Several novel copper (II) complexes of reduced Schiff bases containing fluoride substituents were prepared and structurally characterized by single-crystal X-ray diffraction. The complexes exhibited diverse structures, with the central atom in distorted tetrahedral geometry. The biological effects of the products were evaluated, specifically their cytotoxicity, antimicrobial, and antiurease activities, as well as affinity for albumin (BSA) and DNA (ct-DNA). The complexes showed marked cytotoxic activities in the HepG2 hepatocellular carcinoma cell line, considerably higher than the standard cisplatin. The cytotoxicity depended significantly on the substitution pattern. The best activity was observed in the complex with a trifluoromethyl group in position 4 of the benzene ring-the dichloro[(±)-trans-N,N'-bis-(4-trifluoromethylbenzyl)-cyclohexane-1,2-diamine]copper (II) complex, whose activity (IC50 28.7 μM) was higher than that of the free ligand and markedly better than the activity of the standard cisplatin (IC50 336.8 μM). The same complex also showed the highest antimicrobial effect in vitro. The affinity of the complexes towards bovine serum albumin (BSA) and calf thymus DNA (ct-DNA) was established as well, indicating only marginal differences between the complexes. In addition, all complexes were shown to be excellent inhibitors of the enzyme urease, with the IC50 values in the lower micromolar region.

• MeSH
• buňky Hep G2 MeSH
• DNA metabolismus   chemie   MeSH
• fluor chemie   MeSH
• komplexní sloučeniny * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• ligandy MeSH
• měď * chemie   MeSH
• protinádorové látky * farmakologie   chemie   MeSH
• Schiffovy báze * chemie   farmakologie   MeSH
• sérový albumin hovězí chemie   MeSH
• ureasa antagonisté a inhibitory   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Cyclin-dependent kinases (CDKs) play an important role in the cell-division cycle. Synthetic inhibitors of CDKs are based on 2,6,9-trisubstituted purines and are developed as potential anticancer drugs; however, they have low solubility in water. In this study, we proved that the pharmaco-chemical properties of purine-based inhibitors can be improved by appropriate substitution with the adamantane moiety. We prepared ten new purine derivatives with adamantane skeletons that were linked at position 6 using phenylene spacers of variable geometry and polarity. We demonstrated that the adamantane skeleton does not compromise the biological activity, and some of the new purines displayed even higher inhibition activity towards CDK2/cyclin E than the parental compounds. These findings were supported by a docking study, which showed an adamantane scaffold inside the binding pocket participating in the complex stabilisation with non-polar interactions. In addition, we demonstrated that β-cyclodextrin (CD) increases the drug's solubility in water, although this is at the cost of reducing the biochemical and cellular effect. Most likely, the drug concentration, which is necessary for target engagement, was decreased by competitive drug binding within the complex with β-CD.

• MeSH
• adamantan chemie   MeSH
• beta-cyklodextriny chemie   MeSH
• buňky K562 MeSH
• cyklin-dependentní kinasa 2 antagonisté a inhibitory   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• protinádorové látky chemie   farmakologie   MeSH
• puriny chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: Ion beam radiotherapy offers enhances dose conformity to the tumor volume while better sparing healthy tissue compared to conventional photon radiotherapy. However, the increased dose gradient also makes it more sensitive to uncertainties. While the most important uncertainty source is the patient itself, the beam delivery is also subject to uncertainties. Most of the proton therapy centers used cyclotrons, which deliver typically a stable beam over time, allowing a continuous extraction of the beam. Carbon-ion beam radiotherapy (CIRT) in contrast uses synchrotrons and requires a larger and energy-dependent extrapolation of the nozzle-measured positions to obtain the lateral beam positions in the isocenter, since the nozzle-to-isocenter distance is larger than for cyclotrons. Hence, the control of lateral pencil beam positions at isocenter in CIRT is more sensitive to uncertainties than in proton radiotherapy. Therefore, an independent monitoring of the actual lateral positions close to the isocenter would be very valuable and provide additional information. However, techniques capable to do so are scarce, and they are limited in precision, accuracy and effectivity. METHODS: The detection of secondary ions (charged nuclear fragments) has previously been exploited for the Bragg peak position of C-ion beams. In our previous work, we investigated for the first time the feasibility of lateral position monitoring of pencil beams in CIRT. However, the reported precision and accuracy were not sufficient for a potential implementation into clinical practice. In this work, it is shown how the performance of the method is improved to the point of clinical relevance. To minimize the observed uncertainties, a mini-tracker based on hybrid silicon pixel detectors was repositioned downstream of an anthropomorphic head phantom. However, the secondary-ion fluence rate in the mini-tracker rises up to 1.5 × 105 ions/s/cm2 , causing strong pile-up of secondary-ion signals. To solve this problem, we performed hardware changes, optimized the detector settings, adjusted the setup geometry and developed new algorithms to resolve ambiguities in the track reconstruction. The performance of the method was studied on two treatment plans delivered with a realistic dose of 3 Gy (RBE) and averaged dose rate of 0.27 Gy/s at the Heidelberg Ion-Beam Therapy Center (HIT) in Germany. The measured lateral positions were compared to reference beam positions obtained either from the beam nozzle or from a multi-wire proportional chamber positioned at the room isocenter. RESULTS: The presented method is capable to simultaneously monitor both lateral pencil beam coordinates over the entire tumor volume during the treatment delivery, using only a 2-cm2 mini-tracker. The effectivity (defined as the fraction of analyzed pencil beams) was 100%. The reached precision of (0.6 to 1.5) mm and accuracy of (0.5 to 1.2) mm are in line with the clinically accepted uncertainty for QA measurements of the lateral pencil beam positions. CONCLUSIONS: It was demonstrated that the performance of the method for a non-invasive lateral position monitoring of pencil beams is sufficient for a potential clinical implementation. The next step is to evaluate the method clinically in a group of patients in a future observational clinical study.

• MeSH
• celková dávka radioterapie MeSH
• ionty MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• plánování radioterapie pomocí počítače MeSH
• protonová terapie * MeSH
• radioterapie těžkými ionty * MeSH
• uhlík MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: Microwave ablation (MWA) is a clinically established modality for treatment of lung tumors. A challenge with existing application of MWA, however, is local tumor progression, potentially due to failure to establish an adequate treatment margin. This study presents a robust simulation-based treatment planning methodology to assist operators in comparatively assessing thermal profiles and likelihood of achieving a specified minimum margin as a function of candidate applied energy parameters. METHODS: We employed a biophysical simulation-based probabilistic treatment planning methodology to evaluate the likelihood of achieving a specified minimum margin for candidate treatment parameters (i.e., applied power and ablation duration for a given applicator position within a tumor). A set of simulations with varying tissue properties was evaluated for each considered combination of power and ablation duration, and for four different scenarios of contrast in tissue biophysical properties between tumor and normal lung. A treatment planning graph was then assembled, where distributions of achieved minimum ablation zone margins and collateral damage volumes can be assessed for candidate applied power and treatment duration combinations. For each chosen power and time combination, the operator can also visualize the histogram of ablation zone boundaries overlaid on the tumor and target volumes. We assembled treatment planning graphs for generic 1, 2, and 2.5 cm diameter spherically shaped tumors and also illustrated the impact of tissue heterogeneity on delivered treatment plans and resulting ablation histograms. Finally, we illustrated the treatment planning methodology on two example patient-specific cases of tumors with irregular shapes. RESULTS: The assembled treatment planning graphs indicate that 30 W, 6 min ablations achieve a 5-mm minimum margin across all simulated cases for 1-cm diameter spherical tumors, and 70 W, 10 min ablations achieve a 3-mm minimum margin across 90% of simulations for a 2.5-cm diameter spherical tumor. Different scenarios of tissue heterogeneity between tumor and lung tissue revealed 2 min overall difference in ablation duration, in order to reliably achieve a 4-mm minimum margin or larger each time for 2-cm diameter spherical tumor. CONCLUSIONS: An approach for simulation-based treatment planning for microwave ablation of lung tumors is illustrated to account for the impact of specific geometry of the treatment site, tissue property uncertainty, and heterogeneity between the tumor and normal lung.

• MeSH
• ablace * MeSH
• katetrizační ablace * MeSH
• lidé MeSH
• mikrovlny terapeutické užití   MeSH
• nádory plic * diagnostické zobrazování   chirurgie   MeSH
• počítačová simulace MeSH
• radiofrekvenční ablace * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Path integration is thought to rely on vestibular and proprioceptive cues yet most studies in humans involve primarily visual input, providing limited insight into their respective contributions. We developed a paradigm involving walking in an omnidirectional treadmill in which participants were guided on two sides of a triangle and then found their back way to origin. In Experiment 1, we tested a range of different triangle types while keeping the distance of the unguided side constant to determine the influence of spatial geometry. Participants overshot the angle they needed to turn and undershot the distance they needed to walk, with no consistent effect of triangle type. In Experiment 2, we manipulated distance while keeping angle constant to determine how path integration operated over both shorter and longer distances. Participants underestimated the distance they needed to walk to the origin, with error increasing as a function of the walked distance. To attempt to account for our findings, we developed configural-based computational models involving vector addition, the second of which included terms for the influence of past trials on the current one. We compared against a previously developed configural model of human path integration, the Encoding-Error model. We found that the vector addition models captured the tendency of participants to under-encode guided sides of the triangles and an influence of past trials on current trials. Together, our findings expand our understanding of body-based contributions to human path integration, further suggesting the value of vector addition models in understanding these important components of human navigation.

• MeSH
• chůze fyziologie   MeSH
• dospělí MeSH
• lidé MeSH
• orientace fyziologie   MeSH
• podněty MeSH
• propriocepce fyziologie   MeSH
• prostorová navigace fyziologie   MeSH
• teoretické modely MeSH
• vnímání prostoru fyziologie   MeSH
• výpočetní biologie metody   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

The sesquiterpenoid juvenile hormone (JH) is vital to insect development and reproduction. Intracellular JH receptors have recently been established as basic helix-loop-helix transcription factor (bHLH)/PAS proteins in Drosophila melanogaster known as germ cell-expressed (Gce) and its duplicate paralog, methoprene-tolerant (Met). Upon binding JH, Gce/Met activates its target genes. Insects possess multiple native JH homologs whose molecular activities remain unexplored, and diverse synthetic compounds including insecticides exert JH-like effects. How the JH receptor recognizes its ligands is unknown. To determine which structural features define an active JH receptor agonist, we tested several native JHs and their nonnative geometric and optical isomers for the ability to bind the Drosophila JH receptor Gce, to induce Gce-dependent transcription, and to affect the development of the fly. Our results revealed high ligand stereoselectivity of the receptor. The geometry of the JH skeleton, dictated by two stereogenic double bonds, was the most critical feature followed by the presence of an epoxide moiety at a terminal position. The optical isomerism at carbon C11 proved less important even though Gce preferentially bound a natural JH enantiomer. The results of receptor-ligand-binding and cell-based gene activation assays tightly correlated with the ability of different geometric JH isomers to induce gene expression and morphogenetic effects in the developing insects. Molecular modeling supported the requirement for the proper double-bond geometry of JH, which appears to be its major selective mechanism. The strict stereoselectivity of Gce toward the natural hormone contrasts with the high potency of synthetic Gce agonists of disparate chemistries.

• MeSH
• Drosophila melanogaster chemie   genetika   metabolismus   MeSH
• juvenilní hormony chemie   metabolismus   MeSH
• molekulární modely MeSH
• proteiny Drosophily metabolismus   MeSH
• receptory buněčného povrchu metabolismus   MeSH
• stereoizomerie MeSH
• transkripční faktory bHLH metabolismus   MeSH
• transkripční faktory metabolismus   MeSH
• vazba proteinů MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

An international intercomparison was organized by Working Group 7, Internal Dosimetry, of the European Radiation Dosimetry Group in collaboration with Working Group 6, Computational Dosimetry, for measurement and Monte Carlo simulation of Am in three skull phantoms. The main objectives of this combined exercise were (1) comparison of the results of counting efficiency in fixed positions over each head phantom using different germanium detector systems, (2) calculation of the activity of Am in the skulls, (3) comparison of Monte Carlo simulations with measurements (spectrum and counting efficiency), and (4) comparison of phantom performance. This initiative collected knowledge on equipment, detector arrangements, calibration procedures, and phantoms used around the world for in vivo monitoring of Am in exposed persons, as well as on the Monte Carlo skills and tools of participants. Three skull phantoms (BfS, USTUR, and CSR phantoms) were transported from Europe (10 laboratories) to North America (United States and Canada). The BfS skull was fabricated with real human bone artificially labeled with Am. The USTUR skull phantom was made from the US Transuranium and Uranium Registries whole-body donor (case 0102) who was contaminated due to an occupational intake of Am; one-half of the skull corresponds to real contaminated bone, the other half is real human bone from a noncontaminated person. Finally, the CSR phantom was fabricated as a simple hemisphere of equivalent bone and tissue material. The three phantoms differ in weight, size, and shape, which made them suitable for an efficiency study. Based on their own skull calibration, the participants calculated the activity in the three European Radiation Dosimetry Group head phantoms. The Monte Carlo intercomparison was organized in parallel with the measurement exercise using the voxel representations of the three physical phantoms; there were 16 participants. Three tasks were identified with increasing difficulty: (1) Monte Carlo simulation of the simple CSR hemisphere and the Helmholz Zentrum München high-purity germanium detector for calculating the counting efficiency for the 59.54 keV photons of Am, in established measurement geometry; (2) Monte Carlo simulation of particular measurement geometries using the BfS and USTUR voxel phantoms and the Helmholz Zentrum München high-purity germanium detector detector; and (3) application of Monte Carlo methodology to calculate the calibration factor of each participant for the detector system and counting geometry (single or multidetector arrangement) to be used for monitoring a person in each in vivo facility, using complex skull phantoms. The results of both exercises resulted in the conclusion that none of the three available head phantoms is appropriate as a reference phantom for the calibration of germanium detection systems for measuring Am in exposed adult persons. The main reasons for this are: (1) lack of homogeneous activity distribution in the bone material, or (2) inadequate shape/size for simulating an adult skull. Good agreement was found between Monte Carlo results and measurements, which supports Monte Carlo calibration of body counters as an alternative method when appropriate physical phantoms are not available and the detector and source are well known.

• MeSH
• algoritmy MeSH
• americium analýza   MeSH
• dospělí MeSH
• fantomy radiodiagnostické * MeSH
• lebka účinky záření   MeSH
• lidé MeSH
• metoda Monte Carlo * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Geografické názvy
• Evropa MeSH
• Severní Amerika MeSH

We present the ROCA (ROad Curvature Analyst) software, in the form of an ESRI ArcGIS Toolbox, intended for vector line data processing. The software segments road network data into tangents and horizontal curves. Horizontal curve radii and azimuth of tangents are then automatically computed. Simultaneously, additional frequently used road section characteristics are calculated, such as the sinuosity of a road section (detour ratio), the number of turns along an individual road section and the average cumulative angle for a road section. The identification of curves is based on the naïve Bayes classifier and users are allowed to prepare their own training data files. We applied ROCA software to secondary roads within the Czech road network (9,980 km). The data processing took less than ten minutes. Approximately 43% of the road network in question consists of 42,752 horizontal curves. The ROCA software outperforms other existing automatic methods by 26% with respect to the percentage of correctly identified curves. The segmented secondary roads within the Czech road network can be viewed on the roca.cdvgis.cz/czechia web-map application. We combined data on road geometry with road crashes database to develop the crash modification factors for horizontal curves with various radii. We determined that horizontal curves with radii of 50 m are approximately 3.7 times more hazardous than horizontal curves with radii accounting for 1000 m. ROCA software can be freely downloaded for noncommercial use from https://roca.cdvinfo.cz/ website.

• MeSH
• automobily normy   MeSH
• bezpečnost MeSH
• dopravní nehody prevence a kontrola   MeSH
• geografické informační systémy MeSH
• lidé MeSH
• pomůcky pro sebeobsluhu * MeSH
• řízení motorových vozidel * normy   MeSH
• rotace * MeSH
• rozpoznávání automatizované metody   MeSH
• software * normy   MeSH
• životní prostředí - projekt MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION AND HYPOTHESIS: During vaginal delivery, the levator ani muscle (LAM) undergoes severe deformation. This stress can lead to stretch-related LAM injuries. The objective of this study was to develop a sophisticated MRI-based model to simulate changes in the LAM during vaginal delivery. METHODS: A 3D finite element model of the female pelvic floor and fetal head was developed. The model geometry was based on MRI data from a nulliparous woman and 1-day-old neonate. Material parameters were estimated using uniaxial test data from the literature and by least-square minimization method. The boundary conditions reflected all anatomical constraints and supports. A simulation of vaginal delivery with regard to the cardinal movements of labor was then performed. RESULTS: The mean stress values in the iliococcygeus portion of the LAM during fetal head extension were 4.91-7.93 MPa. The highest stress values were induced in the pubovisceral and puborectal LAM portions (mean 27.46 MPa) at the outset of fetal head extension. The last LAM subdivision engaged in the changes in stress was the posteromedial section of the puborectal muscle. The mean stress values were 16.89 MPa at the end of fetal head extension. The LAM was elongated by nearly 2.5 times from its initial resting position. CONCLUSIONS: The cardinal movements of labor significantly affect the subsequent heterogeneous stress distribution in the LAM. The absolute stress values were highest in portions of the muscle that arise from the pubic bone. These areas are at the highest risk for muscle injuries with long-term complications.

• MeSH
• analýza metodou konečných prvků * MeSH
• anatomické modely * MeSH
• biomechanika MeSH
• distorze a distenze etiologie   MeSH
• dospělí MeSH
• hlava anatomie a histologie   MeSH
• kosterní svaly zranění   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• novorozenec MeSH
• pánevní dno anatomie a histologie   diagnostické zobrazování   fyziologie   MeSH
• plod anatomie a histologie   MeSH
• pružnost MeSH
• těhotenství MeSH
• vedení porodu škodlivé účinky   MeSH
• zobrazování trojrozměrné metody   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH