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Kanta Mukherjee, Nalini. "Analytic description of flame intrinsic instability in one-dimensional model of open–open combustors with ideal and non-ideal end boundaries." International Journal of Spray and Combustion Dynamics 10, no. 4 (August 27, 2018): 287–314. http://dx.doi.org/10.1177/1756827718795518.
Повний текст джерелаАнотація:
This paper is concerned with the theoretical study of thermo-acoustic instabilities in combustors and focuses upon recently discovered flame intrinsic modes. Here, a complete analytical description of the salient properties of intrinsic modes is provided for a linearized one-dimensional model of open–open combustors with temperature and cross-section jump across the flame taken into account. The standard [Formula: see text] model of heat release is adopted, where n is the interaction index and τ is the time lag. We build upon the recent key finding that for a closed–lopen combustor, on the neutral curve, the intrinsic mode frequencies become completely decoupled from the combustor parameters like cross-section jump, temperature jump and flame location. Here, we show that this remarkable decoupling phenomenon holds not only for closed–open combustors but also for all combustors with the ideal boundary conditions (i.e. closed–open, open–open and closed–closed). Making use of this decoupling phenomenon for the open–open combustors, we derive explicit analytic expressions for the neutral curve of intrinsic mode instability on the [Formula: see text] plane as well as for the linear growth/decay rate near the neutral curve taking into account temperature and cross-section jumps. The instability domain on the [Formula: see text] plane is shown to be qualitatively different from that of the closed–open combustor; in open–open combustors it is not confined for large τ. To find the instability domain and growth rate characteristics for non-ideal open–open boundaries the combustor end boundaries are perturbed and explicit analytical formulae derived and verified by numerics.
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Johnson, Luke J., Charlotte M. Norris, Yvonne C. Unruh, Sami K. Solanki, Natalie Krivova, Veronika Witzke, and Alexander I. Shapiro. "Forward modelling of Kepler-band variability due to faculae and spots." Monthly Notices of the Royal Astronomical Society 504, no. 4 (April 29, 2021): 4751–67. http://dx.doi.org/10.1093/mnras/stab1190.
Повний текст джерелаАнотація:
ABSTRACT Variability observed in photometric light curves of late-type stars (on time-scales longer than a day) is a dominant noise source in exoplanet surveys and results predominantly from surface manifestations of stellar magnetic activity, namely faculae and spots. The implementation of faculae in light-curve models is an open problem, with scaling typically based on spectra equivalent to hot stellar atmospheres or assuming a solar-derived facular contrast. We modelled rotational (single period) light curves of active G2, K0, M0, and M2 stars, with Sun-like surface distributions and realistic limb-dependent contrasts for faculae and spots. The sensitivity of light-curve variability to changes in model parameters such as stellar inclination, feature area coverage, spot temperature, facular region magnetic flux density, and active band latitudes is explored. For our light-curve modelling approach we used actress, a geometrically accurate model for stellar variability. actress generates two-sphere maps representing stellar surfaces and populates them with user-prescribed spot and facular region distributions. From this, light curves can be calculated at any inclination. Quiet star limb darkening and limb-dependent facular contrasts were derived from MURaM 3D magnetoconvection simulations using ATLAS9. 1D stellar atmosphere models were used for the spot contrasts. We applied actress in Monte Carlo simulations, calculating light-curve variability amplitudes in the Kepler band. We found that, for a given spectral type and stellar inclination, spot temperature and spot area coverage have the largest effect on variability of all simulation parameters. For a spot coverage of $1{{\ \rm per\ cent}}$, the typical variability of a solar-type star is around 2 parts per thousand. The presence of faculae clearly affects the mean brightness and light-curve shape, but has relatively little influence on the variability.
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Dinis, Ana, Filipe Alves, Cátia Nicolau, Cláudia Ribeiro, Manfred Kaufmann, Ana Cañadas, and Luís Freitas. "Social structure of a population of bottlenose dolphins (Tursiops truncatus) in the oceanic archipelago of Madeira, Portugal." Journal of the Marine Biological Association of the United Kingdom 98, no. 5 (May 30, 2017): 1141–49. http://dx.doi.org/10.1017/s0025315417000650.
Повний текст джерелаАнотація:
In order to investigate social structure, 11 years of individual photo-identification data of bottlenose dolphin were analysed. We examined the type of association indices between pairs of identified individuals; the patterns of affiliation between individual dolphins and the probabilities of association between individuals over time. Between 2001 and 2012, there were 272 encounters which resulted in the identification of 501 individuals. The discovery curve resulting from the photo-identification analysis indicated an open population with regular recruitment of new individuals. All individuals were found to be associated at an association index of <0.05. A total of 291 individuals recorded from 2004 to 2012 were used to assess the temporal pattern of the social structure. The model fit to the Standardized Lagged Association Rate (SLAR) that best described the studied bottlenose dolphin population was ‘casual acquaintances’, and the analysis of associations over time showed a decreasing SLAR curve that falls until reaching the null rate, confirming random associations. The decline of the SLAR curve after ~500 days (1.4 years) suggests disassociation over that time period which can be explained by demographic events such as mortality or emigration. In an open ocean habitat like Madeira this is not unexpected, as there are neither geographic boundaries nor enclosed environments. This population presented a dynamic and fluctuating social structure, where groups change in size and composition. In future conservation efforts this population should be considered as one large community, where individuals associate, disassociate and reassociate with each other over time.
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Grzegorzewski, Jan, Janosch Brandhorst, Kathleen Green, Dimitra Eleftheriadou, Yannick Duport, Florian Barthorscht, Adrian Köller, Danny Yu Jia Ke, Sara De Angelis, and Matthias König. "PK-DB: pharmacokinetics database for individualized and stratified computational modeling." Nucleic Acids Research 49, no. D1 (November 5, 2020): D1358—D1364. http://dx.doi.org/10.1093/nar/gkaa990.
Повний текст джерелаАнотація:
Abstract A multitude of pharmacokinetics studies have been published. However, due to the lack of an open database, pharmacokinetics data, as well as the corresponding meta-information, have been difficult to access. We present PK-DB (https://pk-db.com), an open database for pharmacokinetics information from clinical trials. PK-DB provides curated information on (i) characteristics of studied patient cohorts and subjects (e.g. age, bodyweight, smoking status, genetic variants); (ii) applied interventions (e.g. dosing, substance, route of application); (iii) pharmacokinetic parameters (e.g. clearance, half-life, area under the curve) and (iv) measured pharmacokinetic time-courses. Key features are the representation of experimental errors, the normalization of measurement units, annotation of information to biological ontologies, calculation of pharmacokinetic parameters from concentration-time profiles, a workflow for collaborative data curation, strong validation rules on the data, computational access via a REST API as well as human access via a web interface. PK-DB enables meta-analysis based on data from multiple studies and data integration with computational models. A special focus lies on meta-data relevant for individualized and stratified computational modeling with methods like physiologically based pharmacokinetic (PBPK), pharmacokinetic/pharmacodynamic (PK/PD), or population pharmacokinetic (pop PK) modeling.
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Duc Tran, Anh-Minh, Huu Hoa Tran, and Viet Hung Tran. "Evaluating the Impact of Social Distancing on COVID-19 Spread in Vietnam by using Logistic Growth Curve Model." Journal of Advanced Engineering and Computation 5, no. 3 (September 30, 2021): 177. http://dx.doi.org/10.55579/jaec.202153.328.
Повний текст джерелаАнотація:
The regular increase in COVID-19 cases and deaths has resulted in a worldwide lockdown, quarantine and some restrictions. Due to the lack of a COVID-19 vaccine, it is critical for developing and least developed countries like Vietnam to investigate the efficacy of non-pharmaceutical treatments like social distance or national lockdown in preventing COVID-19 transmission. To address this need, the goal of this study was to develop a clear and reliable model for assessing the impact of social distancing on the spread of coronavirus in Vietnam. For the case study, the Logistic Growth Curve (LGC) model, also known as the Sigmoid model, was chosen to fit COVID-19 infection data from January 23, 2020 to April 30, 2020 in Vietnam. To determine the optimal set of LGC model parameters, we used the gradient descent technique. We were pleasantly surprised to discover that the LGC model accurately predicted COVID-19 community transmission cases over this time period, with very high correlation coefficient value r = 0.993. The results of this study imply that using social distancing technique to flatten the curve of coronavirus disease infections will help minimize the surge in active COVID-19 cases and the spread of COVID-19 infections. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium provided the original work is properly cited.
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Eftekhari, T., E. Berger, B. D. Metzger, T. Laskar, V. A. Villar, K. D. Alexander, G. P. Holder, J. D. Vieira, N. Whitehorn, and P. K. G. Williams. "Extragalactic Millimeter Transients in the Era of Next-generation CMB Surveys." Astrophysical Journal 935, no. 1 (August 1, 2022): 16. http://dx.doi.org/10.3847/1538-4357/ac7ce8.
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Abstract The next generation of wide-field cosmic microwave background (CMB) surveys are uniquely poised to open a new window into time-domain astronomy in the millimeter band. Here, we explore the discovery phase space for extragalactic transients with near-term and future CMB experiments to characterize the expected population. We use existing millimeter-band light curves of known transients (gamma-ray bursts, tidal disruption events, fast blue optical transients (FBOTs), neutron star mergers) and theoretical models, in conjunction with known and estimated volumetric rates. Using Monte Carlo simulations of various CMB survey designs (area, cadence, depth, duration) we estimate the detection rates and the resulting light-curve characteristics. We find that existing and near-term surveys will find tens to hundreds of long-duration gamma-ray bursts (LGRBs), driven primarily by detections of the reverse shock emission, and including off-axis LGRBs. Next-generation experiments (CMB-S4, CMB-HD) will find tens of FBOTs in the nearby universe and will detect a few tidal disruption events. CMB-HD will additionally detect a small number of short gamma-ray bursts, where these will be discovered within the detection volume of next-generation gravitational wave experiments like the Cosmic Explorer.
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Ando, M., and Jacob Sukumaran. "Tribological behavior of composite-steel on rolling/sliding contacts for various loads." International Journal Sustainable Construction & Design 2, no. 1 (November 6, 2011): 29–34. http://dx.doi.org/10.21825/scad.v2i1.20432.
Повний текст джерелаАнотація:
Composites have replaced metals in the bearing industry for the exclusive performances from itsproperties were it can accommodate resins, fabrics and additives. Roll-slip is common behaviors inapplication were non-conformal contact exhibits like bearings, rollers and cams. Two elements control thetribological behavior of the material which is the rolling and the sliding element. Composite-steel contactswere tested using a twin-disc setup with open tribo-system to study the influence of load on the frictionalbehavior of the polymer composites. The contacts were tested with four different loads under 20% slip ratiofor a regular interval of time. The curves from the friction force with respect to different loads follows atendency of linear increase in friction force were the rolling resistance is the dominating mechanism. For thegiven condition the macro level investigations shows the absence of transfer layer on the steelcounterparts. The tendency of the friction curve and the micrograph explicitly deliberates the involvement ofabrasion and adhesion in the harder polymer from metal counterpart. The temperature variable is isolatedin case of the above research. The examination of the contact surface reveals the formation of craters onthe junction of polymer and textile.
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Calatrava, Carlos Garcia, Yolanda Becerra Fontal, Fernando M. Cucchietti, and Carla Diví Cuesta. "NagareDB: A Resource-Efficient Document-Oriented Time-Series Database." Data 6, no. 8 (August 13, 2021): 91. http://dx.doi.org/10.3390/data6080091.
Повний текст джерелаАнотація:
The recent great technological advance has led to a broad proliferation of Monitoring Infrastructures, which typically keep track of specific assets along time, ranging from factory machinery, device location, or even people. Gathering this data has become crucial for a wide number of applications, like exploration dashboards or Machine Learning techniques, such as Anomaly Detection. Time-Series Databases, designed to handle these data, grew in popularity, becoming the fastest-growing database type from 2019. In consequence, keeping track and mastering those rapidly evolving technologies became increasingly difficult. This paper introduces the holistic design approach followed for building NagareDB, a Time-Series database built on top of MongoDB—the most popular NoSQL Database, typically discouraged in the Time-Series scenario. The goal of NagareDB is to ease the access to three of the essential resources needed to building time-dependent systems: Hardware, since it is able to work in commodity machines; Software, as it is built on top of an open-source solution; and Expert Personnel, as its foundation database is considered the most popular NoSQL DB, lowering its learning curve. Concretely, NagareDB is able to outperform MongoDB recommended implementation up to 4.7 times, when retrieving data, while also offering a stream-ingestion up to 35% faster than InfluxDB, the most popular Time-Series database. Moreover, by relaxing some requirements, NagareDB is able to reduce the disk space usage up to 40%.
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Darolia, Aman, and Rajender Singh Chhillar. "Analyzing Three Predictive Algorithms for Diabetes Mellitus Against the Pima Indians Dataset." ECS Transactions 107, no. 1 (April 24, 2022): 2697–704. http://dx.doi.org/10.1149/10701.2697ecst.
Повний текст джерелаАнотація:
Diabetes mellitus is a metabolic disease in which the pancreas fails to produce enough insulin required for the processing of blood glucose. Most medical institutions analyze Electronic Health Records (EHRs) manually and then predict whether the patient is diabetic or not. The objective of this work is to classify diabetes and non-diabetes patients using predictive algorithms/techniques. These algorithms provide cost, time, and effort-effective solutions for the prognosis and diagnosis of diabetes mellitus. In this work, popular algorithms like Artificial Neural Network (ANN), Random Forest (RF), and Logistic Regression (LR) have been used against the PIMA Indians. Dataset and analysis has been carried out on open-source software WEKA. In addition, this paper provided state-of-the-art by various researchers related to the said topic. This work concluded that LR outperforms other algorithms, with the accuracy of 77.10%, but in the case of area under the curve (0.83), both LR and RF perform equally well.
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Bu, Ling, Shengjiang Quan, Jiarong Han, Feng Li, Qingzhao Li, and Xiaohong Wang. "On-Site Traversal Fractional Open Circuit Voltage with Uninterrupted Output Power for Maximal Power Point Tracking of Photovoltaic Systems." Electronics 9, no. 11 (October 29, 2020): 1802. http://dx.doi.org/10.3390/electronics9111802.
Повний текст джерелаАнотація:
The fractional open-circuit voltage (FOCV) method is commonly adopted to track maximal power point of photovoltaic systems due to easy implementation and cost-effectiveness. However, the FOCV method is confronted with unstable output power and limited tracking accuracy. This paper proposes a novel on-site traversal FOCV method with uninterrupted output power and increased tracking accuracy through simulation and experimental verifications. Each solar cell is connected with a bypass diode and switching circuitry, so that specific solar cell can be traced and measured consecutively for determining its maximal power point (MPP). MATLAB/Simulink simulation results show that, in the time-varying irradiance case, the proposed method achieves a low ripple factor of 0.13% in 11–13 h and 0.88% in 9–15 h, under the typical 24 h irradiance curve. In the spatial-varying irradiance case, the accuracy of the proposed method reaches 99.85%. Compared with other FOCV methods, like pilot cell and semi pilot cell methods, the proposed method is of higher accuracy with a limited ripple effect. Experimental results show that this method can effectively trace different output performance of specific solar cell while generating stable output voltage with a low ripple factor of 1.55%, proving its compatibility with distributed sensing and applicability in smart photovoltaic systems.
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Haslund-Krog, Sissel Sundell, Maria Schmidt, Ron Mathot, Andreas Kryger Jensen, Inger Merete Jørgensen, and Helle Holst. "Pharmacokinetics of prednisolone in children: an open-label, randomised, two-treatment cross-over trial investigating the bioequivalence of different prednisolone formulations in children with airway disease." BMJ Paediatrics Open 3, no. 1 (September 2019): e000520. http://dx.doi.org/10.1136/bmjpo-2019-000520.
Повний текст джерелаАнотація:
IntroductionOne in three Danish children under 3 years of age experience asthma-like symptoms, and one-third will later be diagnosed with asthma. Oral prednisolone is used in various formulations to treat acute asthma. However, the potential differences in bioequivalence between these formulations have never been examined in children despite interchangeable use in clinical practice.Methods and analysisAn open-label, randomised, two-treatment cross-over trial investigating the bioequivalence of different prednisolone formulations in children with airway disease.The included patients (6 months–11 years of age) are admitted to the Department of Paediatric and Adolescent Medicine Nordsjællands University Hospital, Hillerød, with asthma or asthma-like symptoms.The primary objective is to assess the bioequivalence between different prednisolone formulations herein area under the concentration time curve, Cmax and Tmax using saliva samples. The secondary objectives are to evaluate tolerability (five-point face scale), adverse events and severity of the disease. If the patient has an intravenous access for other purposes, the saliva samples will be validated with plasma samples.A total of 66 evaluable patients are needed according to European Medicines Agency Guideline on bioequivalence.Ethics and disseminationTraditional pharmacokinetic trials are burdensome due to the extent of blood samples necessary to capture the time-dependant drug profile. Saliva sampling is far more acceptable for paediatric patients. In addition, this trial adheres to standard dosing strategies. No additional venepunctures are performed, and no additional prednisolone doses are administered.Guidelines for paediatric bioequivalence trials are warranted.Trial registration numberThe Danish Medicines Agency EudraCT: 2017-003590-33, The Ethics Committee case no: H-17027252, and the Danish Data Protection Agency: BFH-2017–103, I-Suite no.: 05935.
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Vallent, Thokozani Felix, Damien Hanyurwimfura, and Chomora Mikeka. "Efficient Certificate-Less Aggregate Signature Scheme with Conditional Privacy-Preservation for Vehicular Ad Hoc Networks Enhanced Smart Grid System." Sensors 21, no. 9 (April 21, 2021): 2900. http://dx.doi.org/10.3390/s21092900.
Повний текст джерелаАнотація:
Vehicular Ad hoc networks (VANETs) as spontaneous wireless communication technology of vehicles has a wide range of applications like road safety, navigation and other electric car technologies, however its practicability is greatly hampered by cyber-attacks. Due to message broadcasting in an open environment during communication, VANETs are inherently vulnerable to security and privacy attacks. However to address the cyber-security issues with optimal computation overhead is a matter of current security research challenge. So this paper designs a secure and efficient certificate-less aggregate scheme (ECLAS) for VANETs applicable in a smart grid scenario. The proposed scheme is based on elliptic curve cryptography to provide conditional privacy-preservation by incorporating usage of time validated pseudo-identification for communicating vehicles besides sorting out the KGC (Key Generation Center) escrow problem. The proposed scheme is comparatively more efficient to relevant related research work because it precludes expensive computation operations likes bilinear pairings as shown by the performance evaluation. Similarly, communication cost is within the ideal range to most related works while considering the security requirements of VANETs system applicable in a smart grid environment.
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Abenavoli, Alessandra, Mattia Lorenzo DiFrancesco, Indra Schroeder, Svetlana Epimashko, Sabrina Gazzarrini, Ulf Peter Hansen, Gerhard Thiel, and Anna Moroni. "Fast and slow gating are inherent properties of the pore module of the K+ channel Kcv." Journal of General Physiology 134, no. 3 (August 31, 2009): 219–29. http://dx.doi.org/10.1085/jgp.200910266.
Повний текст джерелаАнотація:
Kcv from the chlorella virus PBCV-1 is a viral protein that forms a tetrameric, functional K+ channel in heterologous systems. Kcv can serve as a model system to study and manipulate basic properties of the K+ channel pore because its minimalistic structure (94 amino acids) produces basic features of ion channels, such as selectivity, gating, and sensitivity to blockers. We present a characterization of Kcv properties at the single-channel level. In symmetric 100 mM K+, single-channel conductance is 114 ± 11 pS. Two different voltage-dependent mechanisms are responsible for the gating of Kcv. “Fast” gating, analyzed by β distributions, is responsible for the negative slope conductance in the single-channel current–voltage curve at extreme potentials, like in MaxiK potassium channels, and can be explained by depletion-aggravated instability of the filter region. The presence of a “slow” gating is revealed by the very low (in the order of 1–4%) mean open probability that is voltage dependent and underlies the time-dependent component of the macroscopic current.
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Heyrani, Mehdi, Abdolmajid Mohammadian, Ioan Nistor, and Omerul Faruk Dursun. "Application of Numerical and Experimental Modeling to Improve the Efficiency of Parshall Flumes: A Review of the State-of-the-Art." Hydrology 9, no. 2 (February 6, 2022): 26. http://dx.doi.org/10.3390/hydrology9020026.
Повний текст джерелаАнотація:
One of the primary steps in managing the flow in an open channel is determining its properties. Empirical equations are developed to provide further information regarding the flow in open channels. Obtaining such experimental equations is expensive and time consuming; therefore, alternative solutions have been sought. Over the last century, the Parshall flume, a static measuring device with no moving parts, has played a significant role in measuring the flow in open channels. Many researchers have focused their interest on studying the application of Parshall flumes in various fields like irrigation and wastewater management. Although various scholars used experimental results to enhance the rating equation of the Parshall flume, others used an alternative source of data to recalibrate the height–discharge relation equation using numerical simulation. Computational Fluid Dynamic (CFD) software is becoming popular nowadays as computing hardware has advanced significantly within the last few decades, making it possible to go beyond the limited resolution that was experienced in the past. Multiple CFD models, depending on their availability, either open-source or commercially licensed, have been used to perform numerical simulations on different configurations of flumes, especially Parshall flumes, to produce water level results. Regarding various CFD tools that have been used, i.e., FLOW-3D, Ansys Fluent, or OpenFOAM, after precise calibration with experimental data, it has been determined that the output is reliable and can be implemented to the actual scenarios. The benefit of using this technique to produce results is the ability of the CFD approach to adjust the initial conditions, like flow velocity or structural geometry, where necessary. With respect to channel size and the condition of the site where the flume is located, the choices are narrowed to the specific Parshall flume suitable to the situation. It is not always possible to select the standard Parshall flume; therefore, engineers provide some modification to the closest flume size and provide a new rating curve to produce accurate flowrates. This review has been performed on the works of a number of scholars who targeted the application of numerical simulation and physical experimental data in Parshall flumes to either enhance the existing rating equation or propose further modification to the structure’s geometry.
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Haque, Raqeeb M., Gregory M. Mundis, Yousef Ahmed, Tarek Y. El Ahmadieh, Michael Y. Wang, Praveen V. Mummaneni, Juan S. Uribe, et al. "Comparison of radiographic results after minimally invasive, hybrid, and open surgery for adult spinal deformity: a multicenter study of 184 patients." Neurosurgical Focus 36, no. 5 (May 2014): E13. http://dx.doi.org/10.3171/2014.3.focus1424.
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Object Various surgical approaches, including open, minimally invasive, and hybrid techniques, have gained momentum in the management of adult spinal deformity. However, few data exist on the radiographic outcomes of different surgical techniques. The objective of this study was to compare the radiographic and clinical outcomes of the surgical techniques used in the treatment of adult spinal deformity. Methods The authors conducted a retrospective review of two adult spinal deformity patient databases, a prospective open surgery database and a retrospective minimally invasive surgery (MIS) and hybrid surgery database. The time frame of enrollment in this study was from 2007 to 2012. Spinal deformity patients were stratified into 3 surgery groups: MIS, hybrid surgery, and open surgery. The following pre- and postoperative radiographic parameters were assessed: lumbar major Cobb angle, lumbar lordosis, pelvic incidence minus lumbar lordosis (PI−LL), sagittal vertical axis, and pelvic tilt. Scores on the Oswestry Disability Index (ODI) and a visual analog scale (VAS) for both back and leg pain were also obtained from each patient. Results Of the 234 patients with adult spinal deformity, 184 patients had pre- and postoperative radiographs and were thus included in the study (MIS, n = 42; hybrid, n = 33; open, n = 109). Patients were a mean of 61.7 years old and had a mean body mass index of 26.9 kg/m2. Regarding radiographic outcomes, the MIS group maintained a significantly smaller mean lumbar Cobb angle (13.1°) after surgery compared with the open group (20.4°, p = 0.002), while the hybrid group had a significantly larger lumbar curve correction (26.6°) compared with the MIS group (18.8°, p = 0.045). The mean change in the PI−LL was larger for the hybrid group (20.6°) compared with the open (10.2°, p = 0.023) and MIS groups (5.5°, p = 0.003). The mean sagittal vertical axis correction was greater for the open group (25 mm) compared with the MIS group (≤ 1 mm, p = 0.008). Patients in the open group had a significantly larger postoperative thoracic kyphosis (41.45°) compared with the MIS patients (33.5°, p = 0.005). There were no significant differences between groups in terms of pre- and postoperative mean ODI and VAS scores at the 1-year follow-up. However, patients in the MIS group had much lower estimated blood loss and transfusion rates compared with patients in the hybrid or open groups (p < 0.001). Operating room time was significantly longer with the hybrid group compared with the MIS and open groups (p < 0.001). Major complications occurred in 14% of patients in the MIS group, 14% in the hybrid group, and 45% in the open group (p = 0.032). Conclusions This study provides valuable baseline characteristics of radiographic parameters among 3 different surgical techniques used in the treatment of adult spinal deformity. Each technique has advantages, but much like any surgical technique, the positive and negative elements must be considered when tailoring a treatment to a patient. Minimally invasive surgical techniques can result in clinical outcomes at 1 year comparable to those obtained from hybrid and open surgical techniques.
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Govindan, Ramaswamy, Amanda Rose Townsend, Kathy D. Miller, Inderjit Mehmi, Yasutoshi Kuboki, Ecaterina Elena Dumbrava, Erika P. Hamilton, et al. "Trial in progress: A phase 1, multicenter, open-label, dose-exploration and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and efficacy of AMG650 in subjects with advanced solid tumors." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS5600. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps5600.
Повний текст джерелаАнотація:
TPS5600 Background: KIF18A is a mitotic kinesin motor protein that regulates chromosome positioning during cell division and is overexpressed in a subset of human cancers. TP53 mutant unstable aneuploid cancer cells with chromosomal instability (CIN) features are dependent on KIF18A motor activity to prevent lethal multipolar cell division. Preclinical data demonstrate that treatment with AMG 650; an oral, first in class, selective small molecule inhibitor of KIF18A may be safe and tolerable. We are conducting a first-in-human phase 1 study with AMG 650 in adult subjects with locally advanced or metastatic solid tumors with TP53MUT, triple negative breast cancer (TNBC), high grade serous ovarian cancer (HGSOC) or serous like endometrial cancers and other solid tumors. Methods: In this phase 1, multicentric, dose escalation and dose expansion study we evaluate the safety and tolerability of AMG 650 monotherapy in patients with advanced/metastatic solid tumors (NCT04293094). The main objective is to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) based on emerging safety, efficacy, and pharmacodynamics (PD) data prior to reaching the MTD. Key inclusion criteria include the presence of measurable disease and diagnosis of advanced/metastatic triple negative breast cancer (TNBC), high-grade serous ovarian cancer (HGSOC), serous-like endometrial cancer or other solid tumors with documented TP53 mutations. In the dose expansion phase, participants with locally advanced or metastatic TNBC or HGSOC will be treated with the preliminary RP2D identified from the dose exploration part of the study. Primary endpoints include the incidence of Dose Limiting Toxicities (DLTs),Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Treatment-related Adverse Events and the evaluation of the number of participants who experience a clinically significant change from baseline in vital signs, electrocardiogram and laboratory tests parameters. Secondary endpoints include Objective Response Rate, Duration of Response, Progression-free Survival, Clinical Benefit Rate, Time to Response, Time to Progression, Overall Survival (OS), Maximum Plasma Concentration (Cmax) of AMG 650, Time to Maximum Plasma Concentration (Tmax) of AMG 650 as well as Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval for AMG 650. Continuous monitoring of toxicity is conducted. The study began enrolling pts in March 2020 and is ongoing. For more information, please contact Amgen Medical Information: medinfo@amgen.com Clinical trial information: NCT04293094.
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Sharif, Mahjabeen, Dilshad Ahmed Khan, Kulsoom Farhat, Mudassar Noor, Mohammad Asghar Khan, and Saima Rafique. "Pharmacokinetics and bioavailability of tocotrienols in healthy human volunteers: a systematic review." Journal of the Pakistan Medical Association 73, no. 3 (February 15, 2023): 603–10. http://dx.doi.org/10.47391/jpma.6008.
Повний текст джерелаАнотація:
Objectives: To evaluate and compare the pharmacokinetic parameters, especially bioavailability, of annatto-based tocotrienol with palm tocotrienol-rich fraction in healthy human volunteers for better therapeutic outcome. Method: The systematic review was conducted between April and August 2021 in accordance with the Preferred Reporting Items for Systematic Review and Meta Analysis guidelines, and comprised search on PubMed, Google Scholar, Pakmedinet and Google search engines for open-label or double-blind randomised controlled trials involving healthy human volunteers published till January 2021. Key words used included annatto-based tocotrienol, palm tocotrienol-rich fraction, absorption and bioavailability. Boolean operators were also used, like tocotrienol AND bioavailability, annatto tocotrienol AND pharmacokinetics. Results: Of the 230 articles identified, 50(21.7%) articles met the eligibility criteria. Of them, 7(14%) were selected for data extraction and detailed analysis. Pharmacokinetic parameters of annatto-based tocotrienol were better than palm-derived tocotrienol. Oral administration of all the isomers of annatto-based tocotrienols resulted in dose-dependent increase in area under curve and plasma levels. Amongst all the isomers of annatto-based and palm-derived tocotrienol, delta isomer of annatto-based tocotrienol had the highest bioavailability with area under curve 7450±89 ng/ml, time to reach peak plasma levels 4 hours, maximum plasma concentration 1591±43 ng/nl and elimination half-life 2. 68 ±0.29 hrs. Pharmacokinetic parameters of delta isomer of annatto-based tocotrienol was greater than palm tocotrienol-rich fraction. Conclusion: Bioavailability of annatto-based tocotrienol was better than that of palm-derived tocotrienol-rich fraction. Delta isomer of annatto-based tocotrienol had the highest bioavailability amongst all isomers of tocotrienol.
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Panagiotopoulos, A., A. Židonis, G. A. Aggidis, J. S. Anagnostopoulos, and D. E. Papantonis. "Flow Modeling in Pelton Turbines by an Accurate Eulerian and a Fast Lagrangian Evaluation Method." International Journal of Rotating Machinery 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/679576.
Повний текст джерелаАнотація:
The recent development of CFD has allowed the flow modeling in impulse hydro turbines that includes complex phenomena like free surface flow, multifluid interaction, and unsteady, time dependent flow. Some commercial and open-source CFD codes, which implement Eulerian methods, have been validated against experimental results showing satisfactory accuracy. Nevertheless, further improvement of accuracy is still a challenge, while the computational cost is very high and unaffordable for multiparametric design optimization of the turbine’s runner. In the present work a CFD Eulerian approach is applied at first, in order to simulate the flow in the runner of a Pelton turbine model installed at the laboratory. Then, a particulate method, the Fast Lagrangian Simulation (FLS), is used for the same case, which is much faster and hence potentially suitable for numerical design optimization, providing that it can achieve adequate accuracy. The results of both methods for various turbine operation conditions, as also for modified runner and bucket designs, are presented and discussed in the paper. In all examined cases the FLS method shows very good accuracy in predicting the hydraulic efficiency of the runner, although the computed flow evolution and the torque curve exhibit some systematic differences from the Eulerian results.
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Robert, Francisco, George Blumenschein, Roy S. Herbst, Frank V. Fossella, Jennifer Tseng, Mansoor N. Saleh, and Michael Needle. "Phase I/IIa Study of Cetuximab With Gemcitabine Plus Carboplatin in Patients With Chemotherapy-Naïve Advanced Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 23, no. 36 (December 20, 2005): 9089–96. http://dx.doi.org/10.1200/jco.2004.00.1438.
Повний текст джерелаАнотація:
Purpose This multicenter, open-label, phase I/IIa study was undertaken to establish the safety/toxicity profile of cetuximab in combination with gemcitabine and carboplatin in patients with chemotherapy-naïve, epidermal growth factor receptor–positive, stage IV non–small-cell lung cancer. Secondary objectives were to gather preliminary evidence of efficacy including tumor response rate, time to progression, and overall survival. Patients and Methods Thirty-five patients received a total of 264 3-week cycles of treatment with cetuximab, carboplatin, and gemcitabine. An initial dose of cetuximab 400 mg/m2 intravenously was administered the first week, followed by weekly doses of 250 mg/m2. Carboplatin (area under the curve = 5, day 1) and gemcitabine 1,000 mg/m2 on days 1 and 8 were administered every 3 weeks. Patients were evaluated for tumor response after every two cycles of therapy. Results The most frequently reported adverse events related to cetuximab included an acne-like rash (88.6%), dry skin (34.3%), asthenia and skin disorders (31.4%), mucositis/stomatitis (25.7%), fever/chills (20%), and nausea/vomiting (17.1%). The majority of these toxicities were mild to moderate. One patient withdrew from the study because of a grade 3 allergic reaction. Myelosuppression was the most frequently observed toxicity related to chemotherapy. Responses among 35 assessable patients included 10 partial responses (28.6%). Twenty-one patients had stable disease. The median time to progression was 165 days, and the median overall survival was 310 days. Conclusion The combination of cetuximab, carboplatin, and gemcitabine was well tolerated with an acceptable toxicity profile. Most grade 3 adverse events were attributable to chemotherapy. The response rate and median survival are encouraging and warrant additional investigation.
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Popa, Laura, Florentina Mușat, D. N. Păduraru, Alexandra Bolocan, and O. Andronic. "IS LAPAROSCOPIC SURGERY BECOMING THE FIRST CHOICE IN TREATMENT OF PERFORATED PEPTIC ULCER?" Romanian Journal of Emergency Surgery 2, no. 1 (October 18, 2020): 30–35. http://dx.doi.org/10.33695/rojes.v2i1.22.
Повний текст джерелаАнотація:
Perforated peptic ulcer (PPU), a significant complication of peptic ulcer disease, has proven to be associated with high rates of mortality and morbidity and to this day, it remains a clear indication of emergency surgery. Whilst open repair remains a feasible treatment option for this complication, the development of laparoscopic surgery has brought along new perspectives, by revealing the benefits and drawbacks of this procedure and therefore raising the question whether it should be the first choice in treatment of a PPU. A literature search was performed using PubMed, Web of Science and Scopus, with the selection of relevant articles from the last 15 years. By comparing the two surgical approaches, conventional and laparoscopic, we aimed to identify the reasons laparoscopy is gaining ground as a mean of treatment of a PPU. Outcomes such as hospital stay, complication rates, use of postoperative analgesics and visual analogue scale favored laparoscopy. The most heterogeneous result was dictated by the operation time, which seems to correlate with multiple factors, a major one being the learning curve and skills this procedure requires. In addition, a significant number of papers had developed patient inclusion and exclusion criteria, which impacted the results of outcomes like morbidity and mortality. There is a lot of evidence that points to laparoscopy becoming the preferred method of treatment of a PPU, however further research is needed in order to reach a consensus.
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Xie, Chenyang, Xuejie Li, Fan Sun, Junsoo HAN, and Kevin Ogle. "The Spontaneous Repassivation of Cr Containing Steels and Multi-Principal Element Alloys." ECS Meeting Abstracts MA2022-02, no. 11 (October 9, 2022): 735. http://dx.doi.org/10.1149/ma2022-0211735mtgabs.
Повний текст джерелаАнотація:
The corrosion resistance of an alloy in most environments will depend on its ability to spontaneously passivate at the corrosion potential. This is especially true for localized forms of corrosion such as occur in acidic, occluded environments during pitting and crevice corrosion. In the laboratory however, the kinetics of passivation are mainly investigated using electrochemical methods that require polarization of the material via an external power source. Spontaneous passivation cannot directly be observed by this approach. It is therefore of interest to investigate the repassivation phenomena as it occurs at open circuit, driven by the oxidizing agents present in the electrolyte. To this end, we have recently developed a methodology to determine the kinetics of spontaneous passivation using element-resolved electrochemistry (atomic spectroelechemistry, or ASEC) [1-3]. Passivation may be measured by first disrupting the original passive film using an electrochemical perturbation and then monitoring the corrosion rate as a function of time on an element-by-element basis. As the passive film reforms, the corrosion rate decreases allowing a real time monitoring of film formation. The perturbation may be either a cathodic pulse to reduce the passive film as in a conventional polarization curve experiment, or it may be an anodic pulse into the transpassive domain. In addition, the contribution of the individual alloying elements to dissolution and to passive film formation may be quantitatively accessed thereby yielding insight into one of the fundamental questions for engineering new alloys - what is the specific role of the different alloying elements? For example, it is widely recognized that for the Cr containing alloys, Cr is the primary constituent of the passive film, at least when Cr is above about 12%. However, the presence of other elements may affect the efficiency of Cr-oxide film formation, some like Mo in a beneficial way [2], others like Mn in a negative way [3]. Via a simple mass balance, the elemental dissolution rate profiles may be transformed into a time resolved elemental surface enrichment profile. This allows a direct look into the role of the alloying elements. The Figure gives an example of this approach based on the results from Ref. 3. The system under investigation was the high entropy Cantor alloy containing alloyed nitrogen in a sulfuric acid solution. The left-hand side gives the open dissolution rate for an experimental sequence of (a) open circuit, (b) cathodic activation (300 s at -0.8 V vs. SCE), (c) repassivation at open circuit (300 s). Repassivation is indicated by the initially large corrosion rate (active state) followed by the decrease of the corrosion rate as the passive film reforms. The contribution of the individual alloying elements is shown all of which dissolved congruently with the exception of Cr which was below the congruent level (black line) indicative of Cr surface enrichment. The right hand side gives the quantity of Cr enriched on the surface during the sequence calculated by mass balance. Cr dissolves during the cathodic activation but reforms as soon as the potential is released. Also shown is the Cr enrichment during an anodic step to 0.4 V which leads to a more rapid and significant build-up of surface Cr. This presentation will review the methodology of spontaneous passivation measurements for both austenitic stainless steel (304L) and for the high entropy Cantor alloy (equimolar NiFeCrCoMn) with variable Mn content. In particular, we will focus on the differences between repassivation following cathodic activation and transpassive activation. The mechanisms of spontaneous repassivation will be discussed with an emphasis on how the alloying elements influence repassivation under these two conditions. 1) K Ogle “Atomic emission spectroelectrochemistry: real-time rate measurements of dissolution, corrosion, and passivation”, Corrosion 75 (2019)1398-1419. Open access. 2) X Li, J D Henderson, F P Filice, D Zagidulin, M C Biesinger, F Sun, B Qian, D W Shoesmith, J J Noël, K Ogle, “The contribution of Cr and Mo to the passivation of Ni22Cr and Ni22Cr10Mo alloys in sulfuric acid”, Corrosion Science 176, (2020) 109015. 3) X Li, P Zhou, H Feng, Z Jiang, H Li, K Ogle, “Spontaneous passivation of the CoCrFeMnNi high entropy alloy in sulfuric acid solution: The effects of alloyed nitrogen and dissolved oxygen”, Corrosion Science 196(2022)110016. Figure 1
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Zhang, Yinglang, Zhe Zhang, Wei Zhang, Hailong Hu, and Guochang Bao. "Upregulated Transcription Factor PITX1 Predicts Poor Prognosis in Kidney Renal Clear Cell Carcinoma-Based Bioinformatic Analysis and Experimental Verification." Disease Markers 2021 (November 23, 2021): 1–19. http://dx.doi.org/10.1155/2021/7694239.
Повний текст джерелаАнотація:
Paired-like homeodomain transcription factor 1 (PITX1) is involved in numerous biological processes, including cell growth, progression, and invasion in various malignant tumors. Nevertheless, the relationship between PITX1 and kidney renal clear cell carcinoma (KIRC) remains unclear. The clinical role and functions of PITX1 were analyzed by integrating multiple open-access online datasets. Further experimental verification was performed via quantitative real-time PCR (qRT-PCR) to detect the expression of PITX1 in 10 pairs of KIRC tissues. Our results revealed that PITX1 mRNA was overexpressed in tumor tissues compared with normal tissues in the TCGA-KIRC database ( p < 0.001 ) and numerous independent cohorts ( p < 0.05 ). Further, high expression of PITX1 mRNA was detected in KIRC tissues compared with adjacent normal tissues in our center by qRT-PCR ( N = 10 , p < 0.05 ). Logistic regression analysis demonstrated that the PITX1 level was positively associated with KIRC patients, T and M stages, histologic grade, and pathologic stage (all p < 0.05 ). Survival analysis showed that upregulation of PITX1 mRNA was associated with poor overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) (all p < 0.05 ). Univariate/multivariate Cox hazard regression analysis revealed that PITX1 was an independent risk factor for OS in patients with KIRC ( HR = 1.998 , p = 0.003 ). Accordingly, the time-independent receiver operating characteristic (ROC) curve confirmed that PITX1 had good predictive efficacy for OS and DSS. Meanwhile, a prediction model constructed by nomogram was used to predict the OS of KIRC patients, and the calibration plot indicated this model shows high accuracy. We also revealed some downstream target genes of PITX1-related signaling pathways. Our finding suggested that high PITX1 mRNA expression may act as an independent predictive factor of poor prognosis in patients with KIRC. The prognostic model based on the nomogram would be instrumental in evaluating the survival rate in KIRC patients.
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Jamieson, Brian D., Sabrina Ciric, and Prabhavathi Fernandes. "Safety and Pharmacokinetics of Solithromycin in Subjects with Hepatic Impairment." Antimicrobial Agents and Chemotherapy 59, no. 8 (April 13, 2015): 4379–86. http://dx.doi.org/10.1128/aac.04652-14.
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ABSTRACTSolithromycin, a new macrolide and the first fluoroketolide, is in late-stage clinical development and, like older macrolides, is primarily metabolized and excreted through liver-dependent mechanisms. This study evaluated the safety and pharmacokinetics of solithromycin in patients with chronic liver disease. This open-label, multiple-dose study in subjects with hepatic impairment and in healthy control subjects (matched for age, weight, and sex) enrolled 8 Child-Pugh class A (mild), 8 class B (moderate), and 8 class C (severe) patients and 9 healthy controls. Subjects (n= 33) received one 800-mg dose on day 1 followed by once-daily doses of 400 mg on days 2 through 5. The most commonly reported adverse events were mild diarrhea and mild headache, and no significant differences were noted between hepatically impaired subjects and healthy controls. The pharmacokinetics of plasma solithromycin in subjects with mild and moderate impairment was similar to that in control subjects. In subjects with severe impairment, total exposure to solithromycin at steady state (area under the plasma concentration-time curve [AUC0–tau]) was decreased compared to that in control subjects, which may have been related to the higher body mass index of individuals in this group. No greater accumulation was noted in any hepatically impaired cohort on day 5 compared to that in control subjects. No decrease in dosage is therefore needed when administering solithromycin to patients with mild, moderate, or severe hepatic impairment. Solithromycin was well tolerated in this patient population, and no significant differences in safety, compared to healthy controls, were noted.
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Langer, Corey J., Silvia Novello, Keunchil Park, Maciej Krzakowski, Daniel D. Karp, Tony Mok, Rebecca J. Benner, Judith R. Scranton, Anthony J. Olszanski, and Jacek Jassem. "Randomized, Phase III Trial of First-Line Figitumumab in Combination With Paclitaxel and Carboplatin Versus Paclitaxel and Carboplatin Alone in Patients With Advanced Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 32, no. 19 (July 1, 2014): 2059–66. http://dx.doi.org/10.1200/jco.2013.54.4932.
Повний текст джерелаАнотація:
Purpose Figitumumab (CP-751,871), a fully human immunoglobulin G2 monoclonal antibody, inhibits the insulin-like growth factor 1 receptor (IGF-1R). Our multicenter, randomized, phase III study compared figitumumab plus chemotherapy with chemotherapy alone as first-line treatment in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with stage IIIB/IV or recurrent NSCLC disease with nonadenocarcinoma histology received open-label figitumumab (20 mg/kg) plus paclitaxel (200 mg/m2) and carboplatin (area under the concentration-time curve, 6 mg · min/mL) or paclitaxel and carboplatin alone once every 3 weeks for up to six cycles. The primary end point was overall survival (OS). Results Of 681 randomly assigned patients, 671 received treatment. The study was closed early by an independent Data Safety Monitoring Committee because of futility and an increased incidence of serious adverse events (SAEs) and treatment-related deaths with figitumumab. Median OS was 8.6 months for figitumumab plus chemotherapy and 9.8 months for chemotherapy alone (hazard ratio [HR], 1.18; 95% CI, 0.99 to 1.40; P = .06); median progression-free survival was 4.7 months (95% CI, 4.2 to 5.4) and 4.6 months (95% CI, 4.2 to 5.4), respectively (HR, 1.10; P = .27); the objective response rates were 33% and 35%, respectively. The respective rates of all-causality SAEs were 66% and 51%; P < .01). Treatment-related grade 5 adverse events were also more common with figitumumab (5% v 1%; P < .01). Conclusion Adding figitumumab to standard chemotherapy failed to increase OS in patients with advanced nonadenocarcinoma NSCLC. Further clinical development of figitumumab is not being pursued.
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Gana, S. M., P. A. Onyeyili, B. Umaru, H. J. Fomnya, S. I. Ngulde, and A. L. Karatu. "Effect of intramuscular administration of oxytetracycline on serum kinetics of diminazene aceturate in healthy male Sahel goats." Sokoto Journal of Veterinary Sciences 20, no. 3 (October 17, 2022): 197–204. http://dx.doi.org/10.4314/sokjvs.v20i3.6.
Повний текст джерелаАнотація:
Serum kinetics of diminazene aceturate following intramuscular (IM) administration of diminazene aceturate alone at 3.5 mg/kg and its combination with oxytetracycline at 20 mg/kg were evaluated in 6 healthy male Sahel goats to ascertain the effect of oxytetracycline on serum concentration and pharmacokinetic parameters of diminazene aceturate. Two groups (A and B) of three goats each were used, and oxytetracycline was administered 30 minutes prior to diminazene aceturate administration. Blood samples were collected at various intervals (0.17 h – 72 h) post-drug administration, and diminazene serum concentrations were measured using the method of Klatt and Hadju. Kinetic determinants were calculated employing a two-compartment open model. Mean serum concentrations of diminazene aceturate of 2.43 ± 0.95 μg/ml and 1.73 ± 0.44 μg/ml at 0.17 h were measured in groups A and B, respectively. These serum concentrations were found to increase until a peak concentration of 6.91 ± 0.59 μg/ml and 7.55 ± 1.20 μg/ml were reached at 2.0 h in groups A and B, respectively. The peak concentrations subsequently decreased at 72 h post diminazene aceturate administration with serum concentrations of 0.00 ± 0.00 and 0.32 ± 0.28 μg/ml in groups A and B, respectively. Pharmacokinetics parameters like the volume of distribution (Vd), elimination half-life (T½β), concentration maximum (Cmax), absorption rate constant (α), and area under the curve from 0 to 72 h (AUC0 – 72) were significantly higher in goats treated with diminazene aceturate and oxytetracycline combination while total body clearance (Cl), and elimination rate constant (β), were significantly higher in goats treated with diminazene aceturate alone. The mean residence time (MRT) of diminazene aceturate increased from 19.70 ± 2.53 h in diminazene aceturate treatment to 25.11 ± 1.81 h in diminazene aceturate and oxytetracycline treatment. Oxytetracycline was therefore found to alter the elimination pattern of diminazene aceturate in oxytetracycline pre-treated goats.
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Gopalakrishnan, S., A. Krebs-Brown, M. Nogueira Filho, Y. Kuroki, A. Bachmann, A. Becker, F. Schippers, M. Fluck, Ö. Yalkinoglu, and L. Klopp-Schulze. "POS0755 SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF A SINGLE ORALLY ADMINISTERED DOSE OF ENPATORAN IN A PHASE I STUDY OF HEALTHY JAPANESE AND CAUCASIAN PARTICIPANTS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 663.2–664. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2860.
Повний текст джерелаАнотація:
BackgroundEnpatoran, a novel, highly selective and potent dual toll-like receptor (TLR) 7 and TLR8 inhibitor, is in development for the treatment of autoimmune disorders including systemic and cutaneous lupus erythematosus. A first-in-human study in healthy participants has shown that enpatoran is well-tolerated and has a linear pharmacokinetic (PK) profile.ObjectivesTo compare the PK parameters, safety, and tolerability of single ascending oral doses of enpatoran in a Phase I study in Japanese and Caucasian participants, and to explore a potential PK/pharmacodynamic (PD) relationship.MethodsA single-centre, open-label, sequential dose group study enrolled healthy Japanese and Caucasian participants into three dose cohorts. Each Caucasian participant was matched by body weight (± 20%), height (± 15%) and sex to a Japanese participant. Participants received a single orally administered enpatoran dose of 100 mg, 200 mg, or 300 mg as a film-coated tablet under fasting conditions. PK parameters, (maximum plasma concentration [Cmax]; area under the plasma concentration–time curve (AUC) from time 0 to infinity [AUC0-inf]; AUC from time 0 to the last sampling time [AUC0-tlast]) determined using noncompartmental analysis, were estimated post-dose from Day 1–3. Safety was assessed from Day -1 to 8. PK (exposure) between the two ethnic groups was compared using an analysis of covariance (ANCOVA) model including ethnic group, natural log-transformed dose, and ethnic group by natural log dose interaction. Ex vivo secretion of cytokines (PD) under stimulated (using the TLR7/8 agonist, R848) and unstimulated conditions, was assessed pre- and post-dose. A panel of cytokines was analysed by multiplex immunoassay; IL-6 was considered the primary PD biomarker.ResultsThe study included 36 male participants (18 Japanese and 18 Caucasian) with a mean (± SD) age of 35.1 (± 10.8) years and mean (± SD) body mass index of 23.1 (± 2.1) kg/m2. Each dose group included six Japanese and six Caucasian participants. The geometric mean enpatoran plasma exposure parameters (Cmax, AUC0-inf, and AUC0-tlast) were consistent between the two ethnic groups for each dose level (Table 1) and indicated dose proportionality. ANCOVA modeling demonstrated comparable exposure between the two groups (geometric least square mean ratio [Japanese/Caucasian;90% CI] of Cmax: 0.9409 [0.7855–1.1270]; AUC0-inf: 0.8959 [0.7497–1.0704] and AUC0-tlast: 0.8963 [0.7511–1.0695]). Treatment-emergent adverse events (TEAEs) were observed in six Japanese (n = 0, 100 mg; n = 3, 200 mg; n = 3, 300 mg) and four Caucasian (n = 1, 100 mg; n = 0, 200 mg; n = 3, 300 mg) participants. There we no serious TEAEs; most were mild and not dose dependent. Treatment-related TEAEs were mild diarrhoea, mild flatulence, and moderate headache. There were no deaths, withdrawals, or early terminations due to TEAEs. Administering enpatoran effectively reduced ex vivo stimulated cytokine release, with maximal inhibition observed at 2 hours post-dose (IL-6: mean ≥99%). High inhibition levels were sustained through 24 hours in a dose-dependent manner (IL-6: mean ~76–97%). The pattern of cytokine release inhibition was consistent across doses and ethnic groups.Table 1.PK parameters in Japanese and Caucasian participants at the three enpatoran dose levelsParameter100 mg200 mg300 mgJapaneseCaucasianJapaneseCaucasianJapaneseCaucasianN = 6N = 6N = 6N = 6N = 6N = 6Cmax139175260245486490(ng/mL)AUC0-inf7749481910185028403330(h*ng/mL)AUC0-tlast7589311880183028103270(h*ng/mL)All values are Geometric mean.Cmax, maximum plasma concentration AUC0-inf, area under the plasma concentration–time curve (AUC) from time 0 to infinity; AUC0-tlast, AUC from time 0 to the last sampling time.ConclusionThere were no relevant ethnic differences in PK, PD, and safety between healthy Japanese and Caucasian participants across a range of single oral enpatoran doses, thus supporting the inclusion of Asian participants in future global Phase II studies.AcknowledgementsWe would like to thank those who took part in the study. This study was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945), who funded medical writing support by Bioscript Stirling Ltd.Disclosure of InterestsSathej Gopalakrishnan Shareholder of: Merck Healthcare KGaA, Employee of: Merck Healthcare KGaA, Axel Krebs-Brown Employee of: Merck Healthcare KGaA, Marco Nogueira Filho Employee of: Merck Healthcare KGaA, Yoshihiro Kuroki Employee of: Merck Biopharma Co., Ltd., Angelika Bachmann Employee of: Merck Healthcare KGaA, Andreas Becker Shareholder of: Merck Healthcare KGaA, Employee of: Merck Healthcare KGaA, Frank Schippers Employee of: Merck Healthcare KGaA, Markus Fluck Shareholder of: Merck Healthcare KGaA, Employee of: Merck Healthcare KGaA, Özkan Yalkinoglu Employee of: Merck Healthcare KGaA, Lena Klopp-Schulze Employee of: Merck Healthcare KGaA
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Kiemes, Amanda, Felipe Gomes, Diana Cash, Nisha Singh, Federico Turkheimer, Anthony A. Grace, and Gemma Modinos. "T180. REDUCED [3H]RO15-4513 RECEPTOR BINDING IN THE VENTRAL HIPPOCAMPUS IN THE MAM DEVELOPMENTAL DISRUPTION MODEL OF SCHIZOPHRENIA." Schizophrenia Bulletin 46, Supplement_1 (April 2020): S300. http://dx.doi.org/10.1093/schbul/sbaa029.740.
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Abstract Background Post-mortem studies in schizophrenia patients have repeatedly found abnormalities in the γ-aminobutyric acid (GABA) inhibitory neurotransmission system in the form of parvalbumin (PV)-expressing GABAergic interneuron reduction and aberrant glutamic acid decarboxylase mRNA expression and receptor distribution. However, these findings cannot be separated from medication effects. Evidence from the methylazoxymethanol acetate (MAM) animal model of schizophrenia has suggested a reduction of hippocampal PV interneurons in MAM-treated rats results in hippocampal dysfunction in the form of increased pyramidal neuron activity, which contributes to dysregulation of the stress response and concurrent disinhibition of dopaminergic neurons in the midbrain. Administration of a positive allosteric modulator of the α5 subunit-containing GABA-A receptor (α5 GABAAR) reversed dopamine neuron hyperactivation in the ventral tegmental area and attenuated schizophrenia-like behaviour in MAM-treated rats, suggesting this receptor subtype’s involvement in the development of psychosis. Conflictingly, an in vivo PET imaging study found no difference in α5 GABAAR receptor binding compared to controls but demonstrated a negative correlation between binding in the hippocampus and negative symptoms of schizophrenia patients. However, this study included previously medicated patients. To understand the involvement of α5 GABAAR in hippocampal dysfunction without a confound of antipsychotic medication, we investigated whether these receptors are differentially expressed in MAM-treated compared to control rats using autoradiography. Methods MAM-treated (n=21) and saline (vehicle)-treated (n=22) male rats were assessed for schizophrenia- and anxiety-like phenotypes via amphetamine-induced hyperlocomotion (AIH) and the elevated plus maze assays (EPM), respectively. To quantify the density of α5 GABAAR, we used [3H]Ro15-4513, a selective radioligand binding to the benzodiazepine site of this subunit. [3H]Flumazenil, an antagonist of the benzodiazepine-binding site of α1-3,5 GABAAR, was used on adjacent brain slices of the same animals to investigate more general binding to GABAAR. Brain sections were treated with the radioligands and x-ray sensitive films were exposed to the brain sections and radioactivity standards for 4 (flumazenil) or 8 (Ro15-4513) weeks. Developed films were imaged and normalised to background, radioactive binding in images was calculated based on the standard curve using the robust regression method in Graphpad Prism 8. Subsequently, quantified images were sampled for the CA1 of the ventral hippocampus using MCID software. Independent t-tests were used to investigate group differences in time spent in open arms during the EPM, total distance moved during AIH, and receptor binding. The significance threshold was set to p=0.05. Results MAM-treatment induced a schizophrenia-like phenotype (AIH: t(39)=‒3.022, p=0.004) and an anxiety-like phenotype (EPM: t(41)=2.810, p=0.008) compared to saline. We found reduced α5 GABAAR binding in the ventral hippocampus CA1 region of MAM-treated rats compared to saline-treated rats (t(41)=2.563, p=0.014), but no differences in flumazenil binding to α1-3,5 GABAAR (t(41)=1.333, p=0.190). Discussion MAM treatment induced schizophrenia- and anxiety-like phenotypes, accompanied by an α5 GABAAR density decrease in the CA1 region of the ventral hippocampus. Specific reduced binding to α5 was corroborated by the absence of any binding changes in the flumazenil treated sections. These findings reveal part of the molecular mechanisms behind hippocampal dysfunction and implicate the α5 subunit as a potential novel target for treatment of schizophrenia.
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Moustakidis, Eleytherios, Emmanuil Spanoudakis, Irene Bouchliou, Evangelia Nakou, Paraskevi Miltiades, asiliki Kotoula, Dimitrios Margaritis, et al. "The Diagnostic Value of CD1d Expression In Leukemic B-Chronic Lymphoproliferative Disorders (B-CLPDs)." Blood 116, no. 21 (November 19, 2010): 3576. http://dx.doi.org/10.1182/blood.v116.21.3576.3576.
Повний текст джерелаАнотація:
Abstract Abstract 3576 Immunophenotype holds central role in the differential diagnosis of leukemic B-chronic lymphoproliferative disorders (B-CLPDs). However, select cases show overlapping characteristics and represent a diagnostic challenge. CD1d is an MHC-like molecule which presents glycolipids to the CD1d-restricted NKT cells, thus regulating innate and adaptive immune responses. Normal B-cells constitutively express CD1d, but its expression in B-CLPDs is currently unknown, with the exception of B-CLL in which there are only sparse and conflicting data. In the present study we assessed the diagnostic utility of CD1d expression in B-CLPDs and correlated the latter with various prognostic markers of B-CLL. CD1d expression was measured by 4-color flow cytometry on peripheral blood (PB), bone marrow (BM) and lymph node (LN) samples from 147 patients with B-CLL, 24 with mantle cell lymphoma (MCL), 20 with lymphoplasmacytic lymphoma (LPL), 10 with splenic marginal zone lymphoma (SMZL), 14 with hairy cell leukemia (HCL) and 3 with atypical hairy cell leukemia (aHCL).The utility of CD1d as a diagnostic marker for B-CLL versus the rest B-CLPDs was evaluated with receiver operator characteristic (ROC) curve analysis. A cut off value of 40% was selected and subsequently sensitivity, specificity, and likelihood ratios (LR) were calculated. One-way ANOVA was used for the assessment of differences in CD1d mean fluorescence intensity (MFI) between B-CLPDs with very high CD1d expression. The association of CD1d expression with CD38, CD49d and IgHV status was tested with Pearson and Spearman correlation, respectively. CD1d expression in B-CLPDs was as follows: B-CLL: 26%(range 0%-100%), MCL: 76%(15%-100%), LPL: 70%(53%-88%), SMZL: 96%(78%-100%), HCL: 100% and aHCL: 64%(51%-75)%. A CD1d expression of less than 40% was strongly indicative of B-CLL (LR: 26, specificity: 97%, sensitivity: 77%, figures 1 & 2A), as in all non B-CLL patients CD1d was > 40%. CD1d expression remained unaltered during either disease progression or relapse after chemotherapy in 17 patients with B-CLL that were assessed in various time points. Furthermore, CD1d was equally expressed in the BM, LN and PB of 6 patients with B-CLL, whereas it showed no significant correlation with CD38, CD49d and IgHV mutational status. Interestingly, in contrast to the generally low CD1d expression in B-CLL, all patients with trisomy 12 (n=5) expressed high CD1d levels (65-100%), in line with previous data reporting aberrant immunophenotypic features in trisomy 12. Also, HCL cells displayed significantly stronger intensity of CD1d expression (MFI: 196±26) compared to SMZL (MFI: 60±11, p=0.03), aHCL (MFI: 20.6±7, p=0.02) and normal B-cells (MFI: 62±5, p=0.03, figure 2B). In conclusion, our findings suggest that CD1d is a useful immunophenotypic marker for the differential diagnosis of B-CLL versus other B-CLPDs, as it is significantly downregulated in the former and it remains unaffected by disease stage and treatment status. Additionally, CD1d expression could also help in the differential diagnosis of B-CLPDs with prominent splenomegaly and overlapping phenotypes. Figure 1. ROC curve depicting the accuracy of CD1d expression of predicting the diagnosis of B-CLL in 218 patients with B-CLPDs. Figure 1. ROC curve depicting the accuracy of CD1d expression of predicting the diagnosis of B-CLL in 218 patients with B-CLPDs. Figure 2. CD1d expression in normal and clonal B-cells. (A) CD1d expression in a B-CLL (i) and a MCL (ii) patient. Normal B-cells are shown in orange and CD5+ neoplastic lymphocytes in green. (B) Stronger expression of CD1d in HCL (filled histogram in i, green color in ii) compared to SLVL (open histogram, i) and normal B cells (orange color, ii). Figure 2. CD1d expression in normal and clonal B-cells. (A) CD1d expression in a B-CLL (i) and a MCL (ii) patient. Normal B-cells are shown in orange and CD5+ neoplastic lymphocytes in green. (B) Stronger expression of CD1d in HCL (filled histogram in i, green color in ii) compared to SLVL (open histogram, i) and normal B cells (orange color, ii). Disclosures: No relevant conflicts of interest to declare.
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Ghobrial, Irene M., Jonathan L. Kaufman, David S. Siegel, Ravi Vij, Ashraf Badros, Linda Neuman, Hansen Wong, Janet Anderl, and Michael Savona. "Clinical Profile Of Single-Agent Modified-Release Oprozomib Tablets In Patients (Pts) With Hematologic Malignancies: Updated Results From a Multicenter, Open-Label, Dose Escalation Phase 1b/2 Study." Blood 122, no. 21 (November 15, 2013): 3184. http://dx.doi.org/10.1182/blood.v122.21.3184.3184.
Повний текст джерелаАнотація:
Abstract Background Oprozomib (OPZ), a structural analog of carfilzomib (CFZ), is an oral, second-generation epoxyketone proteasome inhibitor that selectively and irreversibly binds to its target. Preliminary findings have shown that modified-release OPZ tablets have acceptable safety and tolerability and promising antitumor activity in pts with hematologic malignancies (HM) (Kaufman JL, et al. EHA 2013, P233). Updated results are presented herein. Methods This open-label, phase 1b/2 study (NCT01416428) is enrolling adult pts with HM who relapsed after failing ≥1 line of therapy. The primary objectives are to determine the safety profile and maximum tolerated dose (MTD) of OPZ. Secondary end points include response, pharmacokinetics, and pharmacodynamics. OPZ dose escalation began at 150 mg/d. Dose levels are being increased in 30-mg increments; there is no maximal planned dose. Modified-release OPZ tablets are being administered once daily on Days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or on Days 1–5 of a 14-day cycle (5/14 schedule). Peripheral blood mononuclear cells (PBMC) and whole blood (WB) samples are being collected for assessment of proteasome inhibition (PI). Results As of July 1, 2013, 42 pts were enrolled, including 15 multiple myeloma (MM) and 4 Waldenström's macroglobulinemia (WM) pts on the 2/7 schedule and 15 MM and 8 WM pts on the 5/14 schedule. Median pt age was 62.0 and 64.0 years (2/7 and 5/14 schedule, respectively). Two-thirds (67%) of pts had prior bortezomib (BTZ) exposure; 43% were refractory to a prior BTZ-containing regimen. Median treatment duration for the 2/7 and 5/14 schedule was 11.3 weeks and 8.7 weeks, respectively. There were 2 dose-limiting toxicities (renal failure [180 mg/d] and tumor lysis syndrome [240 mg/d]; both occurred on the 5/14 schedule). The most common grade 1–2 adverse events (AEs; ≥5 pts) are reported in Table 1. The most common grade 3–4 AEs (≥2 pts) included diarrhea (n=9); anemia, nausea, and neutropenia (n=4 each); hypophosphatemia, thrombocytopenia, and vomiting (n=3 each); and dehydration and fatigue (n=2 each) (Table 2). Two pts experienced grade 1 peripheral neuropathy (PN); both reported PN grade 2 at baseline. No new-onset or worsening of PN was reported. Thirteen pts had their treatments held or delayed; 6 had their dosage reduced at least once. Eleven pts discontinued treatment. Apparent dose-dependent increases in the Day 1 plasma area under the concentration time curve and maximum concentration (Cmax) were observed (150–300 mg/d). The median time to Cmax was 2 hr and the terminal half-life was approximately 0.5–1.5 hr. Pts receiving 240-mg/d OPZ achieved depth and duration of PI that is similar to CFZ (20/27 mg/m2). In WB, ≥90% inhibition of the primary chymotrypsin-like activity was achieved 4 hr following OPZ administration; this inhibition was sustained through Cycle 2. In PBMCs, ≥80% inhibition was observed on the first day of Cycle 1 and showed minimal recovery before dosing on day 1 of Cycle 2. OPZ administration also inhibited the secondary caspase-like and trypsin-like sites of the immunoproteasome (LMP2 and MECL1, respectively). The profile of OPZ target inhibition is similar to previous reports with CFZ. Thirteen MM and 5 WM pts on the 5/14 schedule were included in the response evaluation. The clinical benefit response rate (CBR) was 23.1% (MM) and 80.0% (WM). In pts with MM, 1 (150 mg/d) had a very good partial response, 2 (210 mg/d) had a partial response (PR), 6 (150–240 mg/d) had stable disease (SD), 1 (150 mg/d) had progressive disease (PD), and 3 were not evaluable for response. In WM pts, 4 (150–210 mg/d) had a PR and 1 (180 mg/d) had SD. In 12 MM and 3 WM pts included in the response evaluation (2/7 schedule), the CBR was 16.7% (MM) and 0% (WM). Two MM pts (150–180 mg/d) had a minimal response (MR); 10 MM (150–300 mg/d) and 3 WM (180–240 mg/d) pts had SD. In 14 pts with MM or WM who were refractory to BTZ and eligible for assessment, 3 had a PR, 1 had a MR, 9 had SD, and 1 had PD. Conclusion Once-daily modified release OPZ tablets continue to have acceptable safety and promising antitumor activity in MM and WM pts. The most common grade 3 AE was diarrhea; grade 4 AEs were infrequent. No grade ≥2 PN was reported in pts with baseline PN; no new-onset or worsening of PN was reported. Dose escalation is continuing in the 2/7 (300 mg/d) and 5/14 (270 mg/d) dosing schedules. The phase 2 study will begin once the MTD is reached. Updated data will be presented at the meeting. Disclosures: Ghobrial: Onyx: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi (Genzyme): Research Funding; Noxxon: Research Funding. Kaufman:Jansenn: Consultancy; Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy; Merck: Research Funding. Siegel:Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Vij:BMS: Honoraria; Lilly: Honoraria; Celgene: Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millenium: Speakers Bureau. Neuman:Onyx: Employment, Equity Ownership. Wong:Onyx: Employment, Equity Ownership, Patents & Royalties, Research Funding. Anderl:Onyx: Employment, Equity Ownership.
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Casillas-Trasvina, Alberto, Bart Rogiers, Koen Beerten, Laurent Wouters, and Kristine Walraevens. "Characterizing groundwater heat transport in a complex lowland aquifer using paleo-temperature reconstruction, satellite data, temperature–depth profiles, and numerical models." Hydrology and Earth System Sciences 26, no. 21 (November 9, 2022): 5577–604. http://dx.doi.org/10.5194/hess-26-5577-2022.
Повний текст джерелаАнотація:
Abstract. Heat is a naturally occurring, widespread groundwater tracer that can be used to identify flow patterns in groundwater systems. Temperature measurements, being relatively inexpensive and effortless to gather, represent a valuable source of information which can be exploited to reduce uncertainties on groundwater flow, and, for example, support performance assessment studies on waste disposal sites. In a lowland setting, however, hydraulic gradients are typically small, and whether temperature measurements can be used to inform us about catchment-scale groundwater flow remains an open question. For the Neogene Aquifer in Flanders, groundwater flow and solute transport models have been developed in the framework of safety and feasibility studies for the underlying Boom Clay formation as a potential host rock for geological disposal of radioactive waste. However, the simulated fluxes by these models are still subject to large uncertainties as they are typically constrained by hydraulic heads only. In the current study, we use a state-of-the-art 3D steady-state groundwater flow model, calibrated against hydraulic head measurements, to build a 3D transient heat transport model, for assessing the use of heat as an additional state variable, in a lowland setting and at the catchment scale. We therefore use temperature–depth (TD) profiles as additional state variable observations for inverse conditioning. Furthermore, a Holocene paleo-temperature time curve was constructed based on paleo-temperature reconstructions in Europe from several sources in combination with land surface temperature (LST) remotely sensed monthly data from 2001 to 2019 (retrieved from NASA's Moderate Resolution Imaging Spectroradiometer, MODIS). The aim of the research is to understand the mechanisms of heat transport and to characterize the temperature distribution and dynamics in the Neogene Aquifer. The simulation results clearly underline advection/convection and conduction as the major heat transport mechanisms, with a reduced role of advection/convection in zones where flux magnitudes are low, which suggests that temperature is also a useful indicator in a lowland setting. Furthermore, the performed scenarios highlight the important roles of (i) surface hydrological features and withdrawals driving local groundwater flow systems and (ii) the inclusion of subsurface features like faults in the conceptualization and development of hydrogeological investigations. These findings serve as a proxy of the influence of advective transport and barrier/conduit role of faults, particularly for the Rauw fault in this case, and suggest that solutes released from the Boom Clay might be affected in similar ways.
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Ogura, Michinori, Yukio Kobayashi, Shiro Kubonishi, Michihiro Hidaka, Toshiki Uchida, and Yasushi Takamatsu. "Safety, Efficacy, and Pharmacokinetic Profiles of Intravenous Rigosertib in Japanese Patients with Recurrent/Relapsed or Refractory Myelodysplastic Syndromes: A Multicenter, Open-Label Phase I Clinical Study." Blood 128, no. 22 (December 2, 2016): 5549. http://dx.doi.org/10.1182/blood.v128.22.5549.5549.
Повний текст джерелаАнотація:
Abstract Background and Objectives: Rigosertib, a novel phosphoinositide 3/polo-like kinase pathway inhibitor, promotes G2/M arrest, selectively induces the apoptosis of cancer cells, and has no impact on normal cells. A Phase I/II study in the U.S. showed that rigosertib was safe and well tolerated in patients (pts) with myelodysplastic syndromes (MDS) or acute myeloid leukemia relapsed after or refractory to treatment with hypomethylating agents. A multicenter, open-label Phase I dose-finding study of rigosertib was conducted to evaluate the safety and preliminary efficacy, and to determine the recommended dose for a Phase II study in Japanese patients with recurrent/relapsed or refractory MDS. Patients and Methods: The key eligibility criteria were as follows: patients withrecurrent/relapsed or refractory MDS; FAB classifications (RA, RARS, RAEB, RABE-t, and CMML), excepting patients at IPSS low- or Int-1 risk with respect to RA; aged 20 years or older, ECOG PS of 0 to 2, no major organ dysfunctions, and written informed consent. Rigosertib (1,200 and 1,800 mg daily) was administered intravenously in one 14-day cycle that consisted of continuous intravenous administration for 72 hours followed by monitoring for 14 days. In principle, intravenous rigosertib was administered in up to cycle 8. The primary endpoint was the dose-limiting toxicity (DLT) in each cohort. The secondary endpoints were as follows: 1) safety as assessed with adverse events (AEs) and laboratory results; 2) the hematological remission rate, the hematological improvement rate, and the cytogenetic response rate¾all of which were assessed according to the International Working Group 2006 criteria; and 3) pharmacokinetics. Results: Between June 2012 and February 2015, a total of 9 pts with a median age of 70 (range: 63 to 84) years and with a 7/2 ratio of male/female were enrolled from 5 medical institutions in Japan, and 3 and 6 pts were eventually assigned to the 1,200 and 1,800 mg cohorts, respectively. According to the FAB classification, 6, 2, and 1 pts were categorized to RAEB, RAEB-t, and RA, respectively. There were 3 pts each in the IPSS Int-1, Int-2, and high-risk risk groups, with 1 and 2 pts in each risk group in the 1,200 and 1,800 mg cohorts, respectively. The median numbers of delivered cycles in the 1,200 and 1,800 mg cohorts were 4 (2 to 4) and 2 (1 to 8), respectively. The median relative dose intensity (RDI) in the 1,200 and 1,800 mg cohorts was 100% (98.2 to 100.0%) and 79% (55.6-100%), respectively; lower RDI in the 1,800 mg cohort was caused by dose delay in the next treatment due to toxicities. A total of 169 AEs developed. The most frequently observed grade 4 hematologic toxicities included neutropenia (3/9, 33%), thrombocytopenia (3/9, 33%), and leukopenia (3/9, 33%). Grade 3 or greater non-hematologic toxicities included grade 4 meningitis (1/9, 11%), grade 4 sepsis (1/9, 11%), grade 3 catheter-related infections (2/9, 22%), grade 3 hyponatremia (2/9, 22%), and grade 3 anorexia (2/9, 22%). DLT was not observed in the 1,200 mg cohort, while 2 pts in the 1,800 mg cohort had 5 DLTs (sepsis and meningitis in one pt, as well as hyponatremia, pustular rash, and hypochloremia in the other pt). Three serious AEs, including grade 4 meningitis, grade 4 sepsis, and grade 3 catheter-related infection, developed in the 1,800 mg cohort. No death occurred during the study period. Stable disease was obtained in 2 pts in the 1,800 mg cohort. Any hematological remission, hematological improvement, and cytogenetic response were not obtained in the two cohorts. In the 1,200 mg cohort, maximum plasma concentration (Cmax) was 5.99 ± 1.50 μg/mL (mean ± SD), and the area under the concentration-time curve (AUC0-∞) was 314.6 ± 142.7 μgŸ・hr/mL. In the 1,800 mg cohort, the Cmax was 6.74 ± 2.39 μg/mL, and the AUC0-∞ was 324.8 ± 83.9 μgŸ・hr/mL. The urinary excretion rates of rigosertib in the 1,200 and 1,800 mg cohorts were 12.7 ± 6.6% and 16.2 ± 4.7%, respectively. Conclusions: This Phase I study showed that intravenous rigosertib of 1,800 mg daily for 72 hours was well tolerated, although remarkable efficacy was not observed. The recommended dose for Japanese patients was determined to be 1,800 mg daily for 3 consecutive days as with a Phase III study in the U.S. Based on these data, Japanese MDS patients started to participate in a global randomized Phase III study to compare rigosertib vs. physicians' choice of treatment. Disclosures Ogura: SymBio Pharmaceuticals: Consultancy, Honoraria; Celltrion, Inc.: Consultancy, Honoraria. Kobayashi:Ariad: Research Funding; Ohtsuka Pharmaceutical: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; SymBio Pharmaceuticals: Research Funding. Kubonishi:SymBio Pharmaceuticals: Research Funding. Hidaka:SymBio Pharmaceuticals: Research Funding. Uchida:SymBio Pharmaceuticals: Research Funding. Takamatsu:SymBio Pharmaceuticals: Research Funding.
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Lazar, Arne L., Swantje C. Konradt, and Hermann Rottengruber. "Open-Source Dynamic Matlab/Simulink 1D Proton Exchange Membrane Fuel Cell Model." Energies 12, no. 18 (September 9, 2019): 3478. http://dx.doi.org/10.3390/en12183478.
Повний текст джерелаАнотація:
This work presents an open-source, dynamic, 1D, proton exchange membrane fuel cell model suitable for real-time applications. It estimates the cell voltage based on activation, ohmic and concentration overpotentials and considers water transport through the membrane by means of osmosis, diffusion and hydraulic permeation. Simplified equations reduce the computational load to make it viable for real-time analysis, quick parameter studies and usage in complex systems like complete vehicle models. Two modes of operation for use with or without reference polarization curves allow for a flexible application even without information about cell parameters. The program code is written in MATLAB and provided under the terms and conditions of the Creative Commons Attribution License (CC BY). It is designed to be used inside of a Simulink model, which allows this fuel cell model to be used in a wide variety of 1D simulation platforms by exporting the code as C/C++.
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Fioranelli, Massimo, Alireza Sepehri, Maria Grazia Roccia, and Mahdieh Ghasemi. "The effects of quantum spectrum of 4 + n-dimensional water around a DNA on pure water in four dimensional universe." Open Physics 17, no. 1 (December 31, 2019): 831–38. http://dx.doi.org/10.1515/phys-2019-0086.
Повний текст джерелаАнотація:
Abstract Recently, a method for calculating the quantum spectrum of black holes has been proposed. We show that this method can be applied for radiations of 4 + n - dimensional water around a DNA. In this model, DNA acts like a black hole and produces a curved space-time in a water around it. In these conditions, molecules of water in four dimensional universe are entangled with some DNA-like structures in extra dimension. Consequently, the effects of structures of water in extra dimensions can be observed in four dimensions. The entangled structures emit some quantum spectrum which can be transmitted to pure waters. These waves produce a curved space-time in pure water and make an entanglement between structure of water on four and DNA-like structures in extra dimensions. As a result, some signatures of DNAs can be observed in pure water. This model helps us to understand the reason for the emergence of life on the earth. To explain the model better, we unify Darwin’s theory with string theory in a new Darwinian’s string theory. In this theory, a zero dimensional manifold decays into two types of closed strings. One type decays into open strings and then these strings join to each other and form cosmos. Another type decays into open strings which form biological matters like DNAs and molecules of water in universe and anti-DNAs and anti-water in anti-universe. Thus, DNAs and molecules water are connected to each other and anti-DNAs and molecules of anti-water in anti-universe through some closed strings. These strings helps to molecules of water to store their informations in extra dimension and have long time memory. Because, information that are transformed into extra dimensions through closed strings, could be returned into universe. Also, these closed strings could have the main role in DNA transduction. Because, they connect two tubes one including water and DNA and another pure water in universe to two tubes including anti-DNA and water in anti-universe and transform properties of DNA into pure water. As a result, Darwinian string theory can confirm both water memory and DNA transduction. Finally, this theory response to this question that why memory of water couldnt remain for a long time. In this model, open strings which connects atoms in universe with anti-atoms in anti-universe interact with open strings which connects molecules of water and anti-water and decrease their entanglement. This causes that exchanging information between water and anti-water decreases and memory is dis-appeared.
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Dubosq, C., F. Calvo, M. Rapacioli, E. Dartois, T. Pino, C. Falvo, and A. Simon. "Quantum modeling of the optical spectra of carbon cluster structural families and relation to the interstellar extinction UV bump." Astronomy & Astrophysics 634 (February 2020): A62. http://dx.doi.org/10.1051/0004-6361/201937090.
Повний текст джерелаАнотація:
Context. The UV bump observed in the interstellar medium extinction curve of galaxies has been assigned to π → π⋆ transitions within the sp2 conjugated network of carbon grains. These grains are commonly thought to be graphitic particles or polycyclic aromatic hydrocarbons. However, questions are still open regarding the shape and degree of amorphization of these particles, which could account for the variations in the 2175 Å astronomical bump. Optical spectra of graphitic and onion-like carbon structures were previously obtained from dielectric constant calculations based on oscillating dipole models. In the present study, we compute the optical spectra of entire populations of carbon clusters using an explicit quantum description of their electronic structure for each individual isomer. Aims. Our aim is to determine the optical spectra of pure carbon clusters Cn=24,42,60 sorted into structural populations according to specific order parameters, namely asphericity and sp2 fraction, and to correlate these order parameters to the spectral features of the band in the region of the UV bump. Our comparison involves data measured for the astronomical UV bump as well as experimental spectra of carbon species formed in laboratory flames. Methods. The individual spectrum of each isomer is determined using the time-dependent density functional tight-binding method. The final spectrum for a given population is obtained by averaging the individual spectra for all isomers of a given family. Our method allows for an explicit description of particle shape, as well as structural and electronic disorder with respect to purely graphitic structures. Results. The spectra of the four main populations of cages, flakes, pretzels, and branched structures (Dubosq et al. 2019, A&A, 625, L11) all display strong absorption in the 2–8 eV domain, mainly due to π → π⋆ transitions. The absorption features, however, differ from one family to another and our quantum modeling indicates that the best candidates for the interstellar UV bump at 217.5 nm are cages and then flakes, while the opposite trend is found for the carbonaceous species formed in flame experiments; the other two families of pretzels and branched structures play a lesser role in both cases. Conclusions. Our quantum modeling shows the potential contribution of carbon clusters with a high fraction of conjugated sp2 atoms to the astronomical UV bump and to the spectrum of carbonaceous species formed in flames. While astronomical spectra are better accounted for using rather spherical isomers such as cages, planar flake structures are involved as a much greater component in flame experiments. Interestingly, these flake isomers have been proposed as likely intermediates in the formation mechanisms leading to buckminsterfullerene, which was recently detected in space. This study, although restricted here to the case of pure carbon clusters, will be extended towards several directions of astronomical relevance. In particular, the ability of the present approach to deal with large-scale molecular systems at an explicit quantum level of electronic structure and its transferable character towards different charge states and the possible presence of heteroatoms makes it the method of choice to address the important case of neutral and ionic hydrogenated compounds.
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Nalbo, Dinesh, Divya Dahiya, Ashwani Sood, Sanjay Kumar Bhadada, Arunanshu Behera, and Uma Nahar. "Surgical outcome of radioguided parathyroidectomy in primary hyperparathyroidism." International Surgery Journal 8, no. 2 (January 29, 2021): 681. http://dx.doi.org/10.18203/2349-2902.isj20210384.
Повний текст джерелаАнотація:
Background: Focused parathyroidectomy is the adequate treatment for primary hyperparathyroidism for localised disease. Adequacy of resection is confirmed by the availability of intraoperative parathormone assay (iOPTH). In the absence of availability of iOPTH assay, the radio guided surgery is an option. The aim of this study was to evaluate the feasibility of radioguided parathyroidectomy in tertiary care centre in India and to compare the overall success rate, operative time, hospital stay and postoperative outcome between focused open and radioguided parathyroidectomy.Methods: This was a prospective study which included 30 primary hyperparathyroidism patients with a single gland disease localised on Tc99m Sesta MIBI scan. Patients were randomized into two equal groups, and they underwent focused open or radioguided parathyroidectomy. Patients were followed up for three months.Results: All patients achieved biochemical cure as evident by the normalization of serum calcium and parathormone levels after surgery. The mean incision length, and operative time in this study was significantly better for radioguided parathyroidectomy (p=0.0001, <0.0001 respectively). There was no perioperative complications like recurrent laryngeal nerve injury, gland rupture, or bleeding in either group. However, there seems to be higher grade of pain experience by the patients who underwent open focused parathyroidectomy (p<0.0001).Conclusions: Radioguided parathyroidectomy has excellent cure rate for PHPT with an added advantage of short operative time & incision length and less post-operative pain. Radioguided parathyroidectomy seems to be a good alternative in the absence of availability of iOPTH assay and frozen section.
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Capurso, Alessandro. "The Potential of a Thick Present through Undefined Causality and Non-Locality." Entropy 24, no. 3 (March 15, 2022): 410. http://dx.doi.org/10.3390/e24030410.
Повний текст джерелаАнотація:
This paper elaborates on the interpretation of time and entanglement, offering insights into the possible ontological nature of information in the emergence of spacetime, towards a quantum description of gravity. We first investigate different perspectives on time and identify in the idea of a “thick present” the only element of reality needed to describe evolution, differences, and relations. The thick present is connected to a spacetime information “sampling rate”, and it is intended as a time symmetric potential bounded between a causal past of irreversible events and a still open future. From this potential, spacetime emerges in each instant as a space-like foliation (in a description based on imaginary paths). In the second part, we analyze undefined causal orders to understand how their potential could persist along the thick present instants. Thanks to a C-NOT logic and the concept of an imaginary time, we derive a description of entanglement as the potential of a logically consistent open choice among imaginary paths. We then conceptually map the imaginary paths identified in the entanglement of the undefined orders to Closed Time-like Curves (CTC) in the thick present. Considering a universe described through information, CTC are interpreted as “memory loops”, elementary structures encoding the information potential related to the entanglement in both time and space, manifested as undefined causality and non-locality in the emerging foliation. We conclude by suggesting a possible extension of the introduced concepts in a holographic perspective.
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Kolesnikov, N. S. "Implementation of point-counting algorithms on genus 2 hyperelliptic curves based on the birthday paradox." Prikladnaya Diskretnaya Matematika, no. 55 (2022): 120–28. http://dx.doi.org/10.17223/20710410/55/9.
Повний текст джерелаАнотація:
Our main contribution is an efficient implementation of the Gaudry - Schost and Galbraith - Ruprai point-counting algorithms on Jacobians of hyperelliptic curves. Both of them are low memory variants of Matsuo - Chao - Tsujii (MCT) Baby-Step Giant-Step-like algorithm. We present an optimal memory restriction (a time-memory tradeoff) that minimizes the runtime of the algorithms. This tradeoff allows us to get closer in practical computations to theoretical bounds of expected runtime at 2.45√N and 2.38a√N for the Gaudry - Schost and Galbraith - Ruprai algorithms, respectively. Here N is the size of the 2-dimensional searching space, which is as large as the Jacobian group order, divided by small modulus m, precomputed by using other techniques. Our implementation profits from the multithreaded regime and we provide some performance statistics of operation on different size inputs. This is the first open-source parallel implementation of 2-dimensional Galbraith - Ruprai algorithm.
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Jana, G. K., and C. K. Das. "Mechanochemical Devulcanization of Vulcanized Gum Natural Rubber." Progress in Rubber, Plastics and Recycling Technology 21, no. 3 (August 2005): 183–99. http://dx.doi.org/10.1177/147776060502100302.
Повний текст джерелаАнотація:
De-vulcanization of vulcanized elastomers represents a great challenge because of their three-dimensional network structure. Sulfur-cured gum natural rubbers containing three different sulfur/accelerator ratios were de-vulcanized by thio-acids. The process was carried out at 90 °C for 10 minutes in an open two-roll cracker-cum-mixing mill. Two concentrations of de-vulcanizing agent were tried in order to study the cleavage of the sulfidic bonds. The mechanical properties of the re-vulcanized rubber (like tensile strength, modulus, tear strength and elongation at break) were improved with increasing concentrations of de-vulcanizing agent, because the crosslink density increased. A decrease in scorch time and in optimum cure time and an increase in the state of cure were observed when vulcanized rubber was treated with high amounts of de-vulcanizing agent. The temperature of onset of degradation was also increased with increasing concentration of thio-acid. DMA analysis revealed that the storage modulus increased on re-vulcanization. From IR spectroscopy it was observed that oxidation of the main polymeric chains did not occur at the time of high temperature milling. Over 80% retention of the original mechanical properties (like tensile strength, modulus, tear strength and elongation at break) of the vulcanized natural rubber was achieved by this mechanochemical process.
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Perez, Diego de Miguel, Alessandro Russo, Muthukumar Gunasekaran, Andrés Cardona, Rena Lapidus, Brandon Cooper, Sunjay Kaushal, et al. "31 Dynamic change of PD-L1 expression on extracellular vesicles predicts response to immune-checkpoint inhibitors in non-small cell lung cancer patients." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A30. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0031.
Повний текст джерелаАнотація:
BackgroundImmune-checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced/metastatic non-small cell lung cancer patients (NSCLC), however, only a small subset of patients derives clinical benefit.1–3 To date, PD-L1 immunohistochemical evaluation is the gold-standard assay and the only approved biomarker, but associated with several limitations due to technical and biological factors such as spatial and temporal tumor heterogeneity.4 5 In this context, liquid biopsies emerge as novel powerful tools that could allow the non-invasive real-time characterization of the tumor PD-L1 status. In particular, extracellular vesicles (EVs), defined as cell-derived double-membrane structures involved in cell communication, hold strong potential as tissue surrogates. Recent studies have suggested that EV PD-L1 could stratify melanoma patients receiving ICIs, but none has showed the predictive value of this biomarker in NSCLC patients.6 7 We hypothesize that EV PD-L1 cargo can serve to stratify the response to ICIs in NSCLC patients.MethodsThis study enrolled advanced/metastatic NSCLC patients receiving ICI treatment. Plasma samples were obtained at baseline (T1) and at 8 weeks (T2) during the first response evaluation. Patients were classified as responders when showing partial, stable or complete response or as non-responders when manifesting progressive disease following RECIST v1.1.8 Plasma EVs were isolated by standard serial ultracentrifugation methods and characterized according to ISEV recommendations.9 10 Tissue PD-L1 expression was measured by immunohistochemistry while EV PD-L1 expression was measured by immunoblot. A predictive model was created by logistic-regression and a bootstrap corrected ROC curve to validate the results.ResultsPaired plasma samples from 21 patients were analyzed. PD-L1 tissue expression was not correlated with treatment response (p=0.394) nor matched the baseline EV PD-L1 levels (p=0.337) (figure 1.A). However, the dynamics of EV PD-L1 (T1-T2) correlated with the treatment response, observing an increase of PD-L1 expression in non-responders and a decrease or stable levels in responders (p=0.043) (figure 1.B). The predictive model reported an AUC=0.85, 90% CI=0.72–0.97, with 74.2% sensitivity and 73.5% specificity (figure 1.C). Moreover, the increase of EV PD-L1 was associated with shorter overall survival (HR=4.34, p=0.037) and shorter progression-free survival (HR=5.06, p=0.025) (figure 1 D & E).ConclusionsOur preliminary-study showed, for the first time, the predictive and prognostic value of EV PD-L1 dynamic changes in immunotherapy-treated NSCLC patients. Although larger studies are needed to validate these results, this promising biomarker could have important clinical implications, guiding treatment decisions in near real-time and improving the outcome of patients that could benefit from ICIs.AcknowledgementsWe would like to extend our gratitude to the all the patients that participated in the study.Abstract 31 Figure 1Graphical abstractTop: Study design and methodology. Bottom: Results. A) Representative images of PD-L1 expression in tissue and EV in matching patients showing no correlation between tissue and EV. B) Dynamic change of PD-L1 expression in EVs during the treatment. C) ROC curve and AUC before and after bootstrap correction for the predictive model based on changes in EV PD-L1 expression to identify responders. D & E) Kaplan-meier for overall survival (OS) and progression-free survival (PFS) according to the increase or the stable/decrease of the EV PD-L1 expression [Created with BioRender]Ethics ApprovalAll patients consented to an Institutional Review Board–approved protocol (A.O. Papardo, Messina, Italy). Biological material was transfer to the University of Maryland, USA under signed MTA between both institutions (MTA/2020-13111).ReferencesRittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255–265.Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:1627–1639.Chen DS, Mellman I: Oncology Meets Immunology: The Cancer-Immunity Cycle. Immunity 2013, 39:1–10.Zou WP, Wolchok JD, Chen LP. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016; 8:328rv4.Patel SP, Kurzrock R. PD-L1 Expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 2015;14:847–56.Cordonnier M, Nardin C, Chanteloup G, et al. Tracking the evolution of circulating exosomal-PD-L1 to monitor melanoma patients. J Extracell Vesicles 2020;9:1710899.Del Re M, Marconcini R, Pasquini G, et al. PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC. Br J Cancer 2018;118:820–824.Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47.Reclusa P, Verstraelen P, Taverna S, et al. Improving extracellular vesicles visualization: From static to motion. Sci Rep 2020;10(1):6494.Thery C, Witwer KW, Aikawa E, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for extracellular vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 2018;7:1535750.
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Edwards, R. Nigel. "On the resource evaluation of marine gas hydrate deposits using sea‐floor transient electric dipole‐dipole methods." GEOPHYSICS 62, no. 1 (January 1997): 63–74. http://dx.doi.org/10.1190/1.1444146.
Повний текст джерелаАнотація:
Methane hydrates are solid, nonstoichiometric mixtures of water and the gas methane. They occur worldwide in sediment beneath the sea floor, and estimates of the total mass available there exceed [Formula: see text]. Since each volume of hydrate can yield up to 164 volumes of gas, offshore methane hydrate is recognized as a very important natural energy resource. The depth extent and stability of the hydrate zone is governed by the phase diagram for mixtures of methane and hydrate and determined by ambient pressures and temperatures. In sea depths greater than about 300 m, the pressure is high enough and the temperature low enough for hydrate to occur at the seafloor. The fraction of hydrate in the sediment usually increases with increasing depth. The base of the hydrate zone is a phase boundary between solid hydrate and free gas and water. Its depth is determined principally by the value of the geothermal gradient. It stands out on seismic sections as a bright reflection. The diffuse upper boundary is not as well marked so that the total mass of hydrate is not determined easily by seismic alone. The addition of electrical data, collected with a seafloor transient electric dipole‐dipole system, can aid in the evaluation of the resource. Methane hydrate, like ice, is electrically insulating. Deposits of hydrate in porous sediment cause an increase in the formation resistivity. The data consist of measurements of the time taken for an electrical disturbance to diffuse from the transmitting dipole to the receiving dipole. The traveltime is related simply to the resistivity: the higher the resistivity, the shorter the traveltime. A sounding curve may be obtained by measuring traveltimes as a function of the separation between the dipoles and interpreted in terms of the variation of porosity with depth. Two exploration scenarios are investigated through numerical modeling. In the first, a very simple example illustrating some of the fundamental characteristics of the electrical response, most of the properties of the section including the probable, regional thickness of the hydrate zone (200 m) are assumed known from seismic and spot drilling. The amount of hydrate in the available pore space is the only free parameter. Hydrate content expressed as a percentage may be determined to about ±ε given a measurement of traveltime at just one separation (800 m) to ε%. The rule holds over the complete range of anticipated hydrate content values. In the second example, less information is assumed available a priori and the complementary electrical survey is required to find both the thickness and the hydrate content in a hydrate zone about 200 m thick beneath the sea floor containing 20 and 40% hydrate in the available pore space, respectively. A linear eigenfunction analysis reveals that for these two models, the total mass of hydrate, the product of hydrate content and thickness, may be estimated to an accuracy of about 3ε% given measurements of traveltime to an accuracy of ε% over a range of separations from 100 to 1300 m. The value of the electrical information depends directly on the accuracy to which transient arrivals can be measured on the sea floor in water depths exceeding 300 m over a separation of the order of a kilometer, the error parameter ε. While results of appropriate surveys, or even noise measurements, have not been published in the open literature, surveys on a smaller 100 m scale have been conducted by my group. Based on these data, I suggest that the value of ε may be of the order of 3%.
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Gnatzy, W., O. W. Fischer, A. Kiesel, R. I. Vane-Wright, and M. Boppré. "Diverticula in Male Lycorea halia Butterflies (Lepidoptera: Nymphalidae: Danaini: Itunina)—Support Organs for Everted Hairpencils with Unique Ultrastructure." Neotropical Entomology 49, no. 1 (December 5, 2019): 73–81. http://dx.doi.org/10.1007/s13744-019-00720-6.
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AbstractThe involvement of the diverticula, a synapomorphy for Itunina, in protrusion and expansion of hairpencils by male Lycorea halia (Hübner, 1816) is demonstrated for the first time. They facilitate maintaining the haemolymph pressure necessary to keep the hairpencils everted. The diverticula are curved hook-like lobes, open to the body cavity and densely filled with tracheae and threads made by units of two staggered cells surrounding a central extracellular fibril bundle. Such complex structures, apparently metabolically active, have not been reported for insects previously and might indicate additional functions, but their functional role(s) remains a puzzle. When a male emerges from pupa, the diverticula are not yet formed; this happens only during the first protrusion of the hairpencils.
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Smith, Catherine C., Mark J. Levis, Mark R. Litzow, Alexander E. Perl, Jessica K. Altman, Stanley C. Gill, Takeshi Kadokura, et al. "Pharmacokinetic Profile and Pharmacodynamic Effects of ASP2215, a Selective, Potent Inhibitor of FLT3/AXL, in Patients with Relapsed or Refractory Acute Myeloid Leukemia: Results from a First-in-Human Phase 1/2 Study." Blood 126, no. 23 (December 3, 2015): 4836. http://dx.doi.org/10.1182/blood.v126.23.4836.4836.
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Abstract Introduction: ASP2215, a new tyrosine kinase inhibitor with activity against FMS-like receptor tyrosine kinase-3 (FLT3) and AXL receptor tyrosine kinase, is currently in development for the treatment of acute myeloid leukemia (AML). Methods: In an ongoing, first-in-human Phase 1/2, dose-escalation/dose-expansion study, the pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of ASP2215 were evaluated under fasting conditions in patients with relapsed or refractory AML (R/R AML). Patients who met study criteria were assigned to treatment in the dose-escalation cohorts or were randomized to an open dose level in the dose-expansion cohorts. The dose-escalation cohort was a modified 3+3 with accelerated titration design that evaluated ascending oral doses of ASP2215 (20-450 mg), the dose-expansion cohort was a parallel, multi-dose-expansion cohort. Blood samples were collected and safety/tolerability assessments, including 12-lead electrocardiogram, were evaluated at protocol-specified time points for both cohorts. Effect of increasing ASP2215 exposure on inhibition of FLT3 phosphorylation, assessed via plasma inhibitory assay (PIA), was evaluated using an inhibitory PK/PD Emaxmodel. PK/PD analyses were performed to evaluate the relationship between ASP2215 exposure and changes from baseline in QTcF intervals (ΔQTcF) and changes from baseline in clinical laboratory values (e.g., creatinine kinase [ΔCK], aspartate aminotransferase [ΔAST]). Results: Data from an interim analysis of the dose-escalation/dose-expansion study were available from 215 subjects (n=23 [dose escalation], n=192 [dose expansion]). The ASP2215 PK parameters across the dose range (20-450 mg), evaluated after both single- and multiple-dose administration, are presented (Table); statistical analyses suggest the ASP2215 PK parameters are dose proportional from 20-450 mg. Median time to maximal concentration (Tmax) was observed between 2 hr and 6 hr after single and repeated oral dosing. The estimated median half-life (t1/2) ranged from approximately 45 hr to 159 hr based on the accumulation ratio; ASP2215 accumulation was extensive after multiple dose administration as reflected by the accumulation index (Rac) ranging from approximately 3.2-10. A strong correlation was shown for ASP2215 exposure-related inhibition of FLT3 phosphorylation, with >90% FLT3 inhibition observed by Day 8 at ASP2215 doses of ≥80 mg. Although a positive slope was observed between ΔQTcF and ASP2215 exposure, only 5% of the study population were reported as having a maximum post-baseline QTcF interval >500 msec. A similar trend was observed with ASP2215 concentration-related increases in ΔCK and ΔAST; however, <10% of all subjects experienced a Grade ≥3 shift from baseline in CK or AST concentrations. Conclusions: ASP2215 has demonstrated exposure-related FLT3 inhibition and a pharmacokinetic profile that support once-daily oral administration for the treatment of AML in subjects who relapsed after, or are refractory to, induction or salvage treatment. Table. ASP2215 Pharmacokinetic Parameters after Multiple-Dose Administration 20 mg (n=4) 40 mg (n=3) 80 mg (n=3) 120 mg (n=3) 200 mg (n=2) 300 mg (n=3) 450 mg (n=3) Cmax(ng/mL) 45.6 (30.5, 137) 106 (76.7, 140) 396 (217, 516) 282 (248, 593) 1460 (886, 2040) 1260 (1040, 2280) 1150 (776, 1530) Tmax(hr) 4.01 (4.00, 6.00) 3.87 (0.500, 6.00) 4.33 (4.00, 4.42) 2.02 (1.95, 5.75) 6.03 (6.00, 6.07) 6.05 (4.08, 6.07) 5.00 (4.07, 5.93) AUC0-24(ng·h/mL) 926 (543, 2480) 2460 (1750, 2800) 6280 (4160, 10600) 6190 (4200, 11300) 31500 (16500, 46600) 28700 (22300, 43300) 11500 (8070, 14900) t1/2 (hr) 52.8 (39.7, 83.1) 83.7 (68.5, 243) 91.5 (60.9, 108) 45.3 (30.5, 63.3) 143 (99.7, 186) 159 (83.3, 187) 56.9 (51.5, 62.3) Rac 3.70 (2.92, 5.51) 5.55 (4.64, 15.1) 6.02 (4.18, 7.02) 3.25 (2.38, 4.33) 9.08 (6.51, 11.7) 10.1 (5.53, 11.7) 3.94 (3.62, 4.27) Data are presented as median (minimum, maximum). AUC0-24, area under the concentration-time curve between 0-24 hr; Cmax, maximal concentration; t1/2, elimination half-life; Tmax, time to maximal concentration; Rac, accumulation ratio. Disclosures Smith: Astellas: Research Funding; Plexxikon: Research Funding. Off Label Use: ASP2215 is an investigational product for the treatment of AML. Perl:Astellas US Pharma Inc.: Consultancy; Ambit/Daichi Sankyo: Consultancy; Arog Pharmaceuticals: Consultancy; Asana Biosciences: Consultancy; Actinium Pharmaceuticals: Consultancy. Altman:Novartis: Other: Advisory board; BMS: Other: Advisory board; Seattle Genetics: Other: Advisory board; Spectrum: Other: Advisory board; Ariad: Other: Advisory board; Astellas: Other: Advisory board; assistance with abstract preparation. Gill:Astellas Pharma US, Inc: Employment. Kadokura:Astellas Pharma Global Development: Employment, Other: Personal fees. Yuen:Astellas Pharma, Inc.: Employment. Fisniku:Astellas: Employment. Liu:Astellas: Employment. Nagase:Astellas: Employment. Sargent:Astellas Pharma US, Inc: Employment. Bahceci:Astellas Pharma Global Development: Employment.
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Capolupo, Antonio. "Dark Matter and Dark Energy Induced by Condensates." Advances in High Energy Physics 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/8089142.
Повний текст джерелаАнотація:
It is shown that the vacuum condensate induced by many phenomena behaves as a perfect fluid which, under particular conditions, has zero or negative pressure. In particular, the condensates of thermal states of fields in curved space and of mixed particles have been analyzed. It is shown that the thermal states with the cosmic microwave radiation temperature and the Unruh and the Hawking radiations give negligible contributions to the critical energy density of the universe, while the thermal vacuum of the intercluster medium could contribute to the dark matter, together with the vacuum energy of fields in curved space-time and of mixed neutrinos. Moreover, a component of the dark energy can be represented by the vacuum of axion-like particles mixed with photons and superpartners of neutrinos. The formal analogy among the systems characterized by the condensates can open new scenarios in the possibility of detecting the dark components of the universe in table top experiments.
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Evseev, A. K., E. I. Pervakova, I. V. Goroncharovskaya, E. A. Tarabrin, M. Sh Khubutiya, and M. M. Goldin. "Diagnostic capabilities of monitoring of redox potential in blood plasma of lung transplant patients." Transplantologiya. The Russian Journal of Transplantation 11, no. 2 (June 17, 2019): 128–40. http://dx.doi.org/10.23873/2074-0506-2019-11-2-128-140.
Повний текст джерелаАнотація:
Introduction. Monitoring of redox potential (platinum electrode open circuit potential) in biological media (serum, blood plasma) is one of the promising methods for diagnosing and predicting the development of complications in patients in the early post-transplantation period. The study of the diagnostic capabilities of this technique in patients after lung transplantation is highly relevant.The objective was to assess the diagnostic and prognostic capabilities of monitoring platinum electrode open circuit potential in blood plasma of lung transplant patients.Material and methods. The data obtained at monitoring of platinum electrode open circuit potential in blood plasma and clinical laboratory test results of 14 patients after double lung transplantation surgery were analyzed. The platinum electrode open circuit potential value in the blood plasma was measured by the potentiometric method.Results. The study demonstrated the differences in the dynamics and values of platinum electrode open circuit potential in the blood plasma between the lung transplant patients with a favorable outcome and those with a fatal outcome. Wave-like segments on the relationship curves of the platinum electrode open circuit potential in blood plasma to time coincided with inflammatory markers (C-reactive protein, stab neutrophils, erythrocyte sedimentation rate) activation. Statistically significant correlations between platinum electrode open circuit potential values in blood plasma and clinical laboratory test results were revealed.Conclusion. The informative value and diagnostic capabilities of the technique of the platinum electrode open circuit potential measurement in blood plasma of lung transplant patients have prospects of using its results as a criterion for assessing the patient’s condition and improving the quality of therapy.
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Garber, S. S., and C. Miller. "Single Na+ channels activated by veratridine and batrachotoxin." Journal of General Physiology 89, no. 3 (March 1, 1987): 459–80. http://dx.doi.org/10.1085/jgp.89.3.459.
Повний текст джерелаАнотація:
Voltage-sensitive Na+ channels from rat skeletal muscle plasma membrane vesicles were inserted into planar lipid bilayers in the presence of either of the alkaloid toxins veratridine (VT) or batrachotoxin (BTX). Both of these toxins are known to cause persistent activation of Na+ channels. With BTX as the channel activator, single channels remain open nearly all the time. Channels activated with VT open and close on a time scale of 1-10 s. Increasing the VT concentration enhances the probability of channel opening, primarily by increasing the rate constant of opening. The kinetics and voltage dependence of channel block by 21-sulfo-11-alpha-hydroxysaxitoxin are identical for VT and BTX, as is the ionic selectivity sequence determined by bi-ionic reversal potential (Na+ approximately Li+ greater than K+ greater than Rb+ greater than Cs+). However, there are striking quantitative differences in open channel conduction for channels in the presence of the two activators. Under symmetrical solution conditions, the single channel conductance for Na+ is about twice as high with BTX as with VT. Furthermore, the symmetrical solution single channel conductances show a different selectivity for BTX (Na+ greater than Li+ greater than K+) than for VT (Na+ greater than K+ greater than Li+). Open channel current-voltage curves in symmetrical Na+ and Li+ are roughly linear, while those in symmetrical K+ are inwardly rectifying. Na+ currents are blocked asymmetrically by K+ with both BTX and VT, but the voltage dependence of K+ block is stronger with BTX than with VT. The results show that the alkaloid neurotoxins not only alter the gating process of the Na+ channel, but also affect the structure of the open channel. We further conclude that the rate-determining step for conduction by Na+ does not occur at the channel's "selectivity filter," where poorly permeating ions like K+ are excluded.
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ASSELMEYER-MALUGA, TORSTEN, PAWEŁ GUSIN, and JERZY KRÓL. "THE MODIFICATION OF THE ENERGY SPECTRUM OF CHARGED PARTICLES BY EXOTIC OPEN 4-SMOOTHNESS VIA SUPERSTRING THEORY." International Journal of Geometric Methods in Modern Physics 10, no. 01 (November 15, 2012): 1250079. http://dx.doi.org/10.1142/s021988781250079x.
Повний текст джерелаАнотація:
In this paper we present a model where the modified Landau-like levels of charged particles in a magnetic field are determined due to the modified smoothness of ℝ4 as underlying structure of the Minkowski spacetime. The standard smoothness of ℝ4 is shifted to the exotic [Formula: see text], k = 2p, p = 1, 2, …. This is achieved by superstring theory using gravitational backreaction induced from a strong, almost constant magnetic field on standard ℝ4. The exact string background containing flat ℝ4 is replaced consistently by the curved geometry of SU (2)k × ℝ as part of the modified exact backgrounds. This corresponds to the change of smoothness on ℝ4 from the standard ℝ4 to some exotic [Formula: see text]. The calculations of the spectra are using the CFT marginal deformations and Wess–Zumino–Witten (WZW) models. The marginal deformations capture the effects of the magnetic field as well as its gravitational backreactions. The spectra depend on even level k of WZW on SU(2). At the same time the WZ term as element of H3( SU (2), ℝ) determines also the exotic smooth [Formula: see text]. As the consequence we obtain that a nonzero mass-gap induced by the exotic [Formula: see text] emerges in the spectrum.
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Zhang, Yangfan, Bog E. So, and Anthony P. Farrell. "Hypoxia Performance Curve: Assess a Whole-Organism Metabolic Shift from a Maximum Aerobic Capacity towards a Glycolytic Capacity in Fish." Metabolites 11, no. 7 (July 8, 2021): 447. http://dx.doi.org/10.3390/metabo11070447.
Повний текст джерелаАнотація:
The utility of measuring whole-animal performance to frame the metabolic response to environmental hypoxia is well established. Progressively reducing ambient oxygen (O2) will initially limit maximum metabolic rate as a result of a hypoxemic state and ultimately lead to a time-limited, tolerance state supported by substrate-level phosphorylation when the O2 supply can no longer meet basic needs (standard metabolic rate, SMR). The metabolic consequences of declining ambient O2 were conceptually framed for fishes initially by Fry’s hypoxic performance curve, which characterizes the hypoxemic state and its consequences to absolute aerobic scope (AAS), and Hochachka’s concept of scope for hypoxic survival, which characterizes time-limited life when SMR cannot be supported by O2 supply. Yet, despite these two conceptual frameworks, the toolbox to assess whole-animal metabolic performance remains rather limited. Here, we briefly review the ongoing debate concerning the need to standardize the most commonly used assessments of respiratory performance in hypoxic fishes, namely critical O2 (the ambient O2 level below which maintenance metabolism cannot be sustained) and the incipient lethal O2 (the ambient O2 level at which a fish loses the ability to maintain upright equilibrium), and then we advance the idea that the most useful addition to the toolbox will be the limiting-O2 concentration (LOC) performance curve. Using Fry & Hart’s (1948) hypoxia performance curve concept, an LOC curve was subsequently developed as an eco-physiological framework by Neil et al. and derived for a group of fish during a progressive hypoxia trial by Claireaux and Lagardère (1999). In the present review, we show how only minor modifications to available respirometry tools and techniques are needed to generate an LOC curve for individual fish. This individual approach to the LOC curve determination then increases its statistical robustness and importantly opens up the possibility of examining individual variability. Moreover, if peak aerobic performance at a given ambient O2 level of each individual is expressed as a percentage of its AAS, the water dissolved O2 that supports 50% of the individual’s AAS (DOAAS-50) can be interpolated much like the P50 for an O2 hemoglobin dissociation curve (when hemoglobin is 50% saturated with O2). Thus, critical O2, incipient lethal O2, DOAAS-50 and P50 and can be directly compared within and across species. While an LOC curve for individual fish represents a start to an ongoing need to seamlessly integrate aerobic to anaerobic capacity assessments in a single, multiplexed respirometry trial, we close with a comparative exploration of some of the known whole-organism anaerobic and aerobic capacity traits to examine for correlations among them and guide the next steps.
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Leibowitz, M. D., J. B. Sutro, and B. Hille. "Voltage-dependent gating of veratridine-modified Na channels." Journal of General Physiology 87, no. 1 (January 1, 1986): 25–46. http://dx.doi.org/10.1085/jgp.87.1.25.
Повний текст джерелаАнотація:
Na channels of frog muscle fibers treated with 100 microM veratridine became transiently modified after a train of repetitive depolarizations. They open and close reversibly with a gating process whose midpoint lies 93 mV more negative than the midpoint of normal activation gating and whose time course shows no appreciable delay in the opening or closing kinetics but still requires more than two kinetic states. Like normal activation, the voltage dependence of the modified gating can be shifted by changing the bathing Ca2+ concentration. The instantaneous current-voltage relation of veratridine-modified channels is curved at potentials negative to -90 mV, as if external Ca ions produced a voltage-dependent block but also permeated. Modified channels probably carry less current than normal ones. When the concentration of veratridine is varied between 5 and 100 microM, the initial rate of modification during a pulse train is directly proportional to the concentration, while the rate of recovery from modification after the train is unaffected. These are the properties expected if drug binding and modification of channels can be equated. Hyperpolarizations that close modified channels slow unbinding. Allethrin and DDT also modify channels. They bind and unbind far faster than veratridine does, and their binding requires open channels.
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Panda, Pranati, Satya Narayan Padhi, and Gana Nath Dash. "Comparative Assessment of GaN as a Microwave Source with Si and SiC for Mixed Mode Operation at Submillimetre Wave Band of Frequency." International Journal of Microwave Science and Technology 2016 (February 14, 2016): 1–9. http://dx.doi.org/10.1155/2016/4370345.
Повний текст джерелаАнотація:
The potentials of GaN, SiC, and Si for application as microwave sources in mixed tunnelling avalanche transit time mode operation at submillimetre wave (sub-mm wave) frequency around 0.35 terahertz (THz) are investigated using some computer simulation methods. Design criteria to choose width, doping concentration, and area are highlighted. From the results of our simulation we observed that the Si diode produces the least power output of 41 mW followed by the GaN diode with 760 mW and the SiC diode with 2.89 W. In addition, the GaN diode has more noise than the SiC diode (by 5 dB) as well as the Si diode (by 10 dB). The drastically different performance between the GaN and the SiC diode is attributed to the incorporation of disparate carrier velocity in GaN which were not being used by other authors. In spite of the low power and high noise of the GaN compared to the SiC diode, the presence of several peaks in the mean square noise voltage curves and the existence of several minima in the noise measure curves would open a new direction in the design of GaN low-noise ATT diodes capable of multifrequency tuning like a DAR diode.
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Huang, Weidong, Qian Wang, Xinkai Yao, and Junyan Tian. "CONSTRUCTION OF INDIVIDUAL COGNITIVE MODEL IN THE CONTEXT OF EMOTION AND AFFECTIVE DISORDER." International Journal of Neuropsychopharmacology 25, Supplement_1 (July 1, 2022): A40—A41. http://dx.doi.org/10.1093/ijnp/pyac032.056.
Повний текст джерелаАнотація:
Abstract Background With the development of various information technologies and the popularization of the Internet, great changes have taken place in human life. In particular, social media has become an important channel for people to obtain information and generate event awareness, attitude and emotional tendency. Personal real-time comments on social media have a potential role in guiding public opinion and guiding network public opinion. As one of the most representative online social media, microblog contains a lot of public emotional information. The heterogeneity of microblog users' personal characteristics such as age, work and education leads to their different views, attitudes and values, making their views more representative and universal. Emotional analysis of these information is of great significance for us to understand the spread of public opinion events. By constructing a personal cognitive emotion classification model based on the optimized distributed gradient enhancement library, the emotion classification of microblog short text is realized. The model mainly includes text data collection and preprocessing, text feature extraction based on word embedding model word2vec, high fitting emotion classification model established through training corpus, and emotional tendency judgment according to the emotional tendency results obtained from the model. This paper takes 5 million microblog data and the data set released by CCF international natural language processing and Chinese Computing Conference as the word vector training corpus of word2vec to train the emotion classification model. Research Objects and Methods In order to investigate the semantic analysis of emotion, we formed an open-ended questionnaire by consulting relevant literature, sorted out the recovered effective scales, and conducted data semantic analysis. On this basis, combined with the previous theoretical concepts, the preliminary measurement table of emotional information is compiled; Secondly, the preliminary test is carried out according to the items of the scale, and the data are analyzed through item analysis, exploratory factor analysis and reliability test of the scale; Finally, the formal scale is compiled, tested and recovered, and verified by confirmatory factor analysis and reliability and validity test. In order to test the relationship between emotional information and emotional regulation, the cognitive bias questionnaire (CBQ) was used to measure the negative cognitive bias assumed to be related to depression. The scale measures two dimensions: (1) depression and (2) cognitive distortion. “Depression” expressed by CBQ refers to depressive emotion, or bad mood, rather than a depressive syndrome containing all relevant symptoms. Cognitive distortion is defined as reasoning that is clearly incorrect in terms of known facts. CBQ attempts to evaluate the specific cognitive distortions proposed by Beck (19671970), such as over generalization, out of context, arbitrary and speculative reasoning and judgment, ignoring advantages or good results and exaggerating disadvantages or bad outcomes. The scale describes six situations common to college students or psychiatric patients, three for interpersonal relationships and three for self-achievement. After each situation, three or four questions are put forward. These questions represent four possible combinations of the two dimensions of depression and distortion: depression non distortion, depression distortion, non depression non distortion and non depression distortion. Subjects were asked to answer how they experienced when they were in this situation. The score is to compare the scores of the four combinations of depression and distortion respectively, and the score range is 0-23 points. At the same time, independent sample t-test and analysis of variance were carried out with college students' gender, grade, family location, major, one-child situation, student cadres, family status and parental education as independent variables. Whether it is a student cadre or not has a certain impact on the emotional regulation and self-efficacy of college students. Results The improved model overcomes the shortcomings that the general methods can not explain the context and capture the semantic relationship of the context, and improves the efficiency and accuracy of emotion based classification. The effectiveness of different models can be evaluated according to confusion matrix or ROC curve. In this paper, the classification effect of xgboost emotion classification model is obviously better than that of SVM classification model. Conclusion Our empirical results show that most netizens hold a negative attitude towards yumengyao wrestling competition. Due to its limitations, this paper only uses xgboost model to study the text emotion classification. In the future, deep neural network can more accurately understand the characteristics of microblog short text, realize higher precision emotion analysis, and help practitioners and decision makers comprehensively and effectively identify the public's views and attitudes towards national policies and current events. This paper is of great significance to the real-time public opinion analysis in the network social media environment, and emphasizes the necessity of promoting the establishment of network public opinion early warning mechanism. Acknowledgements Funded by the National Natural Science Foundation of China under Grant No. 71671093. The authors would like to thank other researchers at Nanjing University of Posts and Telecommunications. Supported by the Jiangsu Provincial Department of education, the key research base of philosophy and social sciences.