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Manus och regi: Kjell Peder JohansonMusik: Norrbotten NEONorra Sveriges tuffaste ensemblemusiker spelar här ut hela sitt uttrycks-register i en musikalisk happening för de allra minsta. I föreställningen leker Norrbotten NEO med roller och instrument och nästan vad som helst kan hända.För manus och regi svarar Kjell Peder Johanson, den värmländske teaterräven, pedagogen och radiomannen som är signaturen bakom såväl Sveriges Radios Karlavagnen som succéföreställningarna Jorden runt på 80 dagar och Stråkmysteriet.Föreställningen innehåller musik av bland andra Bach, Vivaldi och Stravinsky men också musik som skapas tillsammans med publiken.För det musikaliska urvalet svarar medlemmarna i Norrbotten NEO – norra Europas nyaste, busigaste och mest mästerliga kammarensemble. NEO är sju musiker som var för sig och tillsammans bygger nya musikaliska rum: slagverk och klarinett, en vänlig stråkfamilj bestående av viola, violoncell, violin, flygel förstås – och ovanpå alltihop flyger en flöjt.Turnéplan:Malmberget 16-17 aprilJokkmokk 18 aprilÖverkalix 19 aprilLuleå 22 aprilHaparanda 23 aprilÄlvsbyn 24-25 aprilValiderad; 2013; 20130429 (johsod)</p

Inhibition of 11β-HSD1 activity in intact cells.

<p>(A), Inhibition of 11β-HSD1-dependent cortisol formation in intact HEK-293 cells. HEK-293 cells stably co-expressing human 11β-HSD1 and H6PDH were incubated for 30 min in the presence of 200 nM radiolabeled cortisone and either 1 μM of the positive control inhibitor glycyrrhetinic acid (CTRL 1) or 100 nM and 1 μM of the respective test compounds. Formation of cortisol was determined by separation of steroids by TLC and scintillation counting. Data represent mean ± SD of three independent experiments, each performed in triplicate. (B), Inhibition of 11β-HSD1-dependent cortisol formation in intact human keratinocytes. Primary human keratinocytes were grown for two days, followed by incubation for 24 h with 1 μM of cortisone and various concentrations of inhibitor. Compound CAS 1009373-58-3 (Merck, CTRL 4) was used as positive control. An additional vehicle control was measured in the absence of exogenous cortisone (black bar). Formation of cortisol was determined by an enzyme immune assay. Data represent mean ± SD from three experiments. Shapiro-Wilk test was used to assess the normality of data. One-way analysis of variance (ANOVA) and Dunnett's multiple-comparison test were performed to evaluate differences between inhibitor treatments compared to the solvent control. All values were significantly different (p<0.01) compared to vehicle control in the presence of cortisone, except treatment of keratinocytes with 10 nM <b>2b</b>.</p

Activity of synthesized compounds toward 11β-HSD1 and 11β-HSD2.

<p>Enzyme activity was measured in lysates of HEK-293 cells expressing recombinant human 11β-HSD1 or 11β-HSD2 as described in Materials and Methods. Data represent mean from three independent experiments. nd: not determined.</p

General structure of bi-aryl amide compounds.

<p>General structure of bi-aryl amide compounds.</p

Reversal of cortisone-mediated decrease in dermal total collagen content upon treatment with selected compounds.

<p>Human skin biopsies were treated topically with 4 μL of 10 μM or 100 μM of the selected compounds for 6 days. After the first 24 h of incubation with the inhibitors, the skin samples were simultaneously treated with inhibitor and 100 nM cortisone for the remaining 5 days. Dermal collagen content was semi-quantitatively assessed by Picrosirius Red histochemical staining. Data represent mean ± SEM from 6 human biopsies. Shapiro-Wilk test indicated that the data followed a normal distribution and unpaired t-test was used to test for significant differences. # <i>p</i><0.01 compared to vehicle control in the absence of cortisone; * <i>p</i><0.05, ** <i>p</i><0.01, *** <i>p</i><0.001 compared to cortisone treated vehicle control.</p

Effect of selected compounds on dermal collagen III content in UV exposed human skin samples.

<p>Human skin biopsies were treated topically with 4 μL of 10 μM or 100 μM of compound <b>3e</b> (A,B), <b>2b</b> (C,D), or <b>12e</b> (E,F) and exposed to 3.0 J/cm² (A,C,E) or 6.0 J/cm² UV irradiation (B,D,F) for 6 days. Dermal collagen III expression was detected using a mouse monoclonal anti-collagen III antibody. Data represent mean ± SEM. Per treatment 12 skin samples were analyzed. The data set presented a normal distribution using Shapiro-Wilk test and an unpaired t-test was used to test for significant differences. ## <i>p</i><0.01 for UV exposed vehicle control <i>vs</i> non-irradiated vehicle control. * <i>p</i><0.05, ** <i>p</i><0.01 for UV exposed inhibitor treated <i>vs</i> UV exposed vehicle control.</p

5‑(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)­pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology

Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound <b>1</b> (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for <b>1</b> in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, <b>1</b> did not bind tubulin, which was observed for the structurally related <b>4</b> (BKM120, buparlisib). Compound <b>1</b> is orally available, crosses the blood–brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound <b>1</b> demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound’s safety profile, identifies <b>1</b> as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound <b>1</b> is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma