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The purpose of this phase III clinical trial was to compare two different extracellular contrast agents, 1.0 M gadobutrol and 0.5 M gadopentate dimeglumine, for magnetic resonance imaging (MRI) in patients with known or suspected focal renal lesions. Using a multicenter, single-blind, interindividual, randomized study design, both contrast agents were compared in a total of 471 patients regarding their diagnostic accuracy, sensitivity, and specificity to correctly classify focal lesions of the kidney. To test for noninferiority the diagnostic accuracy rates for both contrast agents were compared with CT results based on a blinded reading. The average diagnostic accuracy across the three blinded readers (‘average reader’) was 83.7% for gadobutrol and 87.3% for gadopentate dimeglumine. The increase in accuracy from precontrast to combined precontrast and postcontrast MRI was 8.0% for gadobutrol and 6.9% for gadopentate dimeglumine. Sensitivity of the average reader was 85.2% for gadobutrol and 88.7% for gadopentate dimeglumine. Specificity of the average reader was 82.1% for gadobutrol and 86.1% for gadopentate dimeglumine. In conclusion, this study documents evidence for the noninferiority of a single i.v. bolus injection of 1.0 M gadobutrol compared with 0.5 M gadopentate dimeglumine in the diagnostic assessment of renal lesions with CE-MRI.
Background: Preoperative radiochemotherapy (RCT) with 5-FU or capecitabine is the standard of care for patients with locally advanced rectal cancer (LARC). Preoperative RCT achieves pathological complete response rates (pCR) of 10-15%. We conducted a single arm phase II study to investigate the feasibility and efficacy of addition of bevacizumab and oxaliplatin to preoperative standard RCT with capecitabine.
Methods: Eligible patients had LARC (cT3-4; N0/1/2, M0/1) and were treated with preoperative RCT prior to planned surgery. Patients received conventionally fractionated radiotherapy (50.4 Gy in 1.8 Gy fractions) and simultaneous chemotherapy with capecitabine 825 mg/m2 bid (d1-14, d22-35) and oxaliplatin 50 mg/m2 (d1, d8, d22, d29). Bevacizumab 5 mg/kg was added on days 1, 15, and 29. The primary study objective was the pCR rate.
Results: 70 patients with LARC (cT3-4; N0/1, M0/1), ECOG < 2, were enrolled at 6 sites from 07/2008 through 02/2010 (median age 61 years [range 39–89], 68% male). At initial diagnosis, 84% of patients had clinical stage T3, 62% of patients had nodal involvement and 83% of patients were M0. Mean tumor distance from anal verge was 5.92 cm (± 3.68). 58 patients received the complete RCT (full dose RT and full dose of all chemotherapy). During preoperative treatment, grade 3 or 4 toxicities were experienced by 6 and 2 patients, respectively: grade 4 diarrhea and nausea in one patient (1.4%), respectively, grade 3 diarrhea in 2 patients (3%), grade 3 obstipation, anal abscess, anaphylactic reaction, leucopenia and neutropenia in one patient (1.4%), respectively. In total, 30 patients (46%) developed postoperative complications of any grade including one gastrointestinal perforation in one patient (2%), wound-healing problems in 7 patients (11%) and bleedings in 2 patients (3%). pCR was observed in 12/69 (17.4%) patients. Pathological downstaging (ypT < cT and ypN ≤ cN) was achieved in 31 of 69 patients (44.9%). All of the 66 operated patients had a R0 resection. 47 patients (68.1%) underwent sphincter preserving surgery.
Conclusions: The addition of bevacizumab and oxaliplatin to RCT with capecitabine was well tolerated and did not increase perioperative morbidity or mortality. However, the pCR rate was not improved in comparison to other trials that used capecitabine or capecitabine/oxaliplatin in preoperative radiochemotherapy.
Rezensionen [2018]
(2018)
Verzeichnis
Einzelrezensionen
154 Beauvais, Clémentine: The Mighty Child. Time and Power in Children’s Literature (Thomas Kullmann)
155 Dean-Ruzicka, Rachel: Tolerance Discourse and Young Adult Holocaust Literature. Engaging Difference and Identity (Susanne Blumesberger)
157 Dolle-Weinkauff, Bernd (Hrsg.): Geschichte im Comic. Befunde – Theorien – Erzählweisen (Caroline Wittig)
159 Ewers, Hans-Heino (Hrsg.): Erster Weltkrieg: Kindheit, Jugend und Literatur. Deutschland, Österreich, Osteuropa, England, Belgien und Frankreich (Kurt Franz)
161 Franz, Kurt / Lange, Günter (Hrsg.): Der Stoff, aus dem Geschichten sind. Intertextualität im Werk Otfried Preußlers (sabine fuchs)
163 Glasenapp, Gabriele von/Kagelmann, Andre/Giesa, Felix (Hrsg.): Die Zeitalter werden besichtigt. Aktuelle Tendenzen der Kinder- und Jugendliteraturforschung. Festschrift für Otto Brunken (Karin Richter)
165 Josting, Petra/Schmideler, Sebastian (Hrsg.): Bonsels’ Tierleben. Insekten und Kriechtiere in Kinder- und Jugendmedien (Kurt Franz)
167 Kriegleder, Wynfrid/ Lexe, Heidi / Loidl, Sonja/ Seibert, Ernst (Hrsg.): Jugendliteratur im Kontext von Jugendkultur (Lena Hoffmann)
169 Kurwinkel, Tobias: Bilderbuchanalyse. Narrativik – Ästhetik – Didaktik (Annette Kliewer)
171 Langenhorst, Georg/Naurath, Elisabeth (Hrsg.): Kindertora – Kinderbibel – Kinderkoran. Neue Chancen für (inter-)religiöses Lernen (Renate Grubert)
172 Lathey, Gillian: Translating Children’s Literature (heike Elisabeth Jüngst)
174 Mairbäurl, Gunda/Seibert, Ernst (Hrsg.): Kulturelle Austauschprozesse in der Kinder- und Jugendliteratur. Zur genrespezifischen Transformation von Themen, Stoffen und Motiven im medialen Kontext (Sarah Terhorst)
176 Maiwald, Klaus /Meyer, Anna-Maria/Pecher, Claudia Maria (Hrsg.): »Klassiker« des Kinderund Jugendfilms (Michael Stierstorfer)
177 Mills, Claudia (Hrsg.): Ethics in Children’s Literature (Thomas Kullmann)
179 Nast, Mirjam: »Perry Rhodan« lesen. Zur Serialität der Lektürepraktiken einer Heftromanserie (Wolfgang Biesterfeld)
181 O’Sullivan, Emer / Immel, Andrea (Hrsg.): Imagining Sameness and Difference in Children’s Literature. From the Enlightenment to the Present Day (Iris Schäfer)
182 Oetken, Mareile: Wie Bilderbücher erzählen. Analysen multimodaler Strukturen und bimedialen Erzählens im Bilderbuch (Katharina Egerer)
184 Schmideler, Sebastian (Hrsg.): Wissensvermittlung in der Kinder- und Jugendliteratur der DDR. Themen, Formen, Strukturen, Illustrationen (Sabine Planka)
186 Standke, Jan (Hrsg.): Wolfgang Herrndorf lesen. Beiträge zur Didaktik der deutschsprachigen Gegenwartsliteratur (Sabine Planka)
187 Viel, Bernhard: Der Honigsammler. Waldemar Bonsels, Vater der Biene Maja. Eine Biografie (Renate Grubert)
189 Zellerhoff, Rita: Komplexe sprachliche Strukturen in der Jugendliteratur. Aufgezeigt an Beispielen preisgekrönter Werke der Jugendjury des Deutschen Jugendliteraturpreises (Susanne Riegler)
Sammelrezensionen
191 Anker, Martin u.a. (Hrsg.): Grimms Märchenwelten im Bilderbuch. Beiträge zur Entwicklung des Märchenbilderbuches seit Mitte des 20. Jahrhunderts. – Brinker-von der Heyde, Claudia u. a. (Hrsg.): Märchen, Mythen und Moderne. 200 Jahre Kinder- und Hausmärchen der Brüder Grimm. – Joosen, Vanessa/ Lathey, Gillian (Hrsg.): Grimms’ Tales around the Globe. The Dynamics of their International Reception (Thomas Bitterlich)
194 Böhm, Kerstin: Archaisierung und Pinkifizierung. Mythen von Weiblichkeit und Männlichkeit in der Kinder- und Jugendliteratur. – Dangendorf, Sarah: Kleine Mädchen in High Heels. Über die visuelle Sexualisierung frühadoleszenter Mädchen (Annette Kliewer)
197 Gordon, Ian: Kid Comic Strips. A Genre Across Four Countries. – Kupczynska, Kalina/Renata Makarska (Hrsg.): Comic in Polen. Polen im Comic. – Kutch, Lynn Marie (Hrsg.): Novel Perspectives on German-Language Comics Studies. History, Pedagogy, Theory. – Reddition. Zeitschrift für Graphische Literatur (66) 2017: Ein halbes Jahrhundert Carlsen Comics. – Rosenfeldt, Reginald: ComicPioniere. Die deutschen Comic-Künstler der 1950er Jahre (Felix Giesa)
The proton drip-line nucleus 17Ne is investigated experimentally in order to determine its two-proton halo character. A fully exclusive measurement of the 17Ne(p, 2p)16F∗ →15O+p quasi-free one-proton knockout reaction has been performed at GSI at around 500 MeV/nucleon beam energy. All particles resulting from the scattering process have been detected. The relevant reconstructed quantities are the angles of the two protons scattered in quasi-elastic kinematics, the decay of 16F into 15O (including γ decays from excited states) and a proton, as well as the 15O+p relative-energy spectrum and the 16F momentum distributions. The latter two quantities allow an independent and consistent determination of the fractions of l = 0 and l = 2 motion of the valence protons in 17Ne. With a resulting relatively small l = 0 component of only around 35(3)%, it is concluded that 17Ne exhibits a rather modest halo character only. The quantitative agreement of the two values deduced from the energy spectrum and the momentum distributions supports the theoretical treatment of the calculation of momentum distributions after quasi-free knockout reactions at high energies by taking into account distortions based on the Glauber theory. Moreover, the experimental data allow the separation of valence-proton knockout and knockout from the 15O core. The latter process contributes with 11.8(3.1) mb around 40% to the total proton-knockout cross section of 30.3(2.3) mb, which explains previously reported contradicting conclusions derived from inclusive cross sections.
New experimental data for dissociation of relativistic 17Ne projectiles incident on targets of lead, carbon, and polyethylene targets at GSI are presented. Special attention is paid to the excitation and decay of narrow resonant states in 17Ne. Distributions of internal energy in the three-body system have been determined together with angular and partial-energy correlations between the decay products in different energy regions. The analysis was done using existing experimental data on 17Ne and its mirror nucleus 17N. The isobaric multiplet mass equation is used for assignment of observed resonances and their spins and parities. A combination of data from the heavy and light targets yielded cross sections and transition probabilities for the Coulomb excitations of the narrow resonant states. The resulting transition probabilities provide information relevant for a better understanding of the 17Ne structure.
Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.
"Nichts ist variabler als die Bedeutung des Wortes Variabilität", meint Hugo de Vries 1901; und kaum etwas so mutabel wie die des Wortes 'Mutation'. Aber was heißt das schon? Weil wir, so Ludwik Fleck, "fortwährend Zeugen sind, wie 'Mutationen' des Denkstils eintreten"? Fleck führt 1935 die Mutationen ein, als er beschreibt, wie aus "Urideen" moderne Begrifflichkeit entsteht, indem etwa "[m]it einem Mal [...] unklar [wurde], was Art, was Individuum sein soll [...]." Sein wissensgeschichtlicher Bezug auf den seinerzeit bereits biologisch ausgewiesenen Begriff konzediert jedoch selbst einen Denkstil, demnach Erkenntnisse der Wissenschaften vom Leben, namentlich der Mutationstheorie, dazu taugen, kulturelle Entwicklungen zu kennzeichnen. Damit steht er freilich seinerzeit nicht allein. Soziologen, Historiker, Anthropologen, Literaturwissenschaftler und eben auch historische Epistemologen hatten sich dem Begriff der Mutation bereits massiv zugewandt. Maßgeblich nach Hugo de Vries' 'Die Mutationstheorie' (1901/1903) kehren plötzliche Wandlungen in der Konzeption von längeren Entwicklungsverläufen vermehrt in die Natur- und Geisteswissenschaften ein und stellen die Kontinuität von Arten, Ideen, Begriffen zur Disposition. Doch besieht man die Machart des Begriffs in diesem für die Mutationsforschung konstitutiven Buch, so zeigen sich statt einer sprunghaften begrifflichen Neubildung tatsächlich imposante historische Allianzen und intentionale, performative Umwertungen, die eben nicht jählings auf kollektiver Ebene, sondern auch durch einzelne Begriffsautoren einigermaßen aufwändig in einen 'neuen' Begriff überführt werden.
Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0–T1: +3.37±2.17%), while non-responders further decreased in methylation (−2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02–0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.
Die Interaktionen von DNA mit Umwelt, die Kopplungen zwischen biologischen Prozessen und mentaler Erfahrung, deren mögliche Vererbbarkeit sowie das Aufzeigen der potentiellen Reversibilität von "krankhaften" Entwicklungen innerhalb solcher Wechselspiele bilden Faszinationen, die jenseits der molekularbiologischen Labore das öffentliche Interesse entzündet haben. Diese Faszinationen sollen hier im Mittelpunkt stehen. Denn fast unvermeidlich verfallen die Forschungsbefunde einem Deutungsanspruch auf Humankultur, auf einen Bereich, der zunächst einmal jenseits der konkreten Forschung liegt und weit über diesen hinaus zeigt. Die folgende Mischung aus Glosse und Essay zur epigenetischen Weltbildproduktion – höher kann der Anspruch angesichts einer unabgeschlossenen, derzeit noch emergierenden Publizistik nicht sein – hat mehrere Teile. Die beiden ersten sind dem Auftritt der Epigenetik in der Öffentlichkeit gewidmet: Zuerst in einer impressionistischen Bestandsaufnahme der diesbezüglichen Publizistik, danach, um einen prominenten Bildbereich festzuhalten, wie er sich in der öffentlichen Diskussion der Epigenetik sedimentiert hat. Die darauf folgenden Teile widmen sich dem Emporkommen einer molekularen Vergemeinschaftungsrhetorik. Abschließend soll kurz die soteriologische Hoffnung erörtert werden, mit welcher der epigenetischen Forschung zumindest in ausgewählten theologischen Diskursen begegnet wird.
Die in der Neuzeit so auf Universalität abzielende Neubewertung der Geste erscheint in komprimierter Form in den Schriften des Londoner Arztes John Bulwer, der in vielerlei Hinsicht weniger einen radikalen Neuansatz als eine Synthese zeitgenössischer psychophysiologischer Gebärdentheorien vorlegt. Seine Erstschrift Chirologia: or the Naturall Language of the Hand, Composed of the Speaking Motions, and Discoursing Gestures thereof (1644), veröffentlicht im Kontext einer in England zur Mitte des 17. Jahrhunderts bereits blühenden Suche nach einer universalen Sprache, offenbart noch die Nähe zur Rhetorik und der ihr inbegriffenen Affektlehre als Deutungsmuster der Gebärde; und in der Tat ist, wenngleich unter separater Paginierung, diesem Buch ein zweites Buch zur Chironomia angefügt, welches sich explizit mit der Geste als rhetorischem Mittel befasst. Zuvor nimmt Bulwers Chirologia allerdings Anregungen Ciceros, Quintilians und vor allem Giovanni Bonifacios auf und verabsolutiert die Geste selbst zum Universal: "It speakes all languages, and as an universall character of Reason, is generally understood and knowne by all Nations, among all formal differences of their Tongue."
Zu Karl dem Kühnen gibt es sowohl einen Berner Bezug als auch einen Malte-Bezug. Der Schweizer oder Berner Bezug ist, daß der "Fall" Karls des Kühnen, sein "Untergang", wie es in den "Aufzeichnungen des Malte Laurids Brigge" heißt, entscheidend
vorbereitet wurde durch zwei Schlachten, die er gegen die Eidgenossen verloren hatte, bei Grandson und Murten, nicht weit von Bern, beide 1476. Im "Malte Laurids Brigge" spielen diese Schlachten zwar keine Rolle (auch die Schlacht
bei Nancy, von Anfang Januar 1477, die den Fall und den Tod Karls brachte, interessiert nur in ihren Folgen), es wird aber mit den "Hörnern von Uri" auf diese Ereignisse und deren zentrale Bedeutung angespielt. Der zweite Schweizer oder
Berner Bezug sind die Teile der Burgunder Beute, die mit dem Lager der Feinde bei Grandson in die Hände der Sieger gefallen waren und die zum Teil im Historischen Museum in Bern aufbewahrt werden.
While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.
The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.
We report here the nuclear magnetic resonance 19F screening of 14 RNA targets with different secondary and tertiary structure to systematically assess the druggability of RNAs. Our RNA targets include representative bacterial riboswitches that naturally bind with nanomolar affinity and high specificity to cellular metabolites of low molecular weight. Based on counter-screens against five DNAs and five proteins, we can show that RNA can be specifically targeted. To demonstrate the quality of the initial fragment library that has been designed for easy follow-up chemistry, we further show how to increase binding affinity from an initial fragment hit by chemistry that links the identified fragment to the intercalator acridine. Thus, we achieve low-micromolar binding affinity without losing binding specificity between two different terminator structures.
The cell division cycle protein 37 (Cdc37) and the 90-kDa heat shock protein (Hsp90) are molecular chaperones, which are crucial elements in the protein signaling pathway. The largest class of client proteins for Cdc37 and Hsp90 are protein kinases. The catalytic domains of these kinases are stabilized by Cdc37, and their proper folding and functioning is dependent on Hsp90. Here, we present the x-ray crystal structure of the 16-kDa middle domain of human Cdc37 at 1.88 angstroms resolution and the structure of this domain in complex with the 23-kDa N-terminal domain of human Hsp90 based on heteronuclear solution state NMR data and docking. Our results demonstrate that the middle domain of Cdc37 exists as a monomer. NMR and mutagenesis experiments reveal Leu-205 in Cdc37 as a key residue enabling complex formation. These findings can be very useful in the development of small molecule inhibitors against cancer.
Background: The angiogenic function of endothelial cells is regulated by numerous mechanisms, but the impact of long noncoding RNAs (lncRNAs) has hardly been studied. We set out to identify novel and functionally important endothelial lncRNAs.
Methods: Epigenetically controlled lncRNAs in human umbilical vein endothelial cells were searched by exon-array analysis after knockdown of the histone demethylase JARID1B. Molecular mechanisms were investigated by RNA pulldown and immunoprecipitation, mass spectrometry, microarray, several knockdown approaches, CRISPR-Cas9, assay for transposase-accessible chromatin sequencing, and chromatin immunoprecipitation in human umbilical vein endothelial cells. Patient samples from lung and tumors were studied for MANTIS expression.
Results: A search for epigenetically controlled endothelial lncRNAs yielded lncRNA n342419, here termed MANTIS, as the most strongly regulated lncRNA. Controlled by the histone demethylase JARID1B, MANTIS was downregulated in patients with idiopathic pulmonary arterial hypertension and in rats treated with monocrotaline, whereas it was upregulated in carotid arteries of Macaca fascicularis subjected to atherosclerosis regression diet, and in endothelial cells isolated from human glioblastoma patients. CRISPR/Cas9-mediated deletion or silencing of MANTIS with small interfering RNAs or GapmeRs inhibited angiogenic sprouting and alignment of endothelial cells in response to shear stress. Mechanistically, the nuclear-localized MANTIS lncRNA interacted with BRG1, the catalytic subunit of the switch/sucrose nonfermentable chromatin-remodeling complex. This interaction was required for nucleosome remodeling by keeping the ATPase function of BRG1 active. Thereby, the transcription of key endothelial genes such as SOX18, SMAD6, and COUP-TFII was regulated by ensuring efficient RNA polymerase II machinery binding.
Conclusion: MANTIS is a differentially regulated novel lncRNA facilitating endothelial angiogenic function.