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Rippy, Kerry C., Emily Volk, Reagan Beers, Eric Kozubal, Kristin Gauderman, and Judith Vidal. "Corrosion of Metal Alloys in Potassium Acetate Solutions for Liquid Desiccant Dehumidification and Air Conditioning." Energies 15, no. 12 (June 17, 2022): 4421. http://dx.doi.org/10.3390/en15124421.
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For commercial buildings, liquid desiccant air conditioners (LDACs) could provide up to 80% energy savings compared to high-efficiency vapor compression AC, but commonly utilized liquid desiccants are highly corrosive. This precludes the use of metallic components, necessitating specialized plastics and thereby driving up cost, weight, and limiting operational temperature and pressure ranges. Less corrosive alternatives are sought. Here, potassium acetate solutions are investigated as less-corrosive alternatives to the chloride salt solutions that are typically used in LDAC systems. Corrosion evaluations for a Cu alloy (C12200) and two Al alloys (Al3003 and Al1100) in both potassium acetate and chloride salt solutions are presented. We show that yearly corrosion rates are lower in potassium acetate solutions by up to three orders of magnitude. Active corrosion behavior is largely absent in potassium acetate solutions but is present in chloride salt solutions. Furthermore, solid corrosion products are observed in chloride salt solutions. Thus, we conclude that potassium acetate is a promising candidate as a less corrosive alternative liquid desiccant for LDAC systems with metallic components.
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Li, Yang Teng Long, Min Yi Cen, and Xuan Bai. "Study on Methods of Lateral Deviation of Track for Static Inspecting in High-Speed Railway." Applied Mechanics and Materials 638-640 (September 2014): 1195–206. http://dx.doi.org/10.4028/www.scientific.net/amm.638-640.1195.
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According to the critical factor of railway track geometric irregular, the deformations of track can be controlled. The lateral deviation is the key to determine the railway track irregularity. Currently, in the static inspected methods, the combined method of geodetic surveys and track surveying trolleys (inspecting instruments for static geometry parameter of track) is widely used in high-speed railway. Depending on some tests, the model of track irregularity in track surveying trolleys can be reconstructed by another method. According to the special features of track of high-speed railway, it is necessary to study on the accurate and effective lateral deviation algorithm which is suitable for the precise track inspection of high-speed railway. Based on some existing methods of construction layout in highway, the primary contents of this paper are: (1) reduces those methods to three algorithms, such as the Longitudinal Deviation Algorithm with Composite Simpson rule (LDACS), the Distance Function Algorithm of Newton’s method (DFAN) and Normal Perpendicular to Tangent Algorithm of Newton’s method (NPTAN), and (2) completes the algorithm steps of DFAN and NPTAN on circular curve, and proves the results of two algorithms on circular curve same, and (3) proposes the three algorithms to calculate lateral deviation and mileage of any rail detection points for inspecting the static geometric state of track in high-speed railway. Depending on some simulation data, the experimental results are: (1) the calculations of DFAN, NPTAN and LDACS, in which the number of subintervals of equal greater than or equal to five, meet the accuracy of the precise track detection of high-speed railway, and (2) the difference mileage and lateral deviation between DFAN and NPTAN are less than 0.001 mm, and (3) the efficiency of those algorithms is very considerable and the efficiency of DFAN is basically the same with NPTAN and higher than LDACS, and (4) the longer the transition curve is, the lower the efficiency and accuracy of DFAN and NPTAN are. The bigger the radius is, the higher the accuracy of LDACS is. According to the measurement data of the Chengdu Dujiangyan Railway Line (Cheng Guan Line), the above mentioned results of (1) and (2) can be proved correctly.
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Schnell, Michael, Ulrich Epple, Dmitriy Shutin, and Nicolas Schneckenburger. "LDACS: future aeronautical communications for air-traffic management." IEEE Communications Magazine 52, no. 5 (May 2014): 104–10. http://dx.doi.org/10.1109/mcom.2014.6815900.
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Wang, Lei, Mingli Liu, Jin Zhang, and Dongxia Li. "Adaptive Threshold Energy Detection Spectrum Sensing Method for L-Band Digital Aeronautical Communication System." Security and Communication Networks 2022 (October 17, 2022): 1–7. http://dx.doi.org/10.1155/2022/4325515.
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Air travel is growing at an alarming rate. However, according to the latest research report by Eurocontrol on European aviation, the growth of air traffic will be limited by the available spectrum resources. As one of the means to provide air/ground (A/G) broadband communication, the L-band digital aeronautical communication system (LDACS) is becoming the preferred model for final deployment and has received continuous attention. Based on various spectrum measurement studies, the international civil aviation organization (ICAO) has identified multiple 1 MHz vacant bands between adjacent distance measuring equipment (DME) signals for LDACS. In order to improve spectrum efficiency, the concept of dynamic spectrum access (DSA) can be applied to the LDACS, which requires the use of spectrum sensing methods to detect the spectrum holes of DME users. In this paper, an adaptive threshold energy detection spectrum sensing method is proposed based on the characteristics of DME pulse signals. Firstly, the energy of the received signal is estimated to construct the detection statistics, and the equations of detection probability and false alarm probability are established. Secondly, the adaptive threshold is calculated using the maximum likelihood decision criterion under the assumption of a constant probability of false alarm. Thirdly, the detection statistic is compared to the adaptive threshold to determine the spectrum occupancy state in the decision-making stage. Finally, the result is transmitted back to the transmitter for the best spectrum resource allocation. According to the simulation analysis, the adaptive threshold energy detection-based sensing method outperforms the energy-difference detection method under low signal-to-noise ratio (SNR) conditions. Meanwhile, it has superior adaptability since the adaptive threshold can be adaptively changed according to the channel.
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Keshkar, Miziya, Raja Muthalagu, Abdul Rajak, and Libin K. Mathew. "GAE and OBE Enhanced Interference Mitigation Techniques in LDACS." Aerospace 9, no. 1 (January 17, 2022): 45. http://dx.doi.org/10.3390/aerospace9010045.
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Interference mitigation in L-band digital aeronautic communication systems from legacy users is vital due to stringent safety requirements and steady-state increase in air traffic. This paper proposes an L-band digital aeronautic communication systems receiver prototype that employs nonlinear operations to reduce the interference from the prime interference contributor distance measuring equipment. The knowledge of genie-aided estimator and optimum Bayesian estimator is utilized to propose improved and low complexity nonlinear devices, such as a genie-aided estimator enhanced pulse peak attenuator, genie-aided estimator enhanced pulse peak limiter, joint genie-aided estimator enhanced pulse peak attenuator, joint genie-aided estimator enhanced pulse peak limiter, optimum Bayesian estimator enhanced pulse peak attenuator, optimum Bayesian estimator enhanced pulse peak limiter, joint optimum Bayesian estimator enhanced pulse peak attenuator and joint optimum Bayesian estimator enhanced pulse peak limiter. The performance of the proposed methods is compared with the classical pulse blanking in terms of the received bit error rate for different signal-to-noise ratios. The proposed genie-aided estimator enhanced methods exhibited SNR saving in the range of 2 to 2.5 dB at a bit error rate of 10−1. At the same BER, the proposed optimum Bayesian estimator enhanced methods achieved SNR saving in the range of 2.5 to 3 dB.
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Keshkar, Miziya, Raja Muthalagu, and Abdul Rajak. "ROAD Statistics-Based Noise Detection for DME Mitigation in LDACS." Applied Sciences 12, no. 8 (April 8, 2022): 3774. http://dx.doi.org/10.3390/app12083774.
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Interference mitigation in L-band Digital Aeronautic Communication Systems (LDACS) from legacy users is extremely important as any error in data retrieval of aeronautic communication can adversely affect flight safety. This paper proposes an LDACS receiver prototype which uses rank-ordered absolute differences (ROAD) statistics to detect the distance measuring equipment (DME) interference. The detected DME interference is reduced in the next stage by pulse blanking. The performance of the proposed ROAD pulse blanking method (ROAD PB) is compared with the existing interference mitigation methods which use the amplitude of the received signal for the detection of DME interference. In depth analysis of the obtained results affirms that the proposed ROAD value-based interference detection excels amplitude-based detection. For an SNR value of 0 dB, the proposed method of detection could achieve a 3% increase in terms of accuracy with a reduction of 4% in false alarms. With the advantage of ROAD statistics detection, the proposed ROAD PB could achieve an SNR saving of 2.7, 1.1, 0.7, 0.25 and 0.2 dBs at BER 10−1 in comparison with pulse blanking, Genie-aided estimation enhanced pulse peak attenuator (GAEPPA), GAE enhanced pulse peak limiter (GAEPPL), optimum Bayesien estimator enhanced pulse peak attenuator (OBEPPA) and OBE enhanced pulse peak limiter (OBEPPL). The comparative results show that the proposed ROAD pulse blanking outperformed the other techniques for the optimum threshold value of the operation.
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Filip, Alexandra, and Dmitriy Shutin. "Ambiguity Function Analysis for OFDM-Based LDACS Passive Multistatic Radar." IEEE Transactions on Aerospace and Electronic Systems 54, no. 3 (June 2018): 1323–40. http://dx.doi.org/10.1109/taes.2017.2780678.
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Shreejith, Shanker, Libin K. Mathew, Vinod A. Prasad, and Suhaib A. Fahmy. "Efficient Spectrum Sensing for Aeronautical LDACS Using Low-Power Correlators." IEEE Transactions on Very Large Scale Integration (VLSI) Systems 26, no. 6 (June 2018): 1183–91. http://dx.doi.org/10.1109/tvlsi.2018.2806624.
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Agrawal, Niharika, Abhishek Ambede, S. J. Darak, A. P. Vinod, and A. S. Madhukumar. "Design and Implementation of Low Complexity Reconfigurable Filtered-OFDM-Based LDACS." IEEE Transactions on Circuits and Systems II: Express Briefs 68, no. 7 (July 2021): 2399–403. http://dx.doi.org/10.1109/tcsii.2021.3053367.
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Maurer, Nils, Thomas Graupl, Miguel A. Bellido-Manganell, Daniel M. Mielke, Alexandra Filip-Dhaubhadel, Oliver Heirich, Daniel Gerbeth, et al. "Flight Trial Demonstration of Secure GBAS via the L-band Digital Aeronautical Communications System (LDACS)." IEEE Aerospace and Electronic Systems Magazine 36, no. 4 (April 1, 2021): 8–17. http://dx.doi.org/10.1109/maes.2021.3052318.
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Mielke, Daniel M., Nils Mäurer, Thomas Gräupl, and Miguel A. Bellido-Manganell. "1. Quantum Applications - Fachbeitrag: Getting Civil Aviation Ready for the Post Quantum Age with LDACS." Digitale Welt 5, no. 4 (September 20, 2021): 28–33. http://dx.doi.org/10.1007/s42354-021-0401-1.
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Bilzhause, A., B. Belgacem, M. Mostafa, and T. Graupl. "Datalink security in the L-band digital aeronautical communications system (LDACS) for air traffic management." IEEE Aerospace and Electronic Systems Magazine 32, no. 11 (November 2017): 22–33. http://dx.doi.org/10.1109/maes.2017.160282.
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Bartoli, Giulio, Romano Fantacci, Dania Marabissi, Luigia Micciullo, Claudio Armani, and Roberto Merlo. "A Novel Mitigation Scheme for JTIDS Impulsive Interference on LDACS System Based on Sensing and Symbol Retransmission." Journal of Signal Processing Systems 73, no. 3 (June 5, 2013): 255–66. http://dx.doi.org/10.1007/s11265-013-0763-1.
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Agrawal, Niharika, Sumit J. Darak, and Faouzi Bader. "Spectral Coexistence of LDACS and DME: Analysis via Hardware Software Co-Design in Presence of Real Channels and RF Impairments." IEEE Transactions on Vehicular Technology 69, no. 9 (September 2020): 9837–48. http://dx.doi.org/10.1109/tvt.2020.3002978.
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Zhou, Junming, Faming Wang, Nuruzzaman Noor, and Xiaosong Zhang. "An experimental study on liquid regeneration process of a liquid desiccant air conditioning system (LDACs) based on vacuum membrane distillation." Energy 194 (March 2020): 116891. http://dx.doi.org/10.1016/j.energy.2019.116891.
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Han, Eunjin, Wade T. Crow, Thomas Holmes, and John Bolten. "Benchmarking a Soil Moisture Data Assimilation System for Agricultural Drought Monitoring." Journal of Hydrometeorology 15, no. 3 (June 1, 2014): 1117–34. http://dx.doi.org/10.1175/jhm-d-13-0125.1.
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Abstract Despite considerable interest in the application of land surface data assimilation systems (LDASs) for agricultural drought applications, relatively little is known about the large-scale performance of such systems and, thus, the optimal methodological approach for implementing them. To address this need, this paper evaluates an LDAS for agricultural drought monitoring by benchmarking individual components of the system (i.e., a satellite soil moisture retrieval algorithm, a soil water balance model, and a sequential data assimilation filter) against a series of linear models that perform the same function (i.e., have the same basic input/output structure) as the full system component. Benchmarking is based on the calculation of the lagged rank cross correlation between the normalized difference vegetation index (NDVI) and soil moisture estimates acquired for various components of the system. Lagged soil moisture/NDVI correlations obtained using individual LDAS components versus their linear analogs reveal the degree to which nonlinearities and/or complexities contained within each component actually contribute to the performance of the LDAS system as a whole. Here, a particular system based on surface soil moisture retrievals from the Land Parameter Retrieval Model (LPRM), a two-layer Palmer soil water balance model, and an ensemble Kalman filter (EnKF) is benchmarked. Results suggest significant room for improvement in each component of the system.
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Teshima, Takahiro, Akito Matsuoka, Maika Shiba, Kazuho Dairaku, Hirotaka Matsumoto, Ryohei Suzuki, and Hidekazu Koyama. "Comparison of Properties of Stem Cells Isolated from Adipose Tissue and Lipomas in Dogs." Stem Cells International 2019 (November 20, 2019): 1–15. http://dx.doi.org/10.1155/2019/1609876.
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Adipose-derived mesenchymal stem cells (ADSCs) have been suggested their benefits in regenerative medicine for various diseases. Lipomas, benign neoplasms in adipose tissue, have been reported as a potential source of stem cells. These lipoma-derived mesenchymal stem cells (LDSCs) may be useful for regenerative medicine. However, the detailed characteristics of LDSCs have not been fully elucidated. This study investigated the cellular proteomics and secretomes of canine LDSCs in addition to morphology and proliferation and differentiation capacities. Some LDSCs isolated from canine subcutaneous lipomas were morphologically different from ADSCs and showed a rounded shape instead of fibroblast-like morphology. The phenotype of cell surface markers in LDSCs was similar to those in ADSCs, but CD29 and CD90 stem cell markers were more highly expressed compared with those of ADSCs. LDSCs had noticeably high proliferation ability, but no significant differences were observed compared with ADSCs. In regard to differentiation capacity compared to ADSCs, LDSCs showed higher adipogenesis, but no differences were observed with osteogenesis. Cellular proteomic analysis using two-dimensional gel electrophoresis revealed that over 95% of protein spots showed similar expression levels between LDSCs and ADSCs. Secretome analysis was performed using iTRAQ and quantitative cytokine arrays. Over 1900 proteins were detected in conditioned medium (CM) of LDSCs and ADSCs, and 94.0% of detected proteins showed similar expression levels between CM of both cell types. Results from cytokine arrays including 20 cytokines showed no significant differences between CM of LDSCs and that of ADSCs. Our results indicate that canine LDSCs had variability in characteristics among individuals in contrast with those of ADSCs. Cellular proteomics and secretomes were similar in both LDSCs and ADSCs. These findings suggest that LDSCs may be suitable for application in regenerative medicine.
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Stojanović, Sanja, and Stevo Najman. "The Effect of Conditioned Media of Stem Cells Derived from Lipoma and Adipose Tissue on Macrophages’ Response and Wound Healing in Indirect Co-culture System In Vitro." International Journal of Molecular Sciences 20, no. 7 (April 3, 2019): 1671. http://dx.doi.org/10.3390/ijms20071671.
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Immunomodulatory and wound healing activities of adipose-derived stem cells (ADSCs) have been reported in various in vitro and in vivo experimental models suggesting their beneficial role in regenerative medicine and treatments of inflammatory-related disorders. Lipoma-derived stem cells (LDSCs) were reported as a potential tool in regenerative medicine due to the similarity with ADSCs but we have previously shown that LDSCs have different differentiation capacity than ADSCs despite a similar mesenchymal phenotype. To further analyze the potential differences and/or similarities between those two stem cell types, in the present study we examined the macrophages (MΦs)’ response, immunomodulatory and wound healing effect of conditioned media (CM) of LDSCs and ADSCs in indirect co-culture system in vitro. We confirmed similar mesenchymal phenotype and stemness state of LDSCs and ADSCs but indicated differences in expression of some inflammatory-related genes. Anti-inflammatory potential of CM of LDSCs and ADSCs, with pronounced effect of LDSCs, in unstimulated RAW 264.7 MΦs was evaluated by decrease in Tnf and increase in Il10 gene expression, which was confirmed by corresponding cytokines’ secretion analysis. Conditioned media of both LDSCs and ADSCs led to the functional activation of MΦs, with slightly more pronounced effect of CM of LDSCs, while both stimulated wound healing in vitro in a similar manner. Results of this study suggest that LDSCs secrete soluble factors like ADSCs and therefore may have a potential for application in regenerative medicine, due to immunomodulatory and wound healing activity, and indicate that LDSCs through secretome may interact with other cells in lipoma tissue.
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Shi, Qingchuan, George Kurian, Farrukh Hijaz, Srinivas Devadas, and Omer Khan. "LDAC." ACM Transactions on Architecture and Code Optimization 13, no. 4 (December 28, 2016): 1–28. http://dx.doi.org/10.1145/2983632.
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Westley, Tracy, Anna Forsythe, Timothy J. Bell, Joseph C. Cappelleri, Geoffrey Chan, and Gabriel Tremblay. "Comparative Effectiveness of Combination Glasdegib+ Low-Dose Cytarabine (GLAS+LDAC) Vs Combination Venetoclax + Low-Dose Cytarabine (VEN+LDAC) Among Older Acute Myeloid Leukemia (AML) Patients Ineligible for Intensive Chemotherapy (NIC): Indirect Treatment Comparison (ITC) Methods." Blood 132, Supplement 1 (November 29, 2018): 1429. http://dx.doi.org/10.1182/blood-2018-99-111971.
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Abstract BACKGROUND: Older AML patients are often NIC and face poorer prognoses. Among less intensive AML treatments, GLAS+LDAC showed improved efficacy vs LDAC alone in a Phase II randomized controlled trial (RCT). Recently, a phase I/II single arm study of VEN+LDAC showed longer overall survival (OS) in naive comparison to GLAS+LDAC. However, naïve comparisons across trials do not account for within-trial efficacy differences from control or different population characteristics. In the absence of clinical trials comparing GLAS+LDAC vs VEN+LDAC, ITC is a more robust approach, and simulated treatment comparison (STC) adjusts for between-trial differences in patient baseline characteristics. In this study, GLAS+LDAC and VEN+LDAC were indirectly compared for survival efficacy using both ITC and STC. METHODS: Median OS and proportion of patients alive at 12 months (12-month OS) were compared for GLAS+LDAC vs VEN+LDAC using individual patient-level data (IPD) for GLAS+LDAC (n=116) and published results for VEN+LDAC (n=61). As the VEN+LDAC study lacked a control group, ITC and STC methods followed the unanchored, single-arm comparison as guided by the National Institute of Health and Care Excellence Decision Support Unit. Mean differences (MD) in median OS (months) between treatments were estimated using a modified Bucher ITC approach with 95% confidence intervals (CI). For 12-month OS, significance tests for MDs between treatments were conducted in Stata (MD with 95% CI). While ITC did not adjust for patient characteristics, using STC, GLAS+LDAC IPD were adjusted for VEN+LDAC patient baseline covariates. Full models included mutually reported covariates between trials, adjusting for GLAS+LDAC patients being older, having less denovo AML, higher bone marrow blasts, worse ECOG performance status, poorer cytogenetic risk, and more males compared to VEN+LDAC patients. STC models were estimated both with and without proportional hazards (PH) assumptions, and the best fitting models were applied. RESULTS: In the naive comparison, GLAS+LDAC had shorter median OS (8.3 months) vs VEN+LDAC (11.4 months). Similarly, 12-month OS was lower for GLAS+LDAC (39.4%) vs VEN+LDAC (45.9%). ITC found non-significant differences between GLAS+LDAC and VEN+LDAC for median OS [MD=-3.09 (-9.34, 3.17)] and 12-month OS [MD=-0.07 (-0.23, 0.10)], with numeric trends favoring VEN+LDAC (as shown in the Table). With full STC adjustment, PH models showed numeric but not statistical superiority of GLAS+LDAC vs VEN+LDAC for median OS [e.g., Gompertz-derived MD=0.60 (-4.43, 5.62)]. In contrast, full covariate models without the PH assumption estimated numeric but not statistical superiority of VEN+LDAC [e.g., lognormal-derived MD=-0.50 (-5.52, 4.51)]. Stepwise model results reflected full covariate adjustments: PH models numerically favored GLAS+LDAC over VEN+LDAC by about one month [e.g., exponential-derived MD=0.89 (-4.13, 5.90)]. Among models relaxing the PH assumption, the gamma estimate numerically favored GLAS+LDAC over VEN+LDAC [MD=0.39 (-4.63, 5.41)]. For 12-month OS, with all STC approaches, differences between GLAS+LDAC and VEN+LDAC were not statistically significant. After full covariate adjustment, slight numeric improvement with GLAS+LDAC vs VEN+LDAC was found for PH models [e.g., Gompertz-derived MD=0.04 (-0.13, 0.21)] and non-PH models [e.g., lognormal-derived MD=0.01 (-0.16, 0.17)]. Stepwise covariate models generated highly similar results (data not shown). CONCLUSIONS: Although GLAS+LDAC and VEN+LDAC have not been directly compared in a clinical trial, ITC and STC approaches found no difference between the two treatments comparing median OS and 12-month OS. Moreover, indirect approaches may introduce less bias than naïve comparisons, as methods can include statistical testing of differences and adjusting for population baseline differences. Standard ITC, which account for within-trial improvements from placebo could not be performed due to the single-arm design of the VEN+LDAC study. Furthermore, single-arm, open-label trials such as the VEN+LDAC study may overestimate treatment effectiveness, and GLAS+LDAC estimates originated from a robustly conducted RCT. As there was no evidence of statistical differences between treatments, health care stakeholders should continue to prioritize RCT evidence generation and minimize inferences from naïve comparisons. Disclosures Forsythe: Novartis: Consultancy. Bell:Pfizer: Employment, Equity Ownership. Cappelleri:Pfizer: Employment, Equity Ownership. Chan:Pfizer: Employment, Equity Ownership.
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Kim, Dong-Ju, Geon Kang, Do-Yong Kim, and Jae-Jin Kim. "Characteristics of LDAPS-Predicted Surface Wind Speed and Temperature at Automated Weather Stations with Different Surrounding Land Cover and Topography in Korea." Atmosphere 11, no. 11 (November 13, 2020): 1224. http://dx.doi.org/10.3390/atmos11111224.
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We investigated the characteristics of surface wind speeds and temperatures predicted by the local data assimilation and prediction system (LDAPS) operated by the Korean Meteorological Administration. First, we classified automated weather stations (AWSs) into four categories (urban flat (Uf), rural flat (Rf), rural mountainous (Rm), and rural coastal (Rc) terrains) based on the surrounding land cover and topography, and selected 25 AWSs representing each category. Then we calculated the mean bias error of wind speed (WE) and temperature (TE) using AWS observations and LDAPS predictions for the 25 AWSs in each category for a period of 1 year (January–December 2015). We found that LDAPS overestimated wind speed (average WE = 1.26 m s−1) and underestimated temperature (average TE = −0.63 °C) at Uf AWSs located on flat terrain in urban areas because it failed to reflect the drag and local heating caused by buildings. At Rf, located on flat terrain in rural areas, LDAPS showed the best performance in predicting surface wind speed and temperature (average WE = 0.42 m s−1, average TE = 0.12 °C). In mountainous rural terrain (Rm), WE and TE were strongly correlated with differences between LDAPS and actual altitude. LDAPS underestimated (overestimated) wind speed (temperature) for LDAPS altitudes that were lower than actual altitude, and vice versa. In rural coastal terrain (Rc), LDAPS temperature predictions depended on whether the grid was on land or sea, whereas wind speed did not depend on grid location. LDAPS underestimated temperature at grid points on the sea, with smaller TE obtained for grid points on sea than on land.
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Maertens, Johan, Michael Lübbert, Walter Fiedler, Loic Fouillard, Alf Haaland, Joseph M. Brandwein, Stéphane Lepretre, et al. "Phase I/II Study of Volasertib (BI 6727), an Intravenous Polo-Like Kinase (Plk) Inhibitor, in Patients with Acute Myeloid Leukemia (AML): Results From the Randomized Phase II Part for Volasertib in Combination with Low-Dose Cytarabine (LDAC) Versus LDAC Monotherapy in Patients with Previously Untreated AML Ineligible for Intensive Treatment." Blood 120, no. 21 (November 16, 2012): 411. http://dx.doi.org/10.1182/blood.v120.21.411.411.
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Abstract Abstract 411 Background: LDAC is an established treatment option for patients (pts) with AML considered ineligible for intensive remission induction treatment. However, the outlook for pts who receive LDAC remains unsatisfactory, and novel therapeutic strategies are needed to improve clinical outcome in these pts. Plk1 plays a key role in mitosis and cell cycle progression and is an attractive target for novel therapeutic approaches in cancer. Volasertib (V) is a first-in-class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Plks. The phase I part of this trial determined the maximum tolerated dose of V in combination with LDAC (V + LDAC) to be 350 mg and demonstrated antileukemic activity of V and V + LDAC in pts with relapsed/refractory AML ineligible for intensive therapy (Bug et al, ASH 2010 and 2011). Here we present preliminary phase II data for the randomized comparison of V + LDAC vs LDAC in pts with newly diagnosed AML ineligible for intensive treatment. Methods: In the phase II part of this open-label study, eligible pts were randomized to receive V (350 mg 1-hr intravenously, days 1, 15 Q4W) + LDAC (20 mg bid subcutaneously, days 1–10 Q4W), or LDAC alone until progression/relapse or intolerance. The primary endpoint was objective response (complete remission [CR] or CR with incomplete blood count recovery [CRi]); secondary endpoints included event-free survival (EFS), overall survival (OS), safety and pharmacokinetics (PK). Results: 87 pts were treated with V + LDAC (n=42) or LDAC (n=45). Pt characteristics (V + LDAC/LDAC) were largely balanced: median age, 75/76 yrs; secondary AML, 40.5%/64.4%; adverse cytogenetic group, 35.7%/33.3%. At time of analysis (February 22 2012) 15 pts were still on treatment (12 with V + LDAC). Pts received a median (range) of 2 (1–12) cycles of V + LDAC and 2 (1–11) cycles with LDAC. A significantly greater proportion of pts who received V + LDAC achieved a CR or CRi compared with pts who received LDAC (31.0% vs 11.1%; odds ratio 3.59 [95% CI: 1.15, 11.18]; P = 0.0277), with a median (range) time to remission of 71 (29–158) days and 69 (34–125) days, respectively. Remissions with V + LDAC were observed across genetic groups, including pts with adverse cytogenetics. A trend for longer median EFS was observed for pts who received V + LDAC compared with those who received LDAC (HR 0.61 [95% CI: 0.35, 1.05]; P = 0.0725; Figure). Follow-up for OS was ongoing at the time of this analysis. Among pts achieving CR/CRi, only 2 had experienced recurrence or death at the time of analysis (1 in each arm after a remission duration of 57 [V + LDAC] or 67 [LDAC] days). For all other pts ongoing in remission, the remission duration was censored after 53–407 days (LDAC + V) or 32–282 days (LDAC), consistent with prolonged duration of remission in some pts. The most frequent all grade adverse events (AEs) in the V + LDAC arm were febrile neutropenia (50%), constipation (45.2%), nausea (40.5%) and anemia (40.5%). In the LDAC arm, the most common all grade AEs were nausea (33.3%), anemia (28.9%), pyrexia (28.9%), and constipation, asthenia and diarrhea (26.7% each). More pts who received V + LDAC experienced ≥ grade 3 AEs than those who received LDAC (95.2% vs 68.9%), particularly for blood and lymphatic system disorders (81.0% vs 44.4%), gastrointestinal disorders (21.4% vs 6.7%), and infections and infestations (45.2% vs 22.2%). The early death rates (V + LDAC/LDAC) at 30, 60 and 90 days were comparable between the two treatment arms: 30 days, 9.5%/8.9%; 60 days, 21.5%/17.8%; 90 days, 28.9%/33.4% (rates calculated using Kaplan-Meier method). PK analyses demonstrated that V is a moderate clearance drug with multi-compartmental PK behavior, a large volume of distribution and a long terminal half-life. Preliminary data suggest no drug-drug interactions following combination of V with LDAC. Conclusions: These preliminary phase II data demonstrate a significantly improved CR/CRi rate and a trend for EFS benefit with V + LDAC compared with LDAC alone in pts with newly diagnosed AML ineligible for intensive treatment. An increased frequency of AEs was observed with the addition of V, which was expected given its myelosuppressive mechanism of action; available data do not suggest increased early mortality for V + LDAC vs LDAC. A confirmatory phase III trial is needed to determine the clinical benefit of V + LDAC in pts with AML ineligible for intensive treatment. Disclosures: Off Label Use: Volasertib is an investigational agent. Fiedler:Pfizer, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bug:Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees. Müller-Tidow:Boehringer Ingelheim: Research Funding. Voss:Boehringer Ingelheim: Employment. Taube:Boehringer Ingelheim: Employment. Fritsch:Boehringer-Ingelheim: Employment. Döhner:Celgene, Amgen, Ambit, Astellas, Lilly: Consultancy.
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Talluri, Ravi S., Ripal Gaudana, Sudharshan Hariharan, and Ashim K. Mitra. "Pharmacokinetics of Stereoisomeric Dipeptide Prodrugs of Acyclovir following Intravenous and Oral Administrations in Rats: A study Involving in vivo corneal Uptake of Acyclovir following Oral Dosing." Ophthalmology and Eye Diseases 1 (January 2009): OED.S2857. http://dx.doi.org/10.4137/oed.s2857.
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Objective To delineate the plasma pharmacokinetics and determine the corneal uptake of valine based stereoisomeric dipeptide prodrugs of acyclovir (ACV) in rats. Methods Male Sprague-Dawley rats were used for the study. Pharmacokinetics of ACV, L-valine-acyclovir (LACV), L-valine-D-valine-acyclovir (LDACV) and D-valine-L-valine acyclovir (DLACV) prodrugs were delineated. These compounds were administered intravenously as a bolus via jugular vein cannula and orally by gavage. Samples were purified by protein precipitation method and analyzed by LC-MS/MS. Pertinent pharmacokinetic parameters were obtained by using WinNonlin. Corneal uptake studies of LDACV and LACV were studied following oral administration. Results Following i.v. administration, the area under the curve (AUC) in μM*min of generated ACV was in the order of LACV > LDACV > DLACV indicating their rate of metabolism. The AUC values of total drug obtained in the systemic circulation after oral administration LACV and LDACV were 1077.93 ± 236.09 and 1141.76 ± 73.67 μM*min, respectively. DLACV exhibited poor oral absorption. Cmax (μM) and AUC of the intact prodrug obtained in the systemic circulation following oral administration of LDACV were almost 4–5 times higher than LACV. Moreover, concentrations achieved in the cornea after oral administration of LDACV were almost two times of LACV. Conclusions LDACV increased both the oral bioavailability and subsequent in vivo corneal uptake of ACV Hence, LDACV can be considered as the most promising drug candidate for delivery of ACV, in treatment of both genital herpes and ocular herpes keratitis after oral administration.
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Yu, Myungsu, Youngmok Lee, and Jaeeung Yi. "Flood inflow forecasting on HantanRiver reservoir by using forecasted rainfall." Journal of Korea Water Resources Association 49, no. 4 (April 30, 2016): 327–33. http://dx.doi.org/10.3741/jkwra.2016.49.4.327.
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Singh, Vipul Kumar, and Faisal Ahmed. "Econometric analysis of financial cointegration of least developed countries (LDCs) of Asia and the Pacific." China Finance Review International 6, no. 2 (May 16, 2016): 208–27. http://dx.doi.org/10.1108/cfri-06-2015-0056.
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Purpose – The purpose of this paper is to econometrically investigate the level of financial co-integration of the least developed countries (LDCs) of Asia and Pacific region. In addition, the paper also tested the co-integration of LDCs with the world’s second largest economy “China.” For this, the paper employed the foreign exchange data sets of respective LDCs. It also aimed to assess the dynamic conditional correlation (DCC) between the foreign exchange rates of LDCs and China, and further, examined the past and current level of their co-relational dependence. Design/methodology/approach – The authors created data sets namely LDCs of Asia and Pacific, LDCs of SAARC, LDCs of ASEAN, LDCs of Pacific, LDCs of SAARC and ASEAN, LDCs of ASEAN and Pacific, and LDCs of SAARC and Pacific. In addition, the authors tested the co-integration of these seven groups with China, and thus, making a total of 14 data sets. The analysis was carried out using the Johansen and Gregory-Hansen multivariate co-integration econometric techniques. To assess the DCC, multivariate DCC GARCH model was employed. Findings – It was found that at the intra-regional level, exchange rates of LDCs of SAARC, ASEAN and Pacific were co-integrated and showed the existence of 1-3 co-integrating equations. At inter-regional level SAARC-ASEAN, ASEAN-Pacific and SAARC-Pacific were also co-integrated and showed 1-3 co-integrated equations. However, on the inclusion of China in the study, the degree of co-integration of exchange rate of China with LDCs of SAARC and ASEAN increased, while with Pacific, the result was mixed. Conditional correlation estimated of multivariate DCC GARCH model suggested that except for Afghanistan, there was an upward shift in the correlation dynamics of exchange rates of LDCs with China, post global financial crisis. Practical implications – Asia and Pacific region constituted of 53 countries, of which 13 were LDCs. Enhanced financial integration among LDCs of Asia-Pacific region and also between LDCs and major economies of the region like China will strengthen economic and financial integration efforts in the region. Originality/value – The present paper attempted a comparative assessment of the co-movements of the foreign exchange markets of LDCs, the countries which have remained largely neglected in academic discourses on financial integration.
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Heuser, Michael, Tadeusz Robak, Pau Montesinos, Brian Leber, Walter M. Fiedler, Daniel Aaron Pollyea, Andrew Brown, et al. "Glasdegib (GLAS) plus low-dose cytarabine (LDAC) in AML or MDS: BRIGHT AML 1003 final report and four-year overall survival (OS) follow-up." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 7509. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.7509.
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7509 Background: In newly diagnosed AML or high-risk MDS, primary analysis of the randomized phase 2 BRIGHT AML 1003 trial (data cutoff Jan 2017) showed superior OS for GLAS+LDAC vs LDAC alone. The trial then continued to predefined completion 4 years from randomization of all patients (pts), reached in Mar 2019 and presented herein. Methods: Pts with newly diagnosed AML or high-risk MDS and unsuitable for intensive chemotherapy were randomized 2:1 to GLAS+LDAC (n=88) or LDAC alone (n=44). For these groups, median (range) treatment duration was 83 (3-1575) and 47 (6-239) days; median follow-up for survival 47.6 and 48.1 months; 4 (4.5%) and 1 pt (2.3%) completed ≥4 years’ follow-up. Results: Consistent with the primary findings (OS HR 0.51; 80% CI 0.39, 0.67 p=0.0004), GLAS+LDAC prolonged OS vs LDAC alone (table). Results were consistent in AML pts and cytogenetic risk/disease history subgroups (table), as were analyses by pt characteristics and baseline risk factors (not shown). Survival probability was 39.5% vs 9.5% at 1 year and 18.0% vs 2.4% at 2 years. GLAS+LDAC induced higher complete remission (CR) rates overall (16/88 vs 1/44; RR 8.12, 95% CI 1.05, 62.78, p=0.010) and across subgroups. Notably, fewer pts discontinued GLAS+LDAC due to AEs (38.1% and 46.3%) and there was no increased sepsis or bleeding vs LDAC alone despite longer glasdegib treatment. With GLAS+LDAC, SMO-inhibitor-associated AEs included dysgeusia (25.0%), muscle spasms (22.6%) and alopecia (10.7%), with only 1 pt discontinuing due to dysgeusia. Conclusions: Consistent with primary analyses, GLAS+LDAC continued to have an acceptable safety profile and improved OS vs LDAC alone. HRs were consistent across cytogenetic risk subgroups and support use of GLAS+LDAC in de novo and secondary AML. Clinical trial information: NCT01546038 . [Table: see text]
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Liu, Xin, Tina Monzavi, and Ivan Gitsov. "Controlled ATRP Synthesis of Novel Linear-Dendritic Block Copolymers and Their Directed Self-Assembly in Breath Figure Arrays." Polymers 11, no. 3 (March 21, 2019): 539. http://dx.doi.org/10.3390/polym11030539.
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Herein, we report the formation and characterization of novel amphiphilic linear-dendritic block copolymers (LDBCs) composed of hydrophilic dendritic poly(ether-ester), PEE, blocks and hydrophobic linear poly(styrene), PSt. The LDBCs are synthesized via controlled atom transfer radical polymerization (ATRP) initiated by a PEE macroinitiator. The copolymers formed have narrow molecular mass distributions and are designated as LGn-PSt Mn, in which LG represents the PEE fragment, n denotes the generation of the dendron (n = 1–3), and Mn refers to the average molecular mass of the LDBC (Mn = 3.5–68 kDa). The obtained LDBCs are utilized to fabricate honeycomb films by a static “breath figure” (BF) technique. The copolymer composition strongly affects the film morphology. LDBCs bearing acetonide dendron end groups produce honeycomb films when the PEE fraction is lower than 20%. Pore uniformity increases as the PEE content decreases. For LDBCs with hydroxyl end groups, only the first generation LDBCs yield BF films, but with a significantly smaller pore size (0.23 μm vs. 1–2 μm, respectively). Although higher generation LDBCs with free hydroxyl end groups fail to generate honeycomb films by themselves, the use of a cosolvent or addition of homo PSt leads to BF films with a controllable pore size (3.7–0.42 μm), depending on the LDBC content. Palladium complexes within the two triazole groups in each of the dendron’s branching moieties can also fine-tune the morphology of the BF films.
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Andrade, Guilherme Medeiros Soares de, Fernando Wesley Cavalcanti de Araújo, Maurício Pereira Magalhães de Novaes Santos, and Fabio Santana Magnani. "Standardized Comparison of 40 Local Driving Cycles: Energy and Kinematics." Energies 13, no. 20 (October 18, 2020): 5434. http://dx.doi.org/10.3390/en13205434.
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Local driving cycles (LDCs) capture local traffic characteristics, while standard driving cycles (SDCs) compare vehicles in distinct regions. There is a plethora of LDCs, raising the question as to how distinct they are. To quantify it, we first organized a collection of 77 LDCs. From the speed—time images, it was possible to extract numerical vectors of 40 cycles in a standardized way. Comparing the LDCs developed for cars, we found that their parameters fluctuate significantly: the average speed varies from 14.7 to 44.7 km/h, and the fuel economy varies from 10.8 to 20.5 km/L. Comparing the LDCs with FTP-75 cycle, the difference in speed is 7 km/h, and in fuel economy is 1.5 km/L. For WLTC, the difference is 19.4 km/h and 3 km/L, respectively. Thus, given the deviations found between the analyzed LDCs, and between LDCs and SDCs, the numerical results reinforce the relevance of using LDCs for each region.
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Falzarano, Francesca, Jillian Minahan, Verena Cimarolli, Amy Horowitz, and Danielle Jimenez. "LONG-DISTANCE CAREGIVERS’ SATISFACTION AND CHALLENGES WITH FORMAL CARE PROVIDERS." Innovation in Aging 3, Supplement_1 (November 2019): S557. http://dx.doi.org/10.1093/geroni/igz038.2058.
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Abstract The purpose of this study (N=304) was to identify differences in LDCs’ experiences with their care recipient’s (CR) formal care providers (FCPs) among four LDC groups based on CR dementia status and residential setting (community/nursing home [NH]). Results show that LDCs of CRs without dementia living in a NH are less likely to be satisfied with information/communication provided by FCPs compared to LDCs of CRs with dementia in the community. FCP-related challenges were significantly greater among LDCs of CRs in a NH, with or without dementia, compared to LDCs of CRs without dementia living in the community. A significantly greater proportion of LDCs of CRs living in a NH, with or without dementia, reported dealing with inadequate care as a challenge compared to LDCs of CRs with dementia living in the community. This highlights LDCs’ unique experiences related to FCPs based on differences in CR dementia status and residential setting.
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Tremblay, Gabriel, Patrick Daniele, Mike Dolph, Timothy J. Bell, Geoffrey Chan, Andrew Brown, and Joseph C. Cappelleri. "Comparative Effectiveness of Glasdegib or Venetoclax in Combination with Low-Dose Cytarabine Using Simulated Treatment Comparisons." Blood 136, Supplement 1 (November 5, 2020): 17–18. http://dx.doi.org/10.1182/blood-2020-137641.
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Background: Older patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy have a poor prognosis, further encumbered by the lack of well-tolerated standard therapies. Combinations of glasdegib with low-dose cytarabine (GLAS+LDAC) and venetoclax with LDAC (VEN+LDAC) are non-intensive chemotherapy (NIC) options recommended by the National Cancer Comprehensive Network Guidelines. As these regimens have not been compared in a head-to-head trial, indirect treatment comparisons (ITC) are of clinical relevance to assess their comparative effectiveness. Hazard ratios (HR) for overall survival (OS) estimate relative survival valued equally throughout follow-up, unlike landmark measures of OS, which may overvalue or undervalue survival at a single time point. This simulated treatment comparison (STC) study compared OS HRs between GLAS+LDAC and VEN+LDAC among older patients with AML unfit for IC. Methods: This analysis utilized individual AML patient data (IPD) from the BRIGHT AML 1003 GLAS+LDAC trial (N=116) and published summary data extracted from the Phase III VEN+LDAC trial (N=211). STC was used following Decision Support Unit Guidelines from the National Institute for Health and Care Excellence. Parametric time-to-event regression models for OS were generated using the GLAS+LDAC IPD; optimal exponential models are presented based on fit statistics. OS HRs were estimated after adjusting for baseline patient characteristics of the GLAS+LDAC trial to match the VEN+LDAC trial. Full and backwards stepwise models (retention p-value <0.2) were constructed considering all mutually available patient covariates including age, sex, de novo vs secondary AML, bone marrow blast >50%, Eastern Cooperative Oncology Group performance status, and cytogenetic risk. OS HRs were indirectly compared by ITC (unadjusted for covariates) and STC (adjusted) with 95% confidence intervals (CIs). ITC and STC used post-hoc analysis results for VEN+LDAC; a sensitivity analysis of pre-specified analysis results for VEN+LDAC was conducted. Results: Overlapping Kaplan Meier (KM) curves for GLAS+LDAC and VEN+LDAC (Figure 1A) suggest that survival probability was similar throughout follow-up. Comparisons of crude survival rates, however, do not account for differences in patient characteristics between studies. Patients in the GLAS+LDAC trial were more likely to be male, have secondary AML, and had worse cytogenetic risk profiles than the VEN+LDAC trial. Unadjusted ITC estimated that GLAS+LDAC numerically (but not statistically) favored over VEN+LDAC, with a 34% (HR: 0.66; 95%CI: 0.38, 1.15) reduction in mortality (Figure 1B). Similarly, following STC with full covariate adjustment, the estimated comparative advantage of GLAS+LDAC over VEN+LDAC widened to 44% (HR: 0.56; 95%CI: 0.24, 1.31). Results of the sensitivity analyses were consistent with these findings. Conclusion: This study indirectly compared OS HRs of GLAS+LDAC and VEN+LDAC in older patients with AML unfit for intensive chemotherapy. In the absence of a head-to-head trial, a well-conducted STC provides the best adjusted estimate of comparative effectiveness between treatments. Unadjusted ITC and adjusted STC revealed that the OS HR numerically favored GLAS+LDAC over VEN+LDAC, albeit not significantly. These findings suggest that the decision between these two recommended NIC regimens may not be based solely on differences in survival outcomes. Rather, the safety profile, the burden of administration, and patient preference will need to be factored into treatment decisions. Figure 1. KM and ITC/STC Results Figure 1 Disclosures Tremblay: Pfizer Inc.: Consultancy; Purple Squirrel Economics: Current Employment. Daniele:Purple Squirrel Economics: Current Employment; Pfizer Inc: Consultancy. Dolph:Purple Squirrel Economics: Current Employment; Pfizer Inc: Consultancy. Bell:Pfizer: Current Employment, Current equity holder in publicly-traded company. Chan:Pfizer Inc.: Current Employment. Brown:Pfizer: Current Employment, Current equity holder in publicly-traded company. Cappelleri:Pfizer Inc.: Current Employment.
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Huang, Weiwei, Fei Gao, Yuting Zhang, Tianhui Chen, and Chen Xu. "Lipid Droplet-Associated Proteins in Cardiomyopathy." Annals of Nutrition and Metabolism 78, no. 1 (December 2, 2021): 1–13. http://dx.doi.org/10.1159/000520122.
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Background: The heart requires a high rate of fatty-acid oxidation (FAO) to meet its energy needs. Neutral lipids are the main source of energy for the heart and are stored in lipid droplets (LDs), which are cytosolic organelles that primarily serve to store neutral lipids and regulate cellular lipid metabolism. LD-associated proteins (LDAPs) are proteins either located on the surface of the LDs or reside in the cytosol and contribute to lipid metabolism. Therefore, abnormal cardiac lipid accumulation or FAO can alter the redox state of the heart, resulting in cardiomyopathy, a group of diseases that negatively affect the myocardial function, thereby leading to heart failure and even cardiac death. Summary: LDs, along with LDAPs, are pivotal for modulating heart lipid homeostasis. The proper cardiac development and the maintenance of its normal function depend largely on lipid homeostasis regulated by LDs and LDAPs. Overexpression or deletion of specific LDAPs can trigger myocardial dysfunction and may contribute to the development of cardiomyopathy. Extensive connections and interactions may also exist between LDAPs. Key Message: In this review, the various mechanisms involved in LDAP-mediated regulation of lipid metabolism, the association between cardiac development and lipid metabolism, as well as the role of LDAPs in cardiomyopathy progression are discussed.
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Cortes, Jorge E., Florian H. Heidel, Michael Heuser, Walter Fiedler, B. Douglas Smith, Tadeusz Robak, Pau Montesinos Fernandez, et al. "A Phase 2 Randomized Study of Low Dose Ara-C with or without Glasdegib (PF-04449913) in Untreated Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome." Blood 128, no. 22 (December 2, 2016): 99. http://dx.doi.org/10.1182/blood.v128.22.99.99.
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Abstract Background: The Hedgehog signaling pathway (HhP) is aberrantly activated in leukemias and myelodysplastic syndrome (MDS), promoting cancer stem cell maintenance. HhP inhibition reduces leukemic stem cells. Glasdegib is a potent, selective, oral HhP inhibitor, with activity in pre-clinical and clinical studies. The addition of glasdegib to standard chemotherapy (CT) has an acceptable safety profile and appears to have clinical activity in MDS and acute myeloid leukemia (AML). Methods: In this study (NCT01546038), previously untreated AML or high-risk MDS patients (pts) ineligible for intensive CT were randomized 2:1 to receive low-dose cytarabine (LDAC) 20 mg subcutaneously twice a day x 10 days q28 days + oral glasdegib 100 mg daily or LDAC alone for as long as pts received clinical benefit. The primary endpoint was overall survival (OS). The final analysis was conducted after completion of recruitment (Oct 2015) and at least 92 OS events. Results: As of Apr 2016, 132 pts (116 AML, 16 MDS) were randomized to LDAC + glasdegib (n = 88) or LDAC alone (n = 44) (stratified as good/intermediate [int.] vs poor risk) (Table). Demographic and baseline characteristics were similar between arms in median age, baseline cytogenetic risk, and diagnosis. Eighty-four pts received LDAC + glasdegib and 41 pts LDAC alone (7 randomized/not treated pts were followed for survival). Median treatment duration was 83 days for LDAC + glasdegib and 47 days for LDAC alone; median follow up was 14.3 months and 12.4 months, respectively. In the glasdegib arm, 12 pts were continuing treatment and 25 were in follow up; in the LDAC arm, 1 pt was on treatment and 5 in follow up. Cytopenias and gastrointestinal toxicities were the adverse events (AEs) occurring more frequently in the LDAC + glasdegib arm. Hh-associated AEs in the glasdegib arm included dysgeusia (23.8%), muscle spasms (20.2%) and alopecia (10.7%). Serious AEs of febrile neutropenia were more frequent in the glasdegib arm, but sepsis rates were lower and pneumonia rates were similar. The most common cause of death was disease progression in both arms. Grade 2-4 QTcF prolongation was more frequent in the LDAC arm. Investigator-reported complete response (CR) rates were numerically higher for LDAC + glasdegib (n = 17, 15%) vs LDAC alone (n = 1, 2.3%), p-value 0.0142. Based on intent to treat analysis of 96 events, median OS (mOS) for LDAC + glasdegib was 8.3 (80% confidence interval [CI] 6.9, 9.9) vs 4.9 months (80% CI 3.5, 6.0) for LDAC alone (HR 0.511, 80% CI 0.386, 0.675; one-sided log rank p-value 0.0020 stratified by cytogenetic risk). For good/int. risk, mOS for LDAC + glasdegib was 12.2 vs 6.0 months for LDAC alone (HR 0.464, p-value 0.0035). For poor risk, mOS for LDAC + glasdegib was 4.4 vs 2.3 months (HR 0.575, p-value 0.0422). In AML pts, mOS for LDAC + glasdegib was 8.3 vs 4.3 months for LDAC alone (HR 0.462, p-value 0.0004). Conclusions: The addition of glasdegib to LDAC for AML and high-risk MDS pts improved OS compared with LDAC alone. The improvement was consistent among subgroups, particularly in good/int. risk pts. Treatment was associated with an acceptable safety profile. The addition of glasdegib to LDAC may be a treatment option for pts with AML or high-risk MDS. Disclosures Cortes: ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Heuser:Tetralogic: Research Funding; Celgene: Honoraria; Bayer Pharma AG: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; Karyopharm Therapeutics Inc: Research Funding; BerGenBio: Research Funding. Fiedler:Gilead: Other: Travel; Novartis: Consultancy; Ariad/Incyte: Consultancy; Teva: Other: Travel; Pfizer: Research Funding; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; GSO: Other: Travel. Smith:Actinium Pharmaceuticals, Inc.: Research Funding. Robak:Pfizer: Research Funding. Montesinos Fernandez:Gamida Cell: Consultancy. Ma:Pfizer: Employment, Equity Ownership. Shaik:Pfizer: Employment, Equity Ownership. Zeremski:Pfizer: Employment, Equity Ownership. O'Connell:Pfizer: Employment, Equity Ownership. Chan:Pfizer: Employment, Equity Ownership.
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Heuser, Michael, B. Douglas Smith, Walter Fiedler, Mikkael A. Sekeres, Pau Montesinos, Brian Leber, Akil Merchant, et al. "Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial." Annals of Hematology 100, no. 5 (March 19, 2021): 1181–94. http://dx.doi.org/10.1007/s00277-021-04465-4.
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AbstractThis analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395–1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.
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Lin, Swan, Naveed Shaik, Geoffrey Chan, Jorge E. Cortes, and Ana Ruiz-Garcia. "An evaluation of overall survival in patients with newly diagnosed acute myeloid leukemia and the relationship with glasdegib treatment and exposure." Cancer Chemotherapy and Pharmacology 86, no. 4 (September 3, 2020): 451–59. http://dx.doi.org/10.1007/s00280-020-04132-x.
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Abstract Purpose Glasdegib, an oral inhibitor of the Hedgehog signaling pathway, is approved in the United States in combination with low-dose cytarabine (LDAC) to treat patients with newly diagnosed acute myeloid leukemia (AML) ineligible to receive intensive chemotherapy. This population pharmacokinetic/pharmacodynamic analysis characterized the time course of survival with glasdegib + LDAC relative to LDAC alone, and explored whether the differences in glasdegib exposure at the clinical dose of 100 mg once daily (QD) significantly affected overall survival (OS). Methods Data from the BRIGHT AML 1003 trial in patients with AML were included in treatment–response (glasdegib + LDAC, n = 78; LDAC alone, n = 38) and exposure–response (glasdegib + LDAC, n = 75) analyses. Results The analyses demonstrate that patients treated with glasdegib + LDAC (vs LDAC alone) at any time point during the study period were 58% less likely to die, translating to prolonging of median OS by ~ 5 months (hazard ratio 0.42 [95% confidence interval 0.28–0.66]). Variability in glasdegib exposures did not impact the risk of death. Additionally, potential covariates such as patient demographics, prior treatment with a hypomethylating agent, baseline safety laboratory values, and disease characteristics, did not impact the probability of OS. Conclusion Together these results confirm that glasdegib + LDAC treatment (vs. LDAC alone) is associated with a significant survival benefit in patients with newly diagnosed AML, and that variability in glasdegib doses (e.g., for dose reductions) and exposures do not compromise the survival benefit of glasdegib 100 mg QD. Clinical Trial number NCT01546038.
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Ouyang, Qin, Guang Xiao Kou, and Min Ouyang. "Applicability Research on Evaporative Cooling Technology in Hunan Province." Advanced Materials Research 1070-1072 (December 2014): 1679–83. http://dx.doi.org/10.4028/www.scientific.net/amr.1070-1072.1679.
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According to the climate conditions of Hunan province and the design parameters related to air conditioning, the energy consumption and the related characteristics of the liquid desiccant evaporative cooling system (LDECS) are compared with primary return air conditioning system. The results show that energy consumption of LDECS can be decreased by 11.78% compared to the primary return air system. LDECS has a certain degree of energy saving potential in Hunan province, especially when waste heat is available.
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de Melo, Jaime, and Céline Carrère. "The Doha Round and Market Access for LDCs: Scenarios for the EU and US Markets." Journal of World Trade 44, Issue 1 (February 1, 2010): 251–90. http://dx.doi.org/10.54648/trad2010008.
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Least developed countries (LDCs) hoped that the DOHA round would bring them greater market access in the Organization for Economic Cooperation and Development countries than for non-LDCs. Using HS-6 tariff level data for the United States and the EU for 2004, this paper estimates that, once the erosion from preferential access into the EU to non-LDCs is taken into account, LDCs have about a 3% preferential margin in the EU market. In the US market, in spite of preferences under the African Growth and Opportunity Act(AGOA), on a trade-weighted basis, LDCs are discriminated against. Under various ‘Swiss formulas’ for tariff cuts, effective market access for LDCs in the EU will be negligible and still negative in the United States. If the United States were to apply a 97% rule (i.e, duty-free quota-free access for all but 3% of the tariff lines), LDCs could increase exports by 10% or about USD 1 billion annually. Effective market access is further reduced by complicated Rules of Origin (RoO) applied by the EU and the United States. Furthermore, generally, the most restrictive RoO fall on products in which LDCs have the greatest preferential market access.
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Wei, Andrew H., Pau Montesinos, Vladimir Ivanov, Courtney Denton Dinardo, Jan Novak, Kamel Laribi, Inho Kim, et al. "A phase III study of venetoclax plus low-dose cytarabine in previously untreated older patients with acute myeloid leukemia (VIALE-C): A six-month update." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 7511. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.7511.
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7511 Background: VIALE-C was designed to compare the safety and efficacy of the BCL-2 inhibitor venetoclax (VEN) or placebo (PBO) plus low-dose cytarabine (LDAC) in previously untreated patient (pts) with acute myeloid leukemia (AML; ≥75 yr or ≥18 yr with comorbidities precluding intensive chemotherapy). The primary overall survival (OS) analysis showed a clinically meaningful improvement with VEN+LDAC, although the primary endpoint was not met. Herein, we present a 6-mo update after primary analysis, with a focus on OS. Methods: This double-blind, PBO-controlled phase 3 study (NCT03069352) randomized pts 2:1 to VEN (600 mg orally QD, days [d]1–28) with 4-d ramp-up in first cycle or PBO in 28-d cycles, plus LDAC (20 mg/m2 subcutaneously QD, d1–10). The primary endpoint was OS; secondary endpoints included response, transfusion independence (TI; red blood cells [RBC] or platelets), and event-free survival (EFS). OS and EFS were analyzed by the Kaplan-Meier method and compared between arms using the log-rank test stratified by AML status (de novo vs secondary) and age (18 to < 74 vs ≥75). The planned sample size was 210 pts (n = 140, VEN; n = 70, PBO) to detect a hazard ratio (HR) of 0.545 in OS with 2-sided alpha of 5% and power of 90%. Results: As of 15 Aug 2019, 211 pts were randomized (n = 143, VEN; n = 68, PBO); median age: 76 yr in both arms (range: 36–93); secondary AML: 38% (88% post-MDS/CMML); prior hypomethylating agent: 20%. With a median follow-up of 17.5 mo (range: 0.1–23.5), median OS was 8.4 mo vs 4.1 mo in the VEN+LDAC and PBO+LDAC arms (HR 0.70; 95% CI 0.50–0.99; P= .04), representing a 30% reduction in the risk of death. Complete remission (CR)/CRi and CR/CRh (CR with partial hematologic recovery) rates were both 48% for the VEN+LDAC arm, and 13% and 15%, respectively, for PBO+LDAC. RBC/platelets TI rates were 43%/49% vs 19%/32% for VEN+LDAC and PBO+LDAC. Median EFS was 4.9 mo vs 2.1 mo in the VEN+LDAC and PBO+LDAC arms (HR 0.61; 95% CI 0.44–0.84; P= .003). Grade ≥3 adverse events (AEs [ > 30%]; VEN+LDAC/PBO+LDAC) included neutropenia (49%/18%), thrombocytopenia (45%/38%), and febrile neutropenia (32%/29%); serious AEs ( > 10%) were febrile neutropenia (17%/18%) and pneumonia (14%/10%); tumor lysis syndrome occurred in 5.6%/0%. Conclusions: VEN+LDAC demonstrates a clinically meaningful improvement in OS compared with PBO+LDAC, with a tolerable and manageable safety profile. These data support VEN+LDAC as a frontline treatment option for older pts with AML, as well as those considered unfit for intensive chemotherapy. Clinical trial information: NCT03069352 .
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Stojanović, Sanja, Stevo Najman, and Aleksandra Korać. "Stem Cells Derived from Lipoma and Adipose Tissue—Similar Mesenchymal Phenotype but Different Differentiation Capacity Governed by Distinct Molecular Signature." Cells 7, no. 12 (December 8, 2018): 260. http://dx.doi.org/10.3390/cells7120260.
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Lipomas are benign adipose tissue tumors of unknown etiology, which can vary in size, number, body localization and cell populations within the tissue. Lipoma-derived stem cells (LDSCs) are proposed as a potential tool in regenerative medicine and tissue engineering due to their similar characteristics with adipose-derived stem cells (ADSCs) reported so far. Our study is among the first giving detailed insights into the molecular signature and differences in the differentiation capacity of LDSCs in vitro compared to ADSCs. Mesenchymal stem cell phenotype was analyzed by gene expression and flow cytometric analysis of stem cell markers. Adipogenesis and osteogenesis were analyzed by microscopic analysis, cytochemical and immunocytochemical staining, gene and protein expression analyses. We showed that both LDSCs and ADSCs were mesenchymal stem cells with similar phenotype and stemness state but different molecular basis for potential differentiation. Adipogenesis-related genes expression pattern and presence of more mature adipocytes in ADSCs than in LDSCs after 21 days of adipogenic differentiation, indicated that differentiation capacity of LDSCs was significantly lower compared to ADSCs. Analysis of osteogenesis-related markers after 16 days of osteogenic differentiation revealed that both types of cells had characteristic osteoblast-like phenotype, but were at different stages of osteogenesis. Differences observed between LDSCs and ADSCs are probably due to the distinct molecular signature and their commitment in the tissue that governs their different capacity and fate during adipogenic and osteogenic induction in vitro despite their similar mesenchymal phenotype.
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Wang, Eunice S., Michael Heuser, Mikkael A. Sekeres, Cristina Papayannidis, Anna Candoni, Akil Merchant, Andrew Brown, et al. "Effect of early blood counts on overall survival (OS) following glasdegib + LDAC in newly diagnosed AML: BRIGHT AML 1003 post hoc analysis." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 7525. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.7525.
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7525 Background: Addition of glasdegib (GLAS) to LDAC approximately doubled OS without significant worsening of myelosuppression-related complications, ostensibly by targeting leukemic stem cells dependent on the hedgehog pathway, which is not involved in normal adult hematopoiesis. We assessed potential association of early blood counts and OS. Methods: In BRIGHT AML 1003, patients (pts) with newly diagnosed AML were randomized to GLAS + LDAC (n = 78) or LDAC alone (n = 38). GLAS was given once daily continuously and LDAC on days 1–10 of a 28-day cycle. We evaluated peripheral blood counts measured early in the study (cycle 2 day 1 [C2D1]), approximately 1 month before the first bone marrow assessments. OS was compared for GLAS+LDAC vs LDAC alone subgroups meeting thresholds of absolute neutrophil count (ANC; ≥1000 or 500/µL), hemoglobin (Hb; ≥10 or 9 g/dL) or platelets (≥100,000 or 50,000/µL). Data cut-off was Apr 2019. Results: Among all pts regardless of baseline values, achievement of ANC, Hb and platelet thresholds at C2D1 was associated with improved OS with GLAS+LDAC (table, left side). Notably, in pts who did not meet ANC, Hb or platelet thresholds (table, right side), OS benefit with GLAS+LDAC was also observed (table, all p≤0.05). Among pts below threshold at baseline, C2D1 recovery of platelets ≥50,000 or 100,000 and Hb ≥9 or 10 was associated with improved OS (not shown). Clinical trial information: NCT01546038 . Conclusions: In pts with newly diagnosed AML, improved OS was associated with various blood count thresholds after 1 cycle of GLAS+LDAC vs LDAC alone. In pts with baseline measurements below threshold, recovery of specific thresholds was associated with improved OS. These exploratory results are consistent with the hematopoiesis-sparing mechanism of GLAS, and merit further evaluation. [Table: see text]
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Cimarolli, Verena R., Amy Horowitz, and Rachel Pruchno. "LONG-DISTANCE CAREGIVING: MENTAL HEALTH CONSEQUENCES AND USE OF RESOURCES." Innovation in Aging 3, Supplement_1 (November 2019): S556—S557. http://dx.doi.org/10.1093/geroni/igz038.2055.
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Abstract Long-distance caregiving (LDC) is a growing phenomenon and common experience for caregivers of frail older adults. In fact, 11% of family caregivers in the US live more than two hours distance from the care recipient (CR). Unfortunately, there is a paucity of research on unique experiences of LDCs and the impact of LDC on the mental health of LDCs. This symposium presents findings from the NIA funded Fordham Long-Distance Caregiving Study (R21AG050018) analyzing data of 304 long-distance caregivers (LDCs). The overall study goal was to better understand how LDCs deal with the structural constraint of distance, and to examine LDC consequences and resources. First, Horowitz presents the study background, characteristics of the sample, and provides a description of the unique experiences of LDCs. Next, Cimarolli concentrates on the Sociocultural Stress Process Model applied to LDC. Her study tested the impact of LDC on mental health and investigated resources (e.g., coping skills) which could mediate the association between caregiving stressors and mental health outcomes. The third paper (Falzarano) presents data related to satisfaction with formal service providers for four subgroups of LDCs based on CR residence and dementia status. Finally, Jimenez focuses on the characteristics of LDCs’ network of other informal caregivers (IC) providing assistance to the CR and factors are associated with more help received from other ICs. Dr. Pruchno, an expert in caregiving research, will discuss study findings. The symposium provides insights into unique experiences of LDCs, the impact of LDC on mental health, and resource use among LDCs.
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He, Qing, Linlin Liu, Qiaoyu Yang, Ailing Wang, Shuo Chen, Ruiyun Li, Yi Huang, et al. "Invariant natural killer T cells promote immunogenic maturation of lung dendritic cells in mouse models of asthma." American Journal of Physiology-Lung Cellular and Molecular Physiology 313, no. 6 (December 1, 2017): L973—L990. http://dx.doi.org/10.1152/ajplung.00340.2016.
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Our previous study showed that invariant natural killer T (iNKT) cells might act as an adjuvant to promote Th2 inflammatory responses in an OVA-induced mouse model of allergic asthma, but the mechanism remains unknown. To clarify the underlying mechanism through which iNKT cells promote Th2 inflammatory responses, we investigated the modulatory influence of iNKT cells on phenotypic and functional maturation of lung dendritic cells (LDCs) using iNKT cell-knockout mice, specific iNKT cell activation, coculture experiments, and adoptive transfer of iNKT cells in mouse models of asthma. Our data showed that iNKT cell deficiency could downregulate surface maturation markers and proinflammatory cytokine secretion of LDCs from a mouse model of asthma. However, elevated activation of iNKT cells by α-galactosylceramide and adoptive transfer of iNKT cells could upregulate surface maturation markers and proinflammatory cytokine secretion of LDCs from mouse models of asthma. Meanwhile, iNKT cells significantly influenced the function of LDCs, markedly enhancing Th2 responses in vivo and in vitro. In addition, iNKT cell can induce LDCs expression of CD206 and RELM-α, reflecting alternative activation of LDCs in a mouse model of asthma. α-Galactosylceramide treatment significantly enhanced expression of CD40L of lung iNKT cells from a mouse model of asthma, and the coculture experiment of LDCs with iNKT cells showed that the blockade of CD40L strongly suppressed surface maturation markers and proinflammatory cytokine production by LDCs. Our data suggest that iNKT cells can promote immunogenic maturation of LDCs to enhance Th2 responses in mouse models of asthma.
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Smith, B. Douglas, Cristina Papayannidis, Michael Heuser, Pau Montesinos, Mikkael A. Sekeres, Albert Oriol, Gary J. Schiller, et al. "Low-dose cytarabine with or without glasdegib in newly diagnosed patients with acute myeloid leukemia: Long-term analysis of a phase 2 randomized trial." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 7010. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.7010.
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7010 Background: Glasdegib is a potent, selective, oral inhibitor of the Hedgehog signaling pathway, approved in the US – in combination with low-dose cytarabine (LDAC) – for treatment of newly diagnosed acute myeloid leukemia (AML) in patients (pts) unable to receive intensive chemotherapy due to comorbidities or age (≥75 y). Methods: In this follow-up analysis from the phase 2 BRIGHT AML trial (NCT01546038), newly diagnosed pts with AML ineligible for intensive chemotherapy were randomized 2:1 to glasdegib + LDAC or LDAC alone (study design: Cortes et al., Leukemia 2018). This long-term analysis evaluated efficacy and safety after ~20 mo of additional follow-up. Results: As of Oct 11, 2018, 116 pts were assigned to treatment with glasdegib + LDAC (n = 78) or LDAC alone (n = 38) (median follow-up: 43.4 and 42.0 mo, respectively). Median overall survival (OS) was higher with glasdegib + LDAC vs LDAC alone (Table). Improvement in OS was consistent across the prespecified subgroups. The main cause of death in both arms was disease progression (both during study and follow-up). The incidence of adverse events (AEs) and serious AEs on glasdegib was generally lower long term (after 90 days) than short term (during the first 90 days) (83.7% and 51.2% vs 98.7% and 65.3%, respectively). Clinical trial information: NCT01546038. Conclusions: Addition of glasdegib to LDAC vs LDAC alone continued to demonstrate improved OS in pts with AML in this analysis; improvement was consistent across groups stratified by cytogenic risk. Long-term follow-up confirmed treatment with glasdegib was associated with an acceptable safety profile.[Table: see text]
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Tremblay, Gabriel, Patrick Daniele, Timothy Bell, Geoffrey Chan, Andrew Brown, and Joseph C. Cappelleri. "Comparative effectiveness of glasdegib versus venetoclax combined with low-dose cytarabine in acute myeloid leukemia." Journal of Comparative Effectiveness Research 10, no. 7 (May 2021): 603–12. http://dx.doi.org/10.2217/cer-2020-0280.
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Background: Two combination therapies recently approved and recommended for use in combination with low-dose cytarabine (LDAC) in acute myeloid leukemia patients unfit for intensive chemotherapy are glasdegib+LDAC and venetoclax+LDAC. Materials & methods: An indirect treatment comparison used median overall survival, overall survival hazard ratios, complete remission (CR), CR+CR with incomplete blood count recovery and transfusion independence to assess comparative effectiveness, and a simulated treatment comparison accounted for differences in patient characteristics between trials. Results: Differences in efficacy between glasdegib+LDAC and venetoclax+LDAC were suggestive and not statistically significant. Conclusion: With no significant differences in comparative effectiveness, considerations such as safety profiles, burden of administration and patient preference are likely to guide treatment decisions.
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Liu, Ying, Qian Wu, Peng Li, Weijie Liu, Yongri Jin, Xuwen Li, and Xiaolei Shi. "Langerhans cell-like dendritic cells treated with ginsenoside Rh2 regulate the differentiation of Th1 and Th2 cells in vivo." Open Chemistry 17, no. 1 (March 29, 2019): 142–50. http://dx.doi.org/10.1515/chem-2019-0016.
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AbstractGinsenoside Rh2 is one of the rare ginsenosides extracted from Panax ginseng C. A. Mey. The anti-allergic activity of ginsenoside Rh2 has been documented in some literature. In this work, an anti-allergic mechanism of ginsenoside Rh2 was investigated by focusing on the differentiation of T cells through Langerhans cells (LCs). Langerhans cell-like dendritic cells (LDCs) were generated in vitro and were used as substitute for LCs.In vivo the mRNA expression for IFN-γ and CXCR3 of T cells was increased after being injected with ginsenoside Rh2-treated LDCs thereby increasing the concentration of IFN-γ in the culture supernatants of CD3+/CD28+ T lymphocytes. However,in vitro, the expression of mRNA for CD40 and CD80 on ginsenoside Rh2-treated LDCs was up-regulated significantly and the endocytic activity of LDCs was down-regulated slightly. These findings indicate that T cells differentiation could be regulated by ginsenoside Rh2 through LDCs in vivo by altering the antigen presenting capacity, maturation and phagocytosis of LDCs.
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Maggioni, Viviana, Rolf H. Reichle, and Emmanouil N. Anagnostou. "The Efficiency of Assimilating Satellite Soil Moisture Retrievals in a Land Data Assimilation System Using Different Rainfall Error Models." Journal of Hydrometeorology 14, no. 1 (February 1, 2013): 368–74. http://dx.doi.org/10.1175/jhm-d-12-0105.1.
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Abstract The efficiency of assimilating near-surface soil moisture retrievals from Advanced Microwave Scanning Radiometer for Earth Observing System (AMSR-E) observations in a Land Data Assimilation System (LDAS) is assessed using satellite rainfall forcing and two different satellite rainfall error models: a complex, multidimensional satellite rainfall error model (SREM2D) and the simpler (control) model (CTRL) used in the NASA Goddard Earth Observing System Model, version 5 LDAS. For the study domain of Oklahoma, LDAS soil moisture estimates improve over the satellite retrievals and the open-loop (no assimilation) land surface model estimates, exhibiting higher daily anomaly correlation coefficients (e.g., 0.36 in the open loop, 0.38 in the AMSR-E, and 0.50 in LDAS for surface soil moisture). The LDAS soil moisture estimates also match the performance of a benchmark model simulation forced with high-quality radar precipitation. Compared to using the CTRL rainfall error model in LDAS, using the more complex SREM2D exhibits only slight improvements in soil moisture estimates.
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Wei, Andrew H., Pau Montesinos, Vladimir Ivanov, Courtney D. DiNardo, Jan Novak, Kamel Laribi, Inho Kim, et al. "Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial." Blood 135, no. 24 (June 11, 2020): 2137–45. http://dx.doi.org/10.1182/blood.2020004856.
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Abstract Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international phase 3 randomized double-blind placebo-controlled trial. Patients (N = 211) were randomized 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1 to 10. Primary end point was overall survival (OS); secondary end points included response rate, transfusion independence, and event-free survival. Median age was 76 years (range, 36-93 years), 38% had secondary AML, and 20% had received prior hypomethylating agent treatment. Planned primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs LDAC alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.52-1.07; P = .11), although not statistically significant; median OS was 7.2 vs 4.1 months, respectively. Unplanned analysis with additional 6-month follow-up demonstrated median OS of 8.4 months for the venetoclax arm (HR, 0.70; 95% CI, 0.50-0.98; P = .04). Complete remission (CR) plus CR with incomplete blood count recovery rates were 48% and 13% for venetoclax plus LDAC and LDAC alone, respectively. Key grade ≥3 adverse events (venetoclax vs LDAC alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), and thrombocytopenia (45% vs 37%). Venetoclax plus LDAC demonstrates clinically meaningful improvement in remission rate and OS vs LDAC alone, with a manageable safety profile. Results confirm venetoclax plus LDAC as an important frontline treatment for AML patients unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.
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Westley, Tracy, Anna Forsythe, Timothy J. Bell, Joseph C. Cappelleri, Gabriel Tremblay, and Geoffrey Chan. "Clinical Responses of Glasdegibplus Low-Dose Ara-C, Azacitidine, and Decitabine Among Acute Myeloid Leukemia (AML) Patients Ineligible to Receive Intensive Chemotherapy: Comparative Effectiveness Using Indirect Treatment Comparison (ITC) Methods." Blood 132, Supplement 1 (November 29, 2018): 2709. http://dx.doi.org/10.1182/blood-2018-99-111931.
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Abstract OBJECTIVES: Currently there is no standard treatment option for AML patients not fit for intensive chemotherapy. Further clinical challenges include poorer prognosis associated with advanced age. AML treatments among this population have not been directly compared in clinical trials. Furthermore, naïve comparisons of results across multiple trials are subject to bias related to not accounting for within-trial differences from control. Standard (unadjusted) ITC accounts for within-trial efficacy of treatment versus control, providing a valid and robust approach to compare effectiveness between trials. Additionally, simulated treatment comparison (STC) applies ITC methodology and adjusts for differences in population baseline characteristics. Previous ITC and STC of overall survival (OS) demonstrated superiority of combination glasdegib and low-dose ARA-C (GLAS+LDAC) over azacitidine (AZA) or decitabine (DEC). This present study applied ITC and STC of clinical response outcomes between GLAS+LDAC and AZA or DEC among older AML patients unfit for intensive chemotherapy. METHODS: Clinical outcomes for complete remission (CR) and CR plus CR with incomplete blood count recovery (CR+CRi) were indirectly compared between Phase II trial (n=116) GLAS+LDAC individual patient data (IPD) and published Phase III AZA results (n=488), and then between GLAS+LDAC IPD and published Phase III DEC results (n=457). Based on the Decision Support Unit STC guidelines from the National Institute for Health and Care Excellence, GLAS+LDAC IPD regression (which modelled response) was separately adjusted for AZA and DEC patient baseline characteristics. Stepwise models adjusted for key patient covariates and full models adjusted for all patient covariates mutually available between trials including age, sex, having denovo AML or not, bone marrow blast percentage, Eastern Cooperative Oncology Group performance status, cytogenetic risk factors, and hemoglobin level. Between trials, CR and CR+CRi were indirectly compared by standard ITC and STC using risk ratios (RR) with 95% confidence intervals (CIs). RESULTS: Naïve comparisons of CR [GLAS+LDAC (17.95%), AZA (19.50%), and DEC (15.70%)] and CR+CRi [GLAS+LDAC (24.36%), AZA (27.80%), and DEC (25.62%)] favored AZA. However, based on each of the three modelling techniques (standard ITC, STC full covariate adjustment, STC stepwise adjustment), GLAS+LDAC showed superiority over AZA. Compared with AZA, standard ITC estimated that GLAS+LDAC patients were over seven and four times as likely to reach CR [RR=7.67 (1.02, 57.87)] and CR+CRi [RR=4.33 (1.02, 18.29)], respectively. Using STC full covariate adjustment, GLAS+LDAC patients compared with AZA were over nine times as likely to reach CR [RR=9.63 (0.81, 113.95)] and over four times as likely to reach CR+CRi [RR=4.45 (1.01, 19.59)]. In the stepwise STC approach, GLAS+LDAC versus AZA similarly improved the likelihood of CR [RR=8.76 (1.13, 68.21)] and CR+CRi [RR=4.42 (1.04, 18.87)]. Comparing GLAS+LDAC to DEC, standard (unadjusted) ITC found numeric but not statistically significant improvement in CR [RR=3.43 (0.44, 27.00)] and CR+CRi [RR=1.94 (0.45, 8.43)]. STC methods for GLAS+LDAC versus DEC yielded trends similar to ITC. Non-significant trends in numeric favor of GLAS+LDAC were found using both full covariate adjustment [CR, RR=4.31 (0.36, 52.32); CR+Cri, RR=2.00 (0.46, 8.73)] and stepwise adjustment [CR, RR=3.41 (0.28, 41.94); CR+CRi, RR=1.97 (0.45, 8.65)]. CONCLUSIONS: In the absence of clinical trials directly testing less intensive AML treatments, indirect comparison methods apply statistically robust techniques versus naïve comparisons to measure comparative effectiveness. Regarding the likelihood of response to treatment, GLAS+LDAC showed improvement over AZA or DEC. As previously found when comparing OS, both ITC and STC estimated GLAS+LDAC superiority over AZA for both CR and CR+CRi. For GLAS+LDAC versus DEC, ITC and STC found numerical improvement in CR and CR+CRi; however, these treatments were not statistically significant for each of the two response outcomes. Figure 1. ITC and STC results for GLAS+LDAC versus AZA or DEC Figure 1. Figure 1. Disclosures Forsythe: Novartis: Consultancy. Bell:Pfizer: Employment, Equity Ownership. Cappelleri:Pfizer: Employment, Equity Ownership. Chan:Pfizer: Employment, Equity Ownership.
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van Beekhuizen, Sophie, Yannan Hu, Ana Gezin, Bart Heeg, Timothy Bell, Majed Charaan, Andrew Brown, Geoffrey Chan, and Joseph C. Cappelleri. "The comparative effectiveness of glasdegib in combination with low-dose cytarabine versus azacitidine by bone marrow blasts counts among patients with newly-diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e19512-e19512. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e19512.
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e19512 Background: Acute myeloid leukemia (AML) is an orphan disease with one of the lowest five-year survival rates among myeloid malignancies. Recently, a randomized, open label study among previously untreated, chemotherapy-ineligible AML patients demonstrated improved overall survival (OS) among patients treated with glasdegib (GLAS) + LDAC compared with LDAC alone. Two trials of AZA vs. conventional care regimens report data by bone marrow blast (BMB) counts: one with 20-30% and the other with >30%. In the absence of head-to-head comparisons, this study aims to perform the indirect treatment comparison between GLAS+LDAC and AZA by BMB counts. Methods: As there were potential imbalances between the GLAS and AZA trials and within the AZA trial arms in the baseline characteristics (e.g. poor cytogenetics% and de novo%), simulated treatment comparisons (STCs) for GLAS+LDAC vs. LDAC were performed to derive robust estimation by adjusting for the imbalances in the baseline effect modifiers. Afterwards, the classical network meta-analysis (NMA) was conducted. To derive the hazard ratio (HR) of GLAS+LDAC vs. AZA, three NMAs were conducted in each BMB group. Each NMA used a different HR of GLAS+LDAC vs. LDAC: 1) an unadjusted HR (classical NMA), 2) an STC adjusted HR adjusting for potential imbalances between the trials, and 3) an STC adjusted HR additionally accounting for potential imbalances between arms within the AZA trial. Results: In the 20-30% BMB group (N = 30), the OS HRs of GLAS+LDAC vs. AZA resulting from the three respective NMAs were as follows: 1) 0.46 [95% confidence interval: 0.10-2.14], 2) 0.31 [0.06-1.69], and 3) 0.36 [0.06-2.15]. In the > 30% BMB group (N = 80), the HRs were 1) 0.69 [0.39-1.20], 2) 0.48 [0.23-0.97], and 3) 0.48 [0.24-1.00]. All the HRs suggest that patients with GLAS+LDAC have a survival advantage over patients with AZA. Conclusions: Both the classical NMAs and the NMAs based on the STC adjusted HRs correcting for the potential imbalances at baseline suggest that GLAS+LDAC may be preferred over AZA as a treatment option for previously untreated chemotherapy-ineligible AML patients regardless of BMB counts. [Table: see text]
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Russell, Nigel H., Robert K. Hills, Ann E. Hunter, Donald Milligan, William J. Kell, Keith Wheatley, Mary Frances McMullin, John AL Yin, David T. Bowen, and A. Burnett. "Low Dose Ara-C Versus Low Dose Ara-C and Arsenic Trioxide: the UK NCRI AML16 “Pick a Winner” Comparison." Blood 114, no. 22 (November 20, 2009): 486. http://dx.doi.org/10.1182/blood.v114.22.486.486.
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Abstract Abstract 486 A significant proportion of older patients with AML are not treated with conventional intensive chemotherapy [1] because they are unfit or not considered likely to benefit from an intensive treatment approach. Their outcomes are poor. Such patients have typically been treated with low-dose Ara-C (LDAC) or best supportive care (BSC) with hydroxyurea, and unrandomised studies of new agents have been used in this population. A recent randomised trial has shown that LDAC is superior to BSC in these patients [2]. Randomised trials are underway to assess the value of other novel treatments compared to LDAC. In an unrandomised phase 2 trial in 64 patients, Roboz et al found encouraging results using the combination of Arsenic Trioxide and LDAC. [3]. The UK NCRI AML16 trial is a programme of development which aims to test novel agents or combinations in untreated older patients with AML or high risk MDS (marrow blasts >10%) following a “pick a winner” design. The intention is to identify a “winner” which will produce a remission rate in excess of 30%, compared with 15-20% with LDAC. Using LDAC as the standard arm,the design allows unpromising treatments to be identified early (typically after 50 patients per arm), so that only those arms which show promise will continue to a trial with OS and DFS as endpoints. We report our experience of LD Ara-C (20mg bd days 1-10 for 4 courses) versus LDAC combined with Arsenic Trioxide (ATO, 0.25 mg/kg d1-5, d9, d11 for 4 courses at 6-8 week intervals). Patient Details: Between December 2006 and until its conclusion in May 2009, 166 patients were randomised, 84 to LDAC plus ATO, 82 to LDAC. The median age was 74 years; 80% of patients were aged over 70 years, 62% were male. There were no differences between the treatment arms with respect to age distribution, gender, performance status, de novo/secondary AML, high risk MDS, presenting WBC or cytogenetic risk group. Follow-up is complete to 1st January 2009, with median follow up for survivors of 8 months (range 0.1-17), at which point 122 patients had been recruited, and there were a total of 60 deaths (LDAC n=25; LDAC+ ATO, n=35). CR status is known on 113 patients. Overall, 24 patients have entered CR/CRi (LDAC n=13, LDAC+ATO n=11) with 8 relapses (2 vs 6; 1 vs 3 patients have died following relapse). The causes of death (60) were:- The DMEC recommended closure of the LDAC + ATO arm of the trial because follow-up data on the first 50 patients per arm showed that ATO had failed to provide the 2.5% improvement in CR/CRi required for continued recruitment and that the required improvement in remission was unlikely with LDAC + ATO. Conclusions: While ATO has a definite role in treating patients with APL, and may be of benefit in combination with other drugs in AML, the combination of LDAC + ATO in this patient population was not beneficial. [1] Juliusson G et al. Blood 2009; 113: 4179—4187 [2] Burnett et al. Cancer 2007 109: 1114—1124 [3] Roboz Gail J et al. Cancer 2008;113(9):2504—11. Disclosures: Off Label Use: Arsenic Trioxide is not licensed in this indication.
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Brereton, Claire F., and Paul Jagals. "Applications of Systems Science to Understand and Manage Multiple Influences within Children’s Environmental Health in Least Developed Countries: A Causal Loop Diagram Approach." International Journal of Environmental Research and Public Health 18, no. 6 (March 15, 2021): 3010. http://dx.doi.org/10.3390/ijerph18063010.
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Least developed countries (LDCs) are home to over a billion people throughout Africa, Asia-Pacific, and the Caribbean. The people who live in LDCs represent just 13% of the global population but 40% of its growth rate. Characterised by low incomes and low education levels, high proportions of the population practising subsistence living, inadequate infrastructure, and lack of economic diversity and resilience, LDCs face serious health, environmental, social, and economic challenges. Many communities in LDCs have very limited access to adequate sanitation, safe water, and clean cooking fuel. LDCs are environmentally vulnerable; facing depletion of natural resources, the effects of unsustainable urbanization, and the impacts of climate change, leaving them unable to safeguard their children’s lifetime health and wellbeing. This paper reviews and describes the complexity of the causal relationships between children’s health and its environmental, social, and economic influences in LDCs using a causal loop diagram (CLD). The results identify some critical feedbacks between poverty, family size, population growth, children’s and adults’ health, inadequate water, sanitation and hygiene (WASH), air pollution, and education levels in LDCs and suggest leverage points for potential interventions. A CLD can also be a starting point for quantitative systems science approaches in the field, which can predict and compare the effects of interventions.