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A toolbox for the generation of chemical probes for Baculovirus IAP Repeat containing proteins
(2022)
E3 ligases constitute a large and diverse family of proteins that play a central role in regulating protein homeostasis by recruiting substrate proteins via recruitment domains to the proteasomal degradation machinery. Small molecules can either inhibit, modulate or hijack E3 function. The latter class of small molecules led to the development of selective protein degraders, such as PROTACs (PROteolysis TArgeting Chimeras), that recruit protein targets to the ubiquitin system leading to a new class of pharmacologically active drugs and to new therapeutic options. Recent efforts have focused on the E3 family of Baculovirus IAP Repeat (BIR) domains that comprise a structurally conserved but diverse 70 amino acid long protein interaction domain. In the human proteome, 16 BIR domains have been identified, among them promising drug targets such as the Inhibitors of Apoptosis (IAP) family, that typically contain three BIR domains (BIR1, BIR2, and BIR3). To date, this target area lacks assay tools that would allow comprehensive evaluation of inhibitor selectivity. As a consequence, the selectivity of current BIR domain targeting inhibitors is unknown. To this end, we developed assays that allow determination of inhibitor selectivity in vitro as well as in cellulo. Using this toolbox, we have characterized available BIR domain inhibitors. The characterized chemical starting points and selectivity data will be the basis for the generation of new chemical probes for IAP proteins with well-characterized mode of action and provide the basis for future drug discovery efforts and the development of PROTACs and molecular glues.
Non-alcoholic steatohepatitis (NASH) - a hepatic manifestation of the metabolic syndrome - is a multifactorial disease with alarming global prevalence. It involves steatosis, inflammation and fibrosis in the liver, thus demanding multiple modes of action for robust therapeutic efficacy. Aiming to fuse complementary validated anti-NASH strategies in a single molecule, we have designed and systematically optimized a scaffold for triple activation of farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR) α and PPARδ. Pilot profiling of the resulting triple modulator demonstrated target engagement in native cellular settings and in mice, rendering it a suitable tool to probe the triple modulator concept in vivo. In DIO NASH in mice, the triple agonist counteracted hepatic inflammation and reversed hepatic fibrosis highlighting the potential of designed polypharmacology in NASH.
Six p53 wild-type cancer cell lines from infrequently p53-mutated entities (neuroblastoma, rhabdomyosarcoma, and melanoma) were continuously exposed to increasing concentrations of the murine double minute 2 inhibitor nutlin-3, resulting in the emergence of nutlin-3-resistant, p53-mutated sublines displaying a multi-drug resistance phenotype. Only 2 out of 28 sublines adapted to various cytotoxic drugs harboured p53 mutations. Nutlin-3-adapted UKF-NB-3 cells (UKF-NB-3rNutlin10 μM, harbouring a G245C mutation) were also radiation resistant. Analysis of UKF-NB-3 and UKF-NB-3rNutlin10 μM cells by RNA interference experiments and lentiviral transduction of wild-type p53 into p53-mutated UKF-NB-3rNutlin10 μM cells revealed that the loss of p53 function contributes to the multi-drug resistance of UKF-NB-3rNutlin10 μM cells. Bioinformatics PANTHER pathway analysis based on microarray measurements of mRNA abundance indicated a substantial overlap in the signalling pathways differentially regulated between UKF-NB-3rNutlin10 μM and UKF-NB-3 and between UKF-NB-3 and its cisplatin-, doxorubicin-, or vincristine-resistant sublines. Repeated nutlin-3 adaptation of neuroblastoma cells resulted in sublines harbouring various p53 mutations with high frequency. A p53 wild-type single cell-derived UKF-NB-3 clone was adapted to nutlin-3 in independent experiments. Eight out of ten resulting sublines were p53-mutated harbouring six different p53 mutations. This indicates that nutlin-3 induces de novo p53 mutations not initially present in the original cell population. Therefore, nutlin-3-treated cancer patients should be carefully monitored for the emergence of p53-mutated, multi-drug-resistant cells.
Background: Multimorbidity is a common phenomenon in primary care. Until now, no clinical guidelines for multimorbidity exist. For the development of these guidelines, it is necessary to know whether or not patients are aware of their diseases and to what extent they agree with their doctor. The objectives of this paper are to analyze the agreement of self-reported and general practitioner-reported chronic conditions among multimorbid patients in primary care, and to discover which patient characteristics are associated with positive agreement.
Methods: The MultiCare Cohort Study is a multicenter, prospective, observational cohort study of 3,189 multimorbid patients, ages 65 to 85. Data was collected in personal interviews with patients and GPs. The prevalence proportions for 32 diagnosis groups, kappa coefficients and proportions of specific agreement were calculated in order to examine the agreement of patient self-reported and general practitioner-reported chronic conditions. Logistic regression models were calculated to analyze which patient characteristics can be associated with positive agreement.
Results: We identified four chronic conditions with good agreement (e.g. diabetes mellitus κ = 0.80;PA = 0,87), seven with moderate agreement (e.g. cerebral ischemia/chronic stroke κ = 0.55;PA = 0.60), seventeen with fair agreement (e.g. cardiac insufficiency κ = 0.24;PA = 0.36) and four with poor agreement (e.g. gynecological problems κ = 0.05;PA = 0.10).Factors associated with positive agreement concerning different chronic diseases were sex, age, education, income, disease count, depression, EQ VAS score and nursing care dependency. For example: Women had higher odds ratios for positive agreement with their GP regarding osteoporosis (OR = 7.16). The odds ratios for positive agreement increase with increasing multimorbidity in almost all of the observed chronic conditions (OR = 1.22-2.41).
Conclusions: For multimorbidity research, the knowledge of diseases with high disagreement levels between the patients' perceived illnesses and their physicians' reports is important. The analysis shows that different patient characteristics have an impact on the agreement. Findings from this study should be included in the development of clinical guidelines for multimorbidity aiming to optimize health care. Further research is needed to identify more reasons for disagreement and their consequences in health care.
Background: Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (Ph + ALL) are caused by the t(9;22), which fuses BCR to ABL resulting in deregulated ABL-tyrosine kinase activity. The constitutively activated BCR/ABL-kinase "escapes" the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. The ABL-kinase inhibitors (AKIs) Imatinib, Nilotinib or Dasatinib, which target the ATP-binding site, are effective in Ph + leukemia. Another molecular therapy approach targeting BCR/ABL restores allosteric inhibition. Given the fact that all AKIs fail to inhibit BCR/ABL harboring the 'gatekeeper' mutation T315I, we investigated the effects of AKIs in combination with the allosteric inhibitor GNF2 in Ph + leukemia.
Methods: The efficacy of this approach on the leukemogenic potential of BCR/ABL was studied in Ba/F3 cells, primary murine bone marrow cells, and untransformed Rat-1 fibroblasts expressing BCR/ABL or BCR/ABL-T315I as well as in patient-derived long-term cultures (PDLTC) from Ph + ALL-patients.
Results: Here, we show that GNF-2 increased the effects of AKIs on unmutated BCR/ABL. Interestingly, the combination of Dasatinib and GNF-2 overcame resistance of BCR/ABL-T315I in all models used in a synergistic manner.
Conclusions: Our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants using a combination of AKIs and allosteric inhibitors.
In light of increasing division of labour in healthcare, the training and acquisition of both profession-specific and interprofessional competencies have been attributed growing significance, creating the need to test and establish specific teaching formats. Despite ever more complex and interconnected healthcare systems, an increase in patients’ active self-responsibility and innumerable pedagogical and technological innovations, educational systems have not reacted adequately to these new demands. Many authors, not lease the German Council of Science and Humanities, have therefore urged a rethinking of traditional medical education. Student-centred learning activities, such as problem-based and research-based learning, are becoming increasingly significant in view of the numbers of students achieving unsatisfactory levels of competence in critical thinking, communication and writing abilities and complex clinical decision making, for example. The Council of Science and Humanities arrived at a positive evaluation of the various model and reformed courses of study attempting to effectuate a comprehensive reorganisation of medical studies in content and structure as well as methods and didactics. The persistent pervasiveness of instructor-centred learning formats is not only to be found in medical education but in all of the health professions. Although alternative teaching and instruction formats have already been designed and their effectiveness deemed positive in empirical evaluation, the lecture remains the most practised means of transmitting knowledge. In its essence, however, learning is not a question of transmitting information but, moreover, a question of processing information. In traditional instruction units, referred to as “chalk and talk classes” by Becker and Watts, the teaching party presents material in the form of a lecture. As appropriate, questions may be permitted or short processing periods for the students may be integrated into the lecture. The knowledge-assimilating and most essential analysis of the lecture’s contents takes place in the subsequent self-instruction phase, in which the student works alone on concrete tasks. It is during the transfer of knowledge conveyed in the lectures, however, that most questions arise. Of further disadvantage in the traditional lecture is the low level of motivation among students to attend lectures as well as their often heterogeneous knowledge. The Inverted Classroom Model seems to be an eligible instrument for greater facilitation of student-centred and interprofessional learning.
Background: Establishing a strong link early on between preclinical coursework and the clinical context is necessary for students to be able to recognize the practical relevance of the curriculum during their preclinical anatomical courses and to transfer knowledge more easily. Our objective was to enhance the clinical relevance of a preclinical anatomy course for second-year medical students of dentistry by implementing an interdisciplinary skills training course on "Palpation of the Head and Neck Muscles" and to measure the learning outcomes.
Methods: For the curricular development of the expanded course module, Kern’s 6-step approach was applied including subjective evaluation. We used a peer-teaching format supported by an e-learning application. A randomized control study measured effects of the two components (skills training, e-module) on learning outcomes. Four learning methods were compared: (1) lecture, (2) lecture + e-module, (3) lecture + skills training, (4) lecture + skills training + e-module. An objective structured clinical examination (OSCE) was used to measure and compare learning outcomes.
Results: The two-way variance analysis demonstrated that participation in the skills training had a statistically significant effect on the OSCE results (p = 0.0007). Students who participated in the skills training did better (φ 107.4 ± 14.4 points) than students who only attended the lecture (φ 88.8 ± 26.2 points). Students who used the e-module but did not attend the skills training earned a slightly but not significantly higher average number of points (φ 91.8 ± 31.3 points) than those who only attended the lecture. The learning outcomes of the skills training were again significantly increased when the training was combined with the e-module (φ 121.8 ± 21.8 points), thus making it the ideal method for achieving the learning objectives defined in this study.
Conclusions: The "Palpation of the Head and Neck Muscles" interdisciplinary skills training course linking basic anatomical knowledge and clinical skills led to clearly improved learning outcomes for both, anatomical knowledge and clinical skills. The additional use of an e-learning tool (e-module) improved the learning effect.
Zwei traditionelle Wirkungsbereiche von Intellektuellen, die politische Medienöffentlichkeit und das akademische Feld, unterliegen seit über drei Jahrzehnten anhaltenden strukturellen Veränderungen. Diese gelten vielfach als Ursache einer tiefen Krise oder sogar des Verschwindens der Intellektuellen. Doch um welche Veränderungen geht es dabei genau, und wie restrukturieren sie die gegenwärtige Rolle und Funktion von Intellektuellen? Zur Beantwortung dieser Fragen entwickelt der Beitrag einen Ansatz, der die struktur- und erfahrungsbezogenen Bedingungen intellektueller Praxis fokussiert und historisch vergleichend analysiert. Um eine Vergleichsfolie zu gewinnen, wird die intellektuelle Praxis Theodor W. Adornos analysiert. Dabei zeigt sich, dass Adorno die charakteristischen Widersprüche öffentlichen und akademischen intellektuellen Engagements methodisch aufrechterhielt, indem er eine Position des „Dazwischen“ reklamierte. Vor diesem Hintergrund werden seit den 1970er-Jahren forcierte strukturelle Veränderungen der Medienöffentlichkeit und des akademischen Feldes als Prozesse der „Vereindeutigung“ interpretiert, die eine widerspruchsaffine intellektuelle Praxis erschweren. In der Folge lassen sich eine ausgeweitete kommerzielle sowie eine eingeschränkte akademische Intellektuellenpraxis beobachten, die jeweils politisch wirksame Interventionen begrenzen.
Background: Patients with Ph-negative myeloproliferative neoplasms (MPN), such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are at increased risk for thrombosis/thromboembolism and major bleeding. Due to the morbidity and mortality of these events, antiplatelet and/or anticoagulant agents are commonly employed as primary and/or secondary prophylaxis. On the other hand, disease-related bleeding complications (i.e., from esophageal varices) are common in patients with MPN. This analysis was performed to define the frequency of such events, identify risk factors, and assess antiplatelet/anticoagulant therapy in a cohort of patients with MPN.
Methods: The MPN registry of the Study Alliance Leukemia is a non-interventional prospective study including adult patients with an MPN according to WHO criteria (2008). For statistical analysis, descriptive methods and tests for significant differences as well as contingency tables were used to identify the odds of potential risk factors for vascular events.
Results: MPN subgroups significantly differed in sex distribution, age at diagnosis, blood counts, LDH levels, JAK2V617F positivity, and spleen size (length). While most thromboembolic events occurred around the time of MPN diagnosis, one third of these events occurred after that date. Splanchnic vein thrombosis was most frequent in post-PV-MF and MPN-U patients. The chance of developing a thromboembolic event was significantly elevated if patients suffered from post-PV-MF (OR 3.43; 95 % CI = 1.39–8.48) and splenomegaly (OR 1.76; 95 % CI = 1.15–2.71). Significant odds for major bleeding were previous thromboembolic events (OR = 2.71; 95 % CI = 1.36–5.40), splenomegaly (OR = 2.22; 95 % CI 1.01–4.89), and the administration of heparin (OR = 5.64; 95 % CI = 1.84–17.34). Major bleeding episodes were significantly less frequent in ET patients compared to other MPN subgroups.
Conclusions: Together, this report on an unselected "real-world" cohort of German MPN patients reveals important data on the prevalence, diagnosis, and treatment of thromboembolic and major bleeding complications of MPN.
Investigators in the cognitive neurosciences have turned to Big Data to address persistent replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. While there is tremendous potential to advance science through open data sharing, these efforts unveil a host of new questions about how to integrate data arising from distinct sources and instruments. We focus on the most frequently assessed area of cognition - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated raw data from 53 studies from around the world which measured at least one of three distinct verbal learning tasks, totaling N = 10,505 healthy and brain-injured individuals. A mega analysis was conducted using empirical bayes harmonization to isolate and remove site effects, followed by linear models which adjusted for common covariates. After corrections, a continuous item response theory (IRT) model estimated each individual subject’s latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance by 37% while preserving covariate effects. The effects of age, sex, and education on scores were found to be highly consistent across memory tests. IRT methods for equating scores across AVLTs agreed with held-out data of dually-administered tests, and these tools are made available for free online. This work demonstrates that large-scale data sharing and harmonization initiatives can offer opportunities to address reproducibility and integration challenges across the behavioral sciences.