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Immune-modulating therapy is a promising therapy for patients with cholangiocarcinoma (CCA). Microsatellite instability (MSI) might be a favorable predictor for treatment response, but comprehensive data on the prevalence of MSI in CCA are missing. The aim of the current study was to determine the prevalence of MSI in a German tertiary care hospital. Formalin-fixed paraffin-embedded tissue samples, obtained in the study period from 2007 to 2015 from patients with CCA undergoing surgical resection with curative intention at Johann Wolfgang Goethe University hospital, were examined. All samples were investigated immunohistochemically for the presence of MSI (expression of MLH1, PMS2, MSH2, and MSH6) as well as by pentaplex polymerase chain reaction for five quasimonomorphic mononucleotide repeats (BAT-25, BAT-26, NR-21, NR-22, and NR-24). In total, 102 patients were included, presenting intrahepatic (n = 35, 34.3%), perihilar (n = 42, 41.2%), and distal CCA (n = 25, 24.5%). In the immunohistochemical analysis, no loss of expression of DNA repair enzymes was observed. In the PCR-based analysis, one out of 102 patients was found to be MSI-high and one out of 102 was found to be MSI-low. Thus, MSI seems to appear rarely in CCA in Germany. This should be considered when planning immune-modulating therapy trials for patients with CCA.
Scores to identify patients at high risk of progression of coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may become instrumental for clinical decision-making and patient management. We used patient data from the multicentre Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) and applied variable selection to develop a simplified scoring system to identify patients at increased risk of critical illness or death. A total of 1946 patients who tested positive for SARS-CoV-2 were included in the initial analysis and assigned to derivation and validation cohorts (n = 1297 and n = 649, respectively). Stability selection from over 100 baseline predictors for the combined endpoint of progression to the critical phase or COVID-19-related death enabled the development of a simplified score consisting of five predictors: C-reactive protein (CRP), age, clinical disease phase (uncomplicated vs. complicated), serum urea, and D-dimer (abbreviated as CAPS-D score). This score yielded an area under the curve (AUC) of 0.81 (95% confidence interval [CI]: 0.77–0.85) in the validation cohort for predicting the combined endpoint within 7 days of diagnosis and 0.81 (95% CI: 0.77–0.85) during full follow-up. We used an additional prospective cohort of 682 patients, diagnosed largely after the “first wave” of the pandemic to validate the predictive accuracy of the score and observed similar results (AUC for the event within 7 days: 0.83 [95% CI: 0.78–0.87]; for full follow-up: 0.82 [95% CI: 0.78–0.86]). An easily applicable score to calculate the risk of COVID-19 progression to critical illness or death was thus established and validated.
Genetic heterogeneity of primary lesion and metastasis in small intestine neuroendocrine tumors
(2018)
Data on intratumoral heterogeneity of small intestine neuroendocrine tumors (SI-NETs) and related liver metastasis are limited. The aim of this study was to characterize genetic heterogeneity of 5 patients with SI-NETs. Therefore, formalin-fixed, paraffin-embedded tissue samples of primary and metastatic lesions as well as benign liver of five patients with synchronously metastasized, well differentiated SI-NETs were analyzed with whole exome sequencing. For one patient, chip based 850k whole DNA methylome analysis was performed of primary and metastatic tumor tissue as well as control tissue. Thereby, 156 single nucleotide variants (SNVs) in 150 genes were identified and amount of mutations per sample ranged from 9–34 (mean 22). The degree of common (0–94%) and private mutations per sample was strongly varying (6–100%). In all patients, copy number variations (CNV) were found and the degree of intratumoral heterogeneity of CNVs corresponded to SNV analysis. DNA methylation analysis of a patient without common SNVs revealed a large overlap of common methylated CpG sites. In conclusion, SI-NET primary and metastatic lesions show a highly varying degree of intratumoral heterogeneity. Driver events might not be detectable with exome analysis only, and further comprehensive studies including whole genome and epigenetic analyses are warranted.
k-MED entwickelte sich von einem fachbezogenen Projekt im Jahr 1999 zu einem e-Learning-Dienstleister mit umfangreichen Lehr-Lernangeboten sowie einer technischen und organisatorischen Infrastruktur für Autoren und Nutzer. Es bietet heute – Mitte 2006 – 5000 Studierenden, v.a. der Humanmedizin, ca. 170 Lernkurse aus 16 medizinischen Fächern. Das Projekt umfasst erfahrenes Fachpersonal und nutzt eine eigene Online-Autorenumgebung sowie eine internetbasierte Lernplattform, deren Funktionalitäten in Abstimmung mit evaluierten Lehr- und Lern-Szenarien ständig weiter entwickelt werden. Die wichtigste Aufgabe ist die Vollversorgung von Bildungseinrichtungen, darunter vor allem medizinische Fakultäten, mit Lehr-Lern- und Kommunikationsinstrumenten. Aktuelle Informationen sind zu finden unter http://www.k-med.org.
The soluble loop BC region guides, but not dictates, the assembly of the transmembrane cytochrome b6
(2017)
Studying folding and assembly of naturally occurring α-helical transmembrane proteins can inspire the design of membrane proteins with defined functions. Thus far, most studies have focused on the role of membrane-integrated protein regions. However, to fully understand folding pathways and stabilization of α–helical membrane proteins, it is vital to also include the role of soluble loops. We have analyzed the impact of interhelical loops on folding, assembly and stability of the heme-containing four-helix bundle transmembrane protein cytochrome b6 that is involved in charge transfer across biomembranes. Cytochrome b6 consists of two transmembrane helical hairpins that sandwich two heme molecules. Our analyses strongly suggest that the loop connecting the helical hairpins is not crucial for positioning the two protein “halves” for proper folding and assembly of the holo-protein. Furthermore, proteolytic removal of any of the remaining two loops, which connect the two transmembrane helices of a hairpin structure, appears to also not crucially effect folding and assembly. Overall, the transmembrane four-helix bundle appears to be mainly stabilized via interhelical interactions in the transmembrane regions, while the soluble loop regions guide assembly and stabilize the holo-protein. The results of this study might steer future strategies aiming at designing heme-binding four-helix bundle structures, involved in transmembrane charge transfer reactions.
We investigate the production of heavy quarks in continuum and bound states in nuclear collisions. Creation rates for free bb and tt quark pairs and for bottomonium and toponium in the ground state are computed at energies of the BNL Relativistic Heavy Ion Collider, CERN Large Hadron Collider (LHC), and Superconducting Super Collider. Central and peripheral heavy-ion collisions are discussed. For top-quark creation we assumed a mass range of 90≤mt≤250 GeV. The creation rate for top quarks in peripheral collisions is estimated to be by a factor 40 to 130 smaller compared with corresponding central collisions. For mt=130 GeV we calculated a creation rate of about 4760 top-quark pairs per day at the LHC (3.5 TeV/nucleon) for Pb-Pb collisions.
A calculation of the vacuum-polarization contribution to the hyperfine splitting for hydrogenlike atoms is presented. The extended nuclear charge distribution is taken into account. For the experimentally interesting case 209Bi82+ we predict a delta-lambda- -1.6 nm shift for the transition wavelength of the ground-state hyperfine splitting.
The development of insecticides requires valid risk assessment procedures to avoid causing harm to beneficial insects and especially to pollinators such as the honeybee Apis mellifera. In addition to testing according to current guidelines designed to detect bee mortality, tests are needed to determine possible sublethal effects interfering with the animal's vitality and behavioral performance. Several methods have been used to detect sublethal effects of different insecticides under laboratory conditions using olfactory conditioning. Furthermore, studies have been conducted on the influence insecticides have on foraging activity and homing ability which require time-consuming visual observation. We tested an experimental design using the radiofrequency identification (RFID) method to monitor the influence of sublethal doses of insecticides on individual honeybee foragers on an automated basis. With electronic readers positioned at the hive entrance and at an artificial food source, we obtained quantifiable data on honeybee foraging behavior. This enabled us to efficiently retrieve detailed information on flight parameters. We compared several groups of bees, fed simultaneously with different dosages of a tested substance. With this experimental approach we monitored the acute effects of sublethal doses of the neonicotinoids imidacloprid (0.15–6 ng/bee) and clothianidin (0.05–2 ng/bee) under field-like circumstances. At field-relevant doses for nectar and pollen no adverse effects were observed for either substance. Both substances led to a significant reduction of foraging activity and to longer foraging flights at doses of ≥0.5 ng/bee (clothianidin) and ≥1.5 ng/bee (imidacloprid) during the first three hours after treatment. This study demonstrates that the RFID-method is an effective way to record short-term alterations in foraging activity after insecticides have been administered once, orally, to individual bees. We contribute further information on the understanding of how honeybees are affected by sublethal doses of insecticides.
Die EU verabschiedete am 21. Mai 1992 die Richtlinie zur Erhaltung der natürlichen Lebensräume sowie der wildlebenden Tiere und Pflanzen, die sogenannte Fauna-Flora-Habitat-Richtlinie (FFH-Richtlinie). Die Mitgliedsstaaten sind seitdem verpflichtet, ein europaweites Netz von besonderen Schutzgebieten zur Erhaltung der biologischen Vielfalt und zur Förderung einer nachhaltigen Entwicklung aufzubauen. In dieses Natura 2000 genannte Netz sind auch die auf der Grundlage der seit 1979 geltenden EU-Vogelschutzrichtlinie gemeldeten Europäischen Vogelschutzgebiete (EU SPA) integriert. Die reichhaltige Naturausstattung Sachsen-Anhalts ermöglichte die Auswahl von 265 FFH-Gebieten und 32 Vogelschutzgebieten (EU SPA). Die Gebiete wurden als „Gebiete von gemeinschaftlicher Bedeutung der kontinentalen und der atlantischen biogeographischen Region“ im Amtsblatt der EU vom 15.01.2008 veröffentlicht. Nach den Vorgaben der FFH- und Vogelschutzrichtlinie sind die Natura 2000-Gebiete nun als besondere Schutzgebiete national zu sichern. Darüber hinaus sind in den besonderen Schutzgebieten geeignete Maßnahmen zu treffen, um die Verschlechterung der natürlichen Lebensräume und der Habitate der Arten, für die die Gebiete ausgewiesen worden sind, zu vermeiden (vgl. Art. 6, Abs. 2 FFH Richtlinie). Alle erforderlichen Maßnahmen sind an den Ansprüchen der in den jeweiligen Gebieten vorkommenden Lebensraumtypen und Arten auszurichten.
Mit dem vorliegenden Sonderheft wird beispielhaft der Verfahrensweg der Ausweisung des Naturschutzgebietes Aland-Elbe-Niederung zur Umsetzung von Natura 2000 im Land Sachsen-Anhalt dokumentiert. Neben der Darstellung der naturräumlichen Situation des Gebietes und seiner naturschutzfachlichen Bedeutung werden insbes. Inhalt und Ablauf des Verwaltungsverfahrens sowie die Lösung der vielfältigen Nutzungskonflikte dargestellt. Dem Heft liegt eine beidseitig bedruckte Schutzgebietskarte des Landes Sachsen-Anhalt im Maßstab 1:250.000 bei. Auf einer Seite sind Schutzgebiete nach internationalem Recht dargestellt. Die zweite Seite der Karte liefert eine aktuelle Zusammenstellung (Stand 31.12.2009) der nach Landesnaturschutzrecht geschützten Gebiete und Objekte. Ein Beiheft mit Namen, Bezeichnung und Größe aller Gebiete komplettiert die Ausgabe.