Publications by authors named "Andreas Baierl"

48 Publications

Colorectal Cancer Study of Austria (CORSA): A Population-Based Multicenter Study.

Biology (Basel) 2021 Jul 28;10(8). Epub 2021 Jul 28.

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.

The Colorectal cancer Study of Austria (CORSA) is comprised more than 13,500 newly diagnosed colorectal cancer (CRC) patients, patients with high- and low-risk adenomas as well as population-based controls. The recruitment for the CORSA biobank is performed in close cooperation with the invited two-stage CRC screening project "Burgenland PREvention trial of colorectal Disease with ImmunologiCal Testing" (B-PREDICT). Annually, more than 150,000 inhabitants of the Austrian federal state Burgenland aged between 40 and 80 are invited to participate using FIT-tests as an initial screening. FIT-positive tested participants are offered a diagnostic colonoscopy and are asked to take part in CORSA, sign a written informed consent, complete questionnaires concerning dietary and lifestyle habits and provide an ethylenediaminetetraacetic acid (EDTA) blood sample as well as a stool sample. Additional CRC cases have been recruited at four hospitals in Vienna and a hospital in lower Austria. A major strength of CORSA is the population-based controls who are FIT-positive and colonoscopy-confirmed to be free of polyps and/or CRC.
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http://dx.doi.org/10.3390/biology10080722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389216PMC
July 2021

Circulating tryptophan metabolites and risk of colon cancer: Results from case-control and prospective cohort studies.

Int J Cancer 2021 Nov 12;149(9):1659-1669. Epub 2021 Jul 12.

International Agency for Research on Cancer, Lyon, France.

Dysregulation of tryptophan metabolism has been linked to colorectal tumorigenesis; however, epidemiological studies investigating tryptophan metabolites in relation to colorectal cancer risk are limited. We studied associations of plasma tryptophan, serotonin and kynurenine with colon cancer risk in two studies with cancer patients and controls, and in one prospective cohort: ColoCare Study (110 patients/153 controls), the Colorectal Cancer Study of Austria (CORSA; 46 patients/390 controls) and the European Prospective Investigation into Cancer and Nutrition (EPIC; 456 matched case-control pairs). Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for colon cancer risk. Tryptophan was inversely associated with colon cancer risk in ColoCare (OR per 1-SD = 0.44; 95% CI, 0.31-0.64) and EPIC (OR per 1-SD = 0.86; 95% CI, 0.74-0.99). Comparing detectable vs nondetectable levels, serotonin was positively associated with colon cancer in CORSA (OR = 6.39; 95% CI, 3.61-11.3) and EPIC (OR = 2.03; 95% CI, 1.20-3.40). Kynurenine was inversely associated with colon cancer in ColoCare (OR per 1-SD = 0.74; 95% CI, 0.55-0.98), positively associated in CORSA (OR per 1-SD = 1.79; 95% CI, 1.27-2.52), while no association was observed in EPIC. The kynurenine-to-tryptophan ratio was positively associated with colon cancer in ColoCare (OR per 1-SD = 1.38; 95% CI, 1.03-1.84) and CORSA (OR per 1-SD = 1.44; 95% CI, 1.06-1.96), but not in EPIC. These results suggest that higher plasma tryptophan may be associated with lower colon cancer risk, while increased serotonin may be associated with a higher risk of colon cancer. The kynurenine-to-tryptophan ratio may also reflect altered tryptophan catabolism during colon cancer development.
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http://dx.doi.org/10.1002/ijc.33725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429124PMC
November 2021

Thrombin Generation and Platelet Function in ICU Patients Undergoing CVVHD Using Regional Citrate Anticoagulation.

Front Med (Lausanne) 2021 14;8:680540. Epub 2021 Jun 14.

Department of Anaesthesia, Critical Care and Pain Medicine, Division of General Anaesthesia and Intensive Care Medicine, Medical University of Vienna, Vienna, Austria.

To investigate pro- and anticoagulant alterations in uremic critically ill patients prior to and during continuous renal replacement therapy. In addition to the conventional thrombin generation assay (TGA), we performed a thrombomodulin-modified variant to better elucidate procoagulant imbalances. Platelet function was determined via multiple electrode aggregometry (MEA) to round off hemostatic analysis. We prospectively enrolled patients at surgical intensive care units (ICU) with acute kidney injury undergoing continuous veno-venous hemodialysis using regional citrate anticoagulation. TGA and platelet function testing were performed at baseline (≤ 12 h prior to continuous renal replacement therapy) and on 3 consecutive days (day A-C) of extracorporeal therapy. We did not observe significant changes in thrombin generation after start or during renal replacement therapy. Ratios of endogenous thrombin potential in patients were significantly increased ( < 0.001) compared to standardized plasma of healthy donors confirming the assumed procoagulant alterations in ICU patients. Test results of the conventional TGA differed significantly ( < 0.05) from those of the thrombomodulin-modified assay. The area under the curve remained below MEA reference values during the entire observation period, indicating a persistent reduction in platelet function. In summary, in-depth analysis using standard and modified TGA, as well as calculation of endogenous thrombin potential (ETP) ratios, revealed no further aggravation of the procoagulatory shift in the critically ill patient during CVVHD using regional citrate anticoagulation. MEA ruled out the potential impact of platelets. German Clinical Trials Register (DRKS00004336), 29 August 2012; www.drks.de.
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http://dx.doi.org/10.3389/fmed.2021.680540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238086PMC
June 2021

Untargeted Metabolomics Reveals Major Differences in the Plasma Metabolome between Colorectal Cancer and Colorectal Adenomas.

Metabolites 2021 Feb 19;11(2). Epub 2021 Feb 19.

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.

Sporadic colorectal cancer is characterized by a multistep progression from normal epithelium to precancerous low-risk and high-risk adenomas to invasive cancer. Yet, the underlying molecular mechanisms of colorectal carcinogenesis are not completely understood. Within the "Metabolomic profiles throughout the continuum of colorectal cancer" (MetaboCCC) consortium we analyzed data generated by untargeted, mass spectrometry-based metabolomics using plasma from 88 colorectal cancer patients, 200 patients with high-risk adenomas and 200 patients with low-risk adenomas recruited within the "Colorectal Cancer Study of Austria" (CORSA). Univariate logistic regression models comparing colorectal cancer to adenomas resulted in 442 statistically significant molecular features. Metabolites discriminating colorectal cancer patients from those with adenomas in our dataset included acylcarnitines, caffeine, amino acids, glycerophospholipids, fatty acids, bilirubin, bile acids and bacterial metabolites of tryptophan. The data obtained discovers metabolite profiles reflecting metabolic differences between colorectal cancer and colorectal adenomas and delineates a potentially underlying biological interpretation.
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http://dx.doi.org/10.3390/metabo11020119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922413PMC
February 2021

Targeted Plasma Metabolic Profiles and Risk of Recurrence in Stage II and III Colorectal Cancer Patients: Results from an International Cohort Consortium.

Metabolites 2021 Feb 24;11(3). Epub 2021 Feb 24.

Huntsman Cancer Institute Salt Lake City, Salt Lake City, UT 84112, USA.

The identification of patients at high-risk for colorectal cancer (CRC) recurrence remains an unmet clinical need. The aim of this study was to investigate associations of metabolites with risk of recurrence in stage II/III CRC patients. A targeted metabolomics assay (128 metabolites measured) was performed on pre-surgery collected EDTA plasma samples from n = 440 newly diagnosed stage II/III CRC patients. Patients have been recruited from four prospective cohort studies as part of an international consortium: Metabolomic profiles throughout the continuum of CRC (MetaboCCC). Cox proportional hazard models were computed to investigate associations of metabolites with recurrence, adjusted for age, sex, tumor stage, tumor site, body mass index, and cohort; false discovery rate (FDR) was used to account for multiple testing. Sixty-nine patients (15%) had a recurrence after a median follow-up time of 20 months. We identified 13 metabolites that were nominally associated with a reduced risk of recurrence. None of the associations were statistically significant after controlling for multiple testing. Pathway topology analyses did not reveal statistically significant associations between recurrence and alterations in metabolic pathways (e.g., sphingolipid metabolism = 0.04; p = 1.00). To conclude, we did not observe statistically significant associations between metabolites and CRC recurrence using a well-established metabolomics assay. The observed results require follow-up in larger studies.
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http://dx.doi.org/10.3390/metabo11030129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996362PMC
February 2021

Circulating B-vitamin biomarkers and B-vitamin supplement use in relation to quality of life in patients with colorectal cancer: results from the FOCUS consortium.

Am J Clin Nutr 2021 06;113(6):1468-1481

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

Background: B vitamins have been associated with the risk and progression of colorectal cancer (CRC), given their central roles in nucleotide synthesis and methylation, yet their association with quality of life in established CRC is unclear.

Objectives: To investigate whether quality of life 6 months postdiagnosis is associated with: 1) circulating concentrations of B vitamins and related biomarkers 6 months postdiagnosis; 2) changes in these concentrations between diagnosis and 6 months postdiagnosis; 3) B-vitamin supplement use 6 months postdiagnosis; and 4) changes in B-vitamin supplement use between diagnosis and 6 months postdiagnosis.

Methods: We included 1676 newly diagnosed stage I-III CRC patients from 3 prospective European cohorts. Circulating concentrations of 9 biomarkers related to the B vitamins folate, riboflavin, vitamin B6, and cobalamin were measured at diagnosis and 6 months postdiagnosis. Information on dietary supplement use was collected at both time points. Health-related quality of life (global quality of life, functioning scales, and fatigue) was assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 6 months postdiagnosis. Confounder-adjusted linear regression analyses were performed, adjusted for multiple testing.

Results: Higher pyridoxal 5'-phosphate (PLP) was cross-sectionally associated with better physical, role, and social functioning, as well as reduced fatigue, 6 months postdiagnosis. Associations were observed for a doubling in the hydroxykynurenine ratio [3-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3-hydroxyanthranilic acid + anthranilic acid); an inverse marker of vitamin B6] and both reduced global quality of life (β = -3.62; 95% CI: -5.88, -1.36) and worse physical functioning (β = -5.01; 95% CI: -7.09, -2.94). Dose-response relations were observed for PLP and quality of life. No associations were observed for changes in biomarker concentrations between diagnosis and 6 months. Participants who stopped using B-vitamin supplements after diagnosis reported higher fatigue than nonusers.

Conclusions: Higher vitamin B6 status was associated with better quality of life, yet limited associations were observed for the use of B-vitamin supplements. Vitamin B6 needs further study to clarify its role in relation to quality of life.
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http://dx.doi.org/10.1093/ajcn/nqaa422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168355PMC
June 2021

Establishing reference ranges of cord blood: point-of-care hemostatic function assessment in preterm and term neonates.

Pediatr Res 2021 Aug 18;90(2):452-458. Epub 2020 Dec 18.

Department of Anesthesia, Critical Care and Pain Medicine, Division of General Anesthesia and Intensive Care Medicine, Medical University of Vienna, 1090, Vienna, Austria.

Background: Thrombelastometry, allowing timely assessment of global hemostatic function, is increasingly used to guide hemostatic interventions in bleeding patients. Reference values are available for adults and children, including infants but not neonates immediately after birth.

Methods: Neonates were grouped as preterm (30 + 0 to 36 + 6 weeks/days) and term (37 + 0 to 39 + 6 weeks/days). Blood samples were drawn from the umbilical cord immediately after cesarean section and analyzed by thrombelastometry. Reference ranges were determined for the extrinsic and intrinsic coagulation pathways, fibrin polymerization, and hyperfibrinolysis detection.

Results: All extrinsically activated test parameters, but maximum lysis (P = 0.139) differed significantly between both groups (P ≤ 0.001). Maximum clot firmness in the fibrin polymerization test was comparable (P = 0.141). All intrinsically activated test parameters other than coagulation time (P = 0.537) and maximum lysis (P = 0.888) differed significantly (P < 0.001), and so did all aprotinin-related test parameters (P ≤ 0.001) but maximum lysis (P = 0.851).

Conclusions: This is the first study to identify reference ranges for thrombelastometry in preterm and term neonates immediately after birth. We also report differences in clot initiation and clot strength in neonates born <37 versus ≤40 weeks of gestation, mirroring developmental hemostasis.

Impact: Impact: This prospective observational study is the first to present reference ranges in preterm and term infants for all types of commercially available tests of thrombelastometry, notably also including the fibrin polymerization test.

Importance: Viscoelastic coagulation assays such as thrombelastometry have become integral to the management of perioperative bleeding by present-day standards. Reference values are available for adults, children, and infants but not for neonates. Key message: Clot initiation and formation was faster and clot strength higher in the term than in the preterm group. Parameters of thrombelastometry obtained from cord blood do not apply interchangeably to preterm and term neonates.
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http://dx.doi.org/10.1038/s41390-020-01310-8DOI Listing
August 2021

Circulating Folate and Folic Acid Concentrations: Associations With Colorectal Cancer Recurrence and Survival.

JNCI Cancer Spectr 2020 Oct 7;4(5):pkaa051. Epub 2020 Jul 7.

Department of Surgery, Hospital Group Twente ZGT, Almelo, the Netherlands.

Background: Folates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown.

Methods: Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall survival, and disease-free survival.

Results: No statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n = 296), a higher risk of recurrence was observed for each twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival.

Conclusions: Circulating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence.
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http://dx.doi.org/10.1093/jncics/pkaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583160PMC
October 2020

Zoledronic Acid Substantially Improves Bone Microarchitecture and Biomechanical Properties After Rotator Cuff Repair in a Rodent Chronic Defect Model.

Am J Sports Med 2020 07 16;48(9):2151-2160. Epub 2020 Jun 16.

AUVA Trauma Center Vienna-Meidling, Department for Trauma Surgery, Vienna, Austria.

Background: Bone mineral density at the humeral head is reduced in patients with chronic rotator cuff tears. Bone loss in the humeral head is associated with repair failure after rotator cuff reconstruction. Bisphosphonates (eg, zoledronic acid) increase bone mineral density.

Hypothesis: Zoledronic acid improves bone mineral density of the humeral head and biomechanical properties of the enthesis after reconstruction of chronic rotator cuff tears in rats.

Study Design: Controlled laboratory study.

Methods: A total of 32 male Sprague-Dawley rats underwent unilateral (left) supraspinatus tenotomy with delayed transosseous rotator cuff reconstruction after 3 weeks. All rats were sacrificed 8 weeks after rotator cuff repair. Animals were randomly assigned to 1 of 2 groups. At 1 day after rotator cuff reconstruction, the intervention group was treated with a single subcutaneous dose of zoledronic acid at 100 µg/kg bodyweight, and the control group received 1 mL of subcutaneous saline solution. In 12 animals of each group, micro-computed tomography scans of both shoulders were performed as well as biomechanical testing of the supraspinatus enthesis of both sides. In 4 animals of each group, histological analyses were conducted.

Results: In the intervention group, bone volume fraction (bone volume/total volume [BV/TV]) of the operated side was higher at the lateral humeral head ( = .005) and the medial humeral head ( = .010) compared with the control group. Trabecular number on the operated side was higher at the lateral humeral head ( = .004) and the medial humeral head ( = .001) in the intervention group. Maximum load to failure rates on the operated side were higher in the intervention group ( < .001). Cortical thickness positively correlated with higher maximum load to failure rates in the intervention group ( = 0.69; = .026). Histological assessment revealed increased bone formation in the intervention group.

Conclusion: Single-dose therapy of zoledronic acid provided an improvement of bone microarchitecture at the humeral head as well as an increase of maximum load to failure rates after transosseous reconstruction of chronic rotator cuff lesions in rats.

Clinical Relevance: Zoledronic acid improves bone microarchitecture as well as biomechanical properties after reconstruction of chronic rotator cuff tears in rodents. These results need to be verified in clinical investigations.
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http://dx.doi.org/10.1177/0363546520926471DOI Listing
July 2020

Visual stimulation with food pictures in the regulation of hunger hormones and nutrient deposition, a potential contributor to the obesity crisis.

PLoS One 2020 24;15(4):e0232099. Epub 2020 Apr 24.

Department of Nutritional Sciences, University of Vienna, Vienna, Austria.

Food cues affect hunger and nutritional choices. Omnipresent stimulation with palatable food contributes to the epidemics of obesity. The objective of the study was to investigate the impact of food cues on appetite-related hormones and to assess the functionality of the secreted hormones on macronutrient uptake in healthy subjects. Additionally, we aimed at verifying differences in the response of total and active ghrelin to stimulation with food pictures and to a meal followed by the stimulation. We were also interested in the identification of factors contributing to response to food cues. We recruited healthy, non-obese participants for two independent cross-over studies. During the first study, the subjects were presented random non-food pictures on the first day and pictures of foods on the second day of the study. Throughout the second study, following the picture session, the participants were additionally asked to drink a milkshake. Concentrations of blood glucose, triglycerides and hunger-related hormones were measured. The results showed that concentrations of several hormones measured in the blood are interdependent. In the case of ghrelin and gastric inhibitory peptide (GIP) as well as ghrelin and glucagon-like peptide-1 (GLP-1), this co-occurrence relies on the visual cues. Regulation of total ghrelin concentration following food stimulation is highly individual and responders showed upregulated total ghrelin, while the concentration of active ghrelin decreases following a meal. Protein content and colour intensity of food pictures reversely correlated with participants' rating of the pictures. We conclude that observation of food pictures influences the concentration of several appetite-related hormones. The close link of visual clues to physiological responses is likely of clinical relevance. Additionally, the protein content of displayed foods and green colour intensity in pictures may serve as a predictor of subjective attractiveness of the presented meal.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232099PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182185PMC
July 2020

Genome-wide association study of germline copy number variations reveals an association with prostate cancer aggressiveness.

Mutagenesis 2020 07;35(3):283-290

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Prostate cancer is a major health burden, being the second most commonly diagnosed malignancy in men worldwide. Overtreatment represents a major problem in prostate cancer therapy, leading to significant long-term quality-of-life effects for patients and a broad socio-ecological burden. Biomarkers that could facilitate risk stratification of prostate cancer aggressiveness at the time of diagnosis may help to guide clinical treatment decisions and reduce overtreatment. Previous research on genetic variations in prostate cancer has shown that germline copy number variations as well as somatic copy number alterations are commonly present in cancer patients, altering a greater portion of the cancer genome than any other type of genetic variation. To investigate the effect of germline copy number variations on cancer aggressiveness we have compared genome-wide screening data from genomic DNA isolated from the blood of 120 patients with aggressive prostate cancer, 231 patients with non-aggressive prostate cancer and 87 controls with benign prostatic hyperplasia from the Prostate Cancer Study of Austria biobank using the Affymetrix SNP 6.0 array. We could show that patients with an aggressive form of prostate cancer had a higher frequency of copy number variations [mean count of copy number segments (CNS) = 12.9, median count of CNS = 9] compared to patients with non-aggressive prostate cancer (mean count of CNS = 10.4, median count of CNS = 8) or control patients diagnosed with benign prostatic hyperplasia (mean count of CNS = 9.3, median count of CNS = 8). In general, we observed that copy number gain is a rarer event, compared to copy number loss within all three patient groups. Furthermore, we could show a significant effect of copy number losses located on chromosomes 8, 9 and 10 on prostate cancer aggressiveness (P = 0.040, P = 0.037 and P = 0.005, respectively). Applying a cross-validation analysis yielded an area under the curve of 0.63. Our study reports promising findings suggesting that copy number losses might play an important role in the establishment of novel biomarkers to predict prostate cancer aggressiveness at the time of diagnosis. Such markers could be used to facilitate risk stratification to reduce overtreatment of prostate cancer patients.
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http://dx.doi.org/10.1093/mutage/geaa010DOI Listing
July 2020

Correction to: Serum levels of sclerostin reflect altered bone microarchitecture in patients with hepatic cirrhosis.

Wien Klin Wochenschr 2020 04;132(7-8):216

Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Correction to: Wien Klin Wochenschr 2019 https://doi.org/10.1007/s00508-019-01595-8 The original version of this article unfortunately contained a mistake. The last sentence should read: Patients with ALD had significantly lower sclerostin levels, compared to controls. The authors apologize for the ….
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http://dx.doi.org/10.1007/s00508-020-01613-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645530PMC
April 2020

Low molecular weight heparin versus unfractioned heparin for anticoagulation during perioperative extracorporeal membrane oxygenation: A single center experience in 102 lung transplant patients.

Artif Organs 2020 Jun 18;44(6):638-646. Epub 2020 Feb 18.

Department of Anesthesiology, Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria.

Extracorporeal membrane oxygenation (ECMO) is gaining importance in the perioperative management of lung transplant patients. To date, the ideal substance for anticoagulation of ECMO patients is still a matter of debate. In this study, we describe our experience with the use of low molecular weight heparin (LMWH) in comparison with unfractioned heparin (UFH) in lung transplant patients undergoing perioperative ECMO support. We retrospectively analyzed data from all lung transplant patients who underwent perioperative ECMO support at our institution between 2013 and 2017. Bleeding events served as primary outcome parameter. Secondary outcome parameters consisted of thromboembolic events. 102 patients were included in this study, of which 22 (21.6%) received UFH for anticoagulation, and 80 (78.4%) received LMWH. There was no difference between the two groups in regard to serious bleeding events (22.7% in the UFH group vs 12.5% in the LMWH group, P = .31). However, the proportion of patients experiencing thromboembolic events was significantly higher in the UFH group than in the LMWH group (50% vs 20%, P = .01). After adjusting for baseline differences between the two groups, we still observed a difference with respect to thromboembolic events. These data remain to be validated in future prospective, randomized trials.
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http://dx.doi.org/10.1111/aor.13642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317732PMC
June 2020

Serum levels of sclerostin reflect altered bone microarchitecture in patients with hepatic cirrhosis.

Wien Klin Wochenschr 2020 Jan 7;132(1-2):19-26. Epub 2020 Jan 7.

Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Background: Patients with hepatic cirrhosis are at increased risk of bone loss. Recent work on areal bone mineral density has reported contradictory findings. As the assessment of bone microarchitecture is complex, a search was made for correlations with new serum markers of bone turnover. Current data on serum sclerostin levels in patients with increased fracture risk are divergent and to date only one study has examined patients with hepatic cirrhosis. Therefore, the aim of this study was to evaluate serum sclerostin levels and to test for correlations with microarchitecture.

Methods: This study was performed in 32 patients with recently diagnosed hepatic cirrhosis and 32 controls. The parameters of bone microarchitecture were assessed by high-resolution peripheral quantitative computed tomography. Sclerostin was detected via a new ELISA that detects the active receptor interaction site at loop 2 of the sclerostin core region.

Results: Sclerostin levels were slightly, but not significantly lower in the patient group, compared to controls. In contrast, patients with alcoholic liver cirrhosis had significantly lower levels than the controls. A significant correlation with areal bone mineral density (BMD) and trabecular microarchitecture was observed in the patient group. However, there was hardly any correlation between sclerostin and bone microarchitecture in the controls.

Conclusion: In hepatic cirrhosis, sclerostin is related to altered bone microarchitecture and lower areal BMD. In alcoholic liver disease, low sclerostin concentrations were seen.
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http://dx.doi.org/10.1007/s00508-019-01595-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978289PMC
January 2020

Plasma metabolites associated with colorectal cancer stage: Findings from an international consortium.

Int J Cancer 2020 06 10;146(12):3256-3266. Epub 2019 Oct 10.

Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.

Colorectal cancer is the second most common cause of cancer-related death globally, with marked differences in prognosis by disease stage at diagnosis. We studied circulating metabolites in relation to disease stage to improve the understanding of metabolic pathways related to colorectal cancer progression. We investigated plasma concentrations of 130 metabolites among 744 Stages I-IV colorectal cancer patients from ongoing cohort studies. Plasma samples, collected at diagnosis, were analyzed with liquid chromatography-mass spectrometry using the Biocrates AbsoluteIDQ™ p180 kit. We assessed associations between metabolite concentrations and stage using multinomial and multivariable logistic regression models. Analyses were adjusted for potential confounders as well as multiple testing using false discovery rate (FDR) correction. Patients presented with 23, 28, 39 and 10% of Stages I-IV disease, respectively. Concentrations of sphingomyelin C26:0 were lower in Stage III patients compared to Stage I patients (p  < 0.05). Concentrations of sphingomyelin C18:0 and phosphatidylcholine (diacyl) C32:0 were statistically significantly higher, while citrulline, histidine, phosphatidylcholine (diacyl) C34:4, phosphatidylcholine (acyl-alkyl) C40:1 and lysophosphatidylcholines (acyl) C16:0 and C17:0 concentrations were lower in Stage IV compared to Stage I patients (p  < 0.05). Our results suggest that metabolic pathways involving among others citrulline and histidine, implicated previously in colorectal cancer development, may also be linked to colorectal cancer progression.
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http://dx.doi.org/10.1002/ijc.32666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216900PMC
June 2020

High Systemic Immune-Inflammation Index is an Adverse Prognostic Factor for Patients With Gastroesophageal Adenocarcinoma.

Ann Surg 2021 03;273(3):532-541

Department of Surgery, Medical University of Vienna, and Gastroesophageal Tumor Unit, Comprehensive Cancer Center (CCC), Vienna, Austria.

Objective: The aim of this study was to determine the clinical role of the systemic immune-inflammation index in patients with resectable adenocarcinoma of the gastroesophageal junction treated with or without neoadjuvant therapy.

Background: Adenocarcinoma of the gastroesophageal junction is an aggressive disease, with less than 20% of overall patients surviving more than 5 years after diagnosis, while currently available clinical staging for esophageal cancer is lacking necessary accuracy. The systemic immune-inflammation index (SII) based on peripheral neutrophil, lymphocyte, and platelet counts has shown a prognostic impact in various malignancies.

Methods: Data of consecutive patients undergoing esophagectomy (n = 320, 1992 to 2016) were abstracted. The cut point for high and low SII before neoadjuvant treatment and before surgery was calculated for illustration of the Kaplan-Meier curves. SII was used for the correlation with patients' clinicopathological characteristics as a continuous variable. Survival was analyzed with Cox proportional hazards models using clinical or pathological staging, adjusting for other known survival predictors.

Results: In both neoadjuvantly treated and primarily resected patients, high SII was significantly associated with diminished overall [hazard ratio (HR) 1.3, 95% confidence interval (95% CI) 1.2-1.4; HR 1.2, 95% CI 1.2-1.3, respectively] and disease-free survival (HR 1.3, 95% CI 1.2-1.3; HR 1.2, 95% CI 1.2-1.3, respectively). In multivariable survival analysis, SII remained an independent prognostic factor for overall survival (HR 1.3, 95% CI 1.2-1.4; HR 1.2, 95% CI 1.2-1.3, respectively) and disease-free survival (HR 1.3, 95% CI 1.2-1.3; HR 1.2, 95% CI 1.2-1.3, respectively) in primarily resected and neoadjuvantly treated patients.

Conclusion: Elevated SII is an independent adverse prognostic factor in patients with resectable gastroesophageal adenocarcinomas with and without neoadjuvant treatment.
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http://dx.doi.org/10.1097/SLA.0000000000003370DOI Listing
March 2021

Bone Stress Injuries Are Associated With Differences in Bone Microarchitecture in Male Professional Soldiers.

J Orthop Res 2019 12 26;37(12):2516-2523. Epub 2019 Aug 26.

Medical Department II-VINFORCE Study Group, St. Vincent Hospital, Academic Teaching Hospital of the Medical University of Vienna, Stumpergasse 13, Vienna, A-1060, Austria.

Bone stress injuries are commonly due to repetitive loading, as often described in competitive athletes or military recruits. The underlying pathophysiology of bone stress injuries is multifactorial. The present cross-sectional study investigated (i) cortical and trabecular bone microstructure as well as volumetric bone mineral density in subjects with bone stress injuries at the tibial diaphysis, measured at the distal tibia and the distal radius by means of high-resolution peripheral quantitative computed tomography (CT), (ii) areal bone mineral density using dual-energy X-ray absorptiometry as well as calcaneal dual X-ray absorptiometry and laser, and (iii) the influence on bone turnover markers of formation and resorption at the early phase after injury. A total of 26 Caucasian male professional soldiers with post-training bone stress injury at the tibial diaphysis were included (case group). A total of 50 male, Caucasian professional soldiers from the same military institution served as controls (control group). High-resolution peripheral quantitative CT revealed a higher total area at the radius within the case group. Cortical bone mineral density was reduced at the radius and tibia within the case group. The trabecular number and trabecular thickness were reduced at the tibia in the case group. The trabecular network was more inhomogeneous at the radius and tibia within the case group. Calcaneal dual X-ray absorptiometry and laser was significantly reduced in the case group. This study quantified differences in bone microstructure among otherwise healthy individuals. Differences in bone microarchitecture may impair the biomechanical properties by increasing the susceptibility to sustain bone stress injuries. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2516-2523, 2019.
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http://dx.doi.org/10.1002/jor.24442DOI Listing
December 2019

Fracture patterns in patients with multiple fractures: the probability of multiple fractures and the most frequently associated regions.

Eur J Trauma Emerg Surg 2020 Oct 12;46(5):1151-1158. Epub 2019 Feb 12.

St. Vincent Hospital-Metabolic Bone Diseases Unit, The VINFORCE Study Group, Vienna, Austria.

Introduction: Multiple fractures are of high clinical relevance, as a significant increase in mortality rate has been described. The purpose of this study was to evaluate differences in age and gender distribution in multiple fractures dependent on severity of trauma. Furthermore, affected anatomic regions and frequently associated fracture regions were investigated.

Methods: Patients who had sustained multiple fractures between 2000 and 2012 were included in this study. At hospital admission, patients were divided according to trauma severity (high- vs low-traumatic), gender, and age for demographic analysis. Fractures were grouped in anatomical regions, and multiple fracture event probabilities as well as frequently associated regions were calculated.

Results: In total, 25,043 patients at an age range of 0-100 years (5.8% of all fracture patients; 14,769 male and 10,274 female patients) who sustained 57,862 multiple fractures were included. The lumbar/thoracic spine, cervical spine, femoral shaft, skull, and pelvis showed a probability of more than 40% of the presence of further fractures in each high-traumatic fracture event. In high-traumatic fracture events, male patients were more affected (p < 0.001). Considering low-traumatic fractures, female patients had a significantly higher proportion (p < 0.001) of multiple fractures among all fractures than male patients.

Conclusions: As a novelty, gender as well as age distributions in multiple fracture patients and a probability statement with the most affected anatomic regions, the risk of presence of further fractures for every region, and the frequently associated fracture regions including the percentage of occurrence are provided. These aspects yield new opportunities for clinical work and may reduce the high rate of overlooked fractures stated in the literature.
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http://dx.doi.org/10.1007/s00068-019-01087-4DOI Listing
October 2020

Plasma metabolites associated with colorectal cancer: A discovery-replication strategy.

Int J Cancer 2019 09 14;145(5):1221-1231. Epub 2019 Feb 14.

Huntsman Cancer Institute, Salt Lake City, UT.

Colorectal cancer is known to arise from multiple tumorigenic pathways; however, the underlying mechanisms remain not completely understood. Metabolomics is becoming an increasingly popular tool in assessing biological processes. Previous metabolomics research focusing on colorectal cancer is limited by sample size and did not replicate findings in independent study populations to verify robustness of reported findings. Here, we performed a ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) screening on EDTA plasma from 268 colorectal cancer patients and 353 controls using independent discovery and replication sets from two European cohorts (ColoCare Study: n = 180 patients/n = 153 controls; the Colorectal Cancer Study of Austria (CORSA) n = 88 patients/n = 200 controls), aiming to identify circulating plasma metabolites associated with colorectal cancer and to improve knowledge regarding colorectal cancer etiology. Multiple logistic regression models were used to test the association between disease state and metabolic features. Statistically significant associated features in the discovery set were taken forward and tested in the replication set to assure robustness of our findings. All models were adjusted for sex, age, BMI and smoking status and corrected for multiple testing using False Discovery Rate. Demographic and clinical data were abstracted from questionnaires and medical records.
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http://dx.doi.org/10.1002/ijc.32146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614008PMC
September 2019

PD-L1 expression is an independent predictor of favorable outcome in patients with localized esophageal adenocarcinoma.

Oncoimmunology 2018;7(6):e1435226. Epub 2018 Mar 13.

Department of Surgery and Comprehensive Cancer Center, GET-Unit, Medical University of Vienna, Vienna, Austria.

. The outcome of patients with adenocarcinoma of the esophagogastric junction (AEG) remains poor. The programmed cell-death-protein-1 (PD-1), a co-inhibitory receptor primarily expressed by T-cells, represents a potential new therapeutic target. PD-1, PD-1 ligand 1 (PD-L1), and PD-L2 expression have all been described as prognostic factors in a variety of cancers. Their expression patterns in AEG, however, are poorly understood. We analyzed PD-L1, PD-L2 and PD-1 expression by tumor-infiltrating lymphocytes (TILs) and cancer-cells in tumor-biospecimens in AEG-patients. . 168 patients who underwent esophagectomy because of AEG between 1992-2011 were included in this study. PD-L1, PD-L2 and PD-1 expression were evaluated by immunohistochemistry and correlated with various clinicopathological parameters, disease-free survival (DFS) and long-term overall survival (OS). . PD-L1 expression by cancer-cells (cancer-cell-PD-L1) was found in 43.5% of patients whereas PD-L1 expression by TILs (TILs-PD-L1) was observed in 69%. PD-L2 expression by cancer-cells and TILs was only found in 3.5% and 1.8%, respectively. Additionally, 77.4% of tumors contained PD-1-cancer-cells and 81% PD-1-TILs. Patients with increased expression of PD-1 by cancer-cells and TILs showed significantly reduced OS and DFS, as determined by univariate, but not multivariate analysis. Expression of PD-L1 by cancer-cells was found to be an independent predictor for improved DFS (p = 0.038) and OS (p = 0.042) in multivariate analysis. . Cancer cells and TILs displayed PD-L1 expression in around 50% and PD-1 expression in around 80% of tumor-biospecimens obtained from AEG patients. Expression of PD-L1 is an independent predictor of favorable outcome in AEG, whereas PD-1 expression is associated with worse outcome and advanced tumor stage.
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http://dx.doi.org/10.1080/2162402X.2018.1435226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980377PMC
March 2018

Leukocyte telomere length throughout the continuum of colorectal carcinogenesis.

Oncotarget 2018 Mar 7;9(17):13582-13592. Epub 2018 Feb 7.

Medical University Vienna, Department of Medicine I, Institute of Cancer Research, Vienna, Austria.

Considering the high prevalence of colorectal cancer (CRC) and relatively high mortality there is strong interest in identification of clinically relevant biomarkers. Telomere shortening is supposed to contribute to genomic instability and crucially involved in process of carcinogenesis. Peripheral blood leukocyte (PBL) telomere length was previously investigated in several studies as potential biomarker for CRC but with controversial results. This prompted us to investigate relative PBL telomere length in association with different histological findings throughout the continuum of colorectal carcinogenesis in order to reflect the whole spectrum of putative CRC development in a large study involving 2011 individuals. The study based on the Colorectal Cancer Study of Austria (CORSA), including 384 CRC cases as well as age- and gender-matched 544 high-risk adenomas, 537 low-risk adenoma patients and 546 colonoscopy-negative controls. Relative expression of telomeric repeats and the single copy reference gene, albumin (T/S ratio) was determined using monochrome multiplex quantitative PCR (MMQPCR). Telomeres were found to be significantly longer in CRC patients compared to control subjects ( = 3.61x10). Yet, no significant differences in telomere length could be detected for high-risk ( = 0.05956) and low-risk colorectal adenoma patients ( = 0.05224). In addition, results presented in this manuscript highlight the impact of various epidemiological factors on PBL telomere length and its involvement in CRC. However, further large studies also including colorectal adenomas are necessary to confirm these results.
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http://dx.doi.org/10.18632/oncotarget.24431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862600PMC
March 2018

Bone-related Circulating MicroRNAs miR-29b-3p, miR-550a-3p, and miR-324-3p and their Association to Bone Microstructure and Histomorphometry.

Sci Rep 2018 03 20;8(1):4867. Epub 2018 Mar 20.

Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.

The assessment of bone quality and the prediction of fracture risk in idiopathic osteoporosis (IOP) are complex prospects as bone mineral density (BMD) and bone turnover markers (BTM) do not indicate fracture-risk. MicroRNAs (miRNAs) are promising new biomarkers for bone diseases, but the current understanding of the biological information contained in the variability of miRNAs is limited. Here, we investigated the association between serum-levels of 19 miRNA biomarkers of idiopathic osteoporosis to bone microstructure and bone histomorphometry based upon bone biopsies and µCT (9.3 μm) scans from 36 patients. Four miRNAs were found to be correlated to bone microarchitecture and seven miRNAs to dynamic histomorphometry (p < 0.05). Three miRNAs, namely, miR-29b-3p, miR-324-3p, and miR-550a-3p showed significant correlations to histomorphometric parameters of bone formation as well as microstructure parameters. miR-29b-3p and miR-324-p were found to be reduced in patients undergoing anti-resorptive therapy. This is the first study to report that serum levels of bone-related miRNAs might be surrogates of dynamic histomorphometry and potentially reveal changes in bone microstructure. Although these findings enhance the potential value of circulating miRNAs as bone biomarkers, further experimental studies are required to qualify the clinical utility of miRNAs to reflect dynamic changes in bone formation and microstructure.
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http://dx.doi.org/10.1038/s41598-018-22844-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861059PMC
March 2018

The modified glasgow prognostic score is an independent prognostic indicator in neoadjuvantly treated adenocarcinoma of the esophagogastric junction.

Oncotarget 2018 Jan 8;9(6):6968-6976. Epub 2018 Jan 8.

Department of Surgery, Medical University of Vienna, and Gastroesophageal Tumor Unit, Comprehensive Cancer Center (CCC), 1090 Vienna, Austria.

The modified Glasgow Prognostic Score (mGPS) combines the indicators of decreased plasma albumin and elevated CRP. In a number of malignancies, elevated mGPS is associated with poor survival. Aim of this study was to investigate the prognostic role of mGPS in patients with neoadjuvantly treated adenocarcinomas of the esophagogastric junction 256 patients from a prospective database undergoing surgical resection after neoadjuvant treatment between 2003 and 2014 were evaluated. mGPS was scored as 0, 1, or 2 based on CRP (>1.0 mg/dl) and albumin (<35 g/L) from blood samples taken prior (preNT-mGPS) and after (postNT-mGPS) neoadjuvant therapy. Scores were correlated with clinicopathological patients' characteristics. From 155 Patients, sufficient data was available. Median follow-up was 63.8 months (33.3-89.5 months). In univariate analysis, Cox proportional hazard model shows significant shorter patients OS ( = 0.04) and DFS ( = 0.02) for increased postNT-mGPS, preNT-hypoalbuminemia (OS: = 0.003; DFS: = 0.002) and post-NT-CRP (OS: = 0.03; DFS: = 0.04). Elevated postNT-mGPS and preNT-hypoalbuminemia remained significant prognostic factors in multivariate analysis for OS ( = 0.02; = 0.005,) and DFS ( = 0.02, = 0.004) with tumor differentiation and tumor staging as significant covariates. PostNT-mGPS and preNT-hypoalbuminemia are independent prognostic indicators in patients with neoadjuvantly treated adenocarcinomas of the esophagogastric junction and significantly associated with diminished OS and DFS.
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http://dx.doi.org/10.18632/oncotarget.24087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805529PMC
January 2018

Bayesian and frequentist analysis of an Austrian genome-wide association study of colorectal cancer and advanced adenomas.

Oncotarget 2017 Nov 9;8(58):98623-98634. Epub 2017 Oct 9.

Institute of Cancer Research, Medical University of Vienna, Vienna, Austria.

Most genome-wide association studies (GWAS) were analyzed using single marker tests in combination with stringent correction procedures for multiple testing. Thus, a substantial proportion of associated single nucleotide polymorphisms (SNPs) remained undetected and may account for missing heritability in complex traits. Model selection procedures present a powerful alternative to identify associated SNPs in high-dimensional settings. In this GWAS including 1060 colorectal cancer cases, 689 cases of advanced colorectal adenomas and 4367 controls we pursued a dual approach to investigate genome-wide associations with disease risk applying both, single marker analysis and model selection based on the modified Bayesian information criterion, mBIC2, implemented in the software package MOSGWA. For different case-control comparisons, we report models including between 1-14 candidate SNPs. A genome-wide significant association of rs17659990 (P=5.43×10, , chromosome 3p21.2) with colorectal cancer risk was observed. Furthermore, 56 SNPs known to influence susceptibility to colorectal cancer and advanced adenoma were tested in a hypothesis-driven approach and several of them were found to be relevant in our Austrian cohort. After correction for multiple testing (α=8.9×10), the most significant associations were observed for SNPs rs10505477 (P=6.08×10) and rs6983267 (P=7.35×10) of , rs3802842 (P=8.98×10, ), and rs12953717 (P=4.64×10, ). All previously unreported SNPs demand replication in additional samples. Reanalysis of existing GWAS datasets using model selection as tool to detect SNPs associated with a complex trait may present a promising resource to identify further genetic risk variants not only for colorectal cancer.
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http://dx.doi.org/10.18632/oncotarget.21697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716755PMC
November 2017

Genetic Ablation of Fgf23 or Klotho Does not Modulate Experimental Heart Hypertrophy Induced by Pressure Overload.

Sci Rep 2017 09 12;7(1):11298. Epub 2017 Sep 12.

Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria.

Left ventricular hypertrophy (LVH) ultimately leads to heart failure in conditions of increased cardiac pre- or afterload. The bone-derived phosphaturic and sodium-conserving hormone fibroblast growth factor-23 (FGF23) and its co-receptor Klotho have been implicated in the development of uremic LVH. Using transverse aortic constriction (TAC) in gene-targeted mouse models, we examine the role of Fgf23 and Klotho in cardiac hypertrophy and dysfunction induced by pressure overload. TAC profoundly increases serum intact Fgf23 due to increased cardiac and bony Fgf23 transcription and downregulation of Fgf23 cleavage. Aldosterone receptor blocker spironolactone normalizes serum intact Fgf23 levels after TAC by reducing bony Fgf23 transcription. Notably, genetic Fgf23 or Klotho deficiency does not influence TAC-induced hypertrophic remodelling, LV functional impairment, or LV fibrosis. Despite the profound, aldosterone-mediated increase in circulating intact Fgf23 after TAC, our data do not support an essential role of Fgf23 or Klotho in the pathophysiology of pressure overload-induced cardiac hypertrophy.
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http://dx.doi.org/10.1038/s41598-017-10140-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595838PMC
September 2017

Confocal Raman spectroscopy: In vivo measurement of physiological skin parameters - A pilot study.

J Dermatol Sci 2017 Dec 10;88(3):280-288. Epub 2017 Aug 10.

University of Vienna, Department of Pharmaceutical Technology and Biopharmaceutics, Althanstraße 14, 1090 Vienna, Austria; University of Vienna, Research Platform 'Characterisation of Drug Delivery Systems on Skin and Investigation of Involved Mechanisms', Vienna, Austria. Electronic address:

Background: In vivo application of confocal Raman spectroscopy (CRS) allows non-invasive depth measurement of the skin. Thereby obtained knowledge of the skin composition is essential to reliably assess the actual skin state. Besides other components, the skin cholesterol concentration is of interest; however, little is known about its connection to the cholesterol concentration quantified in venous blood.

Objective: In this study, the skin composition of the volar forearm was characterised in vivo using CRS. In particular, the potential of CRS as a non-invasive method to determine cholesterol levels was validated.

Methods: Raman spectra of the volar forearm of 15 participants were recorded twice within two weeks. Depth concentration profiles for major skin components were generated. Stratum corneum (SC) thickness was calculated from water concentration profiles. In order to examine the usability of dermal CRS for cholesterol level determination, results were compared to fasting total cholesterol values in venous blood as determined by an enzymatic method.

Results: Depth concentration profiles for the skin components of interest showed a comparable curve progression for the participants. It was possible to link changes in concentration to physiological processes. Moreover, age-related differences could be found. Several novel mathematical approaches for the comparison of the skin cholesterol content and the blood cholesterol concentration have been developed. However, no correlation passed the Bonferroni multiple testing correction.

Conclusion: CRS serves as useful tool for the in vivo monitoring of skin components and hydration. Concentration depth profiles provide information about the current skin condition. No distinct correlation between the skin and blood cholesterol concentration was found within the scope of the present study. Concerning this matter, the heterogeneous distribution of cholesterol in the skin may be a factor influencing these results.
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http://dx.doi.org/10.1016/j.jdermsci.2017.08.002DOI Listing
December 2017

How Accurate is Intraoperative Alignment Measurement with a Navigation System in Primary Total Knee Arthroplasty?

J Knee Surg 2018 May 12;31(5):467-471. Epub 2017 Jul 12.

Department of Orthopedic Surgery, Medical University of Vienna, Vienna, Austria.

The primary objective was to compare the intraoperative data assessed by OrthoPilot (Aesculap AG, Tuttlingen, Germany) with postoperative coronal and sagittal long-leg standing radiographs. The secondary objective was to evaluate the influence of sex and body mass index (BMI) on the accuracy and effectiveness of the implantation of the knee prosthesis by OrthoPilot. We included 75 patients in our investigation. Participants received an e.motion (Aesculap AG) knee prosthesis using the OrthoPilot navigation system. Postoperative long-leg standing anteroposterior and lateral radiographs were performed. We compared the intraoperative navigational data with postoperative determined angles of knee geometry. We also compared the sex and BMI of participants to their difference between intraoperative and postoperative measurements to test for an association. We found a difference between intraoperative data and radiographs of 1.8 degrees for the hip-knee-ankle angle. The intraoperative lateral distal femoral angle and medial proximal tibial angle differed from the radiological analysis by 1.2 degrees, respectively. The lateral views revealed a difference of 1.6 degrees for femur lateral and 1.4 degrees for the tibia lateral. There was no significant ( > 0.05) influence of the parameters BMI and sex of the patients on these values. Our results showed that the implemented intraoperative navigation system is reliable. It does not differ on average from postoperative radiographs by more than 1.8 degrees. The findings of our study suggest that a correct postoperative alignment can be achieved in both high and low BMI participants if a precise range is maintained during the surgery.
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http://dx.doi.org/10.1055/s-0037-1604149DOI Listing
May 2018

Long-Term Effects of Severe Burn Injury on Bone Turnover and Microarchitecture.

J Bone Miner Res 2017 Dec 9;32(12):2381-2393. Epub 2017 Nov 9.

St. Vincent Hospital, Medical Department II-VINFORCE, Academic Teaching Hospital of the Medical University of Vienna, Vienna, Austria.

Severe burn injury triggers massive alterations in stress hormone levels with a dose-dependent hypermetabolic status including increased bone resorption. This study evaluated bone microarchitecture measured by noninvasive high-resolution peripheral quantitative computed tomography (HR-pQCT). Changes of serum bone turnover markers (BTM) as well as regulators of bone signaling pathways involved in skeletal health were assessed. Standardized effect sizes as a quantitative measure regarding the impact of serum changes and the prediction of these changes on bone microarchitecture were investigated. In total, 32 male patients with a severe burn injury (median total body surface area [TBSA], 40.5%; median age 40.5 years) and 28 matched male controls (median age 38.3 years) over a period of 24 months were included. In patients who had sustained a thermal injury, trabecular and cortical bone microstructure showed a continuous decline, whereas cortical porosity (Ct.Po) and pore volume increased. Initially, elevated levels of BTM and C-reactive protein (CRP) continuously decreased over time but remained elevated. In contrast, levels of soluble receptor activator of NF-κB ligand (sRANKL) increased over time. Osteocalcin, bone-specific alkaline phosphatase (BALP), intact N-terminal type 1 procollagen propeptide (P1NP), and cross-linked C-telopeptide (CTX) acutely reflected the increase of Ct.Po at the radius (R  = 0.41), followed by the reduction of trabecular thickness at the tibia (R  = 0.28). In adult male patients, early and sustained changes of markers of bone resorption, formation and regulators of bone signaling pathways, prolonged inflammatory cytokine activities in conjunction with muscle catabolism, and vitamin D insufficiency were observed. These alterations are directly linked to a prolonged deterioration of bone microstructure. The probably increased risk of fragility fractures should be of clinical concern and subject to future interventional studies with bone-protective agents. © 2017 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3211DOI Listing
December 2017

MNS16A tandem repeat minisatellite of human telomerase gene: functional studies in colorectal, lung and prostate cancer.

Oncotarget 2017 Apr;8(17):28021-28027

Medical University of Vienna, Institute of Cancer Research, A-1090 Vienna, Austria.

MNS16A, a functional polymorphic tandem repeat minisatellite, is located in the promoter region of an antisense transcript of the human telomerase reverse transcriptase gene. MNS16A promoter activity depends on the variable number of tandem repeats (VNTR) presenting varying numbers of transcription factor binding sites for GATA binding protein 1. Although MNS16A has been investigated in multiple cancer epidemiology studies with incongruent findings, functional data of only two VNTRs (VNTR-243 and VNTR-302) were available thus far, linking the shorter VNTR to higher promoter activity.For the first time, we investigated promoter activity of all six VNTRs of MNS16A in cell lines of colorectal, lung and prostate cancer using Luciferase reporter assay. In all investigated cell lines shorter VNTRs showed higher promoter activity. While this anticipated indirect linear relationship was affirmed for colorectal cancer SW480 (P = 0.006), a piecewise linear regression model provided significantly better model fit in lung cancer A-427 (P = 6.9 × 10-9) and prostate cancer LNCaP (P = 0.039). In silico search for transcription factor binding sites in MNS16A core repeat element suggested a higher degree of complexity involving X-box binding protein 1, general transcription factor II-I, and glucocorticoid receptor alpha in addition to GATA binding protein 1.Further functional studies in additional cancers are requested to extend our knowledge of MNS16A functionality uncovering potential cancer type-specific differences. Risk alleles may vary in different malignancies and their determination in vitro could be relevant for interpretation of genotype data.
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http://dx.doi.org/10.18632/oncotarget.15884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438627PMC
April 2017

Circulating microRNA Signatures in Patients With Idiopathic and Postmenopausal Osteoporosis and Fragility Fractures.

J Clin Endocrinol Metab 2016 11 23;101(11):4125-4134. Epub 2016 Aug 23.

St. Vincent Hospital-Medical Department II (R.K., C.M., R.D., F.P., X.F., H.Res.), The VINFORCE Study Group, Academic Teaching Hospital of Medical University of Vienna, 1090 Vienna, Austria; TAmiRNA, GmbH (E.G., S.S, M.H..), 1190 Vienna, Austria; Department of Statistics and Operations Research (A.B.), University of Vienna, 1090 Vienna, Austria; Ludwig Boltzmann Institute for Experimental and Clinical Traumatology (R.K., P.H., H.Red.), 1200 Vienna, Austria; Karl Donath Laboratory for Hard Tissue and Biomaterial Research, Department of Oral Surgery (P.H.), Medical University of Vienna, 1090 Vienna, Austria; Department of Internal Medicine, Division of Endocrinology and Diabetes (A.F.-P.), Medical University of Graz, 8010 Graz, Austria; Christian Doppler Laboratory on Biotechnology of Skin Aging, Department of Biotechnology (J.G.), University of Natural Resources and Life Sciences Vienna, 1180 Viena, Austria; Austrian Cluster for Tissue Regeneration (H.Red., J.G.), Department of Traumatology, Medical University of Vienna, 1090 Vienna, Austria; and Medical Faculty of Bone Diseases (H.Red.), Sigmund Freud University-Vienna, 1020 Vienna, Austria.

Context: Established bone turnover markers do not reflect fracture risk in idiopathic male and premenopausal osteoporosis and the role of microRNAs (miRNAs) in these patients is currently unclear. miRNAs are a class of small non-coding RNAs that regulate gene expression and bone tissue homeostasis. They are considered a new class of endocrine regulators with promising potential as biomarkers.

Objective: Evaluation of circulating miRNA signatures in male and female subjects with idiopathic and postmenopausal osteoporotic low-traumatic fractures.

Design, Setting, And Patients: This was a case-control study of cross-sectional design of 36 patients with prevalent low-traumatic fractures and 39 control subjects Main Outcome Measures: One hundred eighty-seven miRNAs were quantified in serum by qPCR, compared between groups and correlated with established bone turnover markers.

Results: Significant differences in serum levels of circulating miRNAs were identified in all three subgroups (46 in premenopausal, 52 in postmenopausal, 55 in male). A set of 19 miRNAs was consistently regulated in all three subgroups. Eight miRNAs [miR-152-3p, miR-30e-5p, miR-140-5p, miR-324-3p, miR-19b-3p, miR-335-5p, miR-19a-3p, miR-550a-3p] were excellent discriminators of patients with low-traumatic fractures, regardless of age and sex, with area under the curve values > 0.9. The 11 remaining miRNAs showed area under the curve values between 0.81 and 0.89. Correlation analysis identified significant correlations between miR-29b-3p and P1NP, and miR-365-5p and iPTH, TRAP5b, P1NP and Osteocalcin, as well as BMD and miR-19b-3p, miR-324-3p, miR-532-5p, and miR-93-5p.

Conclusions: Specific serum miRNA profiles are strongly related to bone pathologies. Therefore miRNAs might be directly linked to bone tissue homeostasis. In particular, miR-29b-3p has previously been reported as regulator of osteogenic differentiation and could serve as a novel marker of bone turnover in osteoporotic patients as a member of a miRNA signature.
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http://dx.doi.org/10.1210/jc.2016-2365DOI Listing
November 2016
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