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1.
iScience ; 24(7): 102807, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34337362

RESUMO

Small-molecule tankyrase 1 and tankyrase 2 (TNKS1/2) inhibitors are effective antitumor agents in selected tumor cell lines and mouse models. Here, we characterized the response signatures and the in-depth mechanisms for the antiproliferative effect of tankyrase inhibition (TNKSi). The TNKS1/2-specific inhibitor G007-LK was used to screen 537 human tumor cell lines and a panel of particularly TNKSi-sensitive tumor cell lines was identified. Transcriptome, proteome, and bioinformatic analyses revealed the overall TNKSi-induced response signatures in the selected panel. TNKSi-mediated inhibition of wingless-type mammary tumor virus integration site/ß-catenin, yes-associated protein 1 (YAP), and phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT signaling was validated and correlated with lost expression of the key oncogene MYC and impaired cell growth. Moreover, we show that TNKSi induces accumulation of TNKS1/2-containing ß-catenin degradasomes functioning as core complexes interacting with YAP and angiomotin proteins during attenuation of YAP signaling. These findings provide a contextual and mechanistic framework for using TNKSi in anticancer treatment that warrants further comprehensive preclinical and clinical evaluations.

2.
Biosensors (Basel) ; 11(5)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069506

RESUMO

Polydimethylsiloxane (PDMS) has been used in microfluidic systems for years, as it can be easily structured and its flexibility makes it easy to integrate actuators including pneumatic pumps. In addition, the good optical properties of the material are well suited for analytical systems. In addition to its positive aspects, PDMS is well known to adsorb small molecules, which limits its usability when it comes to drug testing, e.g., in organ-on-a-chip (OoC) systems. Therefore, alternatives to PDMS are in high demand. In this study, we use thermoplastic elastomer (TPE) films thermally bonded to laser-cut poly(methyl methacrylate) (PMMA) sheets to build up multilayered microfluidic devices with integrated pneumatic micro-pumps. We present a low-cost manufacturing technology based on a conventional CO2 laser cutter for structuring, a spin-coating process for TPE film fabrication, and a thermal bonding process using a pneumatic hot-press. UV treatment with an Excimer lamp prior to bonding drastically improves the bonding process. Optimized bonding parameters were characterized by measuring the burst load upon applying pressure and via profilometer-based measurement of channel deformation. Next, flow and long-term stability of the chip layout were measured using microparticle Image Velocimetry (uPIV). Finally, human endothelial cells were seeded in the microchannels to check biocompatibility and flow-directed cell alignment. The presented device is compatible with a real-time live-cell analysis system.


Assuntos
Dimetilpolisiloxanos/química , Dispositivos Lab-On-A-Chip , Elastômeros , Células Endoteliais , Humanos
3.
Front Psychol ; 12: 584689, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912097

RESUMO

In the present paper we empirically investigate the psychometric properties of some of the most famous statistical and logical cognitive illusions from the "heuristics and biases" research program by Daniel Kahneman and Amos Tversky, who nearly 50 years ago introduced fascinating brain teasers such as the famous Linda problem, the Wason card selection task, and so-called Bayesian reasoning problems (e.g., the mammography task). In the meantime, a great number of articles has been published that empirically examine single cognitive illusions, theoretically explaining people's faulty thinking, or proposing and experimentally implementing measures to foster insight and to make these problems accessible to the human mind. Yet these problems have thus far usually been empirically analyzed on an individual-item level only (e.g., by experimentally comparing participants' performance on various versions of one of these problems). In this paper, by contrast, we examine these illusions as a group and look at the ability to solve them as a psychological construct. Based on an sample of N = 2,643 Luxembourgian school students of age 16-18 we investigate the internal psychometric structure of these illusions (i.e., Are they substantially correlated? Do they form a reflexive or a formative construct?), their connection to related constructs (e.g., Are they distinguishable from intelligence or mathematical competence in a confirmatory factor analysis?), and the question of which of a person's abilities can predict the correct solution of these brain teasers (by means of a regression analysis).

4.
Anal Chem ; 93(7): 3576-3585, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33534551

RESUMO

Liver organoids are emerging tools for precision drug development and toxicity screening. We demonstrate that electromembrane extraction (EME) based on electrophoresis across an oil membrane is suited for segregating selected organoid-derived drug metabolites prior to mass spectrometry (MS)-based measurements. EME allowed drugs and drug metabolites to be separated from cell medium components (albumin, etc.) that could interfere with subsequent measurements. Multiwell EME (parallel-EME) holding 100 µL solutions allowed for simple and repeatable monitoring of heroin phase I metabolism kinetics. Organoid parallel-EME extracts were compatible with ultrahigh-performance liquid chromatography (UHPLC) used to separate the analytes prior to detection. Taken together, liver organoids are well-matched with EME followed by MS-based measurements.


Assuntos
Organoides , Preparações Farmacêuticas , Fígado , Espectrometria de Massas , Membranas Artificiais
5.
Blood ; 137(17): 2403-2416, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33529322

RESUMO

Chronic graft-versus-host disease (cGVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. The molecular mechanisms underlying cGVHD remain poorly understood, and targeted therapies for clinical use are not well established. Here, we examined the role of the canonical WNT pathway in sclerodermatous cGVHD (sclGVHD). WNT signaling was activated in human sclGVHD with increased nuclear accumulation of the transcription factor ß-catenin and a WNT-biased gene expression signature in lesional skin. Treatment with the highly selective tankryase inhibitor G007-LK, the CK1α agonist pyrvinium, or the LRP6 inhibitor salinomycin abrogated the activation of WNT signaling and protected against experimental cGVHD, without a significant impact on graft-versus-leukemia effect (GVL). Treatment with G007-LK, pyrvinium, or salinomycin almost completely prevented the development of clinical and histological features in the B10.D2 (H-2d) → BALB/c (H-2d) and LP/J (H-2b) → C57BL/6 (H-2b) models of sclGVHD. Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect inflammation-dependent effects in sclGVHD. Our findings may have direct translational potential, because pyrvinium is in clinical use, and tankyrase inhibitors are in clinical trials for other indications.

6.
Adv Health Sci Educ Theory Pract ; 26(3): 847-863, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33599875

RESUMO

When physicians are asked to determine the positive predictive value from the a priori probability of a disease and the sensitivity and false positive rate of a medical test (Bayesian reasoning), it often comes to misjudgments with serious consequences. In daily clinical practice, however, it is not only important that doctors receive a tool with which they can correctly judge-the speed of these judgments is also a crucial factor. In this study, we analyzed accuracy and efficiency in medical Bayesian inferences. In an empirical study we varied information format (probabilities vs. natural frequencies) and visualization (text only vs. tree only) for four contexts. 111 medical students participated in this study by working on four Bayesian tasks with common medical problems. The correctness of their answers was coded and the time spent on task was recorded. The median time for a correct Bayesian inference is fastest in the version with a frequency tree (2:55 min) compared to the version with a probability tree (5:47 min) or to the text only versions based on natural frequencies (4:13 min) or probabilities (9:59 min).The score diagnostic efficiency (calculated by: median time divided by percentage of correct inferences) is best in the version with a frequency tree (4:53 min). Frequency trees allow more accurate and faster judgments. Improving correctness and efficiency in Bayesian tasks might help to decrease overdiagnosis in daily clinical practice, which on the one hand cause cost and on the other hand might endanger patients' safety.


Assuntos
Médicos , Estudantes de Medicina , Teorema de Bayes , Humanos , Probabilidade , Resolução de Problemas
7.
Curr Diab Rep ; 20(12): 72, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33206261

RESUMO

PURPOSE OF REVIEW: Human pancreas-on-a-chip (PoC) technology is quickly advancing as a platform for complex in vitro modeling of islet physiology. This review summarizes the current progress and evaluates the possibility of using this technology for clinical islet transplantation. RECENT FINDINGS: PoC microfluidic platforms have mainly shown proof of principle for long-term culturing of islets to study islet function in a standardized format. Advancement in microfluidic design by using imaging-compatible biomaterials and biosensor technology might provide a novel future tool for predicting islet transplantation outcome. Progress in combining islets with other tissue types gives a possibility to study diabetic interventions in a minimal equivalent in vitro environment. Although the field of PoC is still in its infancy, considerable progress in the development of functional systems has brought the technology on the verge of a general applicable tool that may be used to study islet quality and to replace animal testing in the development of diabetes interventions.


Assuntos
Diabetes Mellitus Tipo 1 , Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas , Animais , Humanos , Dispositivos Lab-On-A-Chip , Pâncreas , Tecnologia
8.
Cancers (Basel) ; 12(6)2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32575464

RESUMO

Evidence suggests that the growth and therapeutic resistance of glioblastoma (GBM) may be enabled by a population of glioma stem cells (GSCs) that are regulated by typical stem cell pathways, including the WNT/ß-catenin signaling pathway. We wanted to explore the effect of treating GSCs with a small-molecule inhibitor of tankyrase, G007-LK, which has been shown to be a potent modulator of the WNT/ß-catenin and Hippo pathways in colon cancer. Four primary GSC cultures and two primary adult neural stem cell cultures were treated with G007-LK and subsequently evaluated through the measurement of growth characteristics, as well as the expression of WNT/ß-catenin and Hippo signaling pathway-related proteins and genes. Treatment with G007-LK decreased in vitro proliferation and sphere formation in all four primary GSC cultures in a dose-dependent manner. G007-LK treatment altered the expression of key downstream WNT/ß-catenin and Hippo signaling pathway-related proteins and genes. Finally, cotreatment with the established GBM chemotherapeutic compound temozolomide (TMZ) led to an additive reduction in sphere formation, suggesting that WNT/ß-catenin signaling may contribute to TMZ resistance. These observations suggest that tankyrase inhibition may serve as a supplement to current GBM therapy, although more work is needed to determine the exact downstream mechanisms involved.

9.
Front Psychol ; 11: 750, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32528335

RESUMO

In teaching statistics in secondary schools and at university, two visualizations are primarily used when situations with two dichotomous characteristics are represented: 2 × 2 tables and tree diagrams. Both visualizations can be depicted either with probabilities or with frequencies. Visualizations with frequencies have been shown to help students significantly more in Bayesian reasoning problems than probability visualizations do. Because tree diagrams or double-trees (which are largely unknown in school) are node-branch structures, these two visualizations (in contrast to the 2 × 2 table) can even simultaneously display probabilities on branches and frequencies inside the nodes. This is a teaching advantage as it allows the frequency concept to be used to better understand probabilities. However, 2 × 2 tables and (double-)trees have a decisive disadvantage: While joint probabilities [e.g., P(A∩B)] are represented in 2 × 2 tables but no conditional probabilities [e.g., P(A|B)], it is exactly the other way around with (double-)trees. Therefore, a visualization that is equally suitable for the representation of joint probabilities and conditional probabilities is desirable. In this article, we present a new visualization-the frequency net-in which all absolute frequencies and all types of probabilities can be depicted. In addition to a detailed theoretical analysis of the frequency net, we report the results of a study with 249 university students that shows that "net diagrams" can improve reasoning without previous instruction to a similar extent as 2 × 2 tables and double-trees. Regarding questions about conditional probabilities, frequency visualizations (2 × 2 table, double-tree, or net diagram with absolute frequencies) are consistently superior to probability visualizations, and the frequency net performs as well as the frequency double-tree. Only the 2 × 2 table with frequencies-the one visualization that participants were already familiar with-led to higher performance rates. If, on the other hand, a question about a joint probability had to be answered, all implemented visualizations clearly supported participants' performance, but no uniform format effect becomes visible. Here, participants reached the highest performance in the versions with probability 2 × 2 tables and probability net diagrams. Furthermore, after conducting a detailed error analysis, we report interesting error shifts between the two information formats and the different visualizations and give recommendations for teaching probability.

10.
J Med Chem ; 63(13): 6834-6846, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32511917

RESUMO

Tankyrases 1 and 2 are central biotargets in the WNT/ß-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC50 inhibition in WNT/ß-catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.


Assuntos
Desenho de Fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Tanquirases/antagonistas & inibidores , Triazóis/química , Triazóis/farmacologia , Animais , Disponibilidade Biológica , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Solubilidade , Triazóis/farmacocinética
11.
Int J Obes (Lond) ; 44(8): 1691-1702, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32317752

RESUMO

OBJECTIVE: Human TNKS, encoding tankyrase 1 (TNKS1), localizes to a susceptibility locus for obesity and type 2 diabetes mellitus (T2DM). Here, we addressed the therapeutic potential of G007-LK, a TNKS-specific inhibitor, for obesity and T2DM. METHODS: We administered G007-LK to diabetic db/db mice and measured the impact on body weight, abdominal adiposity, and serum metabolites. Muscle, liver, and white adipose tissues were analyzed by quantitative RT-PCR and western blotting to determine TNKS inhibition, lipolysis, beiging, adiponectin level, mitochondrial oxidative metabolism and mass, and gluconeogenesis. Protein interaction and PARylation analyses were carried out by immunoprecipitation, pull-down and in situ proximity ligation assays. RESULTS: TNKS inhibition reduced body weight gain, abdominal fat content, serum cholesterol levels, steatosis, and proteins associated with lipolysis in diabetic db/db mice. We discovered that TNKS associates with PGC-1α and that TNKS inhibition attenuates PARylation of PGC-1α, contributing to increased PGC-1α level in WAT and muscle in db/db mice. PGC-1α upregulation apparently modulated transcriptional reprogramming to increase mitochondrial mass and fatty acid oxidative metabolism in muscle, beiging of WAT, and raised circulating adiponectin level in db/db mice. This was in sharp contrast to the liver, where TNKS inhibition in db/db mice had no effect on PGC-1α expression, lipid metabolism, or gluconeogenesis. CONCLUSION: Our study unravels a novel molecular mechanism whereby pharmacological inhibition of TNKS in obesity and diabetes enhances oxidative metabolism and ameliorates lipid disorder. This happens via tissue-specific PGC-1α-driven transcriptional reprogramming in muscle and WAT, without affecting liver. This highlights inhibition of TNKS as a potential pharmacotherapy for obesity and T2DM.

12.
Commun Biol ; 3(1): 196, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332858

RESUMO

The development of immune checkpoint inhibitors represents a major breakthrough in cancer therapy. Nevertheless, a substantial number of patients fail to respond to checkpoint pathway blockade. Evidence for WNT/ß-catenin signaling-mediated immune evasion is found in a subset of cancers including melanoma. Currently, there are no therapeutic strategies available for targeting WNT/ß-catenin signaling. Here we show that a specific small-molecule tankyrase inhibitor, G007-LK, decreases WNT/ß-catenin and YAP signaling in the syngeneic murine B16-F10 and Clone M-3 melanoma models and sensitizes the tumors to anti-PD-1 immune checkpoint therapy. Mechanistically, we demonstrate that the synergistic effect of tankyrase and checkpoint inhibitor treatment is dependent on loss of ß-catenin in the tumor cells, anti-PD-1-stimulated infiltration of T cells into the tumor and induction of an IFNγ- and CD8+ T cell-mediated anti-tumor immune response. Our study uncovers a combinatorial therapeutical strategy using tankyrase inhibition to overcome ß-catenin-mediated resistance to immune checkpoint blockade in melanoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Melanoma Experimental/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Sulfonas/farmacologia , Tanquirases/antagonistas & inibidores , Triazóis/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Células HEK293 , Humanos , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental/enzimologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Tanquirases/metabolismo , Carga Tumoral/efeitos dos fármacos , beta Catenina/genética , beta Catenina/metabolismo
13.
Commun Biol ; 3(1): 123, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170109

RESUMO

Sjögren syndrome/scleroderma autoantigen 1 (SSSCA1) was first described as an auto-antigen over-expressed in Sjögren's syndrome and in scleroderma patients. SSSCA1 has been linked to mitosis and centromere association and as a potential marker candidate in diverse solid cancers. Here we characterize SSSCA1 for the first time, to our knowledge, at the molecular, structural and subcellular level. We have determined the crystal structure of a zinc finger fold, a zinc ribbon domain type 2 (ZNRD2), at 2.3 Å resolution. We show that the C-terminal domain serves a dual function as it both behaves as the interaction site to Tankyrase 1 (TNKS1) and as a nuclear export signal. We identify TNKS1 as a direct binding partner of SSSCA1, map the binding site to TNKS1 ankyrin repeat cluster 2 (ARC2) and thus define a new binding sequence. We experimentally verify and map a new nuclear export signal sequence in SSSCA1.


Assuntos
Autoantígenos/química , Autoantígenos/metabolismo , Neoplasias/metabolismo , Ribonucleoproteínas/química , Ribonucleoproteínas/metabolismo , Tanquirases/química , Tanquirases/metabolismo , Transporte Ativo do Núcleo Celular/genética , Autoantígenos/genética , Sítios de Ligação , Cristalografia por Raios X , Células HeLa , Humanos , Neoplasias/patologia , Sinais de Exportação Nuclear , Filogenia , Ligação Proteica/genética , Conformação Proteica em alfa-Hélice , Domínios Proteicos , Mapas de Interação de Proteínas/genética , Ribonucleoproteínas/genética , Transfecção
14.
Electrophoresis ; 41(1-2): 56-64, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31544246

RESUMO

In vitro derived simplified 3D representations of human organs or organ functionalities are predicted to play a major role in disease modeling, drug development, and personalized medicine, as they complement traditional cell line approaches and animal models. The cells for 3D organ representations may be derived from primary tissues, embryonic stem cells or induced pluripotent stem cells and come in a variety of formats from aggregates of individual or mixed cell types, self-organizing in vitro developed "organoids" and tissue mimicking chips. Microfluidic devices that allow long-term maintenance and combination with other tissues, cells or organoids are commonly referred to as "microphysiological" or "organ-on-a-chip" systems. Organ-on-a-chip technology allows a broad range of "on-chip" and "off-chip" analytical techniques, whereby "on-chip" techniques offer the possibility of real time tracking and analysis. In the rapidly expanding tool kit for real time analytical assays, mass spectrometry, combined with "on-chip" electrophoresis, and other separation approaches offer attractive emerging tools. In this review, we provide an overview of current 3D cell culture models, a compendium of current analytical strategies, and we make a case for new approaches for integrating separation science and mass spectrometry in this rapidly expanding research field.


Assuntos
Técnicas de Cultura de Células , Eletroforese , Dispositivos Lab-On-A-Chip , Espectrometria de Massas , Organoides , Animais , Cromatografia Líquida , Humanos , Modelos Biológicos , Organoides/efeitos dos fármacos , Organoides/metabolismo , Organoides/fisiologia
15.
Front Psychol ; 10: 632, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31156488

RESUMO

Changing the information format from probabilities into frequencies as well as employing appropriate visualizations such as tree diagrams or 2 × 2 tables are important tools that can facilitate people's statistical reasoning. Previous studies have shown that despite their widespread use in statistical textbooks, both of those visualization types are only of restricted help when they are provided with probabilities, but that they can foster insight when presented with frequencies instead. In the present study, we attempt to replicate this effect and also examine, by the method of eye tracking, why probabilistic 2 × 2 tables and tree diagrams do not facilitate reasoning with regard to Bayesian inferences (i.e., determining what errors occur and whether they can be explained by scan paths), and why the same visualizations are of great help to an individual when they are combined with frequencies. All ten inferences of N = 24 participants were based solely on tree diagrams or 2 × 2 tables that presented either the famous "mammography context" or an "economics context" (without additional textual wording). We first asked participants for marginal, conjoint, and (non-inverted) conditional probabilities (or frequencies), followed by related Bayesian tasks. While solution rates were higher for natural frequency questions as compared to probability versions, eye-tracking analyses indeed yielded noticeable differences regarding eye movements between correct and incorrect solutions. For instance, heat maps (aggregated scan paths) of distinct results differed remarkably, thereby making correct and faulty strategies visible in the line of theoretical classifications. Moreover, the inherent structure of 2 × 2 tables seems to help participants avoid certain Bayesian mistakes (e.g., "Fisherian" error) while tree diagrams seem to help steer them away from others (e.g., "joint occurrence"). We will discuss resulting educational consequences at the end of the paper.

16.
Cancers (Basel) ; 11(2)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717152

RESUMO

The majority of colorectal cancers are induced by subsequent mutations in APC and KRAS genes leading to aberrant activation of both canonical WNT and RAS signaling. However, due to induction of feedback rescue mechanisms some cancers do not respond well to targeted inhibitor treatments. In this study we show that the APC and KRAS mutant human colorectal cancer cell line HCT-15 induces canonical WNT signaling through YAP in a MEK dependent mechanism. This inductive loop is disrupted with combined tankyrase (TNKS) and MEK inhibition. RNA sequencing analysis suggests that combined TNKS/MEK inhibition induces metabolic stress responses in HCT-15 cells promoting a positive FOXO3/FOXM1 ratio to reduce antioxidative and cryoprotective systems.

17.
SLAS Discov ; 24(3): 398-413, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30616481

RESUMO

Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN's compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3 H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.


Assuntos
Comportamento Cooperativo , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos , Europa (Continente) , Ensaios de Triagem em Larga Escala , Humanos , Relação Estrutura-Atividade
18.
Front Psychol ; 9: 1833, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30369891

RESUMO

For more than 20 years, research has proven the beneficial effect of natural frequencies when it comes to solving Bayesian reasoning tasks (Gigerenzer and Hoffrage, 1995). In a recent meta-analysis, McDowell and Jacobs (2017) showed that presenting a task in natural frequency format increases performance rates to 24% compared to only 4% when the same task is presented in probability format. Nevertheless, on average three quarters of participants in their meta-analysis failed to obtain the correct solution for such a task in frequency format. In this paper, we present an empirical study on what participants typically do wrong when confronted with natural frequencies. We found that many of them did not actually use natural frequencies for their calculations, but translated them back into complicated probabilities instead. This switch from the intuitive presentation format to a less intuitive calculation format will be discussed within the framework of psychological theories (e.g., the Einstellung effect).

19.
Nutrients ; 10(7)2018 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-29932143

RESUMO

OBJECTIVES: Pyrrolizidine alkaloids (PA) exist ubiquitously in our environment. More than 6000 plants, about 3% of the world’s flowering plants, are known to synthesize PA. As a consequence, many herbal ingredients, including St. John’s wort (SJW), are contaminated with PA that can possess acute and subchronic toxic effects as well as mutagenic and genotoxic properties. Therefore, the possible benefits of SJW as an herbal remedy against depression need to be weighed against the possible risks of unwanted PA intake. METHODS: We searched the literature regarding the current knowledge on PA and evaluated the evidence on the antidepressant effects of quantified SJW extract based on a Cochrane Review and the current practice guidelines on depression. Risks are depicted in form of a risk ladder and benefits in form of an icon array. RESULTS: Evidence from clinical studies indicates that quantified SJW extract is an effective treatment option for mild to moderate depression with fewer side effects than conventional antidepressants. Health statistics from different countries do not quantify cases of death caused by PA intake. However, deaths due to suicide, often triggered by depression, are common (11 in 1000 in Germany in 2015) and rank between fatalities due to liver diseases (16 in 1000) and household accidents (10 in 1000). CONCLUSIONS: Quantified SJW extract is a safe and effective treatment option, and its potential of treating depression outweighs the (hypothetical) risk of unwanted PA intake.


Assuntos
Antidepressivos/administração & dosagem , Hypericum/química , Fitoterapia , Extratos Vegetais/administração & dosagem , Plantas Medicinais/química , Alcaloides de Pirrolizidina/administração & dosagem , Antidepressivos/efeitos adversos , Depressão/tratamento farmacológico , Humanos , Extratos Vegetais/efeitos adversos , Alcaloides de Pirrolizidina/efeitos adversos , Medição de Risco , Resultado do Tratamento
20.
Acta Radiol ; 59(12): 1422-1430, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29566549

RESUMO

BACKGROUND: Long-term intensive training induces physiological, morphological, and functional adaption of the athlete's heart. PURPOSE: To evaluate the development of athlete's heart during a mid-term follow-up of competitive athletes using cardiac magnetic resonance (CMR). MATERIAL AND METHODS: Eighteen competitive long-distance runners and triathletes (age 43 ± 13 years, 3 women) were prospectively examined in a longitudinal follow-up study 5.05 ± 0.6 years after baseline. CMR at 1.5-T was performed for functional and late gadolinium enhancement (LGE) imaging. Left ventricular (LV) and right ventricular (RV) end-diastolic volume (LVEDV, RVEDV) as well as ejection fraction (LVEF, RVEF), LV myocardial mass (LVMM), and atrial sizes were determined and compared to baseline in matched pairs statistics for paired difference. RESULTS: LVEDV (197 ± 38 mL vs. 196 ± 38 mL, paired difference -0.9 mL, P = 0.7) and LVEF (62 ± 7% vs. 62 ± 5%, paired difference 0.1%, P = 0.9) did not change during the follow-up period, whereas LVMM increased significantly (149 ± 31 g vs.164 ± 32 g, paired difference 14 g, P < 0.0001). RVEDV significantly increased from 221 ± 47 mL at baseline to 230 ± 52 mL (paired difference 10 mL, P = 0.0033). RVEF decreased from baseline 57 ± 8% to 53 ± 7% (paired difference -3%, P = 0.0234). Left atrial size showed no significant changes (24 ± 5 cm2 vs. 25 ± 6 cm2, paired difference 0.5 cm2, P = 0.17) and right atrial size increased significantly (30 ± 5 cm2 vs. 32 ± 4 cm2, paired difference 2 cm2, P = 0.0054). CONCLUSION: This study supports the theory of ongoing remodeling in an athlete's heart. Predominantly the right heart can further enlarge in a mid-term period. This response seems not linearly dependent on a steady, decreased, or increased training volume.


Assuntos
Atletas , Ventrículos do Coração/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Função Ventricular/fisiologia , Adulto , Idoso , Meios de Contraste , Feminino , Seguimentos , Gadolínio , Humanos , Aumento da Imagem/métodos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
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