19 research outputs found
German S3 guideline "actinic keratosis and cutaneous squamous cell carcinoma" â long version of the update 2023
Actinic keratosis (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline âactinic keratosis and cutaneous squamous cell carcinomaâ was updated and expanded by the topics cutanepus squamous cell carcinoma in situ (Bowenâs disease) and actinic cheilitis. This guideline was developed at the highest evidence level (S3) and is aimed at dermatologists, general practitioners, ear nose and throat specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings, as well as other medical specialties, policy makers and insurance funds involved in the diagnosis and treatment of patients with AK and cSCC
New experimental methods of charge density determination
# Inhaltsverzeichnis
Titel i
Inhaltsverzeichnis iii
I Grundlagen 1
1 Einleitung 3
2 Theoretische Grundlagen 7 3 Experimentelle Grundlagen 29 II AminosÀuren
37
4 PrÀparation und Messung 39 5 Asparagin 43 6 GlutaminsÀure 59 7 Lysin
73 8 Prolin 87 9 Serin 103 10 Valin 121 11 Vergleichende Diskussion
der AminosÀuren 133 III Das Antithrombotikum Terbogrel 145
12 Terbogrel 147 Zusammenfassung 171
Summary 173
Literaturverzeichnis 175
Publikationen 183
A Parametertabellen 187# Zusammenfassung
Im Rahmen der vorliegenden Dissertation konnten wichtige methodische
experimentelle Aspekte zur Entwicklung der Ladungsdichtebestimmung beigetragen
werden. Erstmalig konnte der Nachweis erbracht werden, daĂ mit der Kombination
SynchrotronprimÀrstrahlung/CCD-FlÀchendetektion elektronische Eigenschaften
einer Verbindung in kurzer Zeit zugÀnglich sind, deren Genauigkeit
vergleichbar oder höher ist als jene, die mit Punktdetektion erhalten wurden
und wochenlange MeĂzeiten erforderten, was bis zu diesem Zeitpunkt in Frage
gestellt wurde. Dieses Ergebnis eröffnete die Perspektive, einerseits
vergleichende Studien an einer Reihe von Verbindungen einer verwandten Klasse
von MolekĂŒlen vorzunehmen, andererseits erschien es möglich,
Ladungsdichtebestimmungen auch an gröĂeren biologisch relevanten Verbindungen
durchzufĂŒhren. In der vorliegenden Arbeit wurden beide Perspektiven verfolgt.
An sechs AminosĂ€uren wurden umfangreiche Ladungsdichtestudien durchgefĂŒhrt,
die eine vollstÀndige topologische Analyse der Elektronendichte unter
Einbeziehung intra- und intermolekularer Wechselwirkungen beinhalteten. FĂŒr
diese Verbindungsklasse wurde ein hoher Grad an Reproduzierbarkeit und
Transferierbarkeit von atomaren und Gruppeneigenschaften gefunden deren
Varianz sogar noch geringer ist, als jene aus ab initio-Rechnungen mit
unterschiedlichen Methoden und BasissÀtzen. Somit wurde ein experimenteller
Beitrag zur UnterstĂŒtzung der Quantentheorie "Atoms in Molecules" geleistet.
Zudem konnten erstmalig am Beispiel der experimentellen dreidimensionalen
Laplacefunktion feine Ladungsdichtereorganisationen aufgrund schwacher
intermolekularer Wechselwirkungen visualisiert werden und somit Richtungen, in
denen chemische Wechselwirkungen und intermolekulare Erkennungsprozesse
favorisiert sind, bestimmt und charakterisiert werden.
Mit dem Antithrombotikum Terbogrel konnte eine gröĂere biologisch und
pharmakologisch relevante Verbindung ebenfalls mit hoher Genauigkeit
elektronisch charakterisiert werden. Zudem konnte am Beispiel dieses
Wirkstoffes gezeigt werden, daà sogar eine konventionelle Röntgenquelle
zusammen mit flÀchenhafter Detektion, wie sie heutzutage zunehmend zur
Standardausstattung von Forschungslaboratorien gehört, fĂŒr die genaue
experimentelle Ladungsdichtebestimmung gröĂerer MolekĂŒle geeignet ist und
somit diese Methode einem gröĂeren Nutzerkreis zugĂ€nglich wird.
So konnten dank schneller Experimente, deren Zeitbedarf erheblich unter
demjenigen von vergleichbaren ab initio-Rechnungen liegen, quantitative
Ergebnisse auf elektronischem Niveau erhalten werden, wobei eine Zunahme an
Auflösung und Genauigkeit erzielt werden konnte. Neben den hier eingefĂŒhrten
experimentellen BeitrÀgen zur Entwicklung der Ladungsdichtebestimmung trÀgt
die vorliegende Arbeit somit auch zum Molecular Modelling und Drug Design bei.# Summary
Within the framework of the present dissertation important methodological and
experimental aspects could be contributed to the development of charge density
determination. For the first time it could be proven that with the combination
of synchrotron primary radiation/CCD area detection electronic properties are
accessible in a short time and that the accuracy of these properties is
comparable or even superior to that obtained with point detection, requiring
measurement times of several weeks. This has been doubted so far. This result
opened the perspective on the one hand to do comparable studies on a class of
related compounds, on the other hand it seemed possible to perform charge
density studies on larger systems of biological importance. In this thesis
both perspectives were followed.
On six amino acids extensive charge density studies were performed including a
complete topological analysis of the charge density of all the intra- and
intermolecular interactions. For this class of compounds a high degree of
reproducability and transferability of atomic and group properties could be
found. The variance of these properties is even less than the one found when
using ab initio calculations with different methods and basis sets. Therefore
an experimental contribution to support the quantum theory of "Atoms in
Molecules" was given. For the first time fine charge density reorganizations
due to weak intermolecular interactions could be visualized with the help of
the threedimensional experimental Laplacian function and therefore directions
in which chemical interactions are favoured could be located and
characterized.
With the antithrombotic drug Terbogrel it was shown that a larger compound of
biological relevance could be characterized electronically with high accuracy.
In addition, taking the example of this drug, it could be shown that even a
conventional X-ray source combined with area detection, which is getting
nowadays common laboratory equipment, is suitable for charge density
determination of larger molecules und thus opens the method for a larger
community.
Quantitative results on the electronic level could be obtained due to fast
experiments, whose time consumption is far less than that of comparable ab
initio calculations. An enhancement of resolution and accuracy could be
reached. Besides the experimental contribution to the development in charge
density determination introduced here this work also contributes to the fields
of molecular modelling and drug design
Charge Density and Experimental Electrostatic Potentials of Two Penicillin Derivatives
International audienceTwo penicillin derivatives, the active penamecillin and the inactive penamecillin-1beta-sulfoxide, were used to study the relationship between their charge density and their activity. Single crystals of both compounds were measured at the synchrotron beamline F1 at the HASYLAB/DESY, at 100 K and up to resolutions of around 0.4 A. Experimental charge densities were obtained by using the Hansen-Coppens multipole formalism. The cleavage of the amide bond in the beta-lactam ring is of paramount importance in the mechanism of action of penicillins. Topological analysis of this bond in terms of Bader's AIM theory showed that its strength is equal in both compounds; therefore a direct influence of bond strength on the activity can be ruled out. However, the two derivatives differ significantly in their experimental electrostatic potentials. These differences are discussed and provide further insight into the chemistry and activity of penicillins
Topological Properties of the Peptide Bond in Glycyl-L-threonine Dihydrate Based on a Fast Synchrotron/CCD-Diffraction Experiment at 100 K
The charge density of glycyl-L-threonine dihydrate is extracted from a synchrotron data set of 98â405 reflections collected at 100 K with a Bruker CCD area detector up to a resolution of d=0.38 Ă
(sinΞ/λ=1.32 Ă
â1). The data are interpreted in terms of the ârigid pseudoatomâ model. The topology of the experimental density is analyzed and compared with the topology obtained experimentally for the constituting amino acids and to that derived from Hartree-Fock calculations for the isolated molecule. All critical points of the electron density at the covalent and hydrogen bonds, as well as those of the Laplacian, were located, thereby deriving quantitative topological data for the peptide and side chain bonds. Bond topological indices in the dipeptide compare well with those of the corresponding bonds in the building amino acids, thus suggesting transferability of electronic properties of atoms and functional groups when these are derived by Bader's partitioning. Discrepancies between theoretical and experimental results could be attributed to crystal field effects
Schnelle Experimente zur Ladungsdichtebestimmung: topologische Analyse und elektrostatisches Potential der AminosÀuren L-Asn, DL-Glu, DL-Ser und L-Thr
Synchrotronstrahlung und CCD-Detektion ermöglichten schnelle Beugungsexperimente, mit denen genaue Ladungsdichteverteilungen von AminosĂ€uren hergeleitet werden konnten. Ihre topologische Analyse (das Bild zeigt die negative Laplace-Funktion von DL-Serin in der Ebene der Carboxylatgruppe) liefert fĂŒr die AminosĂ€uren nicht nur vergleichbare Informationen ĂŒber intramolekulare, sondern auch ĂŒber schwache intermolekulare Wechselwirkungen
Validation of X-ray Wavefunction Refinement
In this work, the quality of the electron density in crystals reconstructed by the multipolar model (MM) and by X-ray wavefunction refinement (XWR) is tested on a set of high-resolution X-ray diffraction data sets of four amino acids and six tripeptides. It results in the first thorough validation of XWR. Agreement statistics, figures of merit, residual- and deformation-density maps, as well as atomic displacement parameters are used to measure the quality of the reconstruction relative to the measured structure factors. Topological analysis of the reconstructed density is carried out to obtain atomic and bond-topological properties, which are subsequently compared to the values derived from benchmarking periodic DFT geometry optimizations. XWR is simultaneously in better agreement than the MM with both benchmarking theory and the measured diffraction pattern. In particular, the obvious problems with the description of polar bonds in the MM are significantly reduced by using XWR. Similarly, modeling of electron density in the vicinity of hydrogen atoms with XWR is visibly improved
Communication between the ERRalpha homodimer interface and the PGC-1alpha binding surface via the helix 8-9 loop.
International audienceAlthough structural studies on the ligand-binding domain (LBD) have established the general mode of nuclear receptor (NR)/coactivator interaction, determinants of binding specificity are only partially understood. The LBD of estrogen receptor-alpha (ERalpha), for example, interacts only with a region of peroxisome proliferator-activated receptor coactivator (PGC)-1alpha, which contains the canonical LXXLL motif (NR box2), whereas the LBD of estrogen-related receptor-alpha (ERRalpha) also binds efficiently an untypical, LXXYL-containing region (NR box3) of PGC-1alpha. Surprisingly, in a previous structural study, the ERalpha LBD has been observed to bind NR box3 of transcriptional intermediary factor (TIF)-2 untypically via LXXYL, whereas the ERRalpha LBD binds this region of TIF-2 only poorly. Here we present a new crystal structure of the ERRalpha LBD in complex with a PGC-1alpha box3 peptide. In this structure, residues N-terminal of the PGC-1alpha LXXYL motif formed contacts with helix 4, the loop connecting helices 8 and 9, and with the C terminus of the ERRalpha LBD. Interaction studies using wild-type and mutant PGC-1alpha and ERRalpha showed that these contacts are functionally relevant and are required for efficient ERRalpha/PGC-1alpha interaction. Furthermore, a structure comparison between ERRalpha and ERalpha and mutation analyses provided evidence that the helix 8-9 loop, which differs significantly in both nuclear receptors, is a major determinant of coactivator binding specificity. Finally, our results revealed that in ERRalpha the helix 8-9 loop allosterically links the LBD homodimer interface with the coactivator cleft, thus providing a plausible explanation for distinct PGC-1alpha binding to ERRalpha monomers and homodimers
S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma â short version, part 1: diagnosis, interventions for actinic keratoses, care structures and qualityâofâcare indicators
Actinic keratoses (AK) are common lesions in lightâskinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidenceâbased framework for clinical decision making, the guideline âactinic keratosis and cutaneous squamous cell carcinomaâ was developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guideline is aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and officeâbased settings as well as other medical specialties involved in the diagnosis and treatment of patients with AK and cSCC. The guideline is also aimed at affected patients, their relatives, policy makers and insurance funds. In the first part, we will address aspects relating to diagnosis, interventions for AK, care structures and qualityâofâcare indicators.Peer Reviewe