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Human cytomegalovirus (HCMV) is a pathogenic human herpesvirus associated with serious, potentially life-threatening symptoms in the immunocompromised or immunonaïve host. The limitations encountered by antiviral therapy options currently available include a narrow panel of accessible targets, the induction of viral drug resistance as well as severe drug dosage-mediated side-effects. Improved drug-targeting strategies to resolve these issues are the focus of our investigations. In particular, pharmaceutical kinase inhibitors (PKIs), either directed to host kinases or directed to the viral protein kinase pUL97, have been considered to overcome these restrictions. Recently, we reported the identification of a synergistic combination of two PKIs directed to host cyclin-dependent kinase 7 (CDK7) and viral CDK ortholog pUL97. Here, we substantiate these findings with the following results: (i) true drug synergy was exhibited by various chemical classes of PKI pairs directed to pUL97 and CDK7; (ii) no putative amplification of cytotoxicity by these drug combinations was observed; (iii) a reduction in drug dosage levels for synergistic combinations was defined on a quantitative basis and compared to monotreatments; (iv) the quantities of target proteins CDK7 and pUL97 expressed in HCMV-infected cells were assessed by confocal imaging, indicating a strong down-modulation of CDK7 levels as a result of synergistic drug treatment; (v) the functional importance of these target kinases, both binding to cyclin H, was illustrated by assessing HCMV replication under the viral genomic deletion of ORF-UL97 or cellular cyclin knock-out; (vi) new combinations of HCMV-specific drug synergy were demonstrated for solely host-directed treatments using PKIs against CDK2, CDK7, CDK8 and/or CDK9 and (vii) a triple PKI combination provided further support for the synergy approach. With these combined findings, this study highlights the potential of therapeutic drug combinations of approved, developmental and preclinical PKIs for expanding future options for anti-HCMV therapy.

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Human cytomegalovirus (HCMV) is a major pathogenic herpesvirus that is prevalent worldwide and it is associated with a variety of clinical symptoms. Current antiviral therapy options do not fully satisfy the medical needs; thus, improved drug classes and drug-targeting strategies are required. In particular, host-directed antivirals, including pharmaceutical kinase inhibitors, might help improve the drug qualities. Here, we focused on utilizing PROteolysis TArgeting Chimeras (PROTACs), i.e., hetero-bifunctional molecules containing two elements, namely a target-binding molecule and a proteolysis-inducing element. Specifically, a PROTAC that was based on a cyclin-dependent kinase (CDK) inhibitor, i.e., CDK9-directed PROTAC THAL-SNS032, was analyzed and proved to possess strong anti-HCMV AD169-GFP activity, with values of EC50 of 0.030 µM and CC50 of 0.175 µM (SI of 5.8). Comparing the effect of THAL-SNS032 with its non-PROTAC counterpart SNS032, data indicated a 3.7-fold stronger anti-HCMV efficacy. This antiviral activity, as illustrated for further clinically relevant strains of human and murine CMVs, coincided with the mid-nanomolar concentration range necessary for a drug-induced degradation of the primary (CDK9) and secondary targets (CDK1, CDK2, CDK7). In addition, further antiviral activities were demonstrated, such as the inhibition of SARS-CoV-2 replication, whereas other investigated human viruses (i.e., varicella zoster virus, adenovirus type 2, and Zika virus) were found insensitive. Combined, the antiviral quality of this approach is seen in its (i) mechanistic uniqueness; (ii) future options of combinatorial drug treatment; (iii) potential broad-spectrum activity; and (iv) applicability in clinically relevant antiviral models. These novel data are discussed in light of the current achievements of anti-HCMV drug development.

This letter focuses on both the recent history of academic philosophy in Switzerland and its present status. Historically, institutional self-consciousness of philosophy came to life during World War II as a reaction to the isolation of international academic life in Switzerland; moreover, the divide between philosophy in the French part and the German part of the country had to be bridged. One important instrument to achieve this end was the creation of the “Schweizerische Philosophische Gesellschaft” and its “Jahrbuch” (today: “Studia philosophica”) in 1940. At the same time the creation of the journal “Dialectica” (1947), the influence of Joseph Maria Bochensky at the University of Fribourg and Henri Lauener at the University of Berne prepared the ground for the flourishing of analytic philosophy in Switzerland. Today analytic philosophy has established a very successful academic enterprise in Switzerland without suppressing other philosophical traditions. Despite the fact that academic philosophy is somewhat present in the public, there is much more potential for actual philosophical research to enter into public consciousness. The outline sketched in this letter is, of course, a limited account of the recent history and present state of philosophy in Switzerland. There is only very little research on this topic.

Oxidative damage of biopharmaceuticals during manufacturing and storage is a key concern throughout pharmaceutical development. However, few simple and robust analytical methods are available for the determination of oxidation sites. Here, the potential of affinity capillary electrophoresis (ACE) in the separation of proteins with oxidized methionine (Met) residues is shown. Silver(I) and gold(I) ions have the attribute to selectively form complexes with thioethers over sulfoxides. The addition of these ions to the BGE leads to a selective complexation of Met residues and, thus, to a change of charge allowing separation of species according to the different oxidation states of Met. The mechanisms of these interactions are discussed and binding constants for peptides containing Met with silver(I) are calculated. Additionally, the proposed method can be used as an indicator of oxidative stress in large proteins. The presented technique is easily accessible, economical, and has rapid analysis times, adding new approaches to the analytical toolbox of Met sulfoxide detection.

A fundamental and bold claim of Portmann’s philosophy of biology is a thesis about the autonomy of self-representation (Selbstdarstellung) of all living beings: “Self-presentation has to be understood as a basic fact of life, on a par with self-maintenance and the preservation of the species.” In other words, the perceivable appearance of organisms cannot be reduced to its chemical, physiological, morphological or functional causes, but must be understood as a phenomenon in its own right. The aim of the following contribution is threefold. First, it aims at establishing the relevant context for the bold claim by embedding the claim in Portmann’s broader view of biology. Secondly, it aims at reconstructing Portmann’s rather scattered argument for the bold claim by recasting it as an appeal to what Portmann calls “unaddressed authentic appearances” (unadressierte eigentliche Erscheinungen). Finally, it presents Portmann’s partly phenomenological approach to biological phenomena as a reluctant relative of Goethe’s approach, thereby claiming that Portmann is no advocate of a genuine Goethean science of nature.

Human cytomegalovirus (HCMV) infection is associated with serious pathology such as transplant rejection or embryonic developmental defects. Antiviral treatment with currently available drugs targeting viral enzymes is often accompanied with severe side effects and the occurrence of drug-resistant viruses. For this reason, novel ways of anti-HCMV therapy focusing on so far unexploited small molecules, targets and mechanisms are intensively studied. Recently, we described the pronounced antiviral activity of the artesunate-related class of trioxane compounds, comprising NF-κB/signaling inhibitors like the trimeric derivative TF27, which proved to be highly active in a nanomolar range both in vitro and in vivo. Here, we extend this analysis by presenting further TF27/artesunate-derived antiviral compounds designed for their specific use in target verification by click chemistry applied in fluorescence labeling and tag affinity strategies. Our main findings are as follows: (i) compounds TF27, BG95, AC98 and AC173 exert strong inhibitory activity against HCMV replication in cultured primary human cells, (ii) autofluorescence activity could be quantitatively detected for BG95 and AC98, and confocal fluorescence imaging revealed accumulation in mitochondria, (iii) postulated cellular targets including mitochondrial proteins were down-regulated upon TF27 treatment, (iv) a click chemistry-based protocol of target enrichment was established, and (v) mass spectrometry-based proteomic analysis, using proteins from HCMV-infected fibroblasts covalently interacting with AC173, revealed a refined list of targets. Combined, data strongly suggest a complex mode of antiviral drug-target interaction of artesunate-related compounds, now highlighting potential roles of mitochondrial, NF-κB pathway proteins, exportins and possibly more. This strategy may further promote antiviral drug development on the basis of pharmacologically optimized trioxane derivatives.

Representatives of ethical neo-Aristotelian naturalism (henceforth: Aristotelian naturalism) consider themselves naturalists. The term “naturalism” is notoriously vague, however. We can try to compensate for this vagueness by remarking that Aristotelian naturalism is in favour of biological naturalism rather than physical naturalism. Relying on physics as a reference science to demonstrate that certain human capacities (such as language, thought or morals) are natural and scientifically respectable is quite different from relying on biology. The nature of certain activities becomes fully apparent only if we consider humans as biological beings and not as physical objects. This is one of the fundamental aims of Aristotelian naturalism, and it suggests that Aristotelian naturalism should also be, somehow, biological.

Die Frage, ob die Geistes- und Kulturwissenschaften einen Animal Turn brauchen, lasst sich auf mindestens zwei Wegen einer Antwort zufuhren. Man konnte von einem impliziten Vorverstandnis dessen ausgehen, was der Animal Turn ist, und sich die Frage stellen, was eine solche Wende motiviert oder erforderlich macht. Man konnte aber auch damit beginnen, den Begriff einer Wende zu klaren und auf dieser Grundlage Aussagen daruber treffen, was ein Animal Turn sein musste, wenn er erfolgen sollte.

Purpose Radioiodine has been used for the treatment of benign thyroid diseases for over 70 years. However, internationally, there is no common standard for pretherapeutic dosimetry to optimally define the individual therapy activity. Here, we analyze how absorbed tissue doses are influenced by different approaches to pretherapeutic activity calculation of varying complexity. Methods Pretherapeutic determination of treatment activity was retrospectively recalculated in 666 patients who had undergone radioiodine therapy for benign thyroid diseases (Graves’ disease, non-toxic goiter, and uni- and multinodular goiter). Approaches considering none, some, or all of a set of individual factors, including target volume, maximum radioiodine uptake, and effective half-life, were applied. Assuming individually stable radioiodine kinetics, which had been monitored twice a day under therapy, hypothetically achieved tissue doses based on hypothetically administered activities resulting from the different methods of activity calculation were compared to intended target doses. Results The Marinelli formula yields the smallest deviations of hypothetically achieved doses from intended target doses. Approaches taking individual target volume into consideration perform better than fixed therapy activities, which lead to high variances in achieved doses and high deviations of hypothetically achieved doses from intended target doses. Conclusion Elaborate pretherapeutic dose planning, taking individual radioiodine uptake, half-life, and target volume into consideration, should be used whenever possible. The use of disease-specific fixed activities cannot be recommended. Deviations of achieved tissue doses from target doses can already be significantly lowered by application of volume-adapted treatment activities if more elaborate means are not available.

Adjuvant radioiodine therapy (RITh) for differentiated thyroid carcinoma is performed either with thyroid hormone withdrawal or with administration of recombinant human thyroid-stimulating hormone (rhTSH). Heterogeneous results have been obtained on the impact of the method of patient preparation on thyroid uptake and whole-body effective half-life. A higher radiation exposure using thyroid hormone withdrawal for several weeks compared with rhTSH was reported in prior studies. It was the aim to examine whether these findings are reproducible in a modern protocol with a short interval between surgery and RITh. Methods: A retrospective study was performed on patients admitted for adjuvant RITh for differentiated thyroid carcinoma at the University Hospital of Cologne over a 5-y period from 2010. Dose rate measurements were analyzed for 366 patients, and subgroup analyses were performed for papillary thyroid cancer (n = 341) and follicular thyroid cancer (n = 25) patients, sex, length of hypothyroidism, and normal versus decreased glomerular filtration rate (GFR). Results: The median interval between surgery and RITh was 18 d for thyroid hormone withdrawal and 25 d for rhTSH (P < 0.01). The mean thyroid uptake was 4.2% ± 1.8% for the 300 hypothyroid patients versus 3.8% ± 1.6% (P = 0.12) for the 66 rhTSH patients. Whole-body half-life in the hypothyroid group was significantly longer at 19.3 ± 7.7 h versus 16.4 ± 4.6 h in the rhTSH group (P < 0.01). Results were predominantly influenced by data from the largest subgroup, that is, female papillary thyroid cancer patients. Within this group, whole-body half-life was significantly shorter in the rhTSH treatment arm. Duration of hypothyroidism and a decrease in GFR less than 60 mL/min/1.73 m2 significantly influenced results, with an increased whole-body half-life occurring in the hypothyroid group. When patients returned for whole-body scintigraphy, thyroid, half-life, and whole-body half-life were significantly shorter in the rhTSH groups, resulting in a low thyroid and remaining-body dose. Conclusion: With a shortening of the time between surgery and adjuvant RITh, thyroid uptake is not significantly changed but whole-body half-life becomes longer in the hypothyroid group. Radiation exposure for most patients is not significantly different. However, patients with a hypothyroid phase of more than 4 wk, and in particular those with a decreased GFR, experience higher radiation exposure.

Our aim was to evaluate the benefit of early (1 h post-injection (p.i.)) and late (3 h p.i.) [68Ga]PSMA-HBED-CC positron emission tomography (PET)/x-ray computed tomography (CT) imaging for detection of biochemical recurrence (BCR) of prostate cancer (PCa). Seventy patients with BCR of the PCa and prostate-specific antigen (PSA) levels of less than 2.0 μg/l were subjected to [68Ga]PSMA-HBED-CC PET (mean injected activity 180 MBq). While early imaging contained whole body scans, late imaging was confined to the pelvis and the lower abdomen. Uptake in suspicious lesions was analyzed by peak and maximum standardized uptake values (SUVpeak/max). Tumor-to-background ratios were calculated for all lesions in which the liver served as reference organ. The Wilcoxon matched-pair signed-rank test was used to compare the uptake in suspicious lesions between early and late imaging. Follow-up data were used to validate the existence of the additionally detected lesions. Forty-four of the 70 patients thus examined were interpreted as PSMA-positive in early and/or late scans while 26 remained without suspicion of PSMA tracer uptake. A total of 70 suspicious lesions were analyzed. Ten tumor-suspicious lesions from seven different patients were better or exclusively visible in the late measurements while three tumor-suspicious lesions from three different patients were better or exclusively visible in the early images. A validation by follow-up data was possible for 11 of these 13 additionally detected lesions. In direct comparison between early and late imaging, the mean SUVmax in PSMA-positive lesions was 74 % higher (p

Human cytomegalovirus (HCMV) causes serious and even life-threatening diseases, particularly upon congenital or post-transplant infection. Treatment of HCMV infections with currently available drugs targeting viral enzymes is often limited by severe side effects and the emergence of drug-resistant viruses. To avoid this problem, novel therapeutic options directed to host proteins involved in virus replication are being investigated. Recently, we described the pronounced antiherpesviral activity of the trimeric artesunate derivative TF27 at low nanomolar concentrations in vitro and in vivo. In the present study, we report first data on the prophylactic efficacy of TF27 against human and murine CMV and the oncogenic avian alphaherpesvirus Marek's disease virus (MDV). The main findings of this study are (i) a pronounced activity of the experimental drug TF27 against alpha- and betaherpesviruses in vitro upon prophylactic treatment and (ii) a therapeutic and prophylactic efficacy upon oral treatment in an immunocompetent mouse model. Moreover, our data highlight (iii) the tolerability of orally administered TF27 free of compound-associated adverse events and further confirm (iv) the suitability of cellular factors as primary antiviral targets. Thus, we provide evidence for therapeutic and prophylactic antiherpesviral efficacy of TF27 upon oral treatment in immunocompetent hosts and thereby underline its potential for future antiviral drug development.

Charge heterogeneity profiling is important for the quality control (QC) of biopharmaceuticals. Because of the increasing complexity of these therapeutic entities [1], the development of alternative analytical techniques is needed. In this work, flow‐through partial‐filling affinity capillary electrophoresis (FTPFACE) has been established as a method for the analysis of a mixture of two similar monoclonal antibodies (mAbs). The addition of a specific ligand results in the complexation of one mAb in the co‐formulation, thus changing its migration time in the electric field. This allows the characterization of the charged variants of the non‐shifted mAb without interferences. Adsorption of proteins to the inner capillary wall has been circumvented by rinsing with guanidine hydrochloride before each injection. The presented FTPFACE approach requires only very small amounts of ligands and provides complete comparability with a standard CZE of a single mAb.