Professionalization of kindergarten teachers with regards to the implementation of state-wide curriculum guidelines. General experiences of the research project QUASI Heidelberg

Bei der länderspezifischen Umsetzung von Bildungs- und Orientierungsplänen werden die unerwünschten Folgen eines fehlenden bundesweit geltenden und verbindlichen Orientierungsrahmens für den Elementarbereich sichtbar. Ihre Implementierung in den Kindertagesstätten erfolgt - wenn überhaupt - beliebig, unkoordiniert und unterliegt keinerlei Qualitätskontrolle. Am Beispiel des Projektes QUASI Heidelberg wird ein strukturierterer und umfassenderer Weg der Implementierung im Kontext des Baden-Württembergischen Orientierungsplans aufgezeigt. (DIPF/Orig.)The lack of standardized and compulsory national curriculum guidelines on early childhood education entails unintentional and undesirable consequences. Not only does it result in a variety of state-wide frameworks of reference, it also entails that curriculum guidelines are implemented by early childhood education facilities in an arbitrary, uncoordinated way, without adequate supervision. By contrast, the research project QUASI Heidelberg intends to highlight a more structured and comprehensive way of implementing these guidelines according to the framework of reference on early childhood education within the state of Baden-Wuerttemberg (Germany). (DIPF/Orig.

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors

Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are known to be overexpressed in several cancer types, we herein report the design, synthesis, and biological evaluation of a library of dual HDAC-COX inhibitors. The designed compounds were synthesized via an efficient parallel synthesis approach using preloaded solid-phase resins. Biological in vitro assays demonstrated that several of the synthesized compounds possess pronounced inhibitory activities against HDAC and COX isoforms. The membrane permeability and inhibition of cellular HDAC activity of selected compounds were confirmed by whole-cell HDAC inhibition assays and immunoblot experiments. The most promising dual inhibitors, C3 and C4, evoked antiproliferative effects in the low micromolar concentration range and caused a significant increase in apoptotic cells. In contrast to previous reports, the simultaneous inhibition of HDAC and COX activity by dual HDAC-COX inhibitors or combination treatments with vorinostat and celecoxib did not result in additive or synergistic anticancer activities

Design, Synthesis and Biological Evaluation of β-Peptoid-Capped HDAC Inhibitors with Anti-Neuroblastoma and Anti-Glioblastoma Activity

Histone deacetylases (HDACs) have been identified as promising epigenetic drug targets for the treatment of neuroblastomaand glioblastoma. In this work, we have rationally designed a novel type of peptoid‐based histone deacetylase inhibitors(HDACi). A mini library of β‐peptoid‐capped HDACi was synthesized using a four‐step protocol. All compounds were screenedin biochemical assays for its inhibition of HDAC1 and HDAC6 and docking studies were performed to rationalize the observedselectivity profile. The synthesized compounds were further examined for tumor cell‐inhibitory activity against a panel ofneuroblastoma and glioblastoma cell lines. In particular, non‐selective compounds with potent activity against HDAC1 andHDAC6 showed strong antiproliferative effects. The most promising HDACi, compound 6i, displayed submicromolar tumorcell‐inhibitory potential (IC50: 0.21 – 0.67 μM) against all five cancer cell lines investigated and exceeded the activity of theFDA‐approved HDACi vorinostat

Fluorescent analogs of peptoid-based HDAC inhibitors: Synthesis, biological activity and cellular uptake kinetics

Fluorescent tagging of bioactive molecules is a powerful tool to study cellular uptake kinetics and is considered as an attractive alternative to radioligands. In this study, we developed fluorescent histone deacetylase (HDAC) inhibitors and investigated their biological activity and cellular uptake kinetics. Our approach was to introduce a dansyl group as a fluorophore in the solvent-exposed cap region of the HDAC inhibitor pharmacophore model. Three novel fluorescent HDAC inhibitors were synthesized utilizing efficient submonomer protocols followed by the introduction of a hydroxamic acid or 2-aminoanilide moiety as zinc-binding group. All compounds were tested for their inhibition of selected HDAC isoforms, and docking studies were subsequently performed to rationalize the observed selectivity profiles. All HDAC inhibitors were further screened in proliferation assays in the esophageal adenocarcinoma cell lines OE33 and OE19. Compound 2, 6-((N-(2-(benzylamino)-2-oxoethyl)-5-(dimethylamino)naphthalene)-1-sulfonamido)-N-hydroxyhexanamide, displayed the highest HDAC inhibitory capacity as well as the strongest anti-proliferative activity. Fluorescence microscopy studies revealed that compound 2 showed the fastest uptake kinetic and reached the highest absolute fluorescence intensity of all compounds. Hence, the rapid and increased cellular uptake of 2 might contribute to its potent anti-proliferative properties

Balancing Histone Deacetylase (HDAC) Inhibition and Druglikeness: Biological and Physicochemical Evaluation of Class I Selective HDAC Inhibitors

Herein we report the structure-activity and structure-physicochemical property relationships of a series of class I selective ortho-aminoanilides targeting the “foot-pocket” in HDAC1&2. To balance the structural benefits and the physicochemical disadvantages of these substances, we started with a set of HDACi related to tacedinaline (CI-994) and evaluated their solubility, lipophilicity (log D7.4) and inhibition of selected HDAC isoforms. Subsequently, we selected the most promising “capless” HDACi and transferred its ZBG to our previously published scaffold featuring a peptoid-based cap group. The resulting hit compound 10c (LSH-A54) showed favorable physicochemical properties and is a potent, selective HDAC1/2 inhibitor. The following evaluation of its slow binding properties revealed that LSH-A54 binds tightly to HDAC1 in an induced-fit mechanism. The potent HDAC1/2 inhibitory properties were reflected by attenuated cell migration in a modified wound healing assay and reduced cell viability in a clonogenic survival assay in selected breast cancer cell lines