Auswahl der wissenschaftlichen Literatur zum Thema „Oracle Crystal Ball“

Relevance. The assessment of uncertainties for the calculation of hydrocarbon reserves is a timely topic. The quality of hydrocarbon reserves is declining as old oil fields are depleted. Rates of discovery are in decline since most of the territories prospectively rich in hydrocarbon resources have already been explored. Newly discovered fields are classified as small and medium in terms of the amount of hydrocarbon reserves and difficult in terms of the quality of reserves. Purpose of the research is to determine important reservoir properties that have the greatest impact on the variability of the initial hydrocarbon reserves using sensitivity analysis and conducting a probabilistic hydrocarbon reserves assessment by the Monte Carlo method. Methods of research. The probabilistic hydrocarbon reserves assessment was carried out by the Monte Carlo method with the corresponding frequency curves of the probability distribution of volumetric parameters, which were performed using the Oracle Crystal Ball application. The sensitivity analysis of volumetric parameters that have the greatest impact on the amount of the initial hydrocarbons reserves was performed using the Oracle Crystal Ball application as well. Results and their application. An assessment of uncertainties and risks is necessary both for newly discovered fields in order to negate the risk of drilling unproductive wells and mature fields for a targeted program of geological and technological measures (GTM). Conclusions. The formation of bedded sand bodies of the Vasyugan (SE11, SE12, SE13) and Tyumen (SE2) suites took place in various sedimentation conditions, which could not but affect the quality of the reservoir of the studied formations. The analysis of the sensitivity of parameters has shown that different parameters affect the amount of hydrocarbon reserves in places SE11, SE12, SE13 and place SE2 .

Gas Spring is an important component of an energy storing prosthetic knee. The spring stored energy during flexion and released the energy while in the extension. In this research, we discuss a Monte Carlo simulation model of a gas spring in an Energy Storing Prosthetic Knee (ESPK) using Oracle Crystal Ball software. The simulation is used to predict the effects of three important design variables of a gas spring which are cylinder diameter, cylinder length, and displacement to the energy storing performance of the spring. The results of simulation show that there are two design variables which have significant contribution to the variations of energy storing performance: cylinder diameter and displacement. Those design variables account for 99.3% to the total variance of energy storing. Quality improvement must be conducted to lowering the resulted energy storing variance. We proportionally decrease the variance of the design variables to lowering the energy storing variance. The simulation results show a significant quality improvement of about 50% in term of energy storing standard deviation. The results also show that cylinder diameter is more sensitive than the other two design variables in energy storing quality improvement.

Projects for the regulation of torrent basins carry various unforeseen adverse effects that may result in breached deadlines, increased costs, a reduction of quality etc. The paper presents the basic characteristics and most frequent risks associated with erosion control. Furthermore, it provides an overview of risk management through its basic stages - starting from risk identification and risk analysis to risk responses, including the methods used for risk analysis. As a part of quantitative methods for risk analysis, the Monte Carlo method is presented as the one most frequently used in simulations. The Monte Carlo method is a stochastic simulation method consisting of the following stages: the identification of criterion and relevant variables, the allocation of probability for relevant variables, the determination of correlation coefficient among relevant variables, simulation execution and result analysis. This method was applied in the analysis of the total cost of the project for the basin regulation of the Dumaca River in order to determine the funding that would be used as a backup in case of unforeseen events with a negative impact. The project for the regulation of the Dumaca River includes basin regulation in the form of complex flow profile and the lining of zones where necessary in terms of stability. The total cost is presented as a sum of costs of all works (preliminary works, earthworks, masonry works, concrete works and finishing works). The Monte Carlo simulation for cost analysis is carried out using the Oracle Crystal Ball software with its basic steps described in the paper. A sum of funding needed as a financial backup in case of unforeseen events with negative effects is obtained as the simulated total cost of the project.

Abstract Background Appropriate application of antimicrobial PK/PD properties is crucial to optimizing patient outcomes. Although β-lactams are among the most utilized and effective antibiotics, optimal dosing strategies in obese populations are largely unknown. The objective of this study was to compare PK/PD of CPM in non-obese (NO, weight 80–100 kg) and obese (O, weight > 100 kg) patients. Methods A prospective comparative PK/PD analysis was conducted in NO and O patients receiving CPM. Blood samples were obtained at 30, 60, 120, 240, 360, and 480 minutes after CPM infusion. CPM concentrations were determined by reversed-phase high-performance liquid chromatography. Non-compartmental PK analyses were performed, followed by Monte Carlo simulations (Oracle Crystal Ball®, 5,000 simulated patients) to estimate probability of target attainment (PTA) against common Gram-negative pathogens. The desired PD target for CPM was % time above MIC of unbound drug (%fT > MIC) ≥ 60%. Chi-squared and Mann–Whitney U tests were used for analysis. Results Seventeen patients were enrolled and most (94%) received CPM 2 g q8h. A significant difference in actual body weight and body mass index was observed (P < 0.001). There were no differences in other baseline or PK characteristics between the two groups. Utilizing CPM 2 g q8h, PTA ≥ 90% was not observed for organisms with an MIC of 8 μg/mL, the current CLSI breakpoint for P. aeruginosa and A. baumannii (PTA = 88% vs. 81% in NO and O groups, respectively). With a 6 g continuous infusion (CI), however, ≥ 90% PTA was achieved in both groups (PTA = 100%) for organisms with an MIC of 8 μg/mL, while a regimen of 2 g q8h (infused over 3 hours [EI]) also provided PTA of ≥ 90% in both groups (PTA = 98% vs. 92% in NO and O groups, respectively). Goal PTA was not obtained in either group for organisms with an MIC of 4 μg/mL with CPM 1 g q8h or 2 g q12h (i.e., CLSI recommended dosing for organisms with MICs of 4 μg/mL). Conclusion Optimizing PK/PD parameters through novel dosing strategies are essential in both the NO and O populations for optimal CPM exposure in susceptible pathogens with higher MICs. CPM 6 grams/day by either CI or EI provides more optimal PK/PD characteristics in obese patients for pathogens with MICs at or near the current CLSI-recommended breakpoint. Disclosures All authors: No reported disclosures.

The paper discusses issues related to life cycle costs in construction. Life cycle cost is a key element in the assessment of environmental sustainability in construction and it provides a tool for the economic evaluation of alternative sustainability options exhibiting different capital, operating costs or resource usage. The authors reviewed selected models of estimating life cycle costs in construction, drew attention to the complex mathematical models developed so far, namely those which take into account only financial risks and those which involve the possibility of the influence of other risk factors and described the main assumptions accompanying the original model for estimating the whole life costs of buildings, including: reasons for choosing theory of possibility, division and parametrization of input data. The aim of this paper is to confirm the validity of the model structure assumptions adopted by the authors by comparing the originally selected fuzzy approach to calculating life cycle costs taking into account the risk with the probabilistic approach, as well as indicating the domain in which the probabilistic approach will complement the fuzzy approach chosen by the authors. The paper presents a comparison analysis of two approaches used in the authors’ model, a fuzzy and a probabilistic approach, recommended by the ISO standard 15686-5:2008. The authors used the Oracle Crystall Ball software in their simulations.

Abstract BACKGROUND Iocitrate dehydrogenase mutations (mIDH1) are present in >70% of patients with Grade II/III gliomas resulting in production and accumulation of (R)-2-hydroxyglutarate (2-HG) causing DNA hypermethylation and promoting tumorigenesis. This abstract summarizes the structure-based design of FT-2102, a potent and selective inhibitor of mutated IDH1-R132 with brain distribution (Kpuu) that is in context of minimal effective concentrations required in brain to modulate 2-HG. METHODS The crystal structure of mutated IDH1 in complex with FT-2102 and NADPH cofactor (2.1A resolution) was determined via sitting-drop vapour-diffusion set-ups. HCT116/IDH1 R132H were implanted in Balb/c nude mice and FT-2102 was administered orally twice daily. FT-2102 and 2-HG levels in plasma and xenografts were determined by LC/MS. In silico and in vitro models were used to determine the extent of brain distribution and ex-vivo rat data was generated to validate the projected distribution into brain tissue (Kpuu). RESULTS In tumor Xenograft (HCT116/IDH1-R132H), FT-2102 inhibits tumor 2-HG production with an IC50 of 24nM which is consistent with its in vitro IC50 of 18nM. FT-2102 unbound plasma concentrations of 256nM in xenografted mice were found to achieve 90% reduction of 2-HG in tumor. Rat data showed that FT-2102 partitions into brain with a Kpuu of 0.45. Based on these data, the concentration of FT-2102 in brain to significantly reduce 2HG is predicted to be 115nM. Recent publications (Natsume, et al, ASCO19) propose 90% reduction of 2-HG (90%) is associated with tumor reduction in the brain. CONCLUSION The structure-based design of FT-2102 has facilitated CNS penetration in animal models and is undergoing evaluation in ongoing clinical trials including patients with CNS based IDH1m tumors (NCT: 03684811).

Abstract We have identified STAT3 as a convergence point for oncogenic signaling in tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML) lacking BCR-ABL1 kinase domain mutations. In addition, we found that STAT3 activity contributes to disease in other myeloid disorders, including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs). Utilizing TKI-resistant CML as a model system, we identified BP-5-087 as a small molecule inhibitor of STAT3 that reduces STAT3 phosphorylation and nuclear transactivation (Eiring et al. Leukemia, 2014). Binding of BP-5-087 to the STAT3 SH2 domain was initially assessed using fluorescence polarization (FP) assays and high-resolution computational docking simulations. To further validate the binding motif of BP-5-087, we conducted time-resolved electrospray ionization mass spectrometry/hydrogen-deuterium exchange experiments. Fold-change in deuterium uptake was analyzed for 68 STAT3 peptides representing 71% sequence coverage, and mapped onto the crystal structure of STAT3. This analysis precisely defined the binding epitope for BP-5-087 within the STAT3 SH2 domain. We next tested the effects of BP-5-087 in several myeloid malignancies using relevant disease models. (i) CML stem and progenitor cells from TKI-resistant patients without kinase domain mutations were treated with BP-5-087 ex vivo, using short-term liquid culture, clonogenic and LTC-IC assays. BP-5-087 treatment significantly reduced colony formation by CML stem and progenitor cells (p<0.01), with no effect on normal human CD34+ cord blood (CB) cells. (ii) Similarly, BP-5-087 also increased apoptosis and reduced viability (p<0.05) of primary AML blasts treated ex vivo with BP-5-087 for 72 hours in liquid culture. (iii) CD34+ cells from patients with myelofibrosis were also treated with BP-5-087 in clonogenic assays, and similar to CML, BP-5-087 reduced myeloid colony formation, although to a lesser extent. The in vivo activity of BP-5-087 was next evaluated in a murine model of JAK2 V617F-induced MPN. Briefly, Balb/c bone marrow was transduced with JAK2 V617F-GFP, followed by injection into lethally irradiated recipients. After disease induction, mice were treated with BP-5-087 (25 mg/kg) by once-daily oral gavage. No toxicities were observed after 40 days of treatment in BP-5-087-treated mice. While BP-5-087 did not significantly reduce the percentage of GFP+ cells, there was a 41% reduction of spleen weight in BP-5-087-treated mice compared to vehicle-treated controls (p<0.05). Post study analysis revealed BP-5-087 plasma concentrations <1 μM, suggesting that insufficient bioavailability contributed to the modest in vivo effects. To advance the lead optimization of our STAT3 inhibitor series, we instituted a comprehensive screening cascade. We first developed a computational model (quantitative structure-activity relationship, QSAR) to guide and prioritize selection of new inhibitor candidates for synthesis. Compounds are initially ranked using a methanethiosulfonate (MTS)-based cell viability assay in a TKI-resistant, STAT3-dependent CML cell line (AR230R). Inhibition of STAT3 is confirmed using a cell-based STAT3 reporter assay and an in vitro FP-based binding assay. Optimization of potency is balanced by the goals of reducing molecular weight (MW) and calculated LogP (cLogP) compared to BP-5-087 (MW: 694.8; cLogP: 7.3). Compounds with improvements in these categories are then subject to toxicity testing utilizing clonogenic assays with CD34+ CB cells. Non-toxic compounds are evaluated for their pharmacokinetic profile in Balb/c mice and tested for activity in primary samples from CML, AML and MPN patients. These activities have directed us to a lead compound, AM-1-124, which displays significant improvements in potency, MW, cLogP, and in vivo half-life compared to BP-5-087. AM-1-124 had minimal effects in the CB toxicity assay and induced apoptosis in primary AML patient samples at 2-fold lower concentrations than BP-5-087. With AM-1-124 as our current lead compound, we are continuing our iterative evaluation of novel STAT3 inhibitors utilizing our screening cascade. Design and testing of optimized, orally active inhibitors will enable further evaluation of STAT3 as a target in animal models of myeloid leukemia and will justify the clinical development of these compounds for patients in need of new targeted therapies. Disclosures Deininger: BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMA, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy.

This diploma thesis deals with the operational and economic assessment of the installation of new TG3 turbines in the Přerov Heating Plant. The beginning of this thesis deals with a brief theoretical introduction of this investment and describes the classical economic evaluation methods and the Monte Carlo method. Subsequently, the investment project was analyzed and inputs for the economic model were created. The economic model was then evaluated using classical methods and Monte Carlo methods, the results are then compared with each other. Based on the results of the economic evaluation, the most efficient variant of the Přerov Heating Plant technology was chosen.