BTK and PI3K Inhibitors Reveal Synergistic Inhibitory Anti-Tumoral Effects in Canine Diffuse Large B-Cell Lymphoma Cells

Bruton’s tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) in the B-cell receptor (BCR) signaling pathway are considered potential therapeutic targets for the treatment of B-cell lymphomas, among which, diffuse large B-cell lymphoma (DLBCL) is the most common type. Herein, we comparatively evaluated the single and combined application of the BTK inhibitor ibrutinib and the selective PI3Kγ inhibitor AS-605240 in the canine DLBCL cell line CLBL-1. For further comparison, key findings were additionally analyzed in canine B-cell leukemia GL-1 and human DLBCL cell line SU-DHL-4. While ibrutinib alone induced significant anti-proliferative effects on all cell lines in a dose-dependent manner, AS-605240 only induced anti-proliferative effects at high concentrations. Interestingly, ibrutinib and AS-605240 acted synergistically, reducing cell proliferation and increasing apoptosis/necrosis in all cell lines and inducing morphological changes in CLBL-1. Moreover, the combined application of ibrutinib and AS-605240 reduced relative phosphorylation and, in some instances, the levels of the BTK, AKT, GSK3β, and ERK proteins. Comparative variant analysis of RNA-seq data among canine B- and T-lymphoid cell lines and primary B-cell lymphoma samples revealed potentially high-impact somatic variants in the genes that encode PI3K, which may explain why AS-605240 does not singly inhibit the proliferation of cell lines. The combination of ibrutinib and AS-605240 represents a promising approach that warrants further in vivo evaluation in dogs, potentially bearing significant value for the treatment of human DLBCL.     

Total synthesis of tumor inhibiting didemnenone analogues

We have previously described an enantioselective total synthesis of the tumor inhibiting didemnenones 1a , b and 2 . Our investigations reported here shed light on the structure–activity relationships of these natural products. The significantly lower activity found for (3aS*, 6aS*)-3 [(E)-allyliden]-2-oxo-6a-(-hydroxymethyl)-2,3,3a,6a-tetrahydro-4H-cyclo-penta[b]furan]2(3H)-one ( 4 ) supported the hypothesis that the oxonium intermediate 3 is the active species. The strategy of the synthesis of the natural products was used to prepare acceptor substituted analogues (3aS*, 6aS*) [(E)-[3-(4-oxo-pent-2-(E)-enylidene]-6a-(4-hydroxymethyl)-2-methoxy-2,3,3a, 6a-tetrahydro[4H-cyclopenta[b]furan]-4-one ( 18 ) and (3aS*, 6aS*) [(E)-[3-(4-oxo-pent-2-(E)-enylidene]-6a-(4-hydroxymethyl)-2,3,3a,6a-tetrahydro-[4H-cyclopenta[b]furan]-2-(3H)-one ( 20 ). Although there were only moderate structural changes some of the key transformations differed remarkably in yield and general performance from those employed in the former synthesis. Optimization of the synthesis rewardingly led to compounds with increased biological activity against human gastric carcinoma cell-lines.     

Übersicht über numerische Integrationsmethoden für technische Schwingungsprobleme

Zusammenfassung Bei zeitabh?ngigen Belastungen einer technischen Konstruktion treten Schwingungen auf. Um deren zeitlichen Verlauf zu bestimmen, müssen die Bewegungsdifferentialgleichungen eines vereinfachten mechanischen Ersatzsystems gel?st werden. Für die Arbeit mit dem Digitalrechner sind dabei die Methoden der numerischen Integration anzuwenden. Im vorliegenden Text wird zun?chst eine Einführung in Schwingungsprobleme gegeben. Für lineare Schwingungssysteme wird die analytische L?sung zu rechnergerechten Integrationsverfahren aufbereitet. In einem zweiten Teil des Aufsatzes werden die Eigenschaften allgemeiner numerischer Integrationsmethoden er?rtert, mit denen alle zeitabh?ngigen Schwingungsaufgaben, besonders auch nichtlineare, n?herungsweise gel?st werden k?nnen. Für den Anwender von verbreiteten Rechnerprogrammen sowie für den Programmierer selbst werden die Unterschiede der Vorgehensweisen erl?utert, und es terden Kriterien aufgezeigt, nach denen eine Integrationsformel ausgew?hlt werden kann.     

Tuned graft copolymers as controlled coatings for DNA microarrays

DNA microarrays have become a powerful tool for expression profiling and other genomics applications. A critical factor for their sensitivity is the interfacial coating between the chip substrate and the bound DNA. Such a coating has to embrace the divergent requirements of tightly binding the capture probe DNA during the spotting process and of minimizing the nonspecific binding of target DNA during the hybridization assay. To fulfill these conditions, most coatings require a passivation step. Here we demonstrate how the chain density of a graft copolymer with a polycationic backbone, poly(l-lysine)-graft-poly(ethylene glycol), can be tuned such that the binding capacity during capture probe deposition is maximized while the nonspecific binding during hybridization assays is kept to a minimum, thus alleviating the requirement for a separate passivation procedure. Evidence for the superior performance of such coatings in terms of signal-to-noise ratio and spot quality is presented using an evanescent field-based fluorescent sensing technique (the ZeptoREADER). The surface architecture is further characterized using optical waveguide lightmode spectroscopy and time-of-flight secondary ion mass spectrometry. Finally, in a model assay, we demonstrate that expression changes can be detected from 1 microg of total mRNA sample material with a limit of detectable differential expression of +/-1.5.     

Heat transfer phenomenon in the region of dispersed phase injection in a direct-contact liquid-liquid heat exchanger

A novel temperature measurement technique integrated with a high-speed data acquisition system allowed temperature distributions to be obtained in droplets rising in a liquid-liquid, direct-contact heat exchanger. Heat transfer results were computed from the temperature data and were correlated in terms of dimensionless parameters. A significant amount of the total heat transfer in the column occurred in the region near the dispersed phase inlet nozzle where droplet formation and release effects predominated. Heat transfer results are presented and the related droplet hydrodynamics are discussed.     

Chemische Zusammensetzung und Kristallstruktur von Sondercarbiden in warmfesten Cr-Mo- und Cr-Mo-V-Stählen

Entwicklung eines Probentisches, mit dessen Hilfe Untersuchungen von saumförmigen Sondercarbideutektoiden warmfester Cr-Mo- und Cr-Mo-V-Stähle sowie einiger Versuchsschmelzen durchgeführt wurden. Bestimmung von Gitterkonstanten.     

Vorgänge bei der Bildung primärer Desoxydationsprodukte in Stählen

Einfluß der Desoxydation auf den Reinheitsgrad des Stahls. Das Abscheidungsverhalten oxydischer Verunreinigungen. Zweck der Untersuchungen und Versuchsdurchführung unter Anwendung der Vakuumheißextraktion, Mikrosonde und Rückstandsisolierung. Schmelzenführung und Probenahme. Auswertung und Deutung der Versuchsergebnisse. Untersuchung von Einschlüssen durch Ruckstandsuntersuchung.