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Keywords
  • 1
    Keywords: RECEPTOR ; SPECTRA ; ANGIOGENESIS ; CANCER ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INHIBITOR ; proliferation ; SURVIVAL ; tumor ; ADVANCED SOLID TUMORS ; AGENTS ; ANGIOSTATIN ; BLOOD ; carcinoma ; CELL ; CELL LUNG-CANCER ; CELL-PROLIFERATION ; CLINICAL-TRIAL ; COMBINATION ; DOPPLER ; ENDOTHELIAL GROWTH-FACTOR ; evaluation ; FACTOR RECEPTOR ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; LUNG ; MICROSCOPY ; MICROVESSEL DENSITY ; MODEL ; MODELS ; neoplasms ; PATHWAY ; PATHWAYS ; PERFUSION ; PHASE-I ; PROSTATE ; RECOMBINANT HUMAN ENDOSTATIN ; THERAPY ; TOXICITY ; tumor growth ; TYROSINE KINASE ; VITRO ; VIVO
    Abstract: The multifaceted nature of the angiogenic process in malignant neoplasms suggests that protocols that combine antiangiogenic agents may be more effective than single-agent therapies. However it is unclear which combination of agents would be most efficacious and will have the highest degree of synergistic activity while maintaining low overall toxicity. Here we investigate the concept of combining a "direct" angiogenesis inhibitor (endostatin) with an "indirect" antiangiogenic compound [SU5416, a vascular endothelial growth factor receptor 2 (VEGFR2) receptor tyrosine kinase (RTK) inhibitor]. These angiogenic agents were more effective in combination than when used alone in vitro (endothelial cell proliferation, survival, migration/invasion, and tube formation tests) and in vivo. The combination of SU5416 and low-dose endostatin further reduced tumor growth versus monotherapy in human prostate (M), lung (A459), and glioma (U87) xenograft models, and reduced functional microvessel density, tumor microcirculation, and blood perfusion as detected by intravital microscopy and contrast-enhanced Doppler ultrasound. One plausible explanation for the efficacious combination could be that, whereas SU5416 specifically inhibits vascular endothelial growth factor signaling, low-dose endostatin is able to inhibit a broader spectrum of diverse angiogenic pathways directly in the endothelium. The direct antiangiogenic agent might be able to suppress alternative angiogenic pathways up-regulated by the tumor in response to the indirect, specific pathway inhibition. For future clinical evaluation of the concept, a variety of agents with similar mechanistic properties could be tested
    Type of Publication: Journal article published
    PubMed ID: 14695206
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  • 2
    Keywords: CANCER ; Germany ; LUNG ; lung cancer ; LUNG-CANCER ; SYSTEM ; CANCER MORTALITY ; COHORT ; cohort studies ; cohort study ; cohort-studies ; DEATH ; DISEASE ; DISEASES ; DNA adducts ; EPIDEMIOLOGY ; EXPOSURE ; HEPATOCELLULAR-CARCINOMA ; HISTORY ; incidence ; iron foundry ; larynx ; liver ; LONG-TERM ; missing death certificates ; MORTALITY ; mouth ; NEW-YORK ; occupation ; PHARYNX ; POPULATION ; PRIMARY LIVER-CANCER ; RISK ; RISKS ; SITE ; SITES ; WORKERS
    Abstract: Background Observations of an increased incidence of cancers of the upper aero-digestive tract (pharynx, esophagus, larynx, lung) among workers of local German foundries gave rise to concern about a potentially elevated occupational risk of those cancer sites. The purpose of the study was to examine whether occupational exposure in iron foundries increases the risk of cancer. Methods A historical cohort study of 17,708 male German production workers in 37 iron foundries who were first employed in 1950-1985 with a minimum employment period of 1 year was initiated. Employment and occupational histories were collected. Mortality was compared with that of the German general population during 1950-1993 using a new method for computing the SMR when not all causes of death are available (called SMR*). Results Mortality from all causes was elevated to SMR = 115.4 (95% confidence interval (CI) = 111.9-119.1), as was for total cancer (SMR* = 123.8, CI = 102.1-152.6), especially cancers of the lung (SMR* = 163.9, CI = 123.9-223.0) and liver (SMR* = 322.5, CI = 149.5-844.8), and diseases of the respiratory system (SMR* = 147.6, CI = 100.4-221.5). Non- significant elevations of mortality were also found for cancers of the mouth and pharynx (SMR* = 153.5, CI = 82.3-359.8) and larynx (SMR* = 173.1, CI = 85.5-550.5). Mortality from various causes of death was higher among workers with shorter exposure periods than among long-term employees. The elevated mortality persisted for years and decades after termination of employment. Conclusions The results provide further evidence for an increased risk of lung cancer and possibly other cancers of the upper aero-digestive tract among foundry workers. Special attention should be paid to the strongly increased mortality from liver cancer and the mortality pattern among employees having terminated work. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 12594777
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  • 3
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; Germany ; human ; DISEASE ; DISEASES ; MICE ; ACTIVATION ; COMPLEX ; MESANGIAL CELLS ; ARTHRITIS ; CELL ACTIVATION ; COMPLEXES ; CUTTING EDGE ; DNA ; IFN-GAMMA ; INFECTION ; kidney ; MACROPHAGES ; MECHANISM ; MESSENGER-RNA ; MESSENGER-RNA EXPRESSION ; MOTIFS ; murine ; OLIGODEOXYNUCLEOTIDES ; RECEPTOR EXPRESSION ; SERA ; TH1 RESPONSES ; TRIGGER
    Abstract: Immune complex glomerulonephritis (GN) often deteriorates during infection with viruses and bacteria that, in contrast to mammals, have DNA that contains many unmethylated CpG motifs. Balb/c mice with horse apoferritin-induced GN (HAF-GN) were treated with either saline, CpG-oligodeoxynucleotides (ODN), or control GpC-ODN. Only CpG-ODN exacerbated HAF-GN with an increase of glomerular macrophages, which was associated with massive albuminuria and increased renal MCP-1/CCL2, RANTES/CCL5, CCR1, CCR2, and CCR5 mRNA expression. CpG-ODN induced a Th1 response as indicated by serum anti-HAF IgG(2a) titers, mesangial IgG(2a) deposits, and splenocyte IFN-gamma secretion. Messenger RNA for the CpG-DNA receptor Toll-like reeptor 9 (TLR9) was present in kidneys with HAF-GN but not in normal kidneys. The source of TLR9 mRNA in HAF-GN could. be infiltrating macrophages or intrinsic renal cells, e.g., mesangial cells; but, in vitro, only murine J774 macrophages expressed TLR9. In J774 cells, CpG-ODN induced the chemokines MCP-1/CCL2 and RANTES/CCL5 and the chemokine receptors CCR1 and CCR5. It is concluded that CpG-DNA can aggravate preexisting GN via a shift toward a Th1 response but also by a novel pathway involving TLR9-mediated chemokine and chemokine receptor expression by macrophages, which may contribute to the enhanced glomerular macrophage recruitment and activation. This mechanism may be relevant during infection-triggered exacerbation of human immune-complex GN and other immune- mediated diseases in general
    Type of Publication: Journal article published
    PubMed ID: 12538732
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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VIVO ; LUNG-CANCER ; DNA adducts ; RISK ; GENE ; LINES ; ACTIVATION ; DNA ; 3-aminobenzanthrone ; 3-nitrobenzanthrone ; AIR ; CARCINOGENESIS ; CYP1A2 ; CYTO-TOXIC METABOLITES ; DIESEL EXHAUST ; DNA ADDUCT FORMATION ; ENVIRONMENTAL CONTAMINANT 3-NITROBENZANTHRONE ; GENETIC POLYMORPHISMS ; HETEROCYCLIC AMINES ; HETEROLOGOUS EXPRESSION ; HUMAN CYTOSOLIC SULFOTRANSFERASES ; IONS ; metabolic activation ; NAT : SULT ; nitro-PAH ; P-32- postlabeling ; PHENOL SULFOTRANSFERASES ; POSTLABELING ANALYSIS
    Abstract: 3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust and ambient air pollution. 3-Aminobenzanthrone (3-ABA), 3- acetylaminobenzanthrone (3-Ac-ABA) and N-acetyl-N-hydroxy-3- aminobenzanthrone (N-Ac-N-OH-ABA) have been identified as 3-NBA metabolites. Recently we found that 3-NBA and its metabolites (3-ABA, 3-Ac-ABA and N-Ac-N-OH-ABA) form the same DNA adducts in vivo in rats. In order to investigate whether human cytochrome P450 (CYP) enzymes (i.e., CYPIA2), human N,O- acetyltransferases (NATs) and sulfotransferases (SULTs) contribute to the metabolic activation of 3-NBA and its metabolites we developed a panel of Chinese hamster V79MZ-hIA2 derived cell lines expressing human CYPIA2 in conjunction with human NATI, NAT2, SULTIAI or SULTIA2, respectively. Cells were treated with 0.01, 0.1 or I muM 3-NBA, or its metabolites (3- ABA, 3-Ac-ABA and N-Ac-N-OH-ABA). Using both enrichment versions of the P-32-postlabeling assay, nuclease P I digestion and butanol extraction, essentially 4 major and 2 minor DNA adducts were detected in the appropriate cell lines with all 4 compounds. The major ones were identical to those detected in rat tissue; the adducts lack an N-acetyl group. Human CYPIA2 was required for the metabolic activation of 3-ABA and 3-Ac-ABA (probably via N-oxidation) and enhanced the activity of 3-NBA (probably via nitroreduction). The lack of acetylated adducts suggests N-deacetylation of 3-Ac-ABA and N-Ac-N-OH-ABA. Thus, N-hydroxy-3-aminobenzanthrone (N-OH-ABA) appears to be a common intermediate for the formation of the electrophilic arylnitrenium ions capable of reacting with DNA. Human NAT I and NAT2 as well as human SULTIAI and SULTIA2 strongly contributed to the high genotoxicity of 3-NBA and its metabolites. Moreover, N,O-acetyltransfer reactions catalyzed by human NATs leading to the corresponding N-acetoxyester may be important in the bioactivation of N-Ac-N-OH-ABA. As human exposure to 3-NBA is likely to occur primarily via the respiratory tract, expression of CYPs, NATs and SULTs in respiratory tissues may contribute significantly and specifically to the metabolic activation of 3-NBA and its metabolites. Consequently, polymorphisms in these genes could be important determinants of lung cancer risk from 3-NBA
    Type of Publication: Journal article published
    PubMed ID: 12740904
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  • 5
    Keywords: Germany ; human ; GENE-EXPRESSION ; RNA ; papillomavirus ; IMMUNE-RESPONSES ; PARTICLES ; transgenic ; CERVICAL-CANCER ; CAPSID PROTEIN ; CODON USAGE ; FUSION PROTEIN PROTECTS ; human papillomavirus ; L1 PROTEIN ; ORAL IMMUNIZATION ; TYPE-16 ; VACCINES ; VIRUS-LIKE PARTICLES
    Type of Publication: Journal article published
    PubMed ID: 12915537
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  • 6
    Keywords: CANCER ; PROTECTION ; MODEL ; DISEASE ; EPIDEMIOLOGY ; HISTORY ; RISK ; GENE ; GENES ; SAMPLE ; FAMILY ; RISK-FACTORS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; AGE ; BRCA1 ; case-only design ; family history ; gene carrier probability ; LINKAGE ANALYSIS ; mixture logistic model ; ovarian cancer ; OVARIAN-CANCER ; population and sibling controls ; WOMEN
    Abstract: Background The effect of environmental/lifestyle factors on breast cancer risk may be modified by genetic predisposition. Methods In a population-based case-control-family study performed in Germany including 706 cases by age 50 years, 1381 population, and 252 sister controls, we investigated main effects for environmental/lifestyle factors and genetic susceptibility and gene-environment interaction (G x E). Different surrogate measures for genetic predisposition using pedigree information were used: first-degree family history of breast or ovarian cancer; and gene carrier probability using a genetic model based on rare dominant genes. Possible G x E interaction was studied by (1) logistic regression using cases and population controls including an interaction term; (2) comparing results using sister controls and population controls; (3) case-only analysis with logistic regression and (4) a mixture logistic model. Results Familial predisposition showed the strongest main effect and the estimated gene carrier probability gave the best fit. High parity and longer duration of breastfeeding reduced breast cancer risk significantly, a history of abortions increased risk and age at menarche showed no significant effect. We found significant G x E interaction between parity and genetic susceptibility using different surrogate measures. In women most likely to have a high genetic susceptibility, high parity was less protective. Later age at menarche was protective in women with a positive family history. No evidence for G x E interaction was found for breastfeeding and abortion. Conclusions These findings corroborate results from other studies and provide further evidence that the magnitude of protection from parity is reduced in women most likely to have a genetic risk in spite of the limitations of using surrogate genetic measures
    Type of Publication: Journal article published
    PubMed ID: 12690006
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  • 7
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    Internist 44 (9), 1131-1139 
    Keywords: Germany ; THERAPY ; COMMON ; DIAGNOSIS ; DISEASE ; NEW-YORK ; POPULATION ; RISK ; TIME ; PATIENT ; NEPHRITIS ; INFECTION ; GRAFT ; renal ; STAGE ; IDENTIFICATION ; PROGRESSION ; EXPERIENCE ; RISK FACTOR ; RECURRENCE ; FREQUENT ; CLINICAL-FEATURES ; CLINICALLY-RELEVANT ; CYCLOPHOSPHAMIDE ; FAILURE ; glomerulonephritis ; HYPERTENSION ; INFECTIONS ; NATURAL-HISTORY ; NEPHROPATHY ; PREDICTORS ; PREVALENCE ; proteinuria ; RECURRENT ; renal insufficiency ; renoparenchymal hypertension ; RISK GROUP ; STAGE RENAL-FAILURE
    Abstract: IgA nephropathy (IgAN) is the most common type of glomerulonephritis in the western world. In the majority of cases, it manifests in adolescence or early adulthood as recurrent macrohematuria, frequently triggered by infections, or persistent microhematuria as well as mild proteinuria, hypertension and/or renal insufficiency. In view of the later, it is not surprising that IgAN is often a chance finding. The majority of affected persons probably never come to medical attention, since in autopsies a prevalence of up to 1% of the population has been reported. About 20-30% of patients with a diagnosis of IgAN suffer from chronic, slowly progressive renal failure. Predictors include the degree of proteinuria and arterial hypertension as well as the established renal impairment at the time of diagnosis. Early identification of this risk group is of particular importance, since adequate therapy can stop or at least retard the progression of renal failure. When end stage renal failure has developed and a renal transplant is performed, about 25% of the patients will experience a clinically relevant recurrence of IgAN with progressive graft dysfunction
    Type of Publication: Journal article published
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  • 8
    Keywords: SURVIVAL ; tumor ; Germany ; INHIBITION ; MODEL ; MODELS ; DISEASE ; DISEASES ; incidence ; liver ; RISK ; SITE ; SITES ; GENE ; TUMORS ; STORAGE ; TIME ; PATIENT ; NITRIC-OXIDE SYNTHASE ; INJURIES ; DNA ; INFECTION ; RISK-FACTORS ; CARCINOGENESIS ; RAT ; RATS ; PROTEIN-KINASE ; treatment ; virus ; prevention ; STRESS ; risk factors ; metastases ; DAMAGE ; chemoprevention ; COLON CARCINOGENESIS ; copper toxicity ; curcumin ; ETHENO-DNA ADDUCTS ; HEREDITARY HEPATITIS ; LEC rats ; LIPID-PEROXIDATION ; MOUSE FIBROBLAST CELLS ; NIH 3T3 ; ORNITHINE DECARBOXYLASE ; OXIDATIVE STRESS
    Abstract: Long-Evans Cinnamon (LEC) rats, an inbred mutant strain which accumulates copper due to an aberrant copper-transporting ATPase gene, develop acute hepatitis, chronic liver injury and liver tumors as a result of copper-induced oxidative stress, lipid peroxidation and DNA damage. Curcumin, an antioxidant and anti-inflammatory agent, has shown anticancer properties in many rodent models. We investigated the modulating role of curcumin in liver and kidney carcinogenesis in LEC rats. Two groups of 4-week-old LEC rats (n = 60 each) were fed either a standard diet (control) or received 0.5% curcumin in the diet for life. In untreated LEC rats, the rate of acute liver failure, the incidence of liver tumors and of kidney tumors were 32, 100 and 10% respectively, which was not altered by curcumin treatment. However, curcumin reduced tumor incidence at other organ sites (15% versus 0%; P = 0.025) and suppressed formation of metastases (18% versus 0%; P = 0.01). Median survival time was decreased from 88.7 to 78.1 weeks in curcumin-treated rats (P = 0.002). The lack of chemoprevention of liver and kidney tumors in LEC rats by curcumin may be caused by enhanced toxicity and oxidative stress due to excess copper. We conclude that curcumin should be contra-indicated for patients suffering from inherited and acquired metal storage diseases that include patients with hepatitis C virus infection. (C) 2002 Elsevier Science B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 12628510
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  • 9
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; human ; SYSTEM ; DISTINCT ; PROTEIN ; EPITHELIA ; MOLECULES ; TISSUE ; TISSUES ; SKIN ; GLYCOPROTEIN ; ELEMENTS ; SURFACE ; LOCALIZATION ; GLANDS ; SEGMENTS ; calnexin ; ESTABLISHMENT ; MUCINS ; salivary gland ; sebaceous gland ; SEBACEOUS GLANDS
    Abstract: Calnexin (Cnx) has been characterized as a membrane-bound protein that transiently interacts in a unique chaperone system with newly synthesized glycoproteins in order to allow the establishment of their proper tertiary and, in most cases, quarternary structures. The aim of the study was to identify and to locate the expression of Cnx in the three major salivary glands of humans by different methods. Strong expression of Cnx protein and mRNA were generally found in serous salivary secretory units. With regard to mucous secretory units, expression of Cnx was only detectable at a low level in mucous acinar cells of sublingual glands, but not of submandibular glands. Expression of Cnx was always preserved in the surface epithelium of intralobar and interlobular duct segments. In addition, expression of Cnx was detected in sebaceous glands of parotid tissues, with a distribution pattern resembling that seen in sebaceous glands of the normal skin. In conclusion, production of saliva is associated with the expression of Cnx. Synthesis of molecules in mucous secretory units is not necessarily associated with a strong Cnx expression, whereas synthesis in serous secretory units apparently is. The tissue- specific Cnx expression is also paralleled by the observation that the secretions produced by the major salivary glands differ in their composition and amount
    Type of Publication: Journal article published
    PubMed ID: 12507291
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  • 10
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; IN-VIVO ; INHIBITION ; DEATH ; GENE ; GENE-EXPRESSION ; RNA ; TUMORS ; ACTIVATION ; PROTEIN FAMILY ; INDUCTION ; SUSCEPTIBILITY ; TARGET ; gene expression ; resistance ; HUMAN-TUMORS ; STIMULI ; CANCER-CELLS ; DELIVERY ; MAMMALIAN-CELLS ; SMALL INTERFERING RNAS ; doxorubicin ; HUMAN-TUMOR-CELLS ; IAP PROTEINS ; POSITIVE CANCER-CELLS ; RNA interference,inhibitors of apoptosis,chemotherapy,HeLa,melanoma ; STRATEGIES
    Abstract: Increased resistance to apoptosis is a hallmark of many tumor cells. The functional inhibition of specific antiapoptotic factors may provide a rational basis for the development of novel therapeutic strategies. We investigated here whether the RNA interference (RNAi) technology could be used to increase the apoptotic susceptibility of cancer cells. As a molecular target, we chose the antiapoptotic livin (ML-IAP, KIAP) gene, which is expressed in a subset of human tumors. We identified vector-borne small interfering (si)RNAs, which could efficiently block endogenous livin gene expression. Silencing of livin was associated with caspase-3 activation and a strongly increased apoptotic rate in response to different proapoptotic stimuli, such as doxorubicin, UV-irradiation, or TNFalpha. The effects were specific for Livin-expressing tumor cells. Our results (i) provide direct evidence that the intracellular interference with livin gene expression resensitizes human tumor cells to apoptosis, (ii) define the livin gene as a promising molecular target for therapeutic inhibition, and (iii) show that the livin gene is susceptible to efficient and specific silencing by the siRNA technology
    Type of Publication: Journal article published
    PubMed ID: 14614456
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  • 11
    Keywords: CELLS ; INHIBITOR ; tumor ; BLOOD ; Germany ; human ; liver ; DRUG ; LIGAND ; SERA ; RAT ; hepatocytes ; BINDING ; ACIDS ; TRANSPORT ; IDENTIFICATION ; PLASMA ; POLYPEPTIDE ; albumin receptor ; bilirubin ; BOVINE SERUM-ALBUMIN ; BSP ; fatty acids ; FATTY-ACIDS ; FREE FATTY-ACIDS ; hepatic uptake ; HEPATIC-UPTAKE ; HSA ; HUMAN LIVER ; organic anion transporters ; ORGANIC-ANIONS
    Abstract: Background. Despite their strong binding to albumin while circulating in blood, many organic anions, such as bilirubin and fatty acids, are removed efficiently by the liver. The uptake transporters of human hepatocytes, OATP2 (symbol, SLC21A6) and OATP8 (SLC21A8), play important roles in the hepatic uptake of endogenous substances and drugs. The two transporters show different affinities for the organic anion sulfobromophthalein (BSP), which binds with high affinity to albumin in blood. Methods. In this study, we investigated whether a direct interaction of albumin with OATP2 or OATP8 occurs during the uptake of BSP. The uptake of BSP, at varying concentrations of human serum albumin (HSA), into transfected HEK293 cells expressing recombinant human OATP2 or OATP8 was measured. The influence of other organic anions on the uptake of albumin-bound BSP by OATP2 or OATP8 was also studied. Results. OATP8-mediated transport was affected more strongly by HSA than OATP2-mediated transport. Albumin affected both transporters in the manner of a noncompetitive inhibitor. Uptake studies using OATP2-transfected MDCKII cells indicated that a direct interaction between albumin and OATP2 is not necessary for uptake, a finding that was further confirmed by the effects of bilirubin and palmitate on the binding of BSP to albumin and on the uptake of BSP by OATP2 or OATP8. Conclusions. Our results indicated that uptake of albumin-bound BSP occurs only from the pool of unbound ligand
    Type of Publication: Journal article published
    PubMed ID: 12560923
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  • 12
    Keywords: CELLS ; EXPRESSION ; tumor ; BLOOD ; carcinoma ; human ; MICROSCOPY ; liver ; PROTEIN ; PROTEINS ; TUMORS ; FAMILY ; RAT ; hepatocytes ; MEMBER ; MEMBERS ; antibodies ; MOUSE ; IDENTIFICATION ; RAT-LIVER ; MEMBRANE ; metastases ; CONJUGATE ; LOCALIZATION ; EPITHELIAL-CELLS ; HEPATOCYTE CANALICULAR ISOFORM ; METASTATIC CARCINOMAS ; MULTIDRUG-RESISTANCE PROTEIN ; POLYPEPTIDE OATP2
    Abstract: Transport proteins mediating the selective uptake of organic anions into human hepatocytes include the organic anion transporters SLC21A6 (also termed OATP2, OATP-C, or LST-1) and SLC21A8 (OATP8). Both transporters are localized to the basolateral membrane of human hepatocytes. Because of the importance of these transporters for hepatobiliary elimination, including the removal of bilirubin and its conjugates from the blood circulation, we have generated monoclonal antibodies for studies on the expression and localization of these transport proteins. We describe two antibodies, designated monoclonal antibody MDQ (mMDQ) and monoclonal antibody ESL (mESL), directed against the amino terminus and the carboxyl terminus of human SLC21A6, respectively. Both antibodies have been characterized by immunoblot analysis, immunoprecipitation, and immunofluorescence microscopy. While mESL reacted specifically with SLC21A6, mMDQ detects both SLC21A6 and SLC21A8. Neither of the two antibodies reacted with other human, or with dog, rat, or mouse liver SLC21A family members. Antibody mMDQ may be used for the simultaneous detection of SLC21A6 and SLC21A8 in immunoblotting because of its immunoreactivity with both molecules and because of the different molecular masses of both glycosylated proteins in human hepatocytes. This is exemplified in hepatocellular carcinomas where SLC21A6 and SLC21A8 were differentially synthesized and showed an irregular staining pattern. Both transport proteins have not been detected in human hepatoma HepG2 cells. In routine paraffin sections, 10 of 12 hepatocellular carcinomas were focally positive with antibody mMDQ. In contrast, cholangiocarcinomas and liver metastases of colorectal and pancreatic adenocarcinoma were negative without exception. This suggests the usefulness of SLC21A6/SLC21A8 within a panel of tumor markers for hepatocellular carcinomas. Moreover, both antibodies should be useful in studies on the expression and localization of two important uptake transporters of human hepatocytes under physiologic and pathophysiologic conditions
    Type of Publication: Journal article published
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  • 13
    Keywords: CANCER ; FOLLOW-UP ; lung cancer ; LUNG-CANCER ; COHORT ; MORTALITY ; POPULATION ; RISK ; RISKS ; SITE ; SITES ; TIME ; SKIN ; IN-SITU ; MALIGNANCIES ; WOMEN ; smoking ; skin cancer ; bladder cancer ; BLADDER-CANCER ; SWEDEN ; cancer risk ; SQUAMOUS-CELL CARCINOMA ; CANCER RISKS ; COSMETOLOGISTS ; hair dyes ; hairdressers ; HEMATOPOIETIC NEOPLASMS ; NECK ; OCCUPATIONAL RISKS ; SAFETY ; SIR ; UNITED-STATES
    Abstract: More than a decade ago, an increased risk for bladder cancer among male hairdressers was established. Frequent changes of hair dye formulations together with their widespread use call for safety guarantees. We carried out a follow-up study of a cohort of 38,866 female and 6,824 male hairdressers from Sweden and analyzed all of their malignancies over a period of 39 years. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for 28 cancer sites were calculated using the economically active population as a reference. During the years 1960-1998 a total of 1,043 cancer cases were recorded in male hairdressers. Excess risks for cancers of the upper aerodigestive tract and lung and colorectal adenocarcinoma were observed. Additionally, male hairdressers working in 1960 had an increased risk for urinary bladder cancer, which was highest in the 1960s with an SIR of 2.56 (95% CI 1.36-4.39) and decreased with the follow-up time. A total of 2,858 cancers were recorded in female hairdressers. An increased risk was observed for cancers of the pancreas, lung and cervix and in situ cancer of the skin. The increased risk for in situ skin cancer specifically affected the scalp and neck, sites of contact for hair dyes, with an SIR of 2.43 (95% CI 1.14-4.44). The increase in lung cancer, the only site for which cancer was increased in either sex, may depend on confounding from smoking. Bladder cancer was not increased among hairdressers in the recent decades and is therefore not likely to be associated with modern hair dyes. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 12672039
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  • 14
    Keywords: CANCER ; IN-VITRO ; tumor ; AGENTS ; Germany ; IN-VIVO ; INHIBITION ; screening ; SYSTEM ; SYSTEMS ; RISK ; ENZYMES ; DRUG ; NITRIC-OXIDE ; murine ; RISK-FACTORS ; CARCINOGENESIS ; INDUCTION ; KERATINOCYTES ; mechanisms ; culture ; IDENTIFICATION ; prevention ; risk factors ; MODULATION ; RISK FACTOR ; butyrate ; HEPATOMA ; fatty acids ; FATTY-ACIDS ; NF-kappa B ; ALCOHOL ; SODIUM-BUTYRATE ; curcumin ; ORNITHINE DECARBOXYLASE ; ANTIOXIDANT ; bioassay systems ; cancer chernoprevention ; CONSTITUENTS ; iNOS ; PEITC ; SULFORAPHANE ; SUPEROXIDE
    Abstract: Identification and use of effective cancer chemopreventive agents have become an important issue in public health-related research. For identification of potential cancer chemopreventive constituents we have set up a battery of cell- and enzyme-based in vitro marker systems relevant for prevention of carcinogenesis in vivo. These systems include modulation of drug metabolism (inhibition of Cyp1A activity, induction of NAD(P)H:quinone reductase (QR) activity in Hepalclc7 murine hepatoma cell culture), determination of radical scavenging (DPPH scavenging) and antioxidant effects (scavenging of superoxide anion-, hydroxyl- and peroxyl- radicals), anti-inflammatory mechanisms (inhibition of lipopolysaccharide (LPS)-mediated nitric oxide (NO) generation by inducible NO synthase (iNOS) in Raw 264.7 murine macrophages, cyclooxygenase-1 (Cox-1) inhibition), and anti- tumor promoting activities (inhibition of phorbol ester-induced ornithine decarboxylase (ODC) activity in 308 murine keratinocytes). We have tested a series of known chemopreventive substances belonging to several structural classes as reference compounds for the identification of novel chemopreventive agents or mechanisms. These include organosulfur compounds (phenethylisothiocyanate (PEITC), diallylsulfide, diallyldisulfide), terpenes (limonene, perillyl alcohol, oleanolic acid, 18-beta-glycyrrhetinic acid), short- chain fatty acids (sodium butyrate), indoles (indole-3- carbinol), isoflavonoids (quercetin, silymarin, genistein), catechins ((-)-epigallocatechin gallate (EGCG)), simple phenols (ellagic acid, resveratrol, piceatannol, curcumin), pharmaceutical agents (piroxicam, acetylsalicylic acid, tamoxifen), and vitamins/derivatives (ascorbic acid, Trolox). We confirmed known chemopreventive mechanisms of these compounds. Additionally, we could demonstrate the usefulness of our approach by identification of hitherto unknown mechanisms of selected agents. As an example, we detected anti- inflammatory properties of PEITC, based on NF-kappaB-mediated inhibition of NO production. Further, PEITC inhibited phorbol ester-induced superoxide anion radical production in granulocytes, and ODC induction in the 308 cell line. These mechanisms might contribute to the chemopreventive potential of PEITC. (C) 2002 Elsevier Science B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 12628514
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  • 15
    Keywords: CANCER ; EXPRESSION ; carcinoma ; CELL ; Germany ; human ; LUNG ; lung cancer ; LUNG-CANCER ; EXPOSURE ; RISK ; GENE ; PROTEIN ; METABOLISM ; TISSUE ; PATIENT ; RISK-FACTORS ; FREQUENCY ; polymorphism ; SUSCEPTIBILITY ; PROMOTER ; OVARIAN-CANCER ; WOMEN ; MEN ; risk factors ; smoking ; PROSTATE-CANCER ; cancer risk ; RISK FACTOR ; CYP3A4 ; LINKAGE DISEQUILIBRIUM ; CANCER-PATIENTS ; CARCINOMAS ; POLYMERASE-CHAIN-REACTION ; adenocarcinoma ; ADENOCARCINOMAS ; CARRIERS ; case-control studies ; CLINICAL PRESENTATION ; CYP3A,genetic polymorphism,lung cancer susceptibility,small cell lung cancer,LightCycler ; EXPRESSED HUMAN CYTOCHROME-P450S ; GENETIC VARIANT ; HUMAN LIVER-MICROSOMES ; PROSTATE TUMORS ; PROTEIN LEVELS ; squamous cell carcinoma ; TOBACCO
    Abstract: CYP3A isozymes are involved in tobacco carcinogen- and steroid-metabolism, and are expressed in human lung tissue showing interindividual variation in expression and activity. The CYP3A4* 1 B allele has been associated with a two-fold higher promoter activity and with high-grade prostate cancers. The very frequent intron 3 polymorphism in the CYP3A5 gene (CYP3A5*3) results in decreased CYP3A5 protein levels. A case-control study was conducted in 801 Caucasian lung cancer patients that included 330 adenocarcinomas, 260 squamous cell carcinomas, 171 small cell lung cancers (SCLC) and 432 Caucasian hospital-based controls. CYP3A-genotyping was performed by capillary polymerase chain reaction followed by fluorescence-based melting curve analysis. A significantly increased SCLC risk for CYP3A4* 1B allele carriers [odds ratio (OR) 2.25, 95% confidence interval (CI) 1.11-4.55, P = 0.02] was found. After dividing cases and controls by gender, an increased lung cancer risk for CYP3A4* 1B carriers (OR 3.04, 95% CI 0.94-9.90, P= 0.06) for women but not for men (OR 1.00, 95% CI 0.56-1.81) was revealed. Heavier smoking men (greater than or equal to 20 pack-years) with the CYP3A4* 1 B allele had a significant OR for lung cancer of 3.42 (95% CI 1.65-7.14, P= 0.001) compared to * 1A/1* 1A carriers with lower tobacco exposure (〈 20 pack-years). For women, the respective OR was 8.00 (95% CI 2.12-30.30, P = 0.005). Genotype frequencies were generally in Hardy-Weinberg equilibrium, except for CYP3A5 where a greater than expected number of CYP3A5* 1 homozygotes was observed among cases (P = 0.006). In addition, we observed linkage disequilibrium of CYP3A4 and CYP3A5 (P 〈 0.00001), but a nonsignificantly increased lung cancer risk was only found for homozygous CYP3A5* 1 allele carriers (OR 5.24,95% CI 0.85-102.28, P = 0.14) but not for heterozygotes. To confirm our observation that the CYP3A4* 1B allele increases SCLC risk and modifies the smoking-related lung cancer risk in a gender-specific manner, further studies, including CYP3A haplotype analysis, will be necessary. Pharmacogenetics 13:607-618 (C) 2003 Lippincott Williams Wilkins
    Type of Publication: Journal article published
    PubMed ID: 14515059
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  • 16
    Keywords: PEPTIDE ; human ; DISEASE ; SITE ; SITES ; PROTEIN ; SAMPLE ; SAMPLES ; SERA ; INDUCTION ; BINDING ; treatment ; ACID ; IDENTIFICATION ; SUBUNIT ; DIFFERENCE ; MOBILITY ; GAS ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; IONIZATION ; ACETYLATED SIALIC ACIDS ; sialic acid ; VISCERAL LEISHMANIASIS ; C-REACTIVE PROTEIN ; acute-phase protein ; BINDING CHARACTERISTICS ; CATLA-CATLA ; CHROMATOGRAPHY ; ELECTROPHORESIS ; FRAGMENTS ; GLUCOSE ; glycosylation ; INDIVIDUALS ; LABEO-ROHITA ; LECTIN ; lectin binding ; LIQUID-CHROMATOGRAPHY ; MAJOR CARP ; matrix-assisted laser-desorption ionization analysis (MALDI analysis) ; molecular modelling ; protein-protein interaction ; PROTEIN-PROTEIN INTERACTIONS ; SIALIC-ACID ; SUBUNITS
    Abstract: As an acute-phase protein, human C-reactive protein (CRP) is clinically important. CRPs were purified from several samples in six different pathological conditions, where their levels ranged from 22 to 342 mug/ml. Small, but significant, variations in electrophoretic mobilities on native PAGE suggested differences in molecular mass, charge and/or shape. Following separation by 9 SDS/PAGE, the), showed single subunits with some differences in their molecular masses ranging between 27 and 30.5 kDa, but for a particular disease, the mobility was the same for CRPs purified from multiple individuals or pooled sera. Isoelectric focusing (IEF) also indicated that the purified CRPs differed from each other. Glycosylation was demonstrated in these purified CRPs by Digoxigenin kits, neuraminidase treatment and binding with lectins. The presence of N-linked sugar moiety was confirmed by N-glycosidase F digestion. The presence of sialic acid, glucose, galactose and mannose has been demonstrated by gas liquid chromatography, mass spectroscopic and fluorimetric analysis. Matrix-assisted laser-desorption ionization analysis of the tryptic digests of three CRPs showed systematic absence of two peptide fragments, one at the N-terminus and the other near the C-terminus. Model-building suggested that the loss of these fragments exposed two potential glycosylation sites on a cleft floor keeping the protein-protein interactions in pentraxins and calcium-dependent phosphorylcholine-binding qualitatively unaffected. Thus we have convincingly demonstrated that human CRP is glycosylated in some pathological conditions
    Type of Publication: Journal article published
    PubMed ID: 12693993
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  • 17
    Keywords: CANCER ; tumor ; carcinoma ; Germany ; LONG-TERM ; NEW-YORK ; RISK ; transcription ; TRANSCRIPTION FACTOR ; CARCINOGENESIS ; hormone ; NEOPLASIA ; WOMEN ; cervical cancer ; cervical intraepithelial neoplasia ; HPV ; HUMAN KERATINOCYTES ; ORAL-CONTRACEPTIVES ; intraepithelial neoplasia ; cervical carcinoma ; DEPENDENT TRANSFORMATION ; ESTROGEN METABOLISM ; GLUCOCORTICOID RESPONSE ELEMENTS ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; LONG CONTROL REGIONS ; SQUAMOUS-CELL CARCINOMAS ; VIRAL GENE-EXPRESSION
    Abstract: Available data demonstrate an increase in the transcription of high-risk papillomaviruses by the 16alpha-hydroxylation of estrogens, which is in line with the epidemiologic data showing an increased cervical carcinogenesis risk for long-term contraceptive-using, HPV-infected women. No evidence exists for an increase in HPV-negative contraceptive users. (C) 2002 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 12516087
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  • 18
    Keywords: CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; carcinoma ; CELL ; Germany ; human ; DISEASE ; NEW-YORK ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; RNA ; cell line ; TISSUE ; validation ; LINES ; MARKER ; TISSUES ; tumour ; CELL-LINES ; BREAST-CANCER ; TARGET ; immunohistochemistry ; gene expression ; affymetrix ; CELL-LINE ; LINE ; MARKERS ; CARCINOMAS ; adenocarcinoma ; OVEREXPRESSION ; PERIPHERAL-BLOOD ; GASTRIC-CANCER ; ADAM9 ; CDNA MICROARRAYS ; cell lines ; expression profiling ; HUMAN GENES ; K-RAS ; METALLOPROTEASE-DISINTEGRIN ; microarray hybridisation ; microdissection ; OLIGONUCLEOTIDE ARRAYS ; pancreatic cancer ; pancreatic carcinoma ; SERIAL ANALYSIS
    Abstract: In a search for new molecular markers of pancreatic ductal adenocarcinoma (PDAC), we compared the gene expression profiles of seven pancreatic carcinomas and one carcinoma of the papilla Vateri with those of duct cells from three non-neoplastic pancreatic tissues. In addition, the human pancreatic duct cell line and five PDAC cell lines (AsPC-1, BxPC-3, Capan-1, Capan-2, HPAF) were examined. RNA was extracted from microdissected tissue or cultured cell lines and analysed using a custom-made Affymetrix Chip containing 3023 genes, of which 1000 were known to be tumour associated. Hierarchical clustering revealed 81 differentially expressed genes. Of all the genes, 26 were downregulated in PDAC and 14 were upregulated in PDAC. In PDAC cell lines versus normal pancreatic duct cells, 21 genes were downregulated and 20 were upregulated. Of these 81 differentially expressed genes, 15 represented human genes previously implicated in the tumourigenesis of PDAC. From the genes that were so far not known to be associated with PDAC tumorigenesis, we selected ADAM9 for further validation because of its distinct overexpression in tumour tissue. Using immunohistochemistry, the over-expressed gene, ADAM9, was present in 70% of the PDACs analysed. In conclusion, using microarray technology we were able to identify a set of genes whose aberrant expression was associated with PDAC and may be used to target the disease
    Type of Publication: Journal article published
    PubMed ID: 12942322
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  • 19
    Keywords: CANCER ; BLOOD ; DISEASE ; RISK ; GENE ; PROTEIN ; SAMPLES ; PATIENT ; DNA ; FAMILY ; FREQUENCY ; BREAST ; BREAST-CANCER ; family history ; OVARIAN-CANCER ; WOMEN ; MUTATION ; MUTATIONS ; PREVALENCE ; BRCA1/2 ; BRCA2 MUTATIONS ; early-onset breast cancer ; German population ; germline mutations ; POPULATION-BASED SAMPLE
    Abstract: This study was undertaken to investigate the prevalence of BRCA1 and BRCA2 germline mutations in 91 German patients unselected for family history, who were diagnosed with breast cancer before the age of 41 years. Clinical information and blood samples were obtained from all patients. A comprehensive BRCA1 and BRCA2 mutational analysis was performed using the protein truncation assay and single-strand conformational polymorphism analysis followed by DNA sequencing of variant signals detected by these assays. Five different deleterious germline mutations including four frameshift mutations and one missense mutation were identified, three in BRCA1 (3.3%) and two mutations (2.2%) in BRCA2. Both BRCA2 mutations are novel and might be specific for the German population. An additional BRCA1 missense mutation previously described and classified as an unknown variant was found. This mutation was also detected in two breast cancer patients of family P 328 and not in 140 healthy controls suggesting that it is disease associated. In addition, one common polymorphism and five novel intronic sequence variants with unknown significance were found. Our findings show that mutations in BRCA1 and BRCA2 may contribute similarly to early-onset breast cancer in Germany. Given current constraints on health-care resources, these results support the notion that BRCA1 and BRCA2 mutation screening may have the strongest impact on health-care when targeted to high- risk populations
    Type of Publication: Journal article published
    PubMed ID: 12774040
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  • 20
    Keywords: CELLS ; EXPRESSION ; IN-VITRO ; CELL ; human ; IN-VIVO ; VITRO ; VIVO ; NETWORK ; GENE ; PROTEIN ; PROTEINS ; TIME ; INFECTION ; RAT ; CONTRAST ; STAGE ; DISRUPTION ; MUTATION ; MUTATIONS ; MUSCLE ; ASSEMBLY PROPERTIES ; SERIES ; GREEN FLUORESCENT PROTEIN ; ORGANIZATION ; ADENOVIRUS ; ALPHA-B-CRYSTALLIN ; DILATED CARDIOMYOPATHY ; EPIDERMOLYSIS-BULLOSA SIMPLEX ; INTERMEDIATE-FILAMENT PROTEINS ; MICE LACKING DESMIN ; MUSCULAR-DYSTROPHY ; SKELETAL MYOPATHY ; SMOOTH-MUSCLE ; Z-DISCS
    Abstract: Mutations in desmin have been associated with a subset of human myopathies. Symptoms typically appear in the second to third decades of life, but in the most severe cases can manifest themselves earlier. How desmin mutations lead to aberrant muscle function, however, remains poorly defined. We created a series of four mutations in rat desmin and tested their in vitro filament assembly properties. RDM-G, a chimera between desmin and green fluorescent protein, formed protofilament-like structures in vitro. RDM-1 and RDM-2 blocked in vitro assembly at the unit-length filament stage, while RDM-3 had more subtle effects on assembly. When expressed in cultured rat neonatal cardiac myocytes via adenovirus infection, these mutant proteins disrupted the endogenous desmin filament to an extent that correlated with their defects in in vitro assembly properties. Disruption of the desmin network by RDM-1 was also associated with disruption of plectin, myosin, and a-actinin organization in a significant percentage of infected cells. In contrast, expression of RDM-2, which is similar to previously characterized human mutant desmins, took longer to disrupt desmin and plectin organization and had no significant effect on myosin or alpha-actinin organization over the 5-day time course of our studies. RDM-3 had the mildest effect on in vitro assembly and no discernable effect on either desmin, plectin, myosin, or a-actinin organization in vivo. These results indicate that mutations in desmin have both direct and indirect effects on the cytoarchitecture of cardiac myocytes
    Type of Publication: Journal article published
    PubMed ID: 12529857
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  • 21
    Keywords: IN-VITRO ; IONIZING-RADIATION ; IRRADIATION ; CELL ; Germany ; human ; IN-VIVO ; KINASE ; PATHWAY ; VITRO ; VIVO ; SITE ; PROTEIN ; radiation ; ACTIVATION ; COMPLEX ; COMPLEXES ; DNA ; CARCINOGENESIS ; cell cycle ; CELL-CYCLE ; CYCLE ; PHOSPHORYLATION ; MUTANT ; LESIONS ; PROGRESSION ; CYCLE PROGRESSION ; DAMAGE ; DNA-DAMAGE ; DEGRADATION ; ATR ; CHK1 ; CYCLE CONTROL ; G(1)/S TRANSITION ; PROTEASOME ; S-PHASE ; serine
    Abstract: The human Cdc25A phosphatase plays a pivotal role at the G(1)/S transition by activating cyclin E and A/Cdk2 complexes through dephosphorylation. In response to ionizing radiation, Cdc25A is phosphorylated by both Chk1 and Chk2 on Ser-123. This in turn leads to ubiquitylation and rapid degradation of Cdc25A by the proteasome resulting in cell cycle arrest. We found that in response to UV irradiation, Cdc25A is phosphorylated at a different serine residue, Ser-75. Significantly, Cdc25A mutants carrying alanine instead of either Ser-75 or Ser-123 demonstrate that only Ser-75 mediates protein stabilization in response to UV-induced DNA damage. As a consequence, cyclin E/Cdk2 kinase activity was high. Furthermore, we find that Cdc25A was phosphorylated by Chk1 on Ser-75 in vitro and that the same site was also phosphorylated in vivo. Taken together, these data strongly suggest that phosphorylation of Cdc25A on Ser-75 by Chk1 and its subsequent degradation is required to delay cell cycle progression in response to UV-induced DNA lesions
    Type of Publication: Journal article published
    PubMed ID: 12759351
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  • 22
    Keywords: GROWTH ; tumor ; Germany ; MORTALITY ; NEW-YORK ; RISK ; PROTEIN ; PATIENT ; TUMOR-NECROSIS-FACTOR ; INTERVENTION ; treatment ; PLASMA ; DECREASE ; AGE ; MUSCLE ; AMINO-ACIDS ; OXIDATIVE STRESS ; ANTIOXIDANT ; aging-related wasting ; ALPHA-LIPOIC ACID ; antioxidants and aging ; cysteine ; ELDERLY HUMANS ; INJURIOUS FALLS ; MUSCLE PROTEIN-SYNTHESIS ; muscular aging ; P70 S6 KINASE ; PLASMA REDOX STATE ; RAT SKELETAL-MUSCLE ; RESISTANCE EXERCISE ; role in aging ; tumor necrosis factor in aging
    Abstract: Aging-related loss of muscle function is a predictor of mortality and a surrogate parameter of the aging process. Its consequences include a high risk for falls, hip fractures, and loss of autonomy. Aging is associated with changes in the oxidant/antioxidant balance including a decrease in plasma thiol (cysteine) concentration. To assess the importance of cysteine, we determined in a double-blind study the effects of N-acetylcysteine on the functional capacity of frail geriatric patients and their response to physical exercise. The subjects on placebo showed only a relatively weak response, and 31% showed even a decrease in more than one parameter during the observation period. Low plasma arginine levels were correlated with a weak overall performance before exercise and a poor response to exercise. N-Acetyl-cysteine strongly enhanced the increase in knee extensor strength and significantly increased the sum of all strength parameters if adjusted for baseline arginine level as a confounding parameter. N-acetylcysteine had no significant effect on growth hormone and IGF-1 levels but caused a significant decrease in plasma TNF-alpha. These findings may provide a basis for therapeutic intervention and suggest that the loss of function involves limitations in cysteine and one or more other amino acids which may compromise muscular protein synthesis
    Type of Publication: Journal article published
    PubMed ID: 12601528
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  • 23
    Keywords: RISK ; MELANOMA ; DATABASE ; MUTATIONS ; CANCER RISKS ; AUSTRALIA ; INCIDENCE RATES ; SPOUSES
    Type of Publication: Journal article published
    PubMed ID: 12873883
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  • 24
    Keywords: CANCER ; FOLLOW-UP ; DISEASE ; RISK ; SAMPLE ; TIME ; RISK-FACTORS ; AGE ; WOMEN ; risk factors ; SWEDEN ; RISK FACTOR ; SIR ; ASBESTOS ; time trends ; TRENDS ; mesothelioma
    Abstract: Epidemiologic data on peritoneal mesothelioma are scarce but exposure to asbestos is an identified risk factor. To characterize the disease, time trends, age-incidence relationships, and occupational risk factors for peritoneal mesothelioma were studied based on the Swedish Family-Database covering years 1961 to 1998. Peritoneal mesothelioma is a rare disease and only 96 male and 113 female cases were recorded during the 38-year period, Age-standardized incidence of the disease has increased for men until 1985 and leveled off thereafter. The incidence in women has been equally high but it has continued to increase toward the end of the follow-up period. The incidence was maximal at an age around 80 years for both genders. No female occupational or socioeconomic group was at risk. For men, 29% of the cases had typical asbestos related jobs with a SIR of 1.70. Bricklayers and plumbers had the highest risk of 7.22 and 5.12 respectively Within limits of the sample,. size, no evidence was noted for risk from environmental exposures to asbestos because the risk of farmers and that of urban residents were not different
    Type of Publication: Journal article published
    PubMed ID: 12708149
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  • 25
    Keywords: FOLLOW-UP ; LUNG-CANCER ; CANCER MORTALITY ; DISEASE ; RISK ; RISKS ; WORKERS ; TIME ; PATIENT ; RISK-FACTORS ; AGE ; MEN ; risk factors ; RATES ; SWEDEN ; DATABASE ; SIR ; INCIDENCE RATES ; FAMILY-CANCER DATABASE ; ASBESTOS ; ASBESTOS EXPOSURE ; EUROPE ; MALIGNANT MESOTHELIOMA ; REFINERY/PETROCHEMICAL PLANT COHORTS
    Abstract: Epidemiologic data on pleural mesothelioma are scarce on regional and occupational time trends, which would monitor the effects of changes in exposure to asbestos. We aim to characterize time trends, regional, socioeconomic, and occupational risk factors for pleural mesothelioma in Sweden in the years from 1961 to 1998. The Swedish Family-Cancer Database was used to identify patients with pleural mesothelioma. Age- standardized incidence rates and standardized incidence ratio (SIR) were calculated for the population in the Database. A total of 1298 male and 233 female pleural mesotheliomas were retrieved. Age-standardized incidence of the disease was highest, and the trend increased in residents of large industrial and shipbuilding cities. In the last follow-up period, the male rate exceeded the female rate about 10-fold. Among male socioeconomic groups, manual workers showed the highest and ever-increasing SIR. No female socioeconomic group was at risk. For men, plumbers and seamen had the highest risk of 4.56 and 2.83, respectively, but the risks appeared to be decreasing for plumbers, whereas no clear trend was noted for seamen, probably because of indirect expose in ships. Farmers showed an SIR of 0.28, indicating that the population at large was at four times higher risk than farmers. The SIRs of many academic/college-educated groups were two to six times higher than those of farmers, suggesting indirect exposure to asbestos in these groups
    Type of Publication: Journal article published
    PubMed ID: 12708150
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  • 26
    Keywords: CANCER ; LUNG-CANCER ; RISK ; SITES ; TIME ; SKIN ; lifestyle ; WOMEN ; risk factors ; MELANOMA ; DATABASE ; GASTRIC-CANCER ; HELICOBACTER-PYLORI ; ATTRIBUTABLE RISKS ; CARCINOID-TUMORS ; causes of cancer ; ENDOMETRIAL CANCER ; environmental risks ; EPSTEIN-BARR-VIRUS ; LIFE-STYLE ; sociol factors ; SWEDISH POPULATION
    Abstract: It is well known that certain cancers have shown clustering in socioeconomic groups, but limited data are available on recent results and time trends in such clustering. We determined standardized incidence ratios (SIR) for cancer, adjusted for age, period, region, parity and age at first childbirth among men and women in 6 socioeconomic groups based on the Swedish Family-Cancer Database. Persons had to be identified with the same socioeconomic status in the census of years 1960 and 1970, or of years 1960, 1970 and 1980; the comparison group was all people according to the same censuses. Cancers were followed from years 1970 to 1998 or from 1980 to 1998. Both increased and decreased SIRs were found, and a consistent pattern emerged, although the overall SIRs for cancer did not differ much, the lowest being for farmers (0.8S) and the highest for professional men (1.07) and women (1.11). At individual sites, manual workers were at risk of tobacco-, alcohol- and occupation- and human papilloma virus-related cancers and at a decreased risk at most other cancers. Manual workers and farmers showed an excess of stomach cancer; professionals had an excess of melanoma and squamous cell skin cancer. Male and female SIRs correlated highly for manual and blue-collar workers and for professionals. The overall population- attributable fraction for selected sites was 16.7% for men and 10.9% for women and it was highest, over 50%, for lung cancer in both genders
    Type of Publication: Journal article published
    PubMed ID: 12740920
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  • 27
    Keywords: CANCER ; human ; RISK ; SWEDEN ; POPULATIONS ; SPOUSES ; LANGUAGE
    Type of Publication: Journal article published
    PubMed ID: 12673273
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  • 28
    Keywords: CANCER ; carcinoma ; SYSTEM ; HEPATOCELLULAR-CARCINOMA ; incidence ; liver ; POPULATION ; RISK ; RISKS ; GENE ; GENES ; FAMILY ; primary ; tumour ; MEMBER ; MEMBERS ; ASSOCIATION ; CANDIDATE GENE ; SUSCEPTIBILITY ; AGE ; ovarian cancer ; OVARIAN-CANCER ; CERVICAL-CANCER ; bladder cancer ; BLADDER-CANCER ; SWEDEN ; DATABASE ; SIR ; familial risk ; CARRIERS ; FAMILY-CANCER DATABASE ; bile duct ; BILE-DUCTS ; CHOLECYSTECTOMY ; GALLBLADDER-CANCER ; RELATIVES ; VIRAL-HEPATITIS
    Abstract: Background and aims: Familial risks in liver and biliary cancers have been assessed in small case control studies, usually based on reported, but not medically verified, cancers in family members. Thus the degree of familial clustering for these cancers remains to be established. Methods: The nationwide Swedish Family-Cancer Database was used, covering 10.2 million individuals for the years 1961-1998 from the Swedish Cancer Registry. Liver and biliary tract cancers were identified from 1121 offspring between the ages of 0 and 66 years and 17 131 parents. Standardised incidence ratios (SIRs) and 95% confidence intervals (Cls) were calculated for cancers in family members. Results: All cancers in the liver and biliary system showed a familial SIR of 1.65 (95% Cl 1.05- 2.46). This was mainly explained by a high risk for familial gall bladder cancer (SIR 5.21 (95% Cl 2.07-10.80)) and for familial primary liver cancer with hepatocellular carcinoma histology (SIR 4.69 (95% Cl 1.48-11.04)). For gall bladder and hepatocellular cancer, maternal transmission appeared to be favoured. Gall bladder cancer was associated with pancreatic cancer (SIR 2.39 (95% Cl 1.23-4.18)). Primary liver cancer was associated with cervical, urinary bladder, and endocrine gland tumours. Cancer in extrahepatic bile ducts was associated with ovarian cancer and that in ampulla of Vater with thyroid cancer; however, these associations may have been fortuitous. Conclusions: This study has provided the first data on familial clustering of liver and gall bladder cancers, based on medically confirmed records. The risks were so high that heritable factors were likely to contribute, possibly modified by environmental factors. The demonstration of candidate genes would help to further characterise the familial risks
    Type of Publication: Journal article published
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  • 29
    Keywords: CANCER ; neoplasms ; THERAPY ; DISEASE ; incidence ; RISK ; RISKS ; SITE ; SITES ; PATIENT ; primary ; SKIN ; LYMPHOMA ; MALIGNANCIES ; skin cancer ; MELANOMA ; SWEDEN ; DATABASE ; SQUAMOUS-CELL CARCINOMA ; SIR ; PRIMARY CANCERS ; FAMILY-CANCER DATABASE ; 2ND PRIMARY NEOPLASMS ; CANCER-THERAPY ; immunological factors ; immunosuppression ; LONG-TERM SURVIVORS ; MULTIPLE PRIMARY CANCERS ; non-hodgkin's lymphoma ; second cancer ; therapeutic effects
    Abstract: Successes in cancer therapy have led to increasing numbers of cancer survivors, who are at risk of developing second primary cancers. Therapy- or disease-induced suppression of the immune function may predispose cancer patients to a second malignancy. An excess of squamous cell skin cancers (SCC) and non-Hodgkin's lymphomas has been found in immunosuppressed patients. We used the nationwide Swedish Family-Cancer Database on 10.2 million individuals to calculate the risk of second primary skin cancers and non-Hodgkin's lymphomas following a previous malignancy. A total of 4301 second skin cancers and 1672 non- Hodgkin's lymphomas were identified. Standardised incidence ratios (SIR)s and 95% Confidence Intervals (CIs) were calculated and compared. Among 14 different sites for male or female first primary malignancies, 11 of these sites were followed by an increased risk of skin cancer (SIRs for males for risk of skin cancer as a second primary cancer: 14.1 for SCC; 9.7 for melanoma; 6.1 for leukaemia as the first site; SIRs for females for risk of skin cancer: 14.6 for SCC; 6.8 for larynx; 6.2 for upper aerodigestive tract (UADT) as the first site). The risk of non-Hodgkin's lymphoma was increased after 10 of 14 different male neoplasms and 12 of 17 different female neoplasms. (SIRs for males for risk of non-Hodgkin's lymphoma as a second primary cancer: 6.4 for non-Hodgkin's lymphoma; 3.2 for leukaemias; 3.1 for multiple myeloma as the first site; SIRs for females for risk of non-Hodgkin's lymphoma as a second primary cancer: 12.5 for leukaemias; 7.0 for Hodgkin's disease; 3.6 for UADT as the first site). The high, and after certain sites, very high risks of second skin cancer and non-Hodgkin's lymphoma suggest that immune suppression may be a contributory mechanism. (C) 2002 Elsevier Science Ltd. All rights reserved
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  • 30
    Keywords: CANCER ; NEW-YORK ; RISK ; SKIN ; ASSOCIATION ; BREAST-CANCER ; IN-SITU ; RATES ; MELANOMA ; SWEDEN ; DATABASE ; SQUAMOUS-CELL CARCINOMA ; NATIONWIDE ; CUTANEOUS MELANOMA ; OCULAR MELANOMA ; FAMILY-CANCER DATABASE ; 2ND PRIMARY CANCERS ; MALIGNANT- MELANOMA
    Type of Publication: Journal article published
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  • 31
    Keywords: CANCER ; tumor ; carcinoma ; neoplasms ; FOLLOW-UP ; RISK ; RISKS ; SITE ; SITES ; TISSUE ; TUMORS ; primary ; RISK-FACTORS ; SKIN ; treatment ; ASSOCIATION ; BREAST-CANCER ; PATTERNS ; WOMEN ; leukemia ; SWEDEN ; DATABASE ; HEREDITARY ; SIR ; familial risk ; SMALL-INTESTINE ; BRCA2 MUTATIONS ; germline mutations ; double primaries ; endometrioid tumor ; FAMILY-CANCER DATABASE ; FIRST- DEGREE RELATIVES ; heritable effects ; HODGKINS- DISEASE ; multiple primaries ; NONPOLYPOSIS COLORECTAL-CANCER ; second carcinoma ; synchronous carcinoma
    Abstract: BACKGROUND. Population-based data on subsequent neoplasms after women are diagnosed with endometrial and ovarian carcinomas are limited, particularly regarding specific histologic tumor types. METHODS. The nationwide Swedish Family-Cancer Database of 10.2 million individuals, which includes 19,128 invasive endometrial carcinomas and 19,440 ovarian carcinomas, was used to calculate standardized incidence ratios (SIRs) and 95% confidence intervals (95% CIs) for second primary carcinomas. SIRs were calculated for specific follow-up periods. Data on histopathologic types also were used. RESULTS. An excess of subsequent malignancies after women were diagnosed with endometrial carcinoma was noted at 11 sites. The highest SIRs were recorded for synchronous or metasynchronous ovarian carcinomas (SIR, 55.77; 95% CI, 48.82-63.43) and carcinomas of the small intestines (SIR, 14.71; 95% Cl, 4.64-34.59). Primary ovarian carcinoma was followed by an increased risk of developing endometrial carcinoma, and the risks of developing many other malignancies also were increased after women were diagnosed with endometrial carcinoma, including intestinal malignancies, renal cell carcinoma, bladder carcinoma, squamous cell skin carcinoma, connective tissue malignancies, and leukemia. When ovarian endometrioid histology was diagnosed synchronously with primary endometrial carcinoma, the SIR was 140; when endometrial carcinoma was the subsequent neoplasm, the SIR was 87. A small familial component was found in the cooccurrence of endometrial carcinoma and ovarian carcinoma. CONCLUSIONS. The current data show a strong clustering of endometrial carcinomas and ovarian carcinomas, particularly involving tumors of endometrioid morphology. The patterns of second neoplasms also suggest that hereditary nonpolyposis colorectal. carcinoma may contribute to the association between endometrial and ovarian malignancies. Increased risks for connective tissue tumors and leukemia may signal a response to treatment, and an increased risk for squamous cell skin carcinoma may signal a depressed immune function. (C) 2003 American Cancer Society
    Type of Publication: Journal article published
    PubMed ID: 12733142
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  • 32
    Keywords: CANCER ; LUNG-CANCER ; MORTALITY ; RISK ; SWEDEN ; DATABASE ; GASTRIC-CANCER ; HELICOBACTER-PYLORI ; ATTRIBUTABLE RISKS ; ENDOMETRIAL CANCER ; time trends ; education ; INCIDENCE TRENDS ; SOCIOECONOMIC GROUPS
    Type of Publication: Journal article published
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  • 33
    Keywords: CANCER ; Germany ; human ; incidence ; POPULATION ; RISK ; RISKS ; SITE ; SITES ; IMPACT ; cancer prevention ; prevention ; HEALTH ; lifestyle ; WOMEN ; MEN ; SWEDEN ; cancer risk ; DATABASE ; SIR ; TOBACCO ; ALCOHOL ; FAMILY-CANCER DATABASE ; BRITAIN ; INEQUALITIES ; LONE MOTHERS ; MIDDLE-AGED WOMEN ; NESTED CASE-CONTROL ; NORWEGIAN WOMEN BORN
    Abstract: Limited data are available on the possible changes in cancer risk brought about by widowhood and divorce, an increasing segment of the population. We calculated standardized incidence ratios (SIRs) for cancer among 47,000 widows/widowers and 60,000 divorced people, based on the Swedish Family-Cancer Database. Persons had to be identified with the same civil status in the census of years 1960 and 1970; the comparison group was married people according to the same censuses. Cancers were followed from years 1971 to 1998. Both increased and decreased SIRs were found, and a consistent pattern emerged. The effects on the divorced were always stronger than those in widows/widowers, irrespective of the direction of the effect. Every significant SIR for a cancer site in widows/widowers was accompanied by a more deviant and significant SIR in the divorced. SIRs between divorced men and women (r = 0.83, P 〈 0.0001) and between widows and divorcees correlated (r = 0.70, P 〈 0.0001). The overall cancer risk for the divorced was 0.92-0.94, and it was a balance between increased risks at tobacco-, alcohol-, and human papilloma virus-related sites, and decreased risks at most other sites. The data suggest that the changes in lifestyle on the loss of a spouse impact on the incidence of almost every type of cancer. The effects were so large that a failure to consider marital status in epidemiological studies may be a source to bias. Understanding these lifestyle changes may provide new insight in cancer prevention
    Type of Publication: Journal article published
    PubMed ID: 14504201
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    Keywords: CANCER ; Germany ; EPIDEMIOLOGY ; incidence ; RISK ; RISKS ; GENE ; GENES ; SUSCEPTIBILITY ; SUSCEPTIBILITY GENES ; BREAST ; breast cancer ; BREAST-CANCER ; IDENTIFICATION ; prevention ; DESIGN ; DIFFERENCE ; AGE