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1.
Clin Res Cardiol ; 112(7): 923-941, 2023 Jul.
Article in English | MEDLINE | ID: mdl-36884078

ABSTRACT

The German Centre for Cardiovascular Research (DZHK) is one of the German Centres for Health Research and aims to conduct early and guideline-relevant studies to develop new therapies and diagnostics that impact the lives of people with cardiovascular disease. Therefore, DZHK members designed a collaboratively organised and integrated research platform connecting all sites and partners. The overarching objectives of the research platform are the standardisation of prospective data and biological sample collections among all studies and the development of a sustainable centrally standardised storage in compliance with general legal regulations and the FAIR principles. The main elements of the DZHK infrastructure are web-based and central units for data management, LIMS, IDMS, and transfer office, embedded in a framework consisting of the DZHK Use and Access Policy, and the Ethics and Data Protection Concept. This framework is characterised by a modular design allowing a high standardisation across all studies. For studies that require even tighter criteria additional quality levels are defined. In addition, the Public Open Data strategy is an important focus of DZHK. The DZHK operates as one legal entity holding all rights of data and biological sample usage, according to the DZHK Use and Access Policy. All DZHK studies collect a basic set of data and biosamples, accompanied by specific clinical and imaging data and biobanking. The DZHK infrastructure was constructed by scientists with the focus on the needs of scientists conducting clinical studies. Through this, the DZHK enables the interdisciplinary and multiple use of data and biological samples by scientists inside and outside the DZHK. So far, 27 DZHK studies recruited well over 11,200 participants suffering from major cardiovascular disorders such as myocardial infarction or heart failure. Currently, data and samples of five DZHK studies of the DZHK Heart Bank can be applied for.


Subject(s)
Biological Specimen Banks , Humans , Prospective Studies
2.
J Trauma Acute Care Surg ; 87(2): 379-385, 2019 08.
Article in English | MEDLINE | ID: mdl-31349350

ABSTRACT

BACKGROUND: Compared with a pulmonary artery catheter (PAC), transthoracic echocardiography (TTE) has been shown to have good agreement in cardiac output (CO) measurement in nonsurgical populations. Our hypothesis is that the feasibility and accuracy of CO measured by TTE (CO-TTE), relative to CO measured by PAC thermodilution (CO-PAC), is different in surgical intensive care unit patients (SP) and nonsurgical patients (NSP). METHODS: Surgical patients with PAC for hemodynamic monitoring and NSP undergoing right heart catheterization were prospectively enrolled. Cardiac output was measured by CO-PAC and CO-TTE. Pearson coefficients were used to assess correlation. Bland-Altman analysis was used to determine agreement. RESULTS: Over 18 months, 84 patients were enrolled (51 SP, 33 NSP). Cardiac output TTE could be measured in 65% (33/51) of SP versus 79% (26/33) of NSP; p = 0.17. Inability to measure the left ventricular outflow tract diameter was the primary reason for failure in both groups; 94% (17/18) in SP versus 86% (6/7) NSP; p = 0.47. Velocity time integral could be measured in all patients. In both groups, correlation between PAC and TTE measurement was strong; SP (r = 0.76; p < 0.0001), NSP (r = 0.86; p < 0.0001). Bland-Altman analysis demonstrated bias of -0.1 L/min, limits of agreement of -2.5 and +2.3 L/min, percentage error (PE) of 40% for SP, and bias of +0.4 L/min, limits of agreement of -1.8 and +2.5 L/min, and PE of 40% for NSP. CONCLUSION: There was strong correlation and moderate agreement between TTE and PAC in both SP and NSP. In both patient populations, inability to measure the left ventricular outflow tract diameter was a limiting factor. LEVEL OF EVIDENCE: Diagnostic tests or criteria, level III.


Subject(s)
Cardiac Output , Echocardiography , Catheterization, Swan-Ganz , Critical Illness , Female , Humans , Male , Middle Aged , Prospective Studies , Surgical Procedures, Operative , Thermodilution
3.
Cell Tissue Res ; 364(3): 573-584, 2016 06.
Article in English | MEDLINE | ID: mdl-26829941

ABSTRACT

In previous studies human mesenchymal stromal cells (MSCs) maintained the "stemness" of human hematopoietic progenitor cells (HPCs) through direct cell-cell contact in two-dimensional co-culture systems. We establish a three-dimensional (3D) co-culture system based on a custom-made chip, the 3(D)-KITChip, as an in vitro model system of the human hematopoietic stem cell niche. This array of up to 625 microcavities, with 300 µm size in each orientation, was inserted into a microfluidic bioreactor. The microcavities of the 3(D)-KITChip were inoculated with human bone marrow MSCs together with umbilical cord blood HPCs. MSCs used the microcavities as a scaffold to build a complex 3D mesh. HPCs were distributed three-dimensionally inside this MSC network and formed ß-catenin- and N-cadherin-based intercellular junctions to the surrounding MSCs. Using RT(2)-PCR and western blots, we demonstrate that a proportion of HPCs maintained the expression of CD34 throughout a culture period of 14 days. In colony-forming unit assays, the hematopoietic stem cell plasticity remained similar after 14 days of bioreactor co-culture, whereas monolayer co-cultures showed increasing signs of HPC differentiation and loss of stemness. These data support the notion that the 3D microenvironment created within the microcavity array preserves vital stem cell functions of HPCs more efficiently than conventional co-culture systems.


Subject(s)
Bone Marrow Cells/cytology , Cell Culture Techniques/instrumentation , Cell Culture Techniques/methods , Hematopoietic Stem Cells/cytology , Models, Biological , Stem Cell Niche , Antigens, CD/metabolism , Bioreactors , Blotting, Western , Cell Count , Cell Separation , Coculture Techniques , Colony-Forming Units Assay , Fluorescent Antibody Technique , Humans , Mesenchymal Stem Cells/cytology , Real-Time Polymerase Chain Reaction
4.
Growth Factors ; 32(6): 236-46, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25410963

ABSTRACT

EphB2 interacts with cell surface-bound ephrin ligands to relay bidirectional signals. Overexpression of the EphB2 receptor protein has been linked to different types of cancer. The SNEW (SNEWIQPRLPQH) peptide binds with high selectivity and moderate affinity to EphB2, inhibiting Eph-ephrin interactions by competing with ephrin ligands for the EphB2 high-affinity pocket. We used rigorous free energy perturbation (FEP) calculations to re-evaluate the binding interactions of SNEW peptide with the EphB2 receptor, followed by experimental testing of the computational results. Our results provide insight into dynamic interactions of EphB2 with SNEW peptide. While the first four residues of the SNEW peptide are already highly optimized, change of the C-terminal end of the peptide has the potential to improve SNEW-binding affinity. We identified a PXSPY motif that can be similarly aligned with several other EphB2-binding peptides.


Subject(s)
Molecular Docking Simulation , Peptide Fragments/metabolism , Receptor, EphB2/chemistry , Amino Acid Sequence , Binding Sites , Humans , Molecular Sequence Data , Peptide Fragments/chemistry , Protein Binding , Receptor, EphB2/metabolism
5.
Bioorg Med Chem Lett ; 22(24): 7345-50, 2012 Dec 15.
Article in English | MEDLINE | ID: mdl-23141909

ABSTRACT

CDC25 phosphatases are involved in deregulated cell cycle progression and tumor development with poor prognosis. Among the most potent CDC25 inhibitors, quinonoid-based derivatives have been extensively studied. Dimerisation of heterocyclic quinones has led to IRC-083864, a bis-quinone compound with increased CDC25B inhibitory activity. Thirty-one bis-thiazolone derivatives were synthesized and assayed for CDC25 inhibitory activity. Most of the dimers displayed enhanced inhibitory activities with micromolar IC(50) values lower than that observed for each thiazolone scaffold separately. Moreover, most of these compounds were selective CDC25 inhibitors. Dimer 40 showed an IC(50) value of 2.9 µM and could inhibit CDC25 activity without generating reactive oxygen species which is likely to occur with quinone-based inhibitors. Molecular docking studies suggested that the dimers could bind simultaneously to the active site and the inhibitor binding pocket.


Subject(s)
Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , cdc25 Phosphatases/antagonists & inhibitors , Dimerization , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , cdc25 Phosphatases/metabolism
6.
Bioorg Med Chem Lett ; 22(24): 7634-40, 2012 Dec 15.
Article in English | MEDLINE | ID: mdl-23107479

ABSTRACT

The inhibition of FLT-3 activity is an interesting target for the treatment of acute myeloid leukemia (AML). The serendipitous identification of FLT-3 inhibitors from a CK1/γ-secretase programme provided compounds with dual inhibitory activity. We analyzed the structure-activity relationship of these inhibitors and derivatized them to arrive at compounds with reduced impact on γ-secretase activity and enhanced FLT-3 inhibition.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Animals , Dose-Response Relationship, Drug , Embryo, Nonmammalian/drug effects , Enzyme Inhibitors/chemical synthesis , Humans , Molecular Structure , Phenotype , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Structure-Activity Relationship , Substrate Specificity , Zebrafish/embryology , fms-Like Tyrosine Kinase 3/metabolism
7.
Eur J Med Chem ; 45(3): 896-901, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19969400

ABSTRACT

We report herein the synthesis of 5-substituted [1]pyrindine derivatives and the evaluation of their antiproliferative properties on HeLa cells, a cervical carcinoma tumor cell line, and on the melanoma A2058 cell line. The most efficient compounds display cytotoxicity against tumor cells in the micromolar range but have interestingly no effect against the normal human fibroblasts CRL-2796. Generally, these pyrindines are active on both tumor cell lines. Compounds bearing large substituents with structural rigidity at position 5 such as phenyl-furyl show no inhibition of cell growth.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Pyridines/chemistry , Antineoplastic Agents/chemical synthesis , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Fibroblasts/drug effects , HeLa Cells , Humans , Inhibitory Concentration 50 , Molecular Structure
9.
ChemMedChem ; 4(4): 633-48, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19212959

ABSTRACT

The development of CDC25 phosphatase inhibitors is an interesting approach toward new antitumor agents, as CDC25 play key roles in cell-cycle regulation and are overexpressed in numerous cancers. We previously reported a novel compound belonging to the thiazolopyrimidine family that inhibits CDC25 activity with an IC(50) value of 13 microM and displays cytotoxic properties against HeLa cells. Structural modifications were subsequently conducted on this new pharmacophore which led to a library of 45 thiazolopyrimidines. Regarding the in vitro effects, 14 compounds inhibit CDC25B with IC(50)<20 microM, with the most efficient inhibitor 44 improving the potency to 4.5 microM. Steady-state kinetics were performed and showed a mixed inhibition pattern for all tested compounds. Furthermore, 44 was able to revert the bypass of genotoxicity-induced G(2) arrest upon CDC25B overexpression, indicating that this compound targets the dual-specificity phosphatase in cultured cells. Finally, the cytotoxic activities of the compounds were determined against two human cancer cell lines. The results indicate that the prostatic LNCaP cell line is more sensitive to these derivatives than the pancreatic adenocarcinoma MiaPaCa-2 line. With its interesting enzymatic and cellular properties, compound 44 appears to be a promising CDC25B inhibitor for further development.


Subject(s)
Drug Discovery , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Thiazoles/chemistry , cdc25 Phosphatases/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/drug effects , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Pyrimidines/chemistry , Structure-Activity Relationship , cdc25 Phosphatases/metabolism
10.
Bioorg Med Chem ; 16(19): 9040-9, 2008 Oct 01.
Article in English | MEDLINE | ID: mdl-18789703

ABSTRACT

CDC25 phosphatases are considered as attractive targets for anti-cancer therapy. To date, quinone derivatives are among the most potent inhibitors of CDC25 phosphatase activity. We present in this paper the synthesis and the biological evaluation of new quinolinedione and naphthoquinone derivatives, containing carboxylic or malonic acids groups introduced to mimic the role of the phosphate moieties of Cyclin-Dependent Kinase complexes. The most efficient compounds show inhibitory activity against CDC25B with IC(50) values in the 10 microM range, and are cytotoxic against HeLa cells.


Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Naphthoquinones/pharmacology , Quinolones/pharmacology , cdc25 Phosphatases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Carboxylic Acids/chemistry , Cyclin-Dependent Kinases/chemistry , Cyclin-Dependent Kinases/metabolism , Enzyme Inhibitors/chemical synthesis , HeLa Cells , Humans , Inhibitory Concentration 50 , Malonates , Molecular Mimicry , Naphthoquinones/chemical synthesis , Phosphates/chemistry , Quinolones/chemical synthesis , Structure-Activity Relationship
11.
J Chem Inf Model ; 48(1): 157-65, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18154280

ABSTRACT

CDC25 phosphatases play critical roles in cell cycle regulation and are attractive targets for anticancer therapies. Several small non-peptide molecules are known to inhibit CDC25, but many of them appear to form a covalent bond with the enzyme or act through oxidation of the thiolate group of the catalytic cysteine. Structure-based virtual ligand screening computations were performed with FRED, Surflex, and LigandFit, a compound collection of over 310,000 druglike molecules and the crystal structure of CDC25B in order to identify novel classes of ligands. In vitro experiments carried out on a selected list of 1500 molecules led to the discovery of 99 compounds able to inhibit CDC25B activity at 100 microM. Further docking computations were applied, allowing us to propose a binding mode for the most potent molecule (IC50 = 13 microM). Our best compounds represent promising new classes of CDC25 inhibitors that also exhibit antiproliferative properties.


Subject(s)
Drug Evaluation, Preclinical/methods , cdc25 Phosphatases/antagonists & inhibitors , cdc25 Phosphatases/metabolism , Binding Sites , Crystallography, X-Ray , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Ligands , Models, Biological , Models, Molecular , Reproducibility of Results , cdc25 Phosphatases/chemistry
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