Publications by authors named "Jens Fischer"

173 Publications

Fracture load of zirconia implant supported CAD/CAM resin crowns and mechanical properties of restorative material and cement.

J Prosthodont Res 2021 Apr 9. Epub 2021 Apr 9.

Biomaterials and Technology, Department of Reconstructive Dentistry, University Center for Dental Medicine, University of Basel, Basel.

Purpose: To test if resin CAD/CAM materials should be considered for zirconia implants and how their mechanical properties affect the fracture load.

Methods: Fracture load of molar crowns of CAD/CAM materials (VITA CAD-Temp [CT], Cerasmart [CS], Lava Ultimate [LU], Pekkton Ivory [PK]) on zirconia implants (ceramic.implant, 4.0 mm) fixed either with no cement, temporary cement (Harvard Implant semi-permanent [HIS]), self-adhesive (VITA Adiva S-Cem [VAS]) or either one of two adhesive cements (Multilink Automix [MLA], VITA Adiva F-Cem [VAF]) was analyzed. The restorative materials were characterized by their flexural strength, fracture toughness, elemental composition and organic/inorganic ratio while compressive strength of the cements was measured.

Results: For the fracture load significantly highest mean values were fo und overall for PK (2921 ±300 N) > LU (2017 ±499 N) > CS (1463 ±367 N) = CT (1451 ±327 N) (p > 0.05). When analyzing the effect of the cement on the fracture load the overall ranking was VAF (2245 ±650 N) ≥ MLA (2188 ±708 N) ≥ VAS (2017 ±563 N) > HIS (1757 ±668 N) = no cement (1595 ±757 N) (p <0.05), meaning fracture load increased with the compressive strength of the cements. Additionally, a linear trend was found between the fracture load and the fracture toughness of the restorative materials.

Conclusions: All restorative materials exhibited fracture load values similar or higher than lithium disilicate tested previously. Fracture load of CT, CS and LU can be significantly increased when an adhesive cement with a high compressive strength is used.
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http://dx.doi.org/10.2186/jpr.JPR_D_20_00051DOI Listing
April 2021

4-Methylumbelliferone Attenuates Macrophage Invasion and Myocardial Remodeling in Pressure-Overloaded Mouse Hearts.

Hypertension 2021 Jun 22;77(6):1918-1927. Epub 2021 Mar 22.

From the Institute of Pharmacology and Clinical Pharmacology, and Cardiovascular Research Institute Düsseldorf (CARID), University Hospital Düsseldorf, Germany.

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15247DOI Listing
June 2021

Helix-Loop-Helix Factor Id3 (Inhibitor of Differentiation 3): A Novel Regulator of Hyaluronan-Mediated Adipose Tissue Inflammation.

Arterioscler Thromb Vasc Biol 2021 Feb 31;41(2):796-807. Epub 2020 Dec 31.

Robert M. Berne Cardiovascular Research Center (J.C.G., J.M.H., D.B.H., V.O., C.M., M.A.M., C.A.M.), University of Virginia, Charlottesville.

Objective: The aim of this study was to unravel mechanisms whereby deficiency of the transcription factor Id3 (inhibitor of differentiation 3) leads to metabolic dysfunction in visceral obesity. We investigated the impact of loss of Id3 on hyaluronic acid (HA) production by the 3 HAS isoenzymes (HA synthases; -1, -2, and -3) and on obesity-induced adipose tissue (AT) accumulation of proinflammatory B cells. Approach and Results: Male mice and respective wild-type littermate controls were fed a 60% high-fat diet for 4 weeks. An increase in inflammatory B2 cells was detected in epididymal AT. HA accumulated in epididymal AT of high-fat diet-fed mice and circulating levels of HA were elevated. mRNA expression was increased in epididymal AT of mice. Luciferase promoter assays showed that Id3 suppressed promoter activity, while loss of stimulated promoter activity. Functionally, HA strongly promoted B2 cell adhesion in the AT and on cultured vascular smooth muscle cells of mice, an effect sensitive to hyaluronidase.

Conclusions: Our data demonstrate that loss of increases expression in the epididymal AT, thereby promoting HA accumulation. In turn, elevated HA content promotes HA-dependent binding of B2 cells and an increase in the B2 cells in the AT, which contributes to AT inflammation.
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http://dx.doi.org/10.1161/ATVBAHA.120.315588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105274PMC
February 2021

Dose- and time-dependent effects of hyaluronidase on structural cells and the extracellular matrix of the skin.

Eur J Med Res 2020 Nov 23;25(1):60. Epub 2020 Nov 23.

Department of Dermatology, University Hospital Duesseldorf, Duesseldorf, Germany.

Introduction: Hyaluronic acid (hyaluronan; HA) is an essential component of the extracellular matrix (ECM) of the skin. The HA-degrading enzyme hyaluronidase (HYAL) is critically involved in the HA-metabolism. Yet, only little information is available regarding the skin's HA-HYAL interactions on the molecular and cellular levels.

Objective: To analyze the dose- and time-dependent molecular and cellular effects of HYAL on structural cells and the HA-metabolism in the skin.

Materials And Methods: Chip-based, genome-wide expression analyses (Affymetrix® GeneChip PrimeView™ Human Gene Expression Array), quantitative real-time PCR analyses, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (DAB), and in vitro wound healing assays were performed to assess dose-dependent and time-kinetic effects of HA and HYAL (bovine hyaluronidase, Hylase "Dessau") on normal human dermal fibroblasts (NHDF), primary human keratinocytes in vitro and human skin samples ex vivo.

Results: Genome-wide expression analyses revealed an upregulation of HA synthases (HAS) up to 1.8-fold change in HA- and HYAL-treated NHDF. HA and HYAL significantly accelerated wound closure in an in vitro model for cutaneous wound healing. HYAL induced HAS1 and HAS2 mRNA gene expression in NHDF. Interestingly, low concentrations of HYAL (0.015 U/ml) resulted in a significantly higher induction of HAS compared to moderate (0.15 and 1.5 U/ml) and high concentrations (15 U/ml) of HYAL. This observation corresponded to increased concentrations of HA measured by ELISA in conditioned supernatants of HYAL-treated NHDF with the highest concentrations observed for 0.015 U/ml of HYAL. Finally, immunohistochemical analysis of human skin samples incubated with HYAL for up to 48 h ex vivo demonstrated that low concentrations of HYAL (0.015 U/ml) led to a pronounced accumulation of HA, whereas high concentrations of HYAL (15 U/ml) reduced dermal HA-levels.

Conclusion: HYAL is a bioactive enzyme that exerts multiple effects on the HA-metabolism as well as on the structural cells of the skin. Our results indicate that HYAL promotes wound healing and exerts a dose-dependent induction of HA-synthesis in structural cells of the skin. Herein, interestingly the most significant induction of HAS and HA were observed for the lowest concentration of HYAL.
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http://dx.doi.org/10.1186/s40001-020-00460-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686775PMC
November 2020

Atglistatin Pretreatment Preserves Remote Myocardium Function Following Myocardial Infarction.

J Cardiovasc Pharmacol Ther 2021 May 5;26(3):289-297. Epub 2020 Nov 5.

Department of Pharmacology, 2358University of Virginia, Charlottesville, VA, USA.

The pathological role of adipose derived fatty acids following myocardial infarction has long been hypothesized. However, most methods for reducing adipocyte lipolysis have significant non-adipose effects. Atglistatin, a direct inhibitor of the initial lipase in the lipolysis cascade, has been recently shown to inhibit adipose tissue lipolysis after oral administration. To explore the ability of Atglistatin to impact the pathophysiology of cardiac ischemia we performed prophylactic treatment of mice with Atglistatin for 2 days before 1-hour cardiac ischemia. After 7 days of reperfusion, hearts of Atglistatin treated mice showed significantly improved systolic pump function while infarct and scar size were unaffected. Strain analysis of echocardiographic data revealed an enhanced performance of the remote myocardium as cause for overall improved systolic function. The present study provides evidence that inhibition of adipocyte adipose triglyceride lipase (ATGL) using Atglistatin is able to improve cardiac function after MI by targeting the remote myocardium.
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http://dx.doi.org/10.1177/1074248420971113DOI Listing
May 2021

Viscous behavior of resin composite cements.

Dent Mater J 2021 Jan 8;40(1):253-259. Epub 2020 Oct 8.

Division of Dental Materials and Engineering, Department of Reconstructive Dentistry, University Center for Dental Medicine, University of Basel.

The objective of this study was to analyze the viscous behavior during setting reaction of resin composite cements and how it is influenced by temperature. Viscous properties during auto-polymerization at 23°C of three adhesive (Panavia V5 [PV5]; RelyX Ultimate [RUL]; Multilink Automix [MLA]) and three self-adhesive (Panavia SA plus [PSA]; RelyX Unicem 2 Automix [RUN]; Multilink SpeedCem [MSC]) resin composite cements were rheometrically measured. Changes in contact angle and temperature during auto-polymerization were evaluated for each cement at 23°C and 37°C. Rheological analysis and temperature measurements corresponded in terms of curve progression. The tested resin composite cements demonstrated strong variations in their viscous behavior during setting reaction. PV5 and PSA become less viscous at 37°C and then polymerize quickly. For RUL and RUN at 37°C, viscosity rises, and polymerization takes place quickly. MLA and MSC start with high viscosity, then MSC polymerizes very fast and MLA rather slowly.
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http://dx.doi.org/10.4012/dmj.2019-313DOI Listing
January 2021

Efficacy of Plasma-Polymerized Allylamine Coating of Zirconia after Five Years.

J Clin Med 2020 Aug 27;9(9). Epub 2020 Aug 27.

Biomaterials and Technology, Department of Reconstructive Dentistry, University Center for Dental Medicine, University of Basel, 4058 Basel, Switzerland.

Plasma-polymerized allylamine (PPAAm) coatings of titanium enhance the cell behavior of osteoblasts. The purpose of the present study was to evaluate a PPAAm nanolayer on zirconia after a storage period of 5 years. Zirconia specimens were directly coated with PPAAm (ZA0) or stored in aseptic packages at room temperature for 5 years (ZA5). Uncoated zirconia specimens (Zmt) and the micro-structured endosseous surface of a zirconia implant (Z14) served as controls. The elemental compositions of the PPAAm coatings were characterized and the viability, spreading and gene expression of human osteoblastic cells (MG-63) were assessed. The presence of amino groups in the PPAAm layer was significantly decreased after 5 years due to oxidation processes. Cell viability after 24 h was significantly higher on uncoated specimens (Zmt) than on all other surfaces. Cell spreading after 20 min was significantly higher for Zmt = ZA0 > ZA5 > Z14, while, after 24 h, spreading also varied significantly between Zmt > ZA0 > ZA5 > Z14. The expression of the mRNA differentiation markers collagen I and osteocalcin was upregulated on untreated surfaces Z14 and Zmt when compared to the PPAAm specimens. Due to the high biocompatibility of zirconia itself, a PPAAm coating may not additionally improve cell behavior.
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http://dx.doi.org/10.3390/jcm9092776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565740PMC
August 2020

EGFR/Ras-induced CCL20 production modulates the tumour microenvironment.

Br J Cancer 2020 09 30;123(6):942-954. Epub 2020 Jun 30.

Department of Dermatology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.

Background: The activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment.

Methods: The effects of EGFR/Ras on the expression and translation of CCL20 were analysed in a large set of epithelial cancer cell lines and tumour tissues by RT-qPCR and ELISA in vitro. CCL20 production was verified by immunohistochemistry in different tumour tissues and correlated with clinical data. The effects of CCL20 on endothelial cell migration and tumour-associated vascularisation were comprehensively analysed with chemotaxis assays in vitro and in CCR6-deficient mice in vivo.

Results: Tumours facilitate progression by the EGFR/Ras-induced production of CCL20. Expression of the chemokine CCL20 in tumours correlates with advanced tumour stage, increased lymph node metastasis and decreased survival in patients. Microvascular endothelial cells abundantly express the specific CCL20 receptor CCR6. CCR6 signalling in endothelial cells induces angiogenesis. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. The observed phenotype is dependent on CCR6 deficiency in stromal cells but not within the immune system.

Conclusion: We propose that the chemokine axis CCL20-CCR6 represents a novel and promising target to interfere with the tumour microenvironment, and opens an innovative multimodal strategy for cancer therapy.
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http://dx.doi.org/10.1038/s41416-020-0943-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493992PMC
September 2020

The Contorsbody, an antibody format for agonism: Design, structure, and function.

Comput Struct Biotechnol J 2020 14;18:1210-1220. Epub 2020 May 14.

Roche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Nonnenwald 2, 82377 Penzberg, Germany.

The careful design of the antibody architecture is becoming more and more important, especially when the purpose is agonism. We present the design of a novel antibody format that is able to promote receptor dimerization and induce signal transduction resulting in cell proliferation. Mono-specific bivalent Y-shape IgGs made of two light chains and two heavy chains are engineered into single chain dimers of two modified heavy chains, resulting in the fixation of the two Fab fragments along the Fc dimerizing moiety. By this, an antagonist of the Her-receptor family, Trastuzumab, is re-formatted into an agonist by simply incorporating the original binding motif into a different geometrically and sterically constrained conformation. This novel format, named Contorsbody, retains antigen binding properties of the parental IgGs and can be produced by standard technologies established for recombinant IgGs. Structural analyses using molecular dynamics and electron microscopy are described to guide the initial design and to confirm the Contorsbody as a very compact molecule, respectively. Contorsbodies show increased rigidity compared to IgGs and their Fab moieties are positioned parallel and adjacent to each other. This geometry has an increased potential to trigger cell surface antigen or receptor 'cis'-dimerization without 'trans'-bridging of cells or mere receptor blockade.
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http://dx.doi.org/10.1016/j.csbj.2020.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283085PMC
May 2020

Anaemia is associated with severe RBC dysfunction and a reduced circulating NO pool: vascular and cardiac eNOS are crucial for the adaptation to anaemia.

Basic Res Cardiol 2020 06 12;115(4):43. Epub 2020 Jun 12.

Department of Cardiology, Pulmonary Diseases, and Vascular Medicine, Medical Faculty, CARID Cardiovascular Research Institute of Duesseldorf, Heinrich Heine University of Duesseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.

Anaemia is frequently present in patients with acute myocardial infarction (AMI) and contributes to an adverse prognosis. We hypothesised that, besides reduced oxygen carrying capacity, anaemia is associated with (1) red blood cell (RBC) dysfunction and a reduced circulating nitric oxide (NO) pool, (2) compensatory enhancement of vascular and cardiac endothelial nitric oxide synthase (eNOS) activity, and (3) contribution of both, RBC dysfunction and reduced circulatory NO pool to left ventricular (LV) dysfunction and fatal outcome in AMI. In mouse models of subacute and chronic anaemia from repeated mild blood loss the circulating NO pool, RBC, cardiac and vascular function were analysed at baseline and in reperfused AMI. In anaemia, RBC function resulted in profound changes in membrane properties, enhanced turnover, haemolysis, dysregulation of intra-erythrocytotic redox state, and RBC-eNOS. RBC from anaemic mice and from anaemic patients with acute coronary syndrome impaired the recovery of contractile function of isolated mouse hearts following ischaemia/reperfusion. In anaemia, the circulating NO pool was reduced. The cardiac and vascular adaptation to anaemia was characterised by increased arterial eNOS expression and activity and an eNOS-dependent increase of end-diastolic left ventricular volume. Endothelial dysfunction induced through genetic or pharmacologic reduction of eNOS-activity abrogated the anaemia-induced cardio-circulatory compensation. Superimposed AMI was associated with decreased survival. In summary, moderate blood loss anaemia is associated with severe RBC dysfunction and reduced circulating NO pool. Vascular and cardiac eNOS are crucial for the cardio-circulatory adaptation to anaemia. RBC dysfunction together with eNOS dysfunction may contribute to adverse outcomes in AMI.
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http://dx.doi.org/10.1007/s00395-020-0799-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293199PMC
June 2020

Crystal structure of zirconia affects osteoblast behavior.

Dent Mater 2020 07 30;36(7):905-913. Epub 2020 May 30.

Biomaterials and Technology, Department of Reconstructive Dentistry, University Center for Dental Medicine, University of Basel, Basel, Switzerland.

Objectives: Different approaches are currently undertaken to structure the endosseous part of zirconia implants. The purpose of the present study was to evaluate how surface roughness and monoclinic to tetragonal phase ratio of zirconia affect cell behavior of human osteoblasts.

Methods: Zirconia discs with five different surface structures were produced: machined; machined heat-treated; polished; polished heat-treated; sandblasted, etched and heat-treated (cer.face 14, vitaclinical). The specimen surfaces were then characterized in terms of monoclinic to tetragonal phase ratio, wettability, roughness and visualized using scanning electron microscopy. To determine the reaction of the human osteoblastic cells (MG-63) to the surface roughness and monoclinic to tetragonal phase ratio of zirconia, cell spreading, morphology, actin cytoskeleton, viability and gene expression of alkaline phosphatase (ALP), collagen type I (COL) and osteocalcin (OCN) were assessed.

Results: Heat-treatment of the specimens significantly improved the surface wettability. With increased surface roughness Ra of the specimens, cell spreading was reduced. Cell viability after 24h correlated linearly with the tetragonal phase ratio of the specimens. Gene expression after 24h and 3 d was comparable on all specimens irrespective their surface roughness or monoclinic to tetragonal phase ratio.

Significance: Smooth zirconia surfaces with a high tetragonal phase ratio revealed best surface conditions for MG-63 osteoblastic cells and may be considered to design the endosseous part of zirconia implants.
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http://dx.doi.org/10.1016/j.dental.2020.04.017DOI Listing
July 2020

Surface structuring of zirconia to increase fibroblast viability.

Dent Mater 2020 06 27;36(6):779-786. Epub 2020 Apr 27.

Biomaterials and Technology, Department of Reconstructive Dentistry, University Center for Dental Medicine, University of Basel, Basel, Switzerland.

Objective: The neck area of zirconia implants or abutments is currently either machined, polished and in some cases additionally heat-treated. The aim of the present study was to determine how the surface topography and crystalline structure of zirconia affects the viability of human gingival fibroblasts (HGF-1).

Methods: Zirconia discs with a diameter of 13mm were either polished [Zp], polished and heat-treated [Zpt], machined [Zm], machined and heat-treated [Zmt] or sandblasted, etched and heat-treated [Z14] which is the surface topography of the endosseous part of a zirconia implant. The specimen surfaces were analyzed using scanning electron microscopy (SEM), characterized in terms of monoclinic to tetragonal phase ratio, storage effect on wettability and roughness. The viability and morphology of HGF-1 cells was then tested on all surfaces after 24h.

Results: The effect of the heat-treatment was visualized for the polished specimens with SEM. Contact angle of water was significantly decreased after 2 weeks air storage of the zirconia. Cell viability was significantly higher on smooth surfaces (Zpt, Zm, Zmt) when compared to Z14. HGF-1 cells spread very flat and attached tightly to the smoother surfaces Zp, Zpt, Zm and Zmt while on Z14, cells did not fully extend into the etched morphology of zirconia and stretched over longer distances.

Significance: For the structuring of the neck part of zirconia implants or abutments, a smooth surface with exposed grains might be suggested as the optimal substrate for human gingival fibroblasts. The wettability with water of zirconia decreases with prolonged air storage.
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http://dx.doi.org/10.1016/j.dental.2020.03.024DOI Listing
June 2020

Basic Biology of Extracellular Matrix in the Cardiovascular System, Part 1/4: JACC Focus Seminar.

J Am Coll Cardiol 2020 05;75(17):2169-2188

Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia; The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

The extracellular matrix (ECM) is the noncellular component of tissues in the cardiovascular system and other organs throughout the body. It is formed of filamentous proteins, proteoglycans, and glycosaminoglycans, which extensively interact and whose structure and dynamics are modified by cross-linking, bridging proteins, and cleavage by matrix degrading enzymes. The ECM serves important structural and regulatory roles in establishing tissue architecture and cellular function. The ECM of the developing heart has unique properties created by its emerging contractile nature; similarly, ECM lining blood vessels is highly elastic in order to sustain the basal and pulsatile forces imposed on their walls throughout life. In this part 1 of a 4-part JACC Focus Seminar, we focus on the role, function, and basic biology of the ECM in both heart development and in the adult.
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http://dx.doi.org/10.1016/j.jacc.2020.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324287PMC
May 2020

Comparing the mechanical properties of pressed, milled, and 3D-printed resins for occlusal devices.

J Prosthet Dent 2020 Dec 17;124(6):780-786. Epub 2020 Jan 17.

Research Associate, Department of Reconstructive Dentistry, University Center for Dental Medicine, University of Basel, Basel, Switzerland. Electronic address:

Statement Of Problem: Comparisons of the material qualities of pressed, milled, and 3D-printed occlusal devices are sparse, complicating informed decisions on material choice.

Purpose: The purpose of this in vitro study was to compare the material properties of pressed, milled, and 3D-printed resins, as well as how these are affected by thermal aging. These data were then used to estimate the likely clinical performance of the tested materials.

Material And Methods: Three pressed (ProBase Cold; Ivoclar Vivadent AG, Palapress clear; Kulzer GmbH, Aesthetic Blue clear; Candulor), 3 milled (Temp Premium Flexible Transpa; Zirkonzahn, idodentine PMMA transparent; Unión Dental S.A., Yamahachi PMMA clear; Yamahachi Dental MFG), and three 3D-printed (Freeprint splint; DETAX GmbH, LuxaPrint Ortho Plus; DMG GmbH, Nextdent Ortho Clear; Vertex-Dental B.V.) resin materials were evaluated. Flexural strength, Martens hardness (HM), Vickers hardness (HV), water sorption, water solubility, and surface topography were analyzed. The tests were carried out after 50 hours of water storage at 37 °C (baseline) and after simulated aging (50 hours of water storage at 37 °C, followed by 20 000 thermocycles [TC] at 5 °C and 55 °C).

Results: At baseline, the mean flexural strength values were 92.8 to 99.5 MPa for pressed, 95.1 to 122.0 MPa for milled, and 19.5 to 91.3 MPa for 3D-printed materials. After aging, these values were 87.6 to 93.5 MPa for pressed, 93.1 to 116.0 MPa for milled, and 13.0 to 63.3 MPa for 3D-printed resins. The mean HM values were 130.1 to 134.1 N/mm for pressed and 130.3 to 158.5 N/mm for milled resins. After aging, the mean HM ranged from 121.6 to 124.2 N/mm for pressed and 116.2 to 149.7 N/mm for milled resins. The mean HV values were 18.2 to 19.9 for pressed and 18.4 to 23.0 for milled resins before aging and 16.9 to 18.7 for pressed and 17.3 to 22.3 N/mm for milled resins after aging. Printed resins could not be measured. At baseline, the mean modulus of elasticity ranged from 4.6 to 4.8 GPa for pressed and from 4.7 to 5.3 GPa for milled resins. For 3D-printed resins, only 1 material could be measured (3.7 GPa). The mean sorption values were 8.6 to 9.2 μg/mm for pressed, 7.9 to 10.5 μg/mm for milled, and 9.2 to 21.2 μg/mm for additive resins. After aging, these values were 21.1 to 22.6 μg/mm for pressed, 20.5 to 23.7 μg/mm for milled, and 19.4 to 45.5 μg/mm for 3D-printed resins. The mean solubility values ranged from 0.3 to 1.4 μg/mm for pressed, 0.4 to 1.7 μg/mm for milled, and -3.5 to 11 μg/mm for 3D-printed materials.

Conclusions: Pressed and milled resins can be considered equivalent in terms of their material properties. Relative to the pressed and milled resins, the 3D-printed resins had lower flexural strength and hardness values and higher water sorption and solubility.
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http://dx.doi.org/10.1016/j.prosdent.2019.10.024DOI Listing
December 2020

Intra-Patient Heterogeneity of Circulating Tumor Cells and Circulating Tumor DNA in Blood of Melanoma Patients.

Cancers (Basel) 2019 Oct 29;11(11). Epub 2019 Oct 29.

Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Despite remarkable progress in melanoma therapy, the exceptional heterogeneity of the disease has prevented the development of reliable companion biomarkers for the prediction or monitoring of therapy responses. Here, we show that difficulties in detecting blood-based markers, like circulating tumor cells (CTC), might arise from the translation of the mutational heterogeneity of melanoma cells towards their surface marker expression. We provide a unique method, which enables the molecular characterization of clinically relevant CTC subsets, as well as circulating tumor DNA (ctDNA), from a single blood sample. The study demonstrates the benefit of a combined analysis of ctDNA and CTC counts in melanoma patients, revealing that CTC subsets and ctDNA provide synergistic real-time information on the mutational status, RNA and protein expression of melanoma cells in individual patients, in relation to clinical outcome.
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http://dx.doi.org/10.3390/cancers11111685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896052PMC
October 2019

4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue.

Nat Metab 2019 05 22;1(5):546-559. Epub 2019 Apr 22.

Institute of Pharmacology and Clinical Pharmacology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Therapeutic increase of brown adipose tissue (BAT) thermogenesis is of great interest as BAT activation counteracts obesity and insulin resistance. Hyaluronan (HA) is a glycosaminoglycan, found in the extracellular matrix, which is synthesized by HA synthases (Has1/Has2/Has3) from sugar precursors and accumulates in diabetic conditions. Its synthesis can be inhibited by the small molecule 4-methylumbelliferone (4-MU). Here, we show that the inhibition of HA-synthesis by 4-MU or genetic deletion of improves BAT`s thermogenic capacity, reduces body weight gain, and improves glucose homeostasis independently from adrenergic stimulation in mice on diabetogenic diet, as shown by a magnetic resonance T2 mapping approach. Inhibition of HA synthesis increases glycolysis, BAT respiration and uncoupling protein 1 expression. In addition, we show that 4-MU increases BAT capacity without inducing chronic stimulation and propose that 4-MU, a clinically approved prescription-free drug, could be repurposed to treat obesity and diabetes.
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http://dx.doi.org/10.1038/s42255-019-0055-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786893PMC
May 2019

HF etching of CAD/CAM materials: influence of HF concentration and etching time on shear bond strength.

Head Face Med 2019 Aug 8;15(1):21. Epub 2019 Aug 8.

Department of Reconstructive Dentistry, University Center for Dental Medicine, University of Basel, Mattenstrasse 40, CH-4058, Basel, Switzerland.

Background: The required pretreatment of CAD/CAM ceramic materials before resin composite cement application varies among studies. The aim of the present study was to evaluate the effect of hydrofluoric acid concentration and etching time on the shear bond strength (SBS) of two adhesive and two self-adhesive resin composite cements to different CAD/CAM ceramic materials.

Methods: SBS of two adhesive (Panavia V5, Kuraray, [PV5]; Vita Adiva F-Cem, Vita Zahnfabrik, [VAF]) and two self-adhesive (RelyX Unicem 2 Automix, 3 M Espe, [RUN]; Vita Adiva S-Cem, Vita, [VAS]) cements to four different CAD/CAM materials (Vitablocs Mark II, Vita, [VM]; Vita Enamic, Vita, [VE]; e.max CAD, Ivoclar Vivadent, [EC]; Vita Suprinity PC, Vita, [VS]) was measured. The effect of the surface pretreatment by using two different hydrofluoric acid products (HF5% Vita Ceramics Etch, Vita and HF9% buffered, Ultradent Porcelain Etch, Ultradent Products) were assessed at etching times of 0 s, 5 s, 15 s, 30s and 60s for each cement and restorative material combination (n = 10 per group, total n = 1440).

Results: Significant effects were found for the etching time and cement for all materials with highest shear bond strength for etching times of 60s = 30s = 15 s ≥ 5 s > 0 s and for RUN>PV5 = VAF > VAS (p < 0.05). Etching with HF5% for 5 s to 15 s resulted in higher SBS values, while no differences were observed between HF5% and HF9% buffered when the substrates were etched for 30s to 60s (p < 0.05).

Conclusions: Within the limitations of this study the recommended surface pretreatment of silicate ceramics is HF etching with concentrations of 5% or 9% for 15 s to 60s to achieve highest shear bond strength while the glassy matrix is sufficiently dissolved. The tested resin composite cements can be applied with all tested materials and suggested for clinical application.
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http://dx.doi.org/10.1186/s13005-019-0206-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686502PMC
August 2019

Inhibition of the hyaluronan matrix enhances metabolic anticancer therapy by dichloroacetate in vitro and in vivo.

Br J Pharmacol 2019 12 9;176(23):4474-4490. Epub 2019 Dec 9.

Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.

Background And Purpose: Aerobic glycolysis is a unique feature of tumour cells that entails several advantages for cancer progression such as resistance to apoptosis. The low MW compound, dichloroacetate, is a pyruvate dehydrogenase kinase inhibitor, which restores oxidative phosphorylation and induces apoptosis in a variety of cancer entities. However, its therapeutic effectiveness is limited by resistance mechanisms. This study aimed to examine the role of the anti-apoptotic hyaluronan (HA) matrix in this context and to identify a potential add-on treatment option to overcome this limitation.

Experimental Approach: The metabolic connection between dichloroacetate treatment and HA matrix augmentation was analysed in vitro by quantitative PCR and affinity cytochemistry. Metabolic pathways were analysed using Seahorse, HPLC, fluorophore-assisted carbohydrate electrophoresis, colourimetry, immunoblots, and immunochemistry. The effects of combining dichloroacetate with the HA synthesis inhibitor 4-methylumbelliferone was evaluated in 2D and 3D cell cultures and in a nude mouse tumour xenograft regression model by immunoblot, immunochemistry, and FACS analysis.

Key Results: Mitochondrial reactivation induced by dichloroacetate metabolically activated HA synthesis by augmenting precursors as well as O-GlcNAcylation. This process was blocked by 4-methylumbelliferone, resulting in enhanced anti-tumour efficacy in 2D and 3D cell culture and in a nude mouse tumour xenograft regression model.

Conclusions And Implications: The HA rich tumour micro-environment represents a metabolic factor contributing to chemotherapy resistance. HA synthesis inhibition exhibited pronounced synergistic actions with dichloroacetate treatment on oesophageal tumour cell proliferation and survival in vitro and in vivo suggesting the combination of these two strategies is an effective anticancer therapy.
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http://dx.doi.org/10.1111/bph.14808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932941PMC
December 2019

Decreased M1 macrophage polarization in dabigatran-treated Ldlr-deficient mice: Implications for atherosclerosis and adipose tissue inflammation.

Atherosclerosis 2019 08 8;287:81-88. Epub 2019 Jun 8.

Institute for Pharmacology and Clinical Pharmacology, Medical Faculty, University Hospital, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany; Cardiovascular Research Institute Duesseldorf (CARID), University Hospital, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany. Electronic address:

Background And Aims: The non-vitamin K oral anticoagulant dabigatran etexilate (dabigatran) is increasingly prescribed to patients with non-valvular atrial fibrillation and venous thromboembolism. Adipose tissue (AT) inflammation during obesity plays a crucial role in the development of insulin resistance, type II diabetes and atherogenesis. The aim of the present study was to investigate the effects of thrombin inhibition by dabigatran in a combined model of diet-induced obesity and atherosclerosis.

Methods: Female Low density lipoprotein receptor knockout (Lldr) mice were fed a high-fat diet containing 5 mg/g dabigatran or matching control for 20 weeks.

Results: Dabigatran-treated animals showed increased adipocyte hypertrophy, but reduced numbers of pro-inflammatory M1-polarized macrophages in the adipose tissue. Abundance of pro-inflammatory M1 macrophages was also decreased in the aortic wall of dabigatran-fed mice. Multiple circulating cytokines were reduced, indicating an effect in systemically relevant secretory compartments such as the AT.

Conclusions: Dabigatran treatment reduces pro-inflammatory M1 macrophages in atherosclerotic lesions, thereby contributing to plaque stabilizing and atheroprotective effects of the thrombin inhibitor. This finding is not restricted to the vascular wall but is also present in AT where dabigatran treatment reduced the release of pro-inflammatory cytokines and accumulation of M1 macrophages.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.06.897DOI Listing
August 2019

Impact of hyperinsulinemia and hyperglycemia on valvular interstitial cells - A link between aortic heart valve degeneration and type 2 diabetes.

Biochim Biophys Acta Mol Basis Dis 2019 09 30;1865(9):2526-2537. Epub 2019 May 30.

Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany. Electronic address:

Type 2 diabetes is a known risk factor for cardiovascular diseases and is associated with an increased risk to develop aortic heart valve degeneration. Nevertheless, molecular mechanisms leading to the pathogenesis of valve degeneration in the context of diabetes are still not clear. Hence, we hypothesized that classical key factors of type 2 diabetes, hyperinsulinemia and hyperglycemia, may affect signaling, metabolism and degenerative processes of valvular interstitial cells (VIC), the main cell type of heart valves. Therefore, VIC were derived from sheep and were treated with hyperinsulinemia, hyperglycemia and the combination of both. The presence of insulin receptors was shown and insulin led to increased proliferation of the cells, whereas hyperglycemia alone showed no effect. Disturbed insulin response was shown by impaired insulin signaling, i.e. by decreased phosphorylation of Akt/GSK-3α/β pathway. Analysis of glucose transporter expression revealed absence of glucose transporter 4 with glucose transporter 1 being the predominantly expressed transporter. Glucose uptake was not impaired by disturbed insulin response, but was increased by hyperinsulinemia and was decreased by hyperglycemia. Analyses of glycolysis and mitochondrial respiration revealed that VIC react with increased activity to hyperinsulinemia or hyperglycemia, but not to the combination of both. VIC do not show morphological changes and do not acquire an osteogenic phenotype by hyperinsulinemia or hyperglycemia. However, the treatment leads to increased collagen type 1 and decreased α-smooth muscle actin expression. This work implicates a possible role of diabetes in early phases of the degeneration of aortic heart valves.
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http://dx.doi.org/10.1016/j.bbadis.2019.05.019DOI Listing
September 2019

Cardiac Hyaluronan Synthesis Is Critically Involved in the Cardiac Macrophage Response and Promotes Healing After Ischemia Reperfusion Injury.

Circ Res 2019 05;124(10):1433-1447

From the Institut für Pharmakologie und Klinische Pharmakologie (A.P., M.G., D.J.G., M.A., M.P., R.S., S.H., J.M., S.G., J.W.F.), University Hospital, Heinrich-Heine-University Düsseldorf, Germany.

Rationale: Immediate changes in the ECM (extracellular matrix) microenvironment occur after myocardial ischemia and reperfusion (I/R) injury.

Objective: Aim of this study was to unravel the role of the early hyaluronan (HA)-rich ECM after I/R.

Methods And Results: Genetic deletion of Has2 and Has1 was used in a murine model of cardiac I/R. Chemical exchange saturation transfer imaging was adapted to image cardiac ECM post-I/R. Of note, the cardiac chemical exchange saturation transfer signal was severely suppressed by Has2 deletion and pharmacological inhibition of HA synthesis 24 hours after I/R. Has2 KO ( Has2 deficient) mice showed impaired hemodynamic function suggesting a protective role for endogenous HA synthesis. In contrast to Has2 deficiency, Has1-deficient mice developed no specific phenotype compared with control post-I/R. Importantly, in Has2 KO mice, cardiac macrophages were diminished after I/R as detected by F MRI (magnetic resonance imaging) of perfluorcarbon-labeled immune cells, Mac-2/Galectin-3 immunostaining, and FACS (fluorescence-activated cell sorting) analysis (CD45CD11bLy6GCD64F4/80cells). In contrast to macrophages, cardiac Ly6C and Ly6C monocytes were unaffected post-I/R compared with control mice. Mechanistically, inhibition of HA synthesis led to increased macrophage apoptosis in vivo and in vitro. In addition, α-SMA (α-smooth muscle actin)-positive cells were reduced in the infarcted myocardium and in the border zone. In vitro, the myofibroblast response as measured by Acta2 mRNA expression was reduced by inhibition of HA synthesis and of CD44 signaling. Furthermore, Has2 KO fibroblasts were less able to contract collagen gels in vitro. The effects of HA/CD44 on fibroblasts and macrophages post-I/R might also affect intercellular cross talk because cardiac fibroblasts were activated by monocyte/macrophages and, in turn, protected macrophages from apoptosis.

Conclusions: Increased HA synthesis contributes to postinfarct healing by supporting macrophage survival and by promoting the myofibroblast response. Additionally, imaging of cardiac HA by chemical exchange saturation transfer post-I/R might have translational value.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.313285DOI Listing
May 2019

4-Methylumbelliferyl glucuronide contributes to hyaluronan synthesis inhibition.

J Biol Chem 2019 05 26;294(19):7864-7877. Epub 2019 Mar 26.

From the Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305.

4-Methylumbelliferone (4-MU) inhibits hyaluronan (HA) synthesis and is an approved drug used for managing biliary spasm. However, rapid and efficient glucuronidation is thought to limit its utility for systemically inhibiting HA synthesis. In particular, 4-MU in mice has a short half-life, causing most of the drug to be present as the metabolite 4-methylumbelliferyl glucuronide (4-MUG), which makes it remarkable that 4-MU is effective at all. We report here that 4-MUG contributes to HA synthesis inhibition. We observed that oral administration of 4-MUG to mice inhibits HA synthesis, promotes FoxP3 regulatory T-cell expansion, and prevents autoimmune diabetes. Mice fed either 4-MUG or 4-MU had equivalent 4-MU:4-MUG ratios in serum, liver, and pancreas, indicating that 4-MU and 4-MUG reach an equilibrium in these tissues. LC-tandem MS experiments revealed that 4-MUG is hydrolyzed to 4-MU in serum, thereby greatly increasing the effective bioavailability of 4-MU. Moreover, using intravital 2-photon microscopy, we found that 4-MUG (a nonfluorescent molecule) undergoes conversion into 4-MU (a fluorescent molecule) and that 4-MU is extensively tissue bound in the liver, fat, muscle, and pancreas of treated mice. 4-MUG also suppressed HA synthesis independently of its conversion into 4-MU and without depletion of the HA precursor UDP-glucuronic acid (GlcUA). Together, these results indicate that 4-MUG both directly and indirectly inhibits HA synthesis and that the effective bioavailability of 4-MU is higher than previously thought. These findings greatly alter the experimental and therapeutic possibilities for HA synthesis inhibition.
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http://dx.doi.org/10.1074/jbc.RA118.006166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514619PMC
May 2019

Influence of bioactive glass-coating of zirconia implant surfaces on human osteoblast behavior in vitro.

Dent Mater 2019 06 16;35(6):862-870. Epub 2019 Mar 16.

Division of Dental Materials and Engineering, Department of Reconstructive Dentistry, University Center for Dental Medicine, University of Basel, Basel, Switzerland.

Objective: The recently developed bioactive glass PC-XG3, which is suitable to coat zirconia implant surfaces with high adhesion strength may reduce the time of osseointegration and the marginal bone loss following implantation. The glass composition has been previously evaluated for cytotoxicity on fibroblast cells, and will now be used to evaluate the cell behavior of osteoblast cells.

Methods: Three different surface morphologies were created with PC-XG3 on zirconia discs. A clinically tested zirconia implant surface as well as polished and machined zirconia served as a reference. Cell viability after 24 h, cell spreading after 30 min and 24 h and the respective morphology of human osteoblasts using scanning electron microscopy were evaluated. Additionally, the corrosive process of PC-XG3 in cell culture medium up to 7 d was measured.

Results: Initial cell behavior of human osteoblasts was not accelerated by the PC-XG3 surface when compared to zirconia. Additionally, it was found that a decreased surface roughness promoted initial cell spreading. Storage in cell culture medium resulted in the accumulation of C and N on the bioglass surface while Mg, Si, K and Ca were decreased and crack formation was observed.

Significance: Since initial spreading quality to a biomaterial is a crucial factor that will determine the subsequent cell function, proliferation, differentiation, and viability it can be assumed that a coating of zirconia implants with this bioactive glass will unlikely reduce osseointegration time.
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http://dx.doi.org/10.1016/j.dental.2019.02.029DOI Listing
June 2019

Chewing simulation of zirconia implant supported restorations.

J Prosthodont Res 2019 Jul 8;63(3):361-367. Epub 2019 Mar 8.

Division of Dental Materials and Engineering, Department of Reconstructive Dentistry, University Center for Dental Medicine, University of Basel, Basel, Switzerland; Vita Zahnfabrik, Bad Säckingen, Germany.

Purpose: To test three potential prosthetic material options for zirconia implants in regard to their mechanical properties, loading and retention capacity as well as to record abrasion after chewing simulation followed by thermocyclic aging.

Methods: Molar crowns (n = 96) of three different computer-aided design/computer-aided manufacturing (CAD/CAM) materials were produced and cemented on zirconia implants (ceramic.implant, Vita) with a diameter of 4.5 mm. Monolithic zirconia (Vita YZ [YZ] with RelyX Unicem 2 Automix [RUN], polymer-infiltrated ceramic (Vita Enamic [VE]) with Vita Adiva F-Cem [VAF] and acrylate polymer (CAD Temp [CT]) with RelyX Ultimate [RUL]. Fracture load and retentive force of the crowns were measured after 24 h water storage at 37 °C and after a chewing simulation followed by thermocyclic aging. Abrasion was recorded by matching stereolithography-data of the crowns obtained before and after chewing simulation. Additionally, the mechanical properties and bonding capabilities of the crown and cement materials were assessed.

Results: Fracture load values were significantly highest for YZ > VE = CT. Retention force values did not differ significantly between the materials. The aging procedure did not affect the fracture load values nor the retention force significantly. Abrasion depth of the crowns was lowest for YZ followed by VE and CT. On unpolished crowns, abrasion of YZ and VE tended to be higher than on polished specimens.

Conclusions: Based on the obtained in-vitro results, all tested materials can be recommended for the use on zirconia implants, although CT is only approved for temporary crowns. The loading and retention capacity of the materials were not significantly affected by aging.
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http://dx.doi.org/10.1016/j.jpor.2019.02.002DOI Listing
July 2019

Cardiac fibroblast activation and hyaluronan synthesis in response to hyperglycemia and diet-induced insulin resistance.

Sci Rep 2019 02 12;9(1):1827. Epub 2019 Feb 12.

Institut für Pharmakologie und Klinische Pharmakologie, University Hospital, Heinrich-Heine-University, Düsseldorf, Germany.

Diabetic patients are at a greater risk of heart failure due to diabetic cardiomyopathy and worsened outcome post-myocardial infarction. While the molecular mechanisms remain unclear, fibrosis and chronic inflammation are common characteristics of both conditions. Diabetes mellitus (types I and II) results in excessive hyaluronan (HA) deposition in vivo, and hyperglycemia stimulates HA synthesis for several cell types in vitro. HA-rich extracellular matrix contributes to fibrotic, hyperplastic and inflammatory disease progression. We hypothesized that excessive hyperglycemia-driven HA accumulation may contribute to pathological fibroblast activation and fibrotic remodelling in diabetic patients. Therefore, we analysed the impact of both hyperglycemia and diet-induced obesity and insulin resistance on HA matrix formation and cardiac fibroblast activation. Here we report that cardiac fibroblasts isolated from mice on a diabetogenic diet acquire pro-fibrotic gene expression without a concomitant increase in HA matrix deposition. Additionally, hyperglycemia alone does not stimulate HA synthesis or cardiac fibroblast activation in vitro, suggesting that the direct effect of hyperglycemia on fibroblasts is not the primary driver of fibrotic remodelling in cardiac diabetic maladaptation.
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http://dx.doi.org/10.1038/s41598-018-36140-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372628PMC
February 2019

Loading capacity of CAD/CAM-fabricated anterior feldspathic ceramic crowns bonded to one-piece zirconia implants with different cements.

Clin Oral Implants Res 2019 Feb 29;30(2):178-186. Epub 2019 Jan 29.

Department of Preventive and Restorative Sciences, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania.

Objective: This study evaluated the loading capacity of CAD/CAM-fabricated anterior feldspathic ceramic crowns bonded to one-piece zirconia implants with different cements.

Material And Methods: Fifty one-piece zirconia implants were embedded in epoxy resin. The abutment aspect of one implant was optically scanned and a standardized upper canine was designed with CAD-software. Fifty feldspathic ceramic crowns were milled, polished, and mounted on the implants either without any cement, with a temporary cement or with three different composite resin cements after surface pretreatment as recommended by the manufacturers (n = 10). After storage in distilled water at 37°C for 24 hr, specimens were loaded until fracture on the palatal surface of the crown at an angle of 45° to the long axis of the implant and loads until fracture were detected and compared. Compressive strength of the investigated cement materials was determined. Statistical analyses were done with One-way ANOVA followed by post hoc Fisher LSD test (α = 0.05).

Results: The cements revealed significantly different compressive strength values (temporary cement: 37.1 ± 7.0 MPa; composite resin cements: 185.8 ± 21.3, 277.9 ± 22.1, and 389.0 ± 13.6 MPa, respectively). Load-at-fracture values had an overall mean value of 237.1 ± 58.2 N with no significant difference among the composite resin cements (p > 0.05). Fracture load values with the temporary cement or without cement were significantly lower (p < 0.002).

Conclusions: CAD/CAM-fabricated anterior feldspathic ceramic crowns bonded to one-piece zirconia implants provide sufficient resistance to intraoral forces.
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http://dx.doi.org/10.1111/clr.13404DOI Listing
February 2019

Degenerative aortic valve disease and diabetes: Implications for a link between proteoglycans and diabetic disorders in the aortic valve.

Diab Vasc Dis Res 2019 05 19;16(3):254-269. Epub 2018 Dec 19.

1 Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany.

Degenerative aortic valve disease in combination with diabetes is an increasing burden worldwide. There is growing evidence that particularly small leucine-rich proteoglycans are involved in the development of degenerative aortic valve disease. Nevertheless, the role of these molecules in this disease in the course of diabetes has not been elucidated in detail and previous studies remain controversial. Therefore, the aim of this study is to broaden the knowledge about small leucine-rich proteoglycans in degenerative aortic valve disease and the influence of diabetes and hyperglycaemia on aortic valves and valvular interstitial cells is examined. Analyses were performed using reverse-transcription polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay, (immuno)histology and colorimetric assays. We could show that biglycan, but not decorin and lumican, is upregulated in degenerated human aortic valve cusps. Subgroup analysis reveals that upregulation of biglycan is stage-dependent. In vivo, loss of biglycan leads to stage-dependent calcification and also to migratory effects on interstitial cells within the extracellular matrix. In late stages of degenerative aortic valve disease, diabetes increases the expression of biglycan in aortic valves. In vitro, the combinations of hyperglycaemic with pro-degenerative conditions lead to an upregulation of biglycan. In conclusion, biglycan represents a potential link between degenerative aortic valve disease and diabetes.
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http://dx.doi.org/10.1177/1479164118817922DOI Listing
May 2019

Enzymatic Activity Is Not Required for Phospholipase D Mediated TNF-α Regulation and Myocardial Healing.

Front Physiol 2018 29;9:1698. Epub 2018 Nov 29.

Department of Vascular and Endovascular Surgery, Experimental Vascular Medicine, Heinrich-Heine University Medical Center, Düsseldorf, Germany.

Phospholipase D1 is a regulator of tumor necrosis factor-α expression and release upon LPS-induced sepsis and following myocardial infarction (MI). Lack of PLD1 leads to a reduced TNF-α mediated inflammatory response and to enhanced infarct size with declined cardiac function 21 days after ischemia reperfusion (I/R) injury. Deficiency of both PLD isoforms PLD1 and PLD2 as well as pharmacological inhibition of the enzymatic activity of PLD with the PLD inhibitor FIPI protected mice from arterial thrombosis and ischemic brain infarction. Here we treated mice with the PLD inhibitor FIPI to analyze if pharmacological inhibition of PLD after myocardial ischemia protects mice from cardiac damage. Inhibition of PLD with FIPI leads to reduced migration of inflammatory cells into the infarct border zone 24 h after experimental MI in mice, providing first evidence for immune cell migration to be dependent on the enzymatic activity of PLD. In contrast to PLD1 deficient mice, TNF-α plasma level was not altered after FIPI treatment of mice. Consequently, infarct size and left ventricular (LV) function were comparable between FIPI-treated and control mice 21 days post MI. Moreover, cell survival 24 h post I/R was not altered upon FIPI treatment. Our results indicate that the enzymatic activity of PLD is not responsible for PLD mediated TNF-α signaling and myocardial healing after I/R injury in mice. Furthermore, reduced TNF-α plasma levels in PLD1 deficient mice might be responsible for increased infarct size and impaired cardiac function 21 days post MI.
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http://dx.doi.org/10.3389/fphys.2018.01698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281985PMC
November 2018

IGF1 Treatment Improves Cardiac Remodeling after Infarction by Targeting Myeloid Cells.

Mol Ther 2019 01 1;27(1):46-58. Epub 2018 Nov 1.

Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany. Electronic address:

Insulin-like growth factor 1 (IGF1) is an anabolic hormone that controls the growth and metabolism of many cell types. However, IGF1 also mediates cardio-protective effects after acute myocardial infarction (AMI), but the underlying mechanisms and cellular targets are not fully understood. Here we demonstrate that short-term IGF1 treatment for 3 days after AMI improved cardiac function after 1 and 4 weeks. Regional wall motion was improved in ischemic segments, scar size was reduced, and capillary density increased in the infarcted area and the border zone. Unexpectedly, inducible inactivation of the IGF1 receptor (IGF1R) in cardiomyocytes did not attenuate the protective effect of IGF1. Sequential cardiac transcriptomic analysis indicated an altered myeloid cell response in the acute phase after AMI, and, notably, myeloid-cell Igf1r mice lost the protective IGF1 function after I/R. In addition, IGF1 induced an M2-like anti-inflammatory phenotype in bone marrow-derived macrophages and enhanced the number of anti-inflammatory macrophages in heart tissue on day 3 after AMI in vivo. In summary, modulation of the acute inflammatory phase after AMI by IGF1 represents an effective mechanism to preserve cardiac function after I/R.
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http://dx.doi.org/10.1016/j.ymthe.2018.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319026PMC
January 2019

IL-23R Signaling Plays No Role in Myocardial Infarction.

Sci Rep 2018 11 20;8(1):17078. Epub 2018 Nov 20.

Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, 40225, Düsseldorf, Germany.

Ischemic heart diseases are the most frequent diseases in the western world. Apart from Interleukin (IL-)1, inflammatory therapeutic targets in the clinic are still missing. Interestingly, opposing roles of the pro-inflammatory cytokine IL-23 have been described in cardiac ischemia in mice. IL-23 is a composite cytokine consisting of p19 and p40 which binds to IL-23R and IL-12Rβ1 to initiate signal transduction characterized by activation of the Jak/STAT, PI3K and Ras/Raf/MAPK pathways. Here, we generate IL-23R-Y416FΔICD signaling deficient mice and challenged these mice in close- and open-chest left anterior descending coronary arteria ischemia/reperfusion experiments. Our experiments showed only minimal changes in all assayed parameters in IL-23R signaling deficient mice compared to wild-type mice in ischemia and for up to four weeks of reperfusion, including ejection fraction, endsystolic volume, enddiastolic volume, infarct size, gene regulation and α smooth muscle actin (αSMA) and Hyaluronic acid (HA) protein expression. Moreover, injection of IL-23 in wild-type mice after LAD ischemia/reperfusion had also no influence on the outcome of the healing phase. Our data showed that IL-23R deficiency has no effects in myocardial I/R.
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http://dx.doi.org/10.1038/s41598-018-35188-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244091PMC
November 2018