The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients: The Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs

Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome by a combination of three pharmacological agents that improve CFTR channel trafficking and gating, namely, elexacaftor, tezacaftor, and ivacaftor. This study was prompted by the evidence of two CF patients, compound heterozygous for F508del and a minimal function variant, who failed to obtain any beneficial effects following treatment with the triple drug combination. Functional studies on nasal epithelia generated in vitro from these patients confirmed the lack of response to pharmacological treatment. Molecular characterization highlighted the presence of an additional amino acid substitution, L467F, in cis with the F508del variant, demonstrating that both patients were carriers of a complex allele. Functional and biochemical assays in heterologous expression systems demonstrated that the double mutant L467F-F508del has a severely reduced activity, with negligible rescue by CFTR modulators. While further studies are needed to investigate the actual prevalence of the L467F-F508del allele, our results suggest that this complex allele should be taken into consideration as plausible cause in CF patients not responding to CFTR modulators.     

Digital hermeneutics: an outline

The purpose of this paper is to give an outline of digital hermeneutics understood as the encounter between hermeneutics and digital technology, particularly the Internet. In the first part, I want to raise the attention of IT researchers and hermeneuticists to the theoretic and practical relevance of the encounter of their areas of research that are sometimes considered as incompatible to each other. There is still a lot of translation work to be done in order to get these two cultures come closer to and profit from each other. The second part of the paper deals with the foundation of digital hermeneutics on what I call—following Heidegger’s and Vattimo’s paths—digital ontology as opposed to digital metaphysics.     

Ethische Leitlinien der GI

Seit Ihrer Verabschiedung im Jahr 1994 waren die Ethischen Leitlinien der Gesellschaft für Informatik Gegenstand zuweilen kontroverser Diskussionen. Einerseits wurde begrüßt, dass sich die GI verbindlich an ein ethisches Regelwerk bindet und dadurch ihren Mitgliedern einen Leitfaden an die Hand gibt, um in Konfliktsituationen besser entscheiden zu können. Andererseits wurde bemängelt, dass die Ethischen Leitlinien Forderungen stellten, die für professionelles Handeln unabdingbar seien und deshalb keine ethischen Ansprüche darstellten. Des Weiteren wurde kritisiert, dass die Ethischen Leitlinien zu sehr im Abstrakten verharrten und deshalb keine konkrete Handlungsanweisung geben könnten. Die fachlichen und überfachlichen Anforderungen wurden zuweilen als zu anspruchsvoll empfunden. Einige dieser Kritikpunkte sind sicherlich berechtigt.Im November 2001 begann der Arbeitskreis Informatik und Verantwortung im Fachbereich Informatik und Gesellschaft (IuG) mit der Überarbeitung der Ethischen Leitlinien. Der hier vorgelegte Entwurf greift einige dieser Kritikpunkte auf. Seine Publikation soll eine breitere Diskussion innerhalb der GI ermöglichen. Die Autorinnen und Autoren dieses Entwurfs freuen sich auf diese Auseinandersetzung, die in der letzten Sitzung des Arbeitskreises durch den Vertreter der Selbständigen in der GI mit dem Hinweis begonnen wurde, dass den Leitlinien ein Berufsbild zugrunde liegt, in dem die Selbständigen nicht vorkommen.Die anlässlich der Informatik 2003 gegründete Fachgruppe Informatik und Ethik wird sich zu ihrer ersten Aufgabe machen, die Ergebnisse dieser Diskussion in die endgültige Version einfließen zu lassen. Entsprechende Diskussionsbeiträge und Anregungen sollten an Karl-Heinz Rödiger (E-Mail: roediger@informatik.uni-bremen.de), kommissarischer Sprecher der Fachgruppe, gerichtet werden.     

Tailoring brushite for in situ setting bone cements

Current strategies in developing calcium phosphate bone substitutes are focused towards in situ setting of the cements under physiological conditions with adequate mechanical properties, which can be tailored to be resorbable by controlling structure and composition. In this study we report the formulation of brushite cements at both physiological and ambient temperature and its effect on the structure and properties. In addition the influence of using both, an alkaline and acidic retardant on the setting and ageing of the cements are reported. Monosodium citrate (pH 3.5 ± 0.1) or trisodium citrate (pH 8.3 ± 0.1) solutions were used at retardants at 23 °C and 37 °C, which clearly indicated that both these parameters influenced strength and microstructure. The ageing of the cements indicated some conversion to monetite, which was predominant in cements formulated at physiological temperature. The results clearly show that the microstructure, resorbability and strength of these in situ setting cements can be manipulated by compositional and temperature ranges to provide wider application as bone substitute materials.     

A new methodology for the preoperative localization of occult insulinomas

This study describes clinical aspects, treatment, and survival times of 52 dogs with hemangiosarcoma of the spleen, presented at the Department of Veterinary Surgery, University of Munich, Germany. Depending on the dissemination of the disease the dogs were assigned to three clinical stages: 10 dogs were in stage I (tumor confined to the spleen without metastasis), 18 in stage II (tumor confined to the spleen or ruptured, with or without lymph node involvement but without distant metastasis) and 24 in stage III (with distant metastasis). Dogs in stage I displayed mild and nonspecific symptoms. In stage II and II, half of the patients were presented in shock or collapse after an acute rupture of the tumor. Sonographic examination was found superior in diagnosing splenic neoplasia when compared to radiography. Pronounced laboratory abnormalities were present mainly in patients in stages II or III with anemia, leucocytosis, thrombocytopenia and prolonged bleeding times predominating. Survival times following splenectomy were very variable. The median survival time was 100 days. Because of the high standard deviaton there was no statistically significant difference in survival times between animals of different stages.