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  • 1
    Language: English
    In: International journal of cancer, 01 January 2016, Vol.138(1), pp.137-45
    Description: Studies have shown that the calcium-sensing receptor (CaSR) mediates the antitumorigenic effects of calcium against colorectal cancer (CRC). Expression of the CaSR in colorectal tumors is often reduced. We have reported previously that silencing of CaSR in CRC is caused in part by methylation of CaSR promoter 2 and loss of histone acetylation. We investigated the impact of aberrant microRNA expression on loss of CaSR expression. A microarray study in two Caco-2 subclones (Caco2/AQ and Caco2/15) that have similar genetic background, but different CaSR expression levels (Caco2/AQ expressing more CaSR than Caco2/15), identified 22 differentially expressed microRNAs that potentially target the CaSR. We validated these results by performing gain- and loss-of-function studies with the top candidates: miR-9, miR-27a, miR-135b, and miR-146b. Modulation of miR-135b or miR-146b expression by mimicking or inhibiting their expression regulated CaSR protein levels in two different colon cancer cell lines: Caco2/AQ (moderate endogenous CaSR expression) and HT29 (low endogenous CaSR levels). Inhibition of miR-135b and miR-146b expression led to high CaSR levels and significantly reduced proliferation. In samples of colorectal tumors we observed overexpression of miR-135b and miR-146b, and this correlated inversely with CaSR expression (miR-135b: r = -0.684, p 〈 0.001 and miR-146b: r = -0.448, p 〈 0.001), supporting our in vitro findings. We demonstrate that miR-135b and miR-146b target the CaSR and reduce its expression in colorectal tumors, reducing the antiproliferative and prodifferentiating actions of calcium. This provides a new approach for finding means to prevent CaSR loss, developing better treatment strategies for CRC.
    Keywords: Calcium-Sensing Receptor ; Colorectal Cancer ; Mir-135b ; Mir-146b ; Micrornas ; Gene Silencing ; Colorectal Neoplasms -- Genetics ; Micrornas -- Genetics ; Receptors, Calcium-Sensing -- Genetics
    ISSN: 00207136
    E-ISSN: 1097-0215
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  • 2
    Language: English
    In: Drug Discovery Today: Disease Models, 2016, Vol.21, pp.1-2
    Keywords: Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1740-6757
    E-ISSN: 1740-6757
    Source: ScienceDirect Journals (Elsevier)
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  • 3
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(8), p.e103649
    Description: BACKGROUND: Extravasation of cytotoxic drugs is a serious complication of systemic cancer treatment. Still, a reliable method for early assessment of tissue damage and outcome prediction is missing. Here, we demonstrate that the evaluation of blood flow by indocyanine green (ICG) angiography in the extravasation area predicts for the need of surgical intervention. METHODS: Twenty-nine patients were evaluated by ICG angiography after extravasation of vesicant or highly irritant cytotoxic drugs administered by peripheral i.v. infusion. Tissue perfusion as assessed by this standardized method was correlated with clinical outcome. RESULTS: The perfusion index at the site of extravasation differed significantly between patients with reversible tissue damage and thus healing under conservative management (N = 22) versus those who needed surgical intervention due to the development of necrosis (N = 7; P = 0.0001). Furthermore, in patients benefiting from conservative management, the perfusion index was significantly higher in the central extravasation area denoting hyperemia, when compared with the peripheral area (P = 0.0001). CONCLUSIONS: In this patient cohort, ICG angiography as indicator of local perfusion within the extravasation area was of prognostic value for tissue damage. ICG angiography could thus be used for the early identification of patients at risk for irreversible tissue damage after extravasation of cytotoxic drugs.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Histopathology, 04 April 2011, Vol.58(5), p.792
    Description: Aims: The Viennese Museum of Pathological Anatomy represents one of the biggest collections worldwide. Interrogating the quality of these unique specimens, some of them from the 19th century, 31 historic tissue samples were analyzed by modern histopathology. The good conservation of this specimen prompted us to initiate molecular investigations on gDNA. Methods and Results: After isolation of gDNA from 5 µm thick paraffin embedded tissue sections, the DNA integrity was controlled using a sequential multiplex PCR technique. Having established the PCR methodology, the historic specimens were analysed for their KRAS status focusing on mutations in codons 12 and 13. In 4 of 31 samples, mutations of codon 12 were detected. Conclusion: Molecular pathology are feasible on historic formalin fixed specimens. In comparison with molecular routine pathology, these tests require more elaborated experimental approaches (optimised gDNA isolation, DNA quality control by sequential multiplex PCR for β-actin, and sequential PCR for KRAS), which are justified given the value of these samples. The molecular elements driving tumourigenesis today may already be observed in historic specimens. This fact may serve as a first hint at the stability of tumour driving mutations such as KRAS covering an observation period of almost 200 years.
    Keywords: Medicine ; Medicine
    ISSN: 0309-0167
    E-ISSN: 1365-2559
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  • 5
    Language: English
    In: Analytical chemistry, 20 November 2018, Vol.90(22), pp.13178-13182
    Description: Cancer cells communicate with the whole organism via extracellular vesicles (EVs), which propagate molecular information in support of the malignant phenotype. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was employed for protein profiling of EVs derived from CCL-228 as the primary colon tumor, the lymph node metastasis CCL-227, and subclones resistant to 5, 25, and 125 μM 5-fluorouracil (FU). EVs were harvested from cell culture supernatant by ultracentrifugation to serve as a model for circulating cancer cell-derived biomarker carriers from body fluids (i.e., liquid biopsy). Protein mass spectra were recorded using standard MALDI matrixes (e.g., CHCA, sinapinic acid) in the range m/ z 2000-20000 on different MALDI-TOF-MS systems and subjected to multivariate data analysis . By using hierarchical clustering, PCA and PLS-DA, discriminatory protein patterns of the EVs from the different cell populations were obtained. Peaks in the range  m/ z 2000-6500 and m/ z 5500-15500 were found to be unique to EVs and the cells, respectively. This clearly demonstrates the differential expression of proteins in EVs as the result of an increasing chemoresistance of their parent cells. The sensitivity of the MALDI-MS based assay was in the low μg/mL (≈1.2-5 × 10 particles/mL) range. Consequently, our MALDI-MS protein profiling approach shows the potential to serve as novel tool for minimally invasive cancer diagnostics and chemotherapy monitoring in the future, e.g., for early detection of therapy resistance without biopsy.
    Keywords: Biomarkers, Tumor -- Analysis ; Drug Resistance, Neoplasm -- Physiology ; Extracellular Vesicles -- Chemistry ; Neoplasm Proteins -- Analysis ; Proteomics -- Methods
    ISSN: 00032700
    E-ISSN: 1520-6882
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  • 6
    Language: English
    In: memo - Magazine of European Medical Oncology, 2015, Vol.8(4), p.231(4)
    Description: Byline: Daniel Senfter (1), Robert M. Mader (2) Keywords: exosome; cellular communication; biomarker; liquid biopsy Abstract: Extracellular vesicles, particularly small exosomes with a size between 40 and 120 nm, contain complex information. Most importantly, exosomes may transfer this information to recipient cells and alter their cellular programme. If decoded, this information reveals ongoing malignant processes within the organism such as drug resistance or metastases formation (functional biomarker). As this information is composed of RNA, DNA fragments, proteins and metabolites, these molecules may also serve as molecular biomarker. Exosomes are generated from parental cells, frequently under disease conditions. Thus, exosomes share significant information with their origin including mutations of the malignant lesion. Tumour characteristics can therefore be retrieved in circulating exosomes, which opens a complete new approach in cancer diagnosis: the liquid biopsy. Author Affiliation: (1) Department of Pediatrics, Molecular Neuro-Oncology Research Unit, Medical University of Vienna, 1090, Vienna, Austria (2) Department of Medicine I, Clinical Division of Oncology, Comprehensive Cancer Center of the Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria Article History: Registration Date: 17/11/2015 Received Date: 12/08/2015 Accepted Date: 17/11/2015 Online Date: 01/12/2015
    Keywords: Drug Resistance ; Metabolites ; Cancer Diagnosis ; Cancer Treatment ; Proteins ; Medical Schools ; Antineoplastic Agents ; RNA
    ISSN: 1865-5041
    E-ISSN: 18655076
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  • 7
    Language: English
    In: Clinical Therapeutics, May 2012, Vol.34(5), pp.1195-1203
    Description: Methotrexate (MTX) is a cornerstone in the treatment of rheumatoid arthritis. Despite its widespread use, expert opinions differ about the optimal MTX starting dosage to achieve rapid onset of action while averting increased occurrence of adverse effects. Plasma concentrations have not been assessed in previous studies that monitored clinical efficacy. This study was performed to compare the pharmacokinetic parameters and clinical response of a standard (15 mg) and an accelerated (25 mg) dosing regimen, each administered orally once a week. This randomized, controlled, double-blind, parallel, single-site study included 19 MTX-naïve patients older than 18 years with rheumatoid arthritis. Patients participated for 16 weeks. Disease activity was assessed using the Disease Activity Score in 28 joints (DAS-28) as the primary outcome parameter. Plasma MTX concentrations were measured using HPLC at weeks 1, 5, 10, and 16. Tolerability was assessed via routine blood analysis (hematology and clinical chemistry) and a patient questionnaire to monitor adverse events. Reported or observed adverse events were recorded along with information about their severity and causal relationship to the study medication. Nineteen white patients (13 women and 6 men; mean age, 56 years; and mean weight, 74 kg) participated. At study entry, mean (SD) DAS-28-4v (erythrocyte sedimentation rate) was 4.73 (1.02). Health Assessment Questionnaire scores were 1.45 (0.85); for C-reactive protein, 11.45 (10.04) mg/dL; for alkaline phosphatase, 73.58 (19.91) U/L; for aspartate aminotransferase, 23.32 (7.13) U/L; and for creatinine, 0.87 (0.22) mg/dL. Although pharmacokinetic parameters such as AUC and C were significantly higher after the accelerated dosing regimen, clinical activity scores (DAS-28) and inflammation parameters (C-reactive protein) did not indicate a significant benefit of an accelerated starting regimen. Considering toxicity, no elevation in liver function enzymes and no decrease in renal function were observed using the accelerated dosing (statistical significance set at ≤ 0.05). No serious adverse events were noted. All observed adverse events were classified as study related. Overall, adverse events were noted in 58% of patients. Comparison of the two doses revealed that 60% of patients receiving the standard dosing regimen and 56% of patients receiving the accelerated dosing regimen reported adverse events, the most frequent being gastrointestinal. These events were generally self-limiting. Differences in clinical response between these two small selected patient groups who received an initial oral dose of either 15 or 25 mg MTX per week did not reach the level of statistical significance. The overall incidence of adverse effects, all classified as study related, was 58%, with 60% of patients receiving the standard dosage and 56% of patients receiving the accelerated dosing regimen reporting adverse effects. However, because of the small sample size, this study was not powered to detect differences in the incidence of adverse events between the two dosing groups. identifier: .
    Keywords: Clinical Response ; Methotrexate ; Pharmacokinetics ; Rheumatoid Arthritis ; Starting Dosage ; Medicine ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0149-2918
    E-ISSN: 1879-114X
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  • 8
    In: Journal of Clinical Nursing, January 2009, Vol.18(2), pp.263-269
    Description: To assess a possible trend in the genotoxic risk of oncologic nurses during the working year, cytogenetic biomonitoring was performed. Exposure to cytostatic agents is a major occupational concern in oncologic personnel. In contrast to the controlled environment in oncology pharmacies, nurses may be subject to unexpected events of exposure due to the intensive contact with patients. The entire nursing staff of an oncology inpatient ward ( = 15) participated in a biomonitoring study over a period of nine months using the sister chromatid exchange test and the comet assay to detect DNA strand breaks. Blood samples were taken after a three‐week summer break (base level), one, three, six and nine months thereafter. Airborne contaminations of cytotoxics were addressed by chromatographic methods. With regard to the single monitoring points, the comet assay revealed no significant alteration of the genotoxic burden within nine months. By contrast, the sister chromatid exchange levels were significantly increased after six and nine months when compared with base levels. A trend analysis covering the whole observation period revealed an increase in genotoxicity as shown by the sister chromatid exchange test and the alkaline but not the neutral comet assay. This increase, however, was small and reversible as shown by the trend analysis of sister chromatid exchange rates during the years of service. Air samples were negative for cytotoxic contaminants. The small, but statistically significant genotoxic burden observed in oncologic nurses of an inpatient ward emphasises the need for a continuing effort to eliminate residual occupational risks. In comparison with historical controls, the current situation is characterised by beneficial safety improvements over the last years. Nevertheless, periodic training and awareness of the problems should be an integral part of advanced education.
    Keywords: Antineoplastic Agents ; Biomonitoring ; Cytogenetic Methods ; Genotoxic Burden ; Nursing ; Occupational Exposure
    ISSN: 0962-1067
    E-ISSN: 1365-2702
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  • 9
    In: International Journal of Cancer, 01 January 2016, Vol.138(1), pp.137-145
    Description: Studies have shown that the calcium‐sensing receptor (CaSR) mediates the antitumorigenic effects of calcium against colorectal cancer (CRC). Expression of the CaSR in colorectal tumors is often reduced. We have reported previously that silencing of CaSR in CRC is caused in part by methylation of promoter 2 and loss of histone acetylation. We investigated the impact of aberrant microRNA expression on loss of CaSR expression. A microarray study in two Caco‐2 subclones (Caco2/AQ and Caco2/15) that have similar genetic background, but different CaSR expression levels (Caco2/AQ expressing more than Caco2/15), identified 22 differentially expressed microRNAs that potentially target the CaSR. We validated these results by performing gain‐ and loss‐of‐function studies with the top candidates: miR‐9, miR‐27a, miR‐135b, and miR‐146b. Modulation of miR‐135b or miR‐146b expression by mimicking or inhibiting their expression regulated CaSR protein levels in two different colon cancer cell lines: Caco2/AQ (moderate endogenous CaSR expression) and HT29 (low endogenous CaSR levels). Inhibition of miR‐135b and miR‐146b expression led to high CaSR levels and significantly reduced proliferation. In samples of colorectal tumors we observed overexpression of miR‐135b and miR‐146b, and this correlated inversely with CaSR expression (miR‐135b:  = −0.684,  〈 0.001 and miR‐146b:  = −0.448,  〈 0.001), supporting our findings. We demonstrate that miR‐135b and miR‐146b target the CaSR and reduce its expression in colorectal tumors, reducing the antiproliferative and prodifferentiating actions of calcium. This provides a new approach for finding means to prevent CaSR loss, developing better treatment strategies for CRC. What's new? The calcium‐sensing receptor (CaSR) suppresses tumor formation in the colon, and its expression characteristically is decreased in colorectal tumorigenesis. In this study, CaSR expression was inversely correlated with the expression of the microRNAs miR‐135b and miR‐146b. In Caco2/AQ and HT29 colon cancer cells, these molecules targeted the CaSR, and their inhibition was associated with high CaSR expression and reduced cell growth. In colorectal tumor tissue from patients, overexpression of miR‐135b and miR‐146b was correlated with reduced CaSR expression. Targeting of microRNAs and CaSR re‐expression could form the basis for a novel therapeutic approach to colorectal cancer.
    Keywords: Calcium‐Sensing Receptor ; Micrornas ; Colorectal Cancer ; Mir‐135b ; Mir‐146b
    ISSN: 0020-7136
    E-ISSN: 1097-0215
    Source: John Wiley & Sons, Inc.
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  • 10
    Language: English
    In: Cancer biomarkers : section A of Disease markers, 2014, Vol.14(2-3), pp.87-91
    Description: The rapidly evolving understanding of tumour biology offers novel opportunities for therapeutic interventions. This information already has been used to select appropriate systemic treatment. To take full advantage of this knowledge, however, the different levels of interaction in an organism need to be integrated to link cellular mechanisms, stromal effects and the implications for organs and the whole organism. Although very challenging and ambitious, this understanding would closely link tumour biology, biomarker validation and rational therapeutic decisions.
    Keywords: Cancer Biology ; Predictive Biomarkers ; Translational Research ; Translational Medical Research ; Adenoma -- Genetics ; Colorectal Neoplasms -- Genetics ; Epigenesis, Genetic -- Drug Effects ; Molecular Targeted Therapy -- Methods
    ISSN: 15740153
    E-ISSN: 1875-8592
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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