False-positive assay readouts caused by badly behaving compounds-frequent hitters, pan-assay interference compounds (PAINS), aggregators, and others-continue to pose a major challenge to experimental screening. There are only a few in silico methods that allow the prediction of such problematic compounds. We report the development of Hit Dexter, two extremely randomized trees classifiers for the prediction of compounds likely to trigger positive assay readouts either by true promiscuity or by assay interference. The models were trained on a well-prepared dataset extracted from the PubChem Bioassay database, consisting of approximately 311 000 compounds tested for activity on at least 50 proteins. Hit Dexter reached MCC and AUC values of up to 0.67 and 0.96 on an independent test set, respectively. The models are expected to be of high value, in particular to medicinal chemists and biochemists who can use Hit Dexter to identify compounds for which extra caution should be exercised with positive assay readouts. Hit Dexter is available as a free web service at http://hitdexter.zbh. uni-hamburg.de.

• MeSH
• databáze faktografické MeSH
• falešně pozitivní reakce MeSH
• knihovny malých molekul chemie   farmakologie   MeSH
• počítačová simulace MeSH
• rychlé screeningové testy metody   MeSH
• strojové učení * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Low-volume lung injury encompasses local concentration of stresses in the vicinity of collapsed regions in heterogeneously ventilated lungs. We aimed to study the effects on ventilation and perfusion distributions of a sequential lateral positioning (30°) strategy using electrical impedance tomography imaging in a porcine experimental model of early acute respiratory distress syndrome (ARDS). We hypothesized that such strategy, including a real-time individualization of positive end-expiratory pressure (PEEP) whenever in lateral positioning, would provide attenuation of collapse in the dependent lung regions. A two-hit injury acute respiratory distress syndrome experimental model was established by lung lavages followed by injurious mechanical ventilation. Then, all animals were studied in five body positions in a sequential order, 15 min each: Supine 1; Lateral Left; Supine 2; Lateral Right; Supine 3. The following functional images were analyzed by electrical impedance tomography: ventilation distributions and regional lung volumes, and perfusion distributions. The induction of the acute respiratory distress syndrome model resulted in a marked fall in oxygenation along with low regional ventilation and compliance of the dorsal half of the lung (gravitational-dependent in supine position). Both the regional ventilation and compliance of the dorsal half of the lung greatly increased along of the sequential lateral positioning strategy, and maximally at its end. In addition, a corresponding improvement of oxygenation occurred. In conclusion, our sequential lateral positioning strategy, with sufficient positive end-expiratory pressure to prevent collapse of the dependent lung units during lateral positioning, provided a relevant diminution of collapse in the dorsal lung in a porcine experimental model of early acute respiratory distress syndrome.

• Publikační typ
• časopisecké články MeSH

Pharmacophore modeling is usually considered as a special type of virtual screening without probabilistic nature. Correspondence of at least one conformation of a molecule to pharmacophore is considered as evidence of its bioactivity. We show that pharmacophores can be treated as one-class machine learning models, and the probability the reflecting model's confidence can be assigned to a pharmacophore on the basis of their precision of active compounds identification on a calibration set. Two schemes (Max and Mean) of probability calculation for consensus prediction based on individual pharmacophore models were proposed. Both approaches to some extent correspond to commonly used consensus approaches like the common hit approach or the one based on a logical OR operation uniting hit lists of individual models. Unlike some known approaches, the proposed ones can rank compounds retrieved by multiple models. These approaches were benchmarked on multiple ChEMBL datasets used for ligand-based pharmacophore modeling and externally validated on corresponding DUD-E datasets. The influence of complexity of pharmacophores and their performance on a calibration set on results of virtual screening was analyzed. It was shown that Max and Mean approaches have superior early enrichment to the commonly used approaches. Thus, a well-performing, easy-to-implement, and probabilistic alternative to existing approaches for pharmacophore-based virtual screening was proposed.

• MeSH
• chemické modely MeSH
• léčivé přípravky analýza   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• počítačová simulace MeSH
• preklinické hodnocení léčiv metody   MeSH
• strojové učení MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Úvod: Traumatická makulární díra (TMD) je patologie vznikající na podkladě tupého poranění oka s neodloučeným sklivcem, často provázená komocí sítnice v zadním pólu oka (Berlinovo zkalení, commotio retinae). Vzácně se může TMD spontánně zhojit, avšak obvykle je indikována pars plana vitrektomie (PPV) s vnitřní tamponádou sítnice. Cíl: Cílem práce je referovat o výsledcích léčby TMD u čtyř dětí. Metodika: V letech 2007–2012 jsme diagnostikovali TMD u 4 dětí, 4 chlapců (ve věku 9, 10, 13 a 17 let). Poranění pravého i levého oka bylo zastoupeno stejně. Ve všech případech to byla zranění při sportu, u třech pacientů (9, 10 a 17 let) kontuze oka fotbalovým míčem, jeden pacient byl udeřen do oka tenisovou raketou. PPV byla indikována u 3 chlapců, dvakrát byl jako tamponáda použit 20% SF6, jedenkrát silikonový olej, který byl následně za 3,5 měsíce odstraněn. K jedinému spontánnímu zhojení TMD došlo u desetiletého chlapce po kontuzi fotbalovým míčem v průběhu druhého týdne po úrazu, v průběhu doporučeného klidového režimu a přípravy k PPV. Nálezy všech pacientů byly monitorovány prostřednictvím klinického vyšetření včetně biomikroskopie, fotografie fundu a vyšetření optickou koherentní tomografií (OCT). Výsledky: Vstupní nejlepší korigovaná zraková ostrost (NKZO) byla výrazně horší ve skupině léčené chirurgicky, pohybovala se mezi 1/60 (0,016) – 6/60 (0,1), u chlapce zhojeného bez chirurgické léčby byla 6/12 (0,5). U všech chlapců léčených chirurgicky se TMD uzavřela. U spontánně zhojené TMD se zlepšila NKZO na 6/6 (1,0). Pooperační NKZO se zlepšila na 6/24 (0,25) – 6/12 (0,5). Časné ani pozdní pooperační komplikace jsme nepozorovali. Průměrná sledovací doba je 20 měsíců. Závěr: PPV s vnitřní tamponádou sítnice jsme indikovali na základě výsledku OCT vyšetření bez tendence k spontánnímu uzavření TMD. U všech dětí jsme zaznamenali anatomický úspěch a uspokojivý funkční výsledek. Vyslovujeme podezření na predispozici pro TMD v populaci jihovýchodní Asie. Klíčová slova: traumatická makulární díra, kontuze oka, děti, pars plana vitrektomie, optická koherentní tomografie, spontánní zhojení

Purpose: To report the results of treatment of the traumatic macular holes (TMH) in four children. Methods: Retrospective study analyzed data of 4 children, males with a mean age of 12.3 years (range, 9–17 years), with diagnosis of TMH. All patients suffered a blunt trauma of the eye during the sport activities. The symptoms of three patients began after being hit to the face with a soccer balls, one boy was hit to his eye by a tennis rocket. Right eyes and left eyes were occurred identically. All patients were followed with ophthalmic examination, fundus photography and optical coherence tomography (OCT). One patient aged 10 years two weeks after blunt trauma with a soccer ball achieved spontaneous closure of TMH. Three patients aged nine to 17 years with TMH underwent surgical repair between September 2007 and May 2012 with three-port vitrectomy. After induction of posterior vitreous detachment vitrectomy with or without internal limiting membrane (ILM) peeling and gas or silicone oil injection were performed followed by prone positioning of head for ten days. Silicon oil was in an only patient removed within 3.5 month. Results: All four macular holes were closed successfully. Follow-up period was from 10 to 31 month (ranged, 20 month). There were no reoperations. There were no surgical complications during follow-up period. Visual acuity (VA) improved in all eyes. In spontaneously closed TMH was VA improved from 0.5 to 1.0. In surgically treated group VA improved from initial 0.016 to 0.1 (ranged, 0.061) to final 0.25 to 0.5 (ranged, 0.36). Conclusion: Pars plana vitrectomy is a safe method for treatment TMH in children without tends to spontaneous closure of TMD in OCT imaging. Predisposition for TMH in population south-east Asia is suspected.

• MeSH
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• oftalmologické chirurgické výkony metody   využití   MeSH
• optická koherentní tomografie MeSH
• perforace sítnice diagnóza   chirurgie   patofyziologie   MeSH
• poranění oka * diagnóza   chirurgie   patofyziologie   MeSH
• sportovní úrazy MeSH
• vnitřní tamponáda MeSH
• výsledky a postupy - zhodnocení (zdravotní péče) MeSH
• zraková ostrost MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• práce podpořená grantem MeSH

Alzheimer's disease (AD), the most common type of dementia, currently represents an extremely challenging and unmet medical need worldwide. Amyloid-β (Aβ) and Tau proteins are prototypical AD hallmarks, as well as validated drug targets. Accumulating evidence now suggests that they synergistically contribute to disease pathogenesis. This could not only help explain negative results from anti-Aβ clinical trials but also indicate that therapies solely directed at one of them may have to be reconsidered. Based on this, herein, we describe the development of a focused library of 2,4-thiazolidinedione (TZD)-based bivalent derivatives as dual Aβ and Tau aggregation inhibitors. The aggregating activity of the 24 synthesized derivatives was tested in intact Escherichia coli cells overexpressing Aβ42 and Tau proteins. We then evaluated their neuronal toxicity and ability to cross the blood-brain barrier (BBB), together with the in vitro interaction with the two isolated proteins. Finally, the most promising (most active, nontoxic, and BBB-permeable) compounds 22 and 23 were tested in vivo, in a Drosophila melanogaster model of AD. The carbazole derivative 22 (20 μM) showed extremely encouraging results, being able to improve both the lifespan and the climbing abilities of Aβ42 expressing flies and generating a better outcome than doxycycline (50 μM). Moreover, 22 proved to be able to decrease Aβ42 aggregates in the brains of the flies. We conclude that bivalent small molecules based on 22 deserve further attention as hits for dual Aβ/Tau aggregation inhibition in AD.

• MeSH
• Alzheimerova nemoc * farmakoterapie   MeSH
• Drosophila melanogaster MeSH
• Drosophila MeSH
• proteiny tau MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The assessment of fractures is a key issue in forensic anthropology; however, very few studies deal with the features of fractures due to explosion in comparison with other traumatic injuries. This study focuses on fractures resulting from blast trauma and two types of blunt force trauma (manual compression and running over), applied to corpses of pigs; 163 osteons were examined within forty fractures by the transmission light microscopy. Blast lesions showed a higher percentage of fracture lines through the Haversian canal, whereas in other types of trauma, the fractures went across the inner lamellae. Significant differences between samples hit by blast energy and those runover or manually compressed were observed (p<0.05). The frequency of pattern A is significantly higher in exploded bones than in runover and compressed. Microscopic analysis of the fracture line may provide information about the type of trauma, especially for what concerns blast trauma.

• MeSH
• Haversův systém zranění   patologie   MeSH
• kompresivní fraktury patologie   MeSH
• modely u zvířat MeSH
• pilotní projekty MeSH
• poranění tlakovou vlnou patologie   MeSH
• soudní antropologie MeSH
• tříštivé fraktury patologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Východiska: V současnosti je obecně přijímanou představou o kancerogenezi somatická mutační teorie. Podle ní celý proces začíná jednou „odrodilou“ buňkou, která se hromaděním genetických a epigenetických změn postupně proměňuje ze zdravé na plně maligní. Somatická mutační teorie se soustředí na mutace, genetické příčiny a buněčnou úroveň. Nádory považuje za onemocnění buněk, které ztratily kontrolu nad svou proliferací. Somatická mutační teorie, jejímiž protagonisty jsou Robert Weinberg a Douglas Hanahan, představuje převládající koncepci současné nádorové biologie. Naproti tomu teorie pole tkáňové organizace, kterou poprvé představili Carlos Sonnenschein a Ana Sotoová, považuje za klíčovou při vývoji nádorů ztrátu fyziologické struktury a organizace tkáně. Podle ní nádory vznikají na tkáňové úrovni. Vychází z představy, že stav proliferace je přednastaveným stavem buněk v mnohobuněčném organizmu. Cíl: Text nabízí odpovědi na následující dotazy: Platí i v době, kdy hlavní proud nádorové biologie posunuje svou pozornost od nádorových buněk k nádorovému mikroprostředí, nekompatibilnost a neslučitelnost zastánců somatické mutační teorie, tzv. redukcionistů, a teorie pole tkáňové organizace, tzv. organicistů? Kde hledat třetí, spojující, systemickou teorii? Je přínosné uvědomovat si možný spor mezi redukcionisty a organicisty? V čem ten přínos spočívá? Jak ovlivňuje praktickou onkologii a biologii nádorů obecně? Závěr: Není důležité rozhodnout, zda mají pravdu redukcionisté nebo organicisté. Ale je důležité být si vědom těchto dvou pojetí, protože to zpřesňuje způsob, jakým o celé problematice vzniku a vývoje nádorů přemýšlíme, jak experimentujeme a interpretujeme své výsledky.

Background: The somatic mutation theory explaining the process of carcinogenesis is generally accepted. The theory postulates that carcinogenesis begins in a first renegade cell that undergoes gradual transformation from a healthy to a fully malignant state through the accumulation of genetic and epigenetic “hits”. This theory focuses specifically on mutations and genetic aberrations, and their impact on cells. It considers tumors as populations of sick cells that lose control of their own proliferation. The theory was put forward by Robert Weinberg and Douglas Hanahan, and is the predominant view in current cancer biology. By contrast, the tissue organization field theory proposed by Carlos Sonnenschein and Ana Soto considers loss of physiological structure and function by a tissue as key events in tumor development. According to this theory, tumors arise at a tissue rather than at a cellular level. It is based on a presumption that proliferation status, rather than quiescence, is the default position of cells in multicellular organisms. Aim: The article aims to provide answers to following questions: Are the views of proponents of the somatic mutation theory (the reductionists) and proponents of the tissue organization field theory (the organicists) incompatible and incommensurable, even when the mainstream of tumor biology has shifted its attention from tumor cells toward the tumor microenvironment? Where to find a third interconnecting systemic approach? Is it useful to be aware of the controversy between reductionists and organicists? What this awareness contributes to? How do these alternative views influence practical oncology and tumor biology in general? Conclusion: Whether the true position is held by reductionists or organicists is unimportant. What is important is to be aware of the existence of these two concepts because this knowledge makes the way we think about tumor origin and development, and how we set up and interpret our experiments, more precise.

• Klíčová slova
• somatická mutační teorie, teorie pole tkáňové organizace,
• MeSH
• biologické modely * MeSH
• buňky stromatu MeSH
• karcinogeneze * MeSH
• lidé MeSH
• mutace MeSH
• nádorová transformace buněk * MeSH
• nádorové mikroprostředí MeSH
• nádory etiologie   genetika   MeSH
• nestabilita genomu MeSH
• proliferace buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Acute myeloid leukemia (AML) is a malignant neoplasia of the hematopoietic system characterized by the accumulation of immature and nonfunctional leukemic blasts in the bone marrow and peripheral tissues. Mechanistically, the development of AML is explained by the "two-hit" theory, which is based on the accumulation of driver mutations that will cooperate to induce transformation. However, a significant percentage of patients with AML exhibit only one driver mutation, and thus, how leukemic transformation occurs in these cases is unclear. Accumulating evidence suggests that nongenetic factors, such as chronic inflammation, might influence AML development, and accordingly, clinical data have reported that patients with chronic inflammatory disorders have an increased risk of developing hematological malignancies. Here, using a mouse model of chronic inflammation, we demonstrate that systemic elevated levels of cytokines and chemokines and hyperactivation of the Jak/Stat3 signaling pathway may substitute "second hit" mutations and accelerate tumorigenesis. Altogether, our data highlight chronic inflammation as an additional factor in the development of AML, providing additional understanding of the mechanisms of transformation and opening new avenues for the treatment of this disease.

• MeSH
• akutní myeloidní leukemie * genetika   farmakoterapie   MeSH
• hematologické nádory * MeSH
• kostní dřeň patologie   MeSH
• lidé MeSH
• nádorová transformace buněk genetika   MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Honeybee workers undergo metamorphosis in capped cells for approximately 13 days before adult emergence. During the same period, Varroa mites prick the defenseless host many times. We sought to identify proteome differences between emerging Varroa-parasitized and parasite-free honeybees showing the presence or absence of clinical signs of deformed wing virus (DWV) in the capped cells. A label-free proteomic analysis utilizing nanoLC coupled with an Orbitrap Fusion Tribrid mass spectrometer provided a quantitative comparison of 2316 protein hits. Redundancy analysis (RDA) showed that the combination of Varroa parasitism and DWV clinical signs caused proteome changes that occurred in the same direction as those of Varroa alone and were approximately two-fold higher. Furthermore, proteome changes associated with DWV signs alone were positioned above Varroa in the RDA. Multiple markers indicate that Varroa activates TGF-β-induced pathways to suppress wound healing and the immune response and that the collective action of stressors intensifies these effects. Furthermore, we indicate JAK/STAT hyperactivation, p53-BCL-6 feedback loop disruption, Wnt pathway activation, Wnt/Hippo crosstalk disruption, and NF-κB and JAK/STAT signaling conflict in the Varroa-honeybee-DWV interaction. These results illustrate the higher effect of Varroa than of DWV at the time of emergence. Markers for future research are provided.

• MeSH
• biologické markery MeSH
• biologické modely MeSH
• histony metabolismus   MeSH
• Janus kinasy metabolismus   MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• proteiny Wnt metabolismus   MeSH
• proteom * MeSH
• proteomika * MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• RNA-viry * MeSH
• signální transdukce MeSH
• symbióza * MeSH
• transformující růstový faktor beta * MeSH
• transkripční faktory STAT metabolismus   MeSH
• Varroidae * MeSH
• včely metabolismus   parazitologie   virologie   MeSH
• výpočetní biologie metody   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• buňky - růstové procesy MeSH
• dítě MeSH
• hormonální substituční terapie MeSH
• lékařská genetika MeSH
• lékařská onkologie MeSH
• lidský růstový hormon nedostatek   MeSH
• nádory genetika   MeSH
• poruchy růstu genetika   MeSH
• Check Tag
• dítě MeSH
• Publikační typ
• příručky MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• endokrinologie
• genetika, lékařská genetika
• onkologie