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  • 1
    Keywords: CANCER ; PROTEIN ; MALIGNANT-MELANOMA ; relapse ; biomarker ; S100 ; RELEVANCE ; MicroRNAs ; LACTATE-DEHYDROGENASE ; TUMOR-MARKERS
    Abstract: Abstract Background: Melanoma is the most aggressive skin cancer and, despite recent advances in therapy, about 20% of the patients die of their disease. Early relapse detection and monitoring of therapy response are crucial for efficient treatment of advanced melanoma. Thus, there is a need for blood-based biomarkers in melanoma management. Serum-derived U2 small nuclear RNA fragments (RNU2-1f) were previously shown to be blood-based biomarkers for gastrointestinal and gynecologic malignancies. Here we examined whether RNU2-1f may also serve as diagnostic biomarker in advanced melanoma. METHODS: Circulating RNU2-1f levels were quantified by comparative reverse transcription PCR in a training cohort of patients with metastatic melanoma (n=33, thereof regionally metastasized to skin and lymph nodes, n=23, and distantly metastasized, n=10) vs. patients with benign naevi (n=16) vs. healthy controls (n=39). RESULTS were validated in an independent patient cohort with distant metastasis (n=16) vs. controls (n=18). RESULTS: Circulating RNU2-1f levels in the training cohort were significantly increased in serum of regionally and distantly metastatic patients, compared with patients with benign naevi or healthy controls (p〈0.0001) and allowed accurate detection of regional (AUC 0.80) as well as distant (AUC 0.84) metastasis. In the validation cohort, increased RNU2-1f levels were confirmed and enabled highly specific detection of distant metastasis (sensitivity 81%, specificity 100%, AUC 0.94). CONCLUSIONS: This is the first report to suggest a blood-based snRNA serving as a diagnostic biomarker for melanoma metastasis. Our data provide a rationale for further defining clinical utility of circulating RNU2-1f in metastasis detection in the management of melanoma patients at risk of relapse and/or with advanced disease.
    Type of Publication: Journal article published
    PubMed ID: 25741740
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  • 2
    Keywords: DEATH ; MORTALITY ; RISK ; ASSOCIATION ; SERUM CREATININE ; CARDIOVASCULAR EVENTS ; GLOMERULAR-FILTRATION-RATE ; STAGE RENAL-DISEASE ; CHRONIC KIDNEY-DISEASE ; CREATININE RATIO
    Abstract: Background: Despite standard laboratory quality control, drift and day-to-day variability in cystatin C measurements can be observed. We investigated whether correction for drift and day-to-day variation in cystatin C measurements improves the association of estimated glomerular filtration rate (eGFR) with chronic kidney disease (CKD) risk factors and prognosis. Methods: Plasma samples of the PREVEND study (Dutch cohort study, n = 8592) were used to measure cystatin C (Gentian assay) on 243 random days. A correction factor was calculated for each measurement day. GFR was estimated with CKD-EPI equation using routinely measured cystatin C (eGFR(cysC)) and corrected cystatin C (eGFR(cysC corr)). Participants were categorized in six categories of eGFR(cysC) and eGFR(cysC corr) : 〉= 120, 90-119, 75-89, 60-74, 45-59 and 〈 45 mL/min/1.73m(2). Independent replication was performed in the ESTHER study (German cohort study, n = 9949). Results: Compared to non-reclassified participants, participants re-classified upward had significantly lower age, body mass index, blood pressure, cholesterol, glucose and albuminuria, whereas the opposite was true for participants reclassified downward. CKD risk factors explained more variance in eGFR cysC corr than in eGFR cysC (p 〈 0.001). Compared to non-reclassified participants, risk of incident cardiovascular events (n = 789, follow-up 9.3 +/- 2.7 years) tended to be higher in downward reclassified and lower in upward reclassified participants. Net reclassification improvement for incident cardiovascular events using eGFR(cysC corr) was positive (0.102, p = 0.019). The ESTHER study showed similar results. Conclusions: Correction for drift and day-to-day variation in cystatin C measurement improves eGFR using cystatin C for its association with CKD risk factors and incident cardiovascular events.
    Type of Publication: Journal article published
    PubMed ID: 25415637
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  • 3
    Abstract: BACKGROUND: Circulating trimethylamine-N-oxide (TMAO) has been implicated in the development of cardiovascular and chronic kidney diseases (CKD). However, while higher TMAO levels have been associated with increased risks of cardiovascular or renal events in first prospective studies, it remained unclear how much plasma TMAO concentrations vary over time. METHODS: We measured fasting plasma levels of TMAO and two of its precursors, betaine and choline by LC-MS, in two samples of 100 participants of the European Investigation into Cancer and Nutrition (EPIC)-Heidelberg study (age range: 47-80 years, 50% female) that were collected 1 year apart, and assessed their intra-individual variation by Spearman's correlation coefficients (rho). RESULTS: Correlations of metabolite concentrations over 1 year were at rho=0.29 (p=0.003) for TMAO, rho=0.81 (p〈0.001) for betaine, and rho=0.61 (p〈0.001) for choline. Plasma levels of TMAO were not significantly associated with food intake, lifestyle factors, or routine biochemistry parameters such as C-reactive protein (CRP), low-density lipoprotein (LDL)-cholesterol, or creatinine. CONCLUSIONS: In contrast to fasting plasma concentrations of betaine and choline, concentrations of TMAO were more strongly affected by intra-individual variation over 1 year in adults from the general population. The modest correlation of TMAO levels over time should be considered when interpreting associations between TMAO levels and disease endpoints.
    Type of Publication: Journal article published
    PubMed ID: 27447240
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  • 4
    Abstract: Germline mutations in the adenomatous polyposis coli gene cause familial adenomatous polyposis, a colon cancer predisposition syndrome. More than 95% of the identified mutations result in the generation of stop codons or reading frame shifts and encode a truncated gene product, a mutation profile also found in other tumor predisposition genes such as the breast cancer or the hereditary non-polyposis coli. Therefore the protein truncation test is ideally suited for screening of mutations in these genes, starting from simple blood samples. Gene segments of interest are amplified from genomic DNA or mRNA, thereby incorporating a T7 promoter at the 5'-end. After in vitro transcription and translation of the PCR products, the resulting protein is analysed by gel electrophoresis. Truncated translation products indicate the presence of a stop mutation. We have developed a non-radioactive protein truncation test that uses a biotinylated Lys-t-RNA to label the translation products and allows a chemiluminescent detection instead of the standard radioactive method. This generic protein truncation test kit was then used to develop a parameter-specific protein truncation test for adenomatous polyposis coli. The adenomatous polyposis coli gene was divided in 5 overlapping segments, and primers were optimized to produce distinct bands with very low background in the protein truncation test. The assay was tested on 20 familial adenomatous polyposis patient samples, where 18 mutations were found, demonstrating the efficiency of this method.
    Type of Publication: Journal article published
    PubMed ID: 9806461
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