB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2-driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C selectively blocks induction of NF-kappa B-dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim.Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C-dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes
    Type of Publication: Journal article published
    PubMed ID: 17712048
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  • 5
    Keywords: CELLS ; INHIBITOR ; CELL ; Germany ; human ; INHIBITION ; SYSTEM ; ENZYMES ; GENE ; GENOME ; GENOME SEQUENCE ; PROTEIN ; CONTRAST ; SEQUENCE ; SEQUENCES ; chromosome ; VARIANTS ; SUBUNIT ; ACTIVE-SITE ; DESIGN ; DIFFERENCE ; Drosophila ; DROSOPHILA-MELANOGASTER ; ERYTHROCYTES ; ESCHERICHIA-COLI ; genome analysis ; GLUTATHIONE ; GLUTATHIONE-REDUCTASE ; INSECTICIDE RESISTANCE ; MELANOGASTER ; PHAGOCYTOSIS ; resistance ; SELENOCYSTEINE ; SINGLE-COPY ; VECTOR ; Plasmodium falciparum ; Anopheles gambiae ; Drosophila melanogaster ; Diptera ; insect redox metabolism
    Abstract: The mosquito, Anopheles gambiae, is an important vector of Plasmodium falciparum malaria. Full genome analysis revealed that, as in Drosophila melanogaster, the enzyme glutathione reductase is absent in A. gambiae and functionally substituted by the thioredoxin system. The key enzyme of this system is thioredoxin reductase-1, a homodimeric FAD-containing protein of 55.3 kDa per subunit, which catalyses the reaction NADPH + H+ + thioredoxin disulfide. NADP+ + thioredoxin dithiol. The A. gambiae trxr gene is located on chromosome X as a single copy; it represents three splice variants coding for two cytosolic and one mitochondrial variant. The predominant isoform, A. gambiae thioredoxin reductase-1, was recombinantly expressed in Escherichia coli and functionally compared with the wild-type enzyme isolated in a final yield of 1.4 U.ml(-1) of packed insect cells. In redox titrations, the substrate A. gambiae thioredoxin-1 (K-m = 8.5 muM, k(cat) = 15.4 s(-1) at pH 7.4 and 25degreesC) was unable to oxidize NADPH-reduced A. gambiae thioredoxin reductase-1 to the fully oxidized state. This indicates that, in contrast to other disulfide reductases, A. gambiae thioredoxin reductase-1 oscillates during catalysis between the four-electron reduced state and a two-electron reduced state. The thioredoxin reductases of the malaria system were compared. A. gambiae thioredoxin reductase-1 shares 52% and 45% sequence identity with its orthologues from humans and P. falciparum, respectively. A major difference among the three enzymes is the structure of the C-terminal redox centre, reflected in the varying resistance of catalytic intermediates to autoxidation. The relevant sequences of this centre are Thr-Cys-Cys-SerOH in A. gambiae thioredoxin reductase, Gly-Cys-selenocysteine-GlyOH in human thioredoxin reductase, and Cys-X-X-X-X-Cys-GlyOH in the P. falciparum enzyme. These differences offer an interesting approach to the design of species-specific inhibitors. Notably, A. gambiae thioredoxin reductase-1 is not a selenoenzyme but instead contains a highly unusual redoxactive Cys-Cys sequence
    Type of Publication: Journal article published
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  • 6
    Keywords: CANCER ; EXPRESSION ; CELL ; Germany ; GENE ; HYBRIDIZATION ; DNA ; INDEX ; tumour ; CONTRAST ; chromosome ; virus ; IN-SITU ; COMPARATIVE GENOMIC HYBRIDIZATION ; cytogenetics ; LYMPHOMA ; MALIGNANCIES ; NUMBER ; leukemia ; ABERRATIONS ; IN-SITU HYBRIDIZATION ; MORPHOLOGY ; ABNORMALITIES ; FLUORESCENCE ; IMBALANCES ; C-MYC ; INTERPHASE ; EPSTEIN-BARR-VIRUS ; B-CELL LYMPHOMA ; Bcl-2 ; chemoresistance ; F ; CHROMOSOMAL BREAKPOINTS ; Epstein-Barr virus ; FEATURES ; immunohistology ; molecular cytogenetics ; sporadic and endemic Burkitt's lymphoma ; TRANSLOCATIONS
    Abstract: The present study has compared immunohistological marker expression profiles and genomic imbalances in seven African endemic Burkitt's lymphomas (eBLs) with those in ten European B-cell lymphomas with MYC rearrangement as shown by fluorescence in situ hybridization (FISH) analysis. eBLs showed a typical histomorphology and a homogeneous immuno-profile: CD10+, CD38+, CD77+, bcl-2-, and IgM+. Epstein-Barr virus (EBV) DNA was present in all cases. On comparative genomic hybridization (CGH), only three out of six eBLs showed imbalances (median number of imbalances = 2), with gains on chromosome 17 in two eBLs. The European lymphomas were all highly proliferating, with a Ki-67 index of at least 90%, and included seven with morphology typical of sporadic Burkitt's lymphoma (sBL) and three immunoblastic diffuse large B-cell lymphomas with MYC rearrangement (MYC re+DLBCL). In contrast to eBL, the immuno-profiles of the European lymphomas were less homogeneous and inconsistent for CD10, CD38, CD77, IgM and bcl-2 expression. EBV DNA was not detected. In five of seven sBLs, CGH showed a higher number of imbalances (median = 6), with recurrent gains on chromosome 1q (3/7) and losses on 12q and 17p (2/7), whereas all three MYC re+DLBCLs had fewer imbalances (median = 4), with gains on 17q in two of three lymphomas. It is concluded that eBL has a homogeneous immunohistology and few secondary genomic aberrations, whereas MYC-rearranged and highly proliferating European B-cell lymphomas are a heterogeneous group that includes sBL and a subgroup of diffuse large B-cell lymphomas. Copyright (C) 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd
    Type of Publication: Journal article published
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  • 7
    Keywords: CANCER ; carcinoma ; CELL ; Germany ; LUNG ; PATHWAYS ; EXPOSURE ; RISK ; TISSUE ; radiation ; CIGARETTE-SMOKING ; SIGNAL-TRANSDUCTION ; adenocarcinoma ; squamous cell carcinoma ; PREVALENCE ; LUNG-CARCINOMA ; MATRIX ; radon ; INCREASE ; LEVEL ; lung carcinoma ; HISTOLOGY ; RADIATION EXPOSURE ; HEDGEHOG ; DAUGHTERS ; silicosis ; uranium mining
    Abstract: BACKGROUND. In East Germany, uranium mining was undertaken on a large scale from 1946 to 1990. Poor working conditions led to a high level of exposure to ionizing radiation and quartz dust. This analysis evaluates the histopathology of lung carcinoma ill uranium miners in relation to radon exposure and silicosis. METHODS. A database developed for autopsy cases ascertained in a pathological tissue repository, of German uranium miners was used to estimate odds ratios for developing lung carcinoma by major cell type with regard to radon exposure and silicosis. Silicosis information was extracted from autopsy protocols. Working level months (WLM) were calculated with a job-exposure matrix to assess lifetime radon exposure. Risk estimates were based oil 3414 male miners who died from small cell lung carcinoma (SCLC, n = 1446), squamous cell carcinoma (SqCC, n = 1006), or adenocarcinoma (AC, n = 962) between 1957 and 1990. RESULTS. SCLC and SqCC seem more likely to be associated with high radon exposure than AC. Mean Cumulative radon exposure was 868 (SD 631) WLM in SCLC, 871 (SD 652) WLM in SqCC, and 743 (SD 598) WLM in AC. Silicosis prevalence was 26% in SCLC 38% in SqCC, and 30% in AC. In silicotics, AC and SqCC had a relatively higher frequency at the expense of SCLC. SCLC occurred earlier than AC and SqCC. CONCLUSION. High radon exposure was associated with a higher relative frequency of SCLC and SqCC than AC. Silicosis tended to increase the appearance of SqCC and AC
    Type of Publication: Journal article published
    PubMed ID: 16411224
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  • 8
    Keywords: OPTIMIZATION ; tumor ; Germany ; IN-VIVO ; VIVO ; CT ; imaging ; SUPPORT ; SYSTEM ; liver ; TUMORS ; ACCURACY ; computed tomography ; NUCLEAR-MEDICINE ; TIME ; TARGET ; NO ; TRIAL ; TRIALS ; ACQUISITION ; LESIONS ; EXPERIENCE ; RADIOFREQUENCY ABLATION ; REGISTRATION ; tomography ; COMPUTED-TOMOGRAPHY ; MOTION ; TRACKING ; IMAGE REGISTRATION ; nuclear medicine ; ORGAN MOTION ; radiology ; RE ; GUIDANCE ; ABLATION ; radiation therapy ; NUCLEAR ; USA ; SET ; IMPROVEMENT ; navigation ; MEDICINE ; CHALLENGES ; INSERTION ; HEPATIC-TUMORS ; INTERVENTIONS ; tumours ; NEEDLES ; computerised tomography ; needle insertion ; CLINICAL-EVALUATION ; motion compensation ; patient treatment
    Abstract: Computed tomography (CT)-guided percutaneous radiofrequency ablation (RFA) has become a commonly used procedure in the treatment of liver tumors. One of the main challenges related to the method is the exact placement of the instrument within the lesion. To address this issue, a system was developed for computer-assisted needle placement which uses a set of fiducial needles to compensate for organ motion in real time. The purpose of this study was to assess the accuracy of the system in vivo. Two medical experts with experience in CT-guided interventions and two nonexperts used the navigation system to perform 32 needle insertions into contrasted agar nodules injected into the livers of two ventilated swine. Skin-to-target path planning and real-time needle guidance were based on preinterventional 1 mm CT data slices. The lesions were hit in 97% of all trials with a mean user error of 2.4 +/- 2.1 mm, a mean target registration error (TRE) of 2.1 +/- 1.1 mm, and a mean overall targeting error of 3.7 +/- 2.3 mm. The nonexperts achieved significantly better results than the experts with an overall error of 2.8 +/- 1.4 mm (n=16) compared to 4.5 +/- 2.7 mm (n=16). The mean time for performing four needle insertions based on one preinterventional planning CT was 57 +/- 19 min with a mean setup time of 27 min, which includes the steps fiducial insertion (24 +/- 15 min), planning CT acquisition (1 +/- 0 min), and registration (2 +/- 1 min). The mean time for path planning and targeting was 5 +/- 4 and 2 +/- 1 min, respectively. Apart from the fiducial insertion step, experts and nonexperts performed comparably fast. It is concluded that the system allows for accurate needle placement into hepatic tumors based on one planning CT and could thus enable considerable improvement to the clinical treatment standard for RFA procedures and other CT-guided interventions in the liver. To support clinical application of the method, optimization of individual system modules to reduce intervention time is proposed
    Type of Publication: Journal article published
    PubMed ID: 19175098
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  • 9
    Keywords: CANCER ; carcinoma ; CELL ; Germany ; LUNG ; lung cancer ; LUNG-CANCER ; DISEASE ; EXPOSURE ; MORTALITY ; MECHANISM ; mechanisms ; SKIN ; ASSOCIATION ; DISTRIBUTIONS ; PATTERNS ; HEALTH ; smoking ; DATABASE ; STEM-CELLS ; SQUAMOUS-CELL CARCINOMA ; adenocarcinoma ; squamous cell carcinoma ; non-small cell lung cancer ; HETEROGENEITY ; CYTOKERATIN EXPRESSION ; LUNG-DISEASE ; MATRIX ; CELL CARCINOMA ; arsenic ; development ; HISTOLOGY ; USA ; PHOSPHATASE ; SQUAMOUS-CELL ; silicosis ; uranium mining ; PROPORTION ; CELL-LUNG-CANCER ; COPPER SMELTER ; HISTOLOGIC TYPES ; SMELTER WORKERS
    Abstract: The mechanisms of action of arsenic in the development of lung cancer are still not yet elucidated. Considering the relationship between arsenic and squamous cell carcinomas of the skin, we hypothesized that arsenic exposure may be more closely associated with squamous cell carcinoma of the lung. A comprehensive histopathological database and a detailed job-exposure matrix developed for former German uranium miners with exposure to arsenic, radon, and quartz were analyzed to quantitatively assess the effect of arsenic regarding cell type of lung cancer. The distributions of major lung cancer cell types in 1,786 German uranium miners were associated with levels of arsenic exposure under control for the other lung carcinogens. To evaluate the arsenic effects in association with a frequent occupational lung disease in miners stratification by silicosis was performed. There was an arsenic-related increase of the proportion of squamous cell carcinoma of the lung but restricted to miners without silicosis. The increase was found at all levels of co-exposure to radon and quartz dust. In miners with silicosis, the proportion of adenocarcinoma increased with rising arsenic exposure. Arsenic exposure was associated with non-small cell lung cancer. Silicosis turned out as major determinant of the cell type related with arsenic. These results indicate a cell type characteristic effect of arsenic in the development of lung cancer
    Type of Publication: Journal article published
    PubMed ID: 19020892
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  • 10
    Keywords: evaluation ; Germany ; CLASSIFICATION ; CT ; DIAGNOSIS ; imaging ; INFORMATION ; TOOL ; VISUALIZATION ; DISEASE ; DRUG ; computed tomography ; RESOLUTION ; ARTHRITIS ; prognosis ; MRI ; QUANTITATION ; BIOLOGY ; MOLECULAR-BIOLOGY ; treatment ; FIELD ; MAGNETIC-RESONANCE ; magnetic resonance imaging ; STAGE ; EFFICACY ; MARKERS ; US ; tomography ; COMPUTED-TOMOGRAPHY ; inflammation ; rheumatoid arthritis,molecular markers,molecular imaging,radiological diagnostics,fluorescence imagi ; WRIST
    Abstract: Advances in molecular biology and technical developments in the field of imaging are increasingly allowing for non-invasive visualization and quantitation of biological processes at the molecular level. Such technologies, defined as molecular imaging, promise early diagnosis and improved classification of the stage and severity of disease, objective assessment of treatment efficacy, and reliable prognosis based on so-called molecular markers. Furthermore, molecular imaging is an important tool for the evaluation of physiological and pathophysiological processes and for drug development. Various different imaging modalities are available, such as conventional radiography (CR), computed tomography (CT), nuclear imaging, magnetic resonance imaging (MRI), ultrasound (US), as well as other methods including fluorescence-based optical imaging. These methods differ with respect to resolution and their potential to gather information at the anatomical, physiological, cellular and molecular level. Therefore, the choice of the imaging modality for molecular imaging depends on the questions that need to be answered. This review discusses the potential of imaging modalities for molecular imaging in rheumatoid arthritis (RA)
    Type of Publication: Journal article published
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