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1
Dragunov, Valery, Rodion Sinitskiy, and Dmitriy Ostertak. "A microelectromechanical generator based on the Bennet doubler modified circuit." Proceedings of the Russian higher school Academy of sciences, no. 3 (December 18, 2017): 39–51. http://dx.doi.org/10.17212/1727-2769-2017-3-39-51.
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Dragunov, V. P., R. E. Sinitskiy, and E. V. Dragunova. "Single-Capacitor Electrostatic Vibration Energy Converter Based on the Bennet Doubler." Russian Microelectronics 50, no. 3 (May 2021): 178–88. http://dx.doi.org/10.1134/s1063739721020049.
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Dragunov, V. P., D. I. Ostertak, and R. E. Sinitskiy. "New modifications of a Bennet doubler circuit-based electrostatic vibrational energy harvester." Sensors and Actuators A: Physical 302 (February 2020): 111812. http://dx.doi.org/10.1016/j.sna.2019.111812.
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Dragunov, V. P., V. Y. Dorzhiev, D. I. Ostertak, and V. V. Atuchin. "A new autostabilization mechanism in the Bennet doubler circuit-based electrostatic vibrational energy harvester." Sensors and Actuators A: Physical 272 (April 2018): 259–66. http://dx.doi.org/10.1016/j.sna.2018.01.053.
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Elliott, P. "Abraham Bennet, F.R.S. (1749-1799): a provincial electrician in eighteenth-century england." Notes and Records of the Royal Society of London 53, no. 1 (January 22, 1999): 59–78. http://dx.doi.org/10.1098/rsnr.1999.0063.
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Abraham Bennet was a clergyman and electrical experimenter who invented the gold-leaf electroscope and the doubler of electricity. He used a mechanical revolving version of the latter to devise a concept of ‘adhesive electricity’, which had an important influence on Volta in the formulation of his contact theory of electromotivity. Bennet managed to balance his clerical position, obtained by patronage, with the friendship and assistance of the local philosophical community, which included Erasmus Darwin, White Watson and the members of the Lunar and Derby Philosophical Societies. The Lunar members helped him to publish his research and supported his nomination as F.R.S. in 1789; however, the relative harmony of the philosophical community represented by the Royal Society, which temporarily united provinces and metropolis, was shattered by the political turbulence of the revolutionary era. The delicate balancing act that allowed Bennet to claim support from Banks and Kaye at the same time as from Priestley and Darwin became more difficult and Bennet's research activity foundered due to ill health and political division.
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Alneamy, Ayman, Hatem Samaali, and Fehmi Najar. "Electrostatic Energy Harvesting of Kinetic Motions Using a MEMS Device and a Bennet Doubler Conditioning Circuit." IEEE Instrumentation & Measurement Magazine 26, no. 3 (May 2023): 14–20. http://dx.doi.org/10.1109/mim.2023.10121408.
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Zhang, Hemin, Yingxian Lu, A. Ghaffarinejad, and Philippe Basset. "Progressive contact-separate triboelectric nanogenerator based on conductive polyurethane foam regulated with a Bennet doubler conditioning circuit." Nano Energy 51 (September 2018): 10–18. http://dx.doi.org/10.1016/j.nanoen.2018.06.038.
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Zhu, Jianxiong, Zhongda Sun, Jikai Xu, Rafal D. Walczak, Jan A. Dziuban, and Chengkuo Lee. "Volatile organic compounds sensing based on Bennet doubler-inspired triboelectric nanogenerator and machine learning-assisted ion mobility analysis." Science Bulletin 66, no. 12 (June 2021): 1176–85. http://dx.doi.org/10.1016/j.scib.2021.03.021.
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Lu, Wei, Yu Lan, and Tianfang Zhou. "Finite element analysis of double resonance bender disk low frequency transducer." MATEC Web of Conferences 283 (2019): 05008. http://dx.doi.org/10.1051/matecconf/201928305008.
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A bender disk transducer can generate low-frequency sound in a small size and light weight. But traditional bender disk transducer only works at single frequency by using first order bending mode and emits moderate levels of power. In this work, a double resonance bander disk low frequency transducer is investigated by using finite element model. The double resonance bender disk transducer consists of two segmented 3-3 mode piezoelectric ceramic disk on the both side of hollow metal disc, which could generate larger displacement in order to increase power radiation. A simple elastic mass system placed inside the hollow metal disc is introduced in the system to produce other lower resonance modes. Through the FEM calculations, it is found that the transmitting voltage response (TVR) of bender disk transducer could enhance 4dB in the first order bending mode resonance frequency, which is compared with traditional bender disk transducer with the same size. The TVR of lower resonance mode which is produced by additional central simple support elastic mass system in segmented bender disk transducer is more than 130dB. Through the optimization of finite element simulation, a double resonance bender disk transducer is designed, and its resonance frequency is 600Hz and 1kHz, respectively. The value of TVR is 130dB and 134dB corresponding to two resonance frequency. The double resonance bender disk transducer is compact dimension, low weight and it is a high performance low frequency transducer.
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Scarr, Richard. "Alan Bennett: Political Playwright." New Theatre Quarterly 12, no. 48 (November 1996): 309–22. http://dx.doi.org/10.1017/s0266464x00010502.
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Alan Bennett is one of the most popular mainstream dramatists working in Britain today, his canon now a mainstay of regional and amateur theatre companies. Yet for a writer who was once compared to John Osborne as taking ‘the moral temperature of the nation’, his output is widely regarded as apolitical and, at worst, ‘safe’. In the following article, Richard Scarr suggests that this viewpoint is misleading, and argues that Bennett is not only one of the most politically contentious playwrights in dominant theatre, but that the ideological viewpoints he has supported have changed as his career has progressed. Richard Scarr is an English graduate of the University of North London, and has recently completed an MA in Renaissance Studies at Queen Mary and Westfield College. He is currently researching a PhD on the rhetoric of Renaissance comedy, with particular emphasis on the double-entendre.
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Song, C. Y., and Y. Chen. "A family of mixed double-Goldberg 6 R linkages." Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences 468, no. 2139 (November 23, 2011): 871–90. http://dx.doi.org/10.1098/rspa.2011.0345.
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A complete family of double-Goldberg 6 R linkages is reported in this article by combining a subtractive Goldberg 5 R linkage and a Goldberg 5 R linkage through the common link-pair or common Bennett-linkage method. A number of distinct types of overconstrained linkages are built, namely the mixed double-Goldberg 6 R linkages. They all have one degree of freedom and their closure equations are derived in detail. One of them degenerates into a Goldberg 5 R linkage. From the construction process and geometry conditions, the corresponding relationship between the newly found 6 R linkages and the double-Goldberg 6 R linkages, constructed from two Goldberg 5 R linkages or two subtractive Goldberg 5 R linkages, has been established.
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Saetiaw, Charinsak, and Chanchai Thongsopa. "Design of Double-Layer Copper Sheet for RFID Tags Antenna." Advanced Materials Research 787 (September 2013): 461–66. http://dx.doi.org/10.4028/www.scientific.net/amr.787.461.
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This paper demonstrates a design of double-layer copper sheet suitable for RFID tags antenna called extended double-layer flexible strip dipole antenna. RFID tag antenna is widely used with different surfaces. The result found that RFID tag antenna can be bended or curved responding to the cylinder shape of the objects. Our proposed extended double-layer flexible strip dipole antenna has been technically designed to make changes on itself to obtain the result in increasing resonance frequency when it is being bended. The key concept of the study is the designed antenna which can freely change inside each layer when applying itself on curved object. The result of this design reveals that antenna has better performance than modern antenna. The extended double-layer flexible strip dipole antenna for RFID tags was designed for resonance frequency of 2.45 GHz. Consequently, the analysis of antennas efficiency will be affected by thickness. The designed antenna there will be considered and discussed to find out the relative value in order to use creating the design for the antenna that is suitable for the further study.
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Lizama-Perez, Luis A., and J. Mauricio López. "Quantum Key Distillation Using Binary Frames." Symmetry 12, no. 6 (June 24, 2020): 1053. http://dx.doi.org/10.3390/sym12061053.
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We introduce a new integral method for Quantum Key Distribution to perform sifting, reconciliation and amplification processes to establish a cryptographic key through the use of binary matrices called frames which are capable to increase quadratically the secret key rate. Since the eavesdropper has no control on Bob’s double matching detection events, our protocol is not vulnerable to the Intercept and Resend (IR) attack nor the Photon Number Splitting (PNS) attack. The method can be implemented with the usual optical Bennett–Brassard ( B B 84 ) equipment allowing strong pulses in the quantum regime.
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SINHABABU, NEIL. "Unequal Vividness and Double Effect." Utilitas 25, no. 3 (July 8, 2013): 291–315. http://dx.doi.org/10.1017/s0953820812000362.
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I argue that the Doctrine of Double Effect is accepted because of unreliable processes of belief-formation, making it unacceptably likely to be mistaken. We accept the doctrine because we more vividly imagine intended consequences of our actions than merely foreseen ones, making our aversions to the intended harms more violent, and making us judge that producing the intended harms is morally worse. This explanation fits psychological evidence from Schnall and others, and recent neuroscientific research from Greene, Klein, Kahane and Schaich Borg. It explains Mikhail and Hauser's ‘universal moral grammar’ and an interesting phenomenon about Double Effect cases noted by Bennett. When unequally vivid representations determine our decisions, we typically misjudge the merits of our options and make mistakes. So if Double Effect is a product of unequal vividness, it is likely to be mistaken. This argument, I claim, fits Berker's specifications for good empirically grounded arguments in ethics.
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Wang, Ruirong, Zhiheng Fang, Honghai An, Jun Xiong, Zhiyong Xie, Erfu Guo, Chen Wang, Anle Lei, and Wei Wang. "Double-spherically bent crystal high-resolution X-ray spectroscopy of spatially extended sources." Chinese Optics Letters 18, no. 6 (2020): 061101. http://dx.doi.org/10.3788/col202018.061101.
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Cellini, Stephanie Riegg, and Claudia Goldin. "Does Federal Student Aid Raise Tuition? New Evidence on For-Profit Colleges." American Economic Journal: Economic Policy 6, no. 4 (November 1, 2014): 174–206. http://dx.doi.org/10.1257/pol.6.4.174.
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We provide the first comprehensive estimates of the size of the for-profit higher education sector and evaluate whether for-profits increase tuition in response to federal subsidies. By using state administrative data we include institutions that do not participate in federal student aid programs and are missed in official counts. Including these institutions doubles the number of for-profits and increases students by one-third compared with official counts. Aid-eligible institutions charge tuition for sub-baccalaureate (mainly certificate) programs that is about 78 percent higher than that charged by comparable programs in nonparticipating institutions, lending some credence to the “Bennett hypothesis” of federal aid capture. (JEL H52, I22, I23, I28)
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Menzl, Georg, Andreas Singraber, and Christoph Dellago. "S-shooting: a Bennett–Chandler-like method for the computation of rate constants from committor trajectories." Faraday Discussions 195 (2016): 345–64. http://dx.doi.org/10.1039/c6fd00124f.
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Mechanisms of rare transitions between long-lived stable states are often analyzed in terms of commitment probabilities, determined from swarms of short molecular dynamics trajectories. Here, we present a computer simulation method to determine rate constants from such short trajectories combined with free energy calculations. The method, akin to the Bennett–Chandler approach for the calculation of reaction rate constants, requires the definition of a valid reaction coordinate and can be applied to both under- and overdamped dynamics. We verify the correctness of the algorithm using a one-dimensional random walker in a double-well potential and demonstrate its applicability to complex transitions in condensed systems by calculating cavitation rates for water at negative pressures.
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Jochum, Johanna K., Jos F. K. Cooper, Lukas M. Vogl, Peter Link, Olaf Soltwedel, Peter Böni, Christian Pfleiderer, and Christian Franz. "Transmission Bender as an Analyzer Device for MIEZE." Quantum Beam Science 6, no. 3 (August 2, 2022): 26. http://dx.doi.org/10.3390/qubs6030026.
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MIEZE (Modulation of IntEnsity with Zero Effort) spectroscopy is a high-resolution spin echo technique optimized for the study of magnetic samples and samples under depolarizing conditions. It requires a polarization analyzer in between spin flippers and the sample position. For this, the device needs to be compact and insensitive to stray fields from large magnetic fields at the sample position. For MIEZE, in small angle scattering geometry, it is further essential that the analyzer does not affect the beam profile, divergence, or trajectory. Here, we compare different polarization analyzers for MIEZE and show the performance of the final design, a transmission bender, which we compare to McStas simulations. Commissioning experiments have uncovered spurious scattering in the scattering profile of the bender, which most likely originates from double Bragg scattering in bent silicon.
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Chion, Michel. "Mes doigts sont-ils à moi ?" Revue musicale OICRM 5, no. 1 (April 9, 2018): 1–6. http://dx.doi.org/10.7202/1044440ar.
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L’auteur s’attache à une série de films mettant en scène des musiciens classiques dont la carrière est traversée par leurs problèmes sentimentaux ou leurs névroses ; il s’intéresse particulièrement au mélodrame The Seventh Veil (Robert Compton-Bennett, 1945) dont l’action conjugue les motifs du pianiste ténébreux et de la pianiste-victime. Analysant le montage des corps des interprètes (celui de l’actrice, celui de sa doublure), il montre comment ce film dit le faux quand il fait croire par des inserts de mains d’une virtuose que c’est l’actrice qui joue du piano, et comment, en même temps, il dit le vrai par le faux quand il illustre métaphoriquement que les mains de quelqu’un ne lui appartiennent pas complètement : elles sont dressées, menées, mais aussi tentées, happées, entraînées par une autre force dont le reste du corps ne trahit rien.
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Fricker, Karen. "Le goût du risque : KÀ de Robert Lepage et du Cirque du Soleil." Le Québec à Las Vegas, no. 45 (August 25, 2010): 45–68. http://dx.doi.org/10.7202/044274ar.
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Cet article se veut un examen critique de la première collaboration entre Robert Lepage et le Cirque du Soleil, qualifiés par Susan Bennett comme deux des « plus précieux produits (culturels) d’exportation » du Québec. KÀ, qui a débuté au MGM Grand Hotel de Las Vegas en 2005, est considéré comme la production la plus onéreuse jamais montée en Amérique du Nord. Elle constitue une tentative pour mélanger le théâtre avec quelques-unes des tropes de la performance aérienne qui ont fait la réputation du Cirque. Cet article traite de la production de KÀ dans le double parcours du Cirque et de Lepage et défend la thèse suivant laquelle ses créateurs, en dépit d’avoir formulé une proposition scénique visuellement époustouflante et techniquement innovante, n’ont sans doute pas totalement saisi les défis esthétiques que représentait l’union de leur entreprise créative respective.
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Venmathi Maran, Balu Alagar, Panakkool Thamban Aneesh, and Seong Yong Moon. "A New Species of Parasitic Copepod, Nemesis santhadevii (Siphonostomatoida: Eudactylinidae) from the Gills of the Coral Catshark Atelomycterus marmoratus, from Kota Kinabalu, Malaysia." Diversity 14, no. 9 (September 14, 2022): 759. http://dx.doi.org/10.3390/d14090759.
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The copepod Nemesis santhadevii sp. nov. (Siphonostomatoida: Eudactylinidae), which is parasitizing the gill filaments of the Coral catshark Atelomycterus marmoratus (Anonymous (Bennett), 1830) off Kota Kinabalu waters, Malaysia, is described and illustrated in this article. The new species Nemesis santhadevii prominently differs from its congeners in the following features: (1) the cephalothorax sub-circular is 1.3 times as wide as long and overlapping the second pedigerous somite; (2) the fifth somite is 0.4 times the width of the fourth; (3) the genital double somite is slightly narrower than the fifth; (4) the lowest cephalothoracic shield’s body length (0.20:1) proportion; (5) the caudal rami is ovate, it has two large and three small setae; (6) and the second somite has antenna with a patch of 34–38 spinules. It is the first record of parasitic eudactilinid copepod from Sabah, East Malaysia. A checklist of global valid species of Nemesis Risso, 1826, is provided.
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Schein, C. H., and M. Haugg. "Deletions at the C-terminus of interferon γ reduce RNA binding and activation of double-stranded-RNA cleavage by bovine seminal ribonuclease." Biochemical Journal 307, no. 1 (April 1, 1995): 123–27. http://dx.doi.org/10.1042/bj3070123.
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Recombinant interferon gamma (IFN-gamma) from three species activates the cleavage of double stranded (ds-) RNA by the dimeric RNAase isolated from bovine semen (BS-RNAase). Human and bovine IFN-gamma bind RNA tightly enough to inhibit cleavage by RNAase A [Schein, Haugg and Benner (1990) FEBS Lett. 270, 229-232]. Murine IFN-gamma and a proteolytic fragment of human IFN-gamma, both of which lack part of the positively charged C-terminus, bind RNA weakly and do not inhibit RNAase A. Their ability to activate BS-RNAase is proportional to their activity in the anti-viral assay. Two monoclonal antibodies that neutralize the anti-viral activity of human IFN-gamma inhibit the activation of BS-RNAase by both full-length and proteolysed human IFN-gamma. Our results demonstrate that the C-terminus of IFN-gamma contributes to RNA binding and activation of BS-RNAase, as well as to anti-viral activity.
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Nuñez, Carlinda Fragale Pate. "MITOS GREGOS NO TEATRO BRASILEIRO DOS ÚLTIMOS 30 ANOS." Fragmentum, no. 45 (December 19, 2015): 37. http://dx.doi.org/10.5902/20736.
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A experiência exílica é uma tônica em peças brasileiras recentes de tema mítico. Baseado na Trilogia perversa (BENDER, 1986), em Ismene, Princesa de Tebas (SENNA, 2006) e n’ O Olimpo carioca (BRANDÃO, 2012), o artigo mostra que os mitos antigos, enquanto mapeiam problemáticas palpitantes para a época em que eles retornam (o páthos do imigrante, do perseguido político e mesmo da cidade tida como refúgio ideal para problemas “olímpicos”), funcionam como o “tiroir à double entrée” de que fala Espagne (1999, p. 78): não são apenas pontos de passagem entre culturas, mas deflagradores de “itinerários da memória” (ESPAGNE, 1999, p. 138).
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Marras, Alexander E., Lifeng Zhou, Hai-Jun Su, and Carlos E. Castro. "Programmable motion of DNA origami mechanisms." Proceedings of the National Academy of Sciences 112, no. 3 (January 5, 2015): 713–18. http://dx.doi.org/10.1073/pnas.1408869112.
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DNA origami enables the precise fabrication of nanoscale geometries. We demonstrate an approach to engineer complex and reversible motion of nanoscale DNA origami machine elements. We first design, fabricate, and characterize the mechanical behavior of flexible DNA origami rotational and linear joints that integrate stiff double-stranded DNA components and flexible single-stranded DNA components to constrain motion along a single degree of freedom and demonstrate the ability to tune the flexibility and range of motion. Multiple joints with simple 1D motion were then integrated into higher order mechanisms. One mechanism is a crank–slider that couples rotational and linear motion, and the other is a Bennett linkage that moves between a compacted bundle and an expanded frame configuration with a constrained 3D motion path. Finally, we demonstrate distributed actuation of the linkage using DNA input strands to achieve reversible conformational changes of the entire structure on ∼minute timescales. Our results demonstrate programmable motion of 2D and 3D DNA origami mechanisms constructed following a macroscopic machine design approach.
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Plummer, Ralph, Terry Stobbe, Richard Ronk, Warren Myers, Hyunwook Kim, and Majid Jaraiedi. "Manual Dexterity Evaluation of Gloves Used in Handling Hazardous Materials." Proceedings of the Human Factors Society Annual Meeting 29, no. 8 (October 1985): 819–23. http://dx.doi.org/10.1177/154193128502900822.
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The problems associated with hazardous materials control are numerous and complex. One of these problems involves selecting hand protection which will resist permeation for the duration of the exposure while maintaining sufficient levels of dexterity and tactility so that the worker can safely and efficiently perform the required task. This study investigated the effect of nine glove combinations on manual dexterity. These included three single glove and six double glove combinations plus the bare hand condition. The subjects performed a nut-bolt-washer assembly-dissassembly task using the Bennett Hand Tool Dexterity Test apparatus. The task required the use of a screw driver, two sizes of open-end wrenches, and an adjustable wrench, along with handling the bolt, nut, and washer while performing the assembly-disassembly task for three different bolt, nut, and washer sizes (1/2″, 5/16″, 1/4″). The response variables measured in the experiment were the time to complete each task and number of errors committed during each task. An error was defined as a drop of any of the items handled. The data was analyzed using a fixed effects randomized ANOVA model and the Duncan's Multiple Range Test. An alpha level of 5 per cent was used in the analysis. The results of the analyses showed that gloves increased the average completion time by 15 to 37%. Several double gloving combinations had significantly longer task completion times compared to single gloves.
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Lee, Jae-Gon, Dong-Jin Kim, and Jeong-Hae Lee. "Compact Penta-Band Dual ZOR Antenna for Mobile Applications." International Journal of Antennas and Propagation 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/6461805.
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A compact penta-band dual zeroth order resonator (ZOR) antenna with band-stop filter is proposed for mobile applications. The ZOR antenna is designed with modified mushroom-like structures extended on nonground region to obtain good efficiency and broad bandwidth. This modified mushroom-like structure is confirmed as double negative (DNG) transmission line by full wave simulated dispersion relation. Moreover, a bended patch and a band-stop filter (BSF) are employed to increase efficiency and bandwidth, respectively. The length of each antenna is aboutλ0/10at the resonant frequencies of 900 MHz and 1800 MHz, respectively. The overall dimension of the antenna is 54.4 mm (length) × 4 mm (width) × 5 mm (height). The total efficiencies in low and high bands are measured more than 40% and 70%, respectively.
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Sørensen, P. Soelberg, B. Wanscher, K. Schreiber, M. Blinkenberg, C. V. Jensen, and M. Ravnborg. "A double-blind, cross-over trial of intravenous immunoglobulin G in multiple sclerosis: Preliminary results." Multiple Sclerosis Journal 3, no. 2 (April 1997): 145–48. http://dx.doi.org/10.1177/135245859700300216.
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We enrolled 25 patients with relapsing-remitting or relapsing progressive multiple sclerosis (MS) in a randomized placebo-controlled double-blind study of intravenous immunoglobulin G (IVIG). IVIG Iglkg daily for 2 days was administered every 4 weeks for 24 weeks. Seventeen patients completed the whole trial, whereas eight patients discontinued the trial; four during IVIG treatment and four on placebo. Of the 17 patients who completed the trial, II had no exacerbations during IVIG treatment compared with only six on placebo (P=0.05). The total number of exacerbations in the IVIG period was I / and in the placebo period 15 (NS), and the number of severe exacerbations requiring treatment with intravenous methylprednisolone was four during treatment with IVIG and six on placebo (NS). The results suggest that IVIG treatment may be of beneft for prevention of exacerbations in patients with relapsing MS.
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Liu, Guojun, Noriyuki Yasufuku, Ryohei Ishikura, and Qiang Liu. "Correlation between shear wave velocity and effective confining pressure using cyclic triaxial testing apparatus." E3S Web of Conferences 92 (2019): 04009. http://dx.doi.org/10.1051/e3sconf/20199204009.
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The 2016 Kumamoto earthquakes struck Kumamoto and Ōita regions and caused several devastating liquefaction induced damages. The primary damage was due to the extreme ground shaking of the foreshock and main shock sequence. Therefore, it is essential to develop a quick reliable approach with a high accuracy to assess the ground situation after foreshock or several shocks. Velocity of small shear wave (Vs) was widely used for evaluating the potential liquefaction. This study investigates the possibility of using Vs as a new indicator of the stress state in the soil after earthquake and evaluation of post liquefaction resistance of soil. Cyclic tri-axial apparatus equipped with bender elements were used to conduct two consecutives liquefaction tests on sandy soil. The Vs measured by bender elements was discussed on the relationship with effective stress during the liquefying processes. The results showed that for the sandy soils, a) Vs could not clearly reflect the significant reduction in resistance at re-liquefaction stages by directly comparing the Vs at the end of consolidation between first and stages, b) The shear wave velocity is significantly affected by effective confining pressure c) the shear wave velocity of 190 m/s was at confining pressure of 100 kPa. The shear wave velocity reaches to after 100 m/s after consolidations and re-consolidations. The shear wave velocity was found to reduce to 100 m/s when the effective confining stress reaches to 0 and to around 25 m/s when the double amplitude reaches to 5%; d) the velocity and effective stress decreases with a similar rate in liquefying process.
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Pail, Roland, Hsien-Chi Yeh, Wei Feng, Markus Hauk, Anna Purkhauser, Changqing Wang, Min Zhong, et al. "Next-Generation Gravity Missions: Sino-European Numerical Simulation Comparison Exercise." Remote Sensing 11, no. 22 (November 13, 2019): 2654. http://dx.doi.org/10.3390/rs11222654.
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Temporal gravity retrieval simulation results of a future Bender-type double pair mission concept, performed by five processing centers of a Sino-European study team, have been inter-compared and assessed. They were computed in a synthetic closed-loop simulation world by five independent software systems applying different gravity retrieval methods, but were based on jointly defined mission scenarios. The inter-comparison showed that the results achieved a quite similar performance. Exemplarily, the root mean square (RMS) deviations of global equivalent water height fields from their true reference, resolved up to degree and order 30 of a 9-day solution, vary in the order of 10% of the target signal. Also, co-estimated independent daily gravity fields up to degree and order 15, which have been co-estimated by all processing centers, do not show large differences among each other. This positive result is an important pre-requisite and basis for future joint activities towards the realization of next-generation gravity missions.
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Zhong, Z., C. C. Kao, D. P. Siddons, and J. B. Hastings. "Sagittal focusing of high-energy synchrotron X-rays with asymmetric Laue crystals. II. Experimental studies." Journal of Applied Crystallography 34, no. 5 (September 25, 2001): 646–53. http://dx.doi.org/10.1107/s0021889801010627.
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The use of bent asymmetric Laue crystals to focus synchrotron X-rays sagittally from 15 to 50 keV is described. A four-bar bender, bending a rectangular planar crystal, produced the necessary sagittal and meridional bending for this unique application. Adjustments of the tilt angle and height of the bent crystal resulted in first- and second-order corrections, respectively, to the dependence of the angle of diffraction on the horizontal position on the crystal. After these corrections, the remaining variation of the diffraction angle was of the order of 10 µrad. The theoretical sagittal focal length was verified. A prototype of a double-crystal sagittally focusing monochromator was constructed and tested, using two identical Laue crystals. A horizontal divergence of 3 mrad was focused to a horizontal dimension of about 0.4 mm. The X-ray flux density at the focus was a few hundred times larger than that of unfocused X-rays.
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Park-Finch, Heebon. "Alan Bennett’s Single Spies: Lifting the Veil of Personal and Institutional Secrecy." Journal of Contemporary Drama in English 8, no. 2 (November 3, 2020): 218–35. http://dx.doi.org/10.1515/jcde-2020-0019.
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AbstractThis article explores Alan Bennett’s Single Spies (1988), an espionage double bill comprising “An Englishman Abroad” and “A Question of Attribution,” proposing that the personalizing of social, political, and historical themes, as well as the astute documentation of a decaying Englishness and its class system in both plays, are representative of the work of a playwright whose output deserves serious critical attention. The study focuses on how Bennett historicizes the actions of his infamous protagonists (Guy Burgess and Anthony Blunt) while challenging assumptions regarding patriotism. Single Spies is a Cambridge Five franchise, demonstrating the playwright’s characteristic wit, irony, and reflection on personal and national identity, illusion, and sacrifice. The one-act plays each deal with a key figure in the notorious Cambridge spy ring, enhancing the dramatic effect through the use of onstage theatrical and visual allusions. In the first play, references to William Shakespeare’s Hamlet (c 1599), together with English music, highlight Burgess’s duality and the bitter reality of his post-defection life in Russia, while the second play is notable for its use of two paintings (Titian and a Venetian Senator and Allegory of Prudence) as key images and conceits suggesting the gradual uncovering of the Cambridge Five. The paper therefore suggests that Bennett’s ability to lift the veil of personal and institutional secrecy, while airing his own ambivalence, confirms him as a skillful, if academically undervalued, commentator on Englishness.
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Liu, Jinsheng, Zhenxing Xing, Gongjin Cheng, Xiangxin Xue, and Xueyong Ding. "Study on the Grinding Kinetics and Magnetic Separation of Low-Grade Vanadiferous Titanomagnetite Concentrate." Metals 12, no. 4 (March 28, 2022): 575. http://dx.doi.org/10.3390/met12040575.
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In recent years, a low-grade vanadiferous titanomagnetite concentrate (LVTC) produced in the northwest area of Liaoning has attracted more and more attention. However, it is difficult to recover and utilize valuable minerals such as iron, titanium, and vanadium, due to their special physical and chemical properties and complex mineral composition. Grinding and magnetic separation are two important operational units for recovering valuable metal components from vanadiferous titanomagnetite. Therefore, the grinding kinetics of the LVTC in northwestern Liaoning were first studied by means of grinding kinetics equations in this paper. The results show that the grinding process of LVTC is consistent with the grinding kinetics equation, and the sieve residues of particles approached a constant value after grinding for 30 min, resulting from equilibrium between the fragmentation and agglomeration processes. In addition, equivalent particle size (EPS) and specific surface area (SSA) were linearly proportional to the double logarithm of grinding time, and the correlation coefficients for fitted data by the Rosin–Rammler–Bennet (RRB) model were slightly higher than those by the Swebrec model, and could reflect the dispersibility and uniformity of particle size distribution (PSD) quantitatively. Then, the grinding products were separated by magnetic separation, and the influence of grinding conditions on the grade and recovery ratio of Fe and TiO2 in the LVTC was analyzed. As a result, grinding time has a significant impact on the recovery ratio and grade of Fe and TiO2 during the magnetic separation process, and the LVTC grinding duration is not as prolonged as it might be, as the optimal grinding time is 20 min. Titanomagnetite, ilmenite, and titanite are still the predominant phases in all magnetic separation products at optimal grinding time, but the intensity or content of these three minerals varies between magnetic separation products, and 232 kA/m magnetic field intensity has a higher separation efficiency than 134 kA/m magnetic field intensity.
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Hau, G. K. T., M. Balcells, and D. Carter. "Peculiar Kinematics in the Core of NGC 474." Symposium - International Astronomical Union 171 (1996): 388. http://dx.doi.org/10.1017/s007418090023307x.
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We present absorption line profile analysis of NGC 474, an elliptical with prominent, irregular shells. Profiles are parameterized with Gauss-Hermite polynomials (van der Marel & Franx ApJ 407 1993; Rix & White MNRAS 254 1992). The fastest rotation (∼ 50 km s–1) and steepest central velocity gradient along the intermediate photometric axis rules out the possibility that NGC 474 is a face-on S0 (Schombert & Wallin AJ 94 1987) and suggests that it is triaxial. The asymmetry of the LOSVDs (h3 up to 0.08) indicates the presence of a subsystem with rapid, ordered rotation. The minor axis velocity curve shows a kinematic feature at 3–4″ east of the nucleus, with no associated h3 or h4 features. Non-parametric LOSVD analysis (unresolved Gaussian decomposition, Kuijken & Merrifield MNRAS 264 1993) reveals a double-peaked profile at that location. In all position angles line-profiles are distinctly pointy for radii up to 2″, and are consistent with zero further out. We have found similar central positive h4 terms in the shell galaxy NGC 2865 (Hau et al. MNRAS in prep). Cores with pointy LOSVDs are uncommon in ellipticals (Bender, Saglia & Gerhard MNRAS 269 1994). Positive h4 terms might contain important clues on the shell-formation mechanism in ellipticals.
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Bennett, C. B., T. J. Westmoreland, J. R. Snipe, and M. A. Resnick. "A double-strand break within a yeast artificial chromosome (YAC) containing human DNA can result in YAC loss, deletion or cell lethality." Molecular and Cellular Biology 16, no. 8 (August 1996): 4414–25. http://dx.doi.org/10.1128/mcb.16.8.4414.
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Human chromosomal DNA contains many repeats which might provide opportunities for DNA repair. We have examined the consequences of a single double-strand break (DSB) within a 360-kb dispensable yeast artificial chromosome (YAC) containing human DNA (YAC12). An Alu-URA3-YZ sequence was targeted to several Alu sites within the YAC in strains of the yeast Saccharomyces cerevisiae; the strains contained a galactose-inducible HO endonuclease that cut the YAC at the YZ site. The presence of a DSB in most YACs led to deletion of the URA3 cassette, with retention of the telomeric markers, through recombination between surrounding Alus. For two YACs, the DSBs were not repaired and there was a G2 delay associated with the persistent DSBs. The presence of persistent DSBs resulted in cell death even though the YACs were dispensable. Among the survivors of the persistent DSBs, most had lost the YAC. By a pullback procedure, cell death was observed to begin at least 6 h after induction of a break. For YACs in which the DSB was rapidly repaired, the breaks did not cause cell cycle delay or lead to cell death. These results are consistent with our previous conclusion that a persistent DSB in a plasmid (YZ-CEN) also caused lethality (C. B. Bennett, A. L. Lewis, K. K. Baldwin, and M. A. Resnick, Proc. Natl. Acad. Sci. USA 90:5613-5617, 1993). However, a break in the YZ-CEN plasmid did not induce lethality in the strain (CBY) background used in the present study. The differences in survival levels appear to be due to the rapid degradation of the plasmid in the CBY strain. We, therefore, propose that for a DSB to cause cell cycle delay and death by means other than the loss of essential genetic material, it must remain unrepaired and be long-lived.
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Bennett, C. F., D. L. Spector, and L. C. Yeoman. "Nonhistone protein BA is a glutathione S-transferase localized to interchromatinic regions of the cell nucleus." Journal of Cell Biology 102, no. 2 (February 1, 1986): 600–609. http://dx.doi.org/10.1083/jcb.102.2.600.
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A DNA-binding nonhistone protein, protein BA, was previously demonstrated to co-localize with U-snRNPs within discrete nuclear domains (Bennett, F. C., and L. C. Yeoman, 1985, Exp. Cell Res., 157:379-386). To further define the association of protein BA and U-snRNPs within these discrete nuclear domains, cells were fractionated in situ and the localization of the antigens determined by double-labeled immunofluorescence. Protein BA was extracted from the nucleus with the 2.0 M NaCl soluble chromatin fraction, while U-snRNPs were only partially extracted from the 2.0 M NaCl-resistant nuclear structures. U-snRNPs were extracted from the residual nuclear material by combined DNase I/RNase A digestions. Using an indirect immunoperoxidase technique and electron microscopy, protein BA was localized to interchromatinic regions of the cell nucleus. Protein BA was noted to share a number of chemical and physical properties with a family of cytoplasmic enzymes, the glutathione S-transferases. Comparison of the published amino acid composition of protein BA and glutathione S-transferases showed marked similarities. Nonhistone protein BA isolated from saline-EDTA nuclear extracts exhibited glutathione S-transferase activity with a variety of substrates. Substrate specificity and subunit analysis by SDS polyacrylamide gel electrophoresis revealed that it was a mixture of several glutathione S-transferase isoenzymes. Protein BA isolated from rat liver chromatin was shown by immunoblotting and peptide mapping techniques to be two glutathione S-transferase isoenzymes composed of the Yb and Yb' subunits. Glutathione S-transferase Yb subunits were demonstrated to be both nuclear and cytoplasmic proteins by indirect immunolocalization on rat liver cryosections. The identification of protein BA as glutathione S-transferase suggests that this family of multifunctional enzymes may play an important role in those nuclear domains containing U-snRNPs.
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Marutyan, Alexander S. "Optimization of channels and I-shaped bended closed profiles with tubular shelves from sheets of different thicknesses." Structural Mechanics of Engineering Constructions and Buildings 17, no. 2 (December 15, 2021): 140–64. http://dx.doi.org/10.22363/1815-5235-2021-17-2-140-164.
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The continuation of optimization of channels and I-beams bent closed profiles (BCP) with tubular flanges made of rolled sheet of different thicknesses is presented. Such profiles are intended for light steel thin-walled structures (LSWS), which are distinguished by high technical and economic indicators and massive demand in industrial and civil construction, which confirms the relevance of their further development. The main results of the calculation of the optimal bending arrangement of composite sections of I-beams from sheet blanks of different thicknesses, including channel-type BCPs unified in terms of optimal parameters, are also presented. The aim of the study is to show that the characteristics of the LSWS can be further improved by shaping profiles, combining straight and round outlines of closed and open contours in a composite section. Methods. By means of experimental design studies, solution of optimization problems and variant design of I-profiles, their composite sections from sheet blanks of different thicknesses, including blanks of channel profiles, have been refined. The originality of channels and I-shaped BCP has been confirmed by patent examination. Results. The I-shaped BCP consists of two tubular shelves and one double thickness wall. Calculation of the optimal layout of an I-shaped BCP made of rolled sheet of different thicknesses for bending showed that the bearing capacity is limited by the ratio of the thickness of the flanges and the wall of its composite section. In particular, when the thickness of the flanges is 2 times the wall thickness, the strength is maximum at a ratio of width to height of 1/11, and when the thickness of the flanges is 0.6 times the wall thickness, the strength is maximum at a ratio of 1/3.3. With the ratios of the width and height of I-shaped BCP of 1/2.68...1/3 and channel-type BCPs of 1/5.36...1/6, their composite sections should be optimally assembled from standardized blanks.
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Nomoto, Masaki, Ryoji Tokashiki, Hiroyuki Hiramatsu, Ujimoto Konomi, Ray Motohashi, Eriko Sakurai, Fumimasa Toyomura, et al. "Injection Laryngoplasty with Calcium Hydroxylapatite Microspheres Using a Double-bent Cathelin Needle in Patients with Unilateral Vocal Fold Paralysis." Nihon Kikan Shokudoka Gakkai Kaiho 68, no. 1 (2017): 1–8. http://dx.doi.org/10.2468/jbes.68.1.
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Bender, Alexis A., Maggi N. Robert, Nathan S. Quan, Emma M. Klein, and Molly M. Perkins. "BARRIERS TO CARE FOR OLDER ADULTS IN MEDICATION-ASSISTED TREATMENT FOR OPIOID USE DISORDER." Innovation in Aging 3, Supplement_1 (November 2019): S141. http://dx.doi.org/10.1093/geroni/igz038.509.
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Abstract Over the last decade, the number of older adults (people over the age of 50) who misuse opioids doubled and continues to increase. People over the age of 50 also represent one of the fastest growing groups entering into and sustaining medication assisted treatment (MAT) (i.e., methadone and buprenorphine) for opioid use disorder (OUD). Despite increasing awareness of this growing at-risk population, significant knowledge gaps regarding their support and care needs persist. To begin to address these gaps, we conducted interviews with 20 treatment staff, focus groups with 18 patients and surveys with 100 patients over the age of 50 at eight diverse Opioid Treatment Programs (OTPs) participating in a 1-year pilot study (Bender, PI) funded by the Georgia Clinical and Translation Science Alliance supported by the National Center Advancing Translational Sciences. Patients in this study do not always disclose their use of MAT to non-OTP providers. When they do, participants reported numerous negative experiences with non-OTP providers, including perceived discrimination, stigma, and misunderstanding by providers about MAT. These negative experiences potentially contribute to an over reliance on OTP providers to manage age-related health conditions (e.g., COPD, hypertension). Providers report minimal training about aging and varied levels of confidence to manage these conditions. We present the experiences of patients and providers with suggestions for improving care coordination. We conclude with recommendations to improve communication among providers working with older adults in recovery from OUD.
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Kargaudas, Vytautas, and Nerijus Adamukaitis. "PLASTIC DEFORMATIONS OF STEEL FRAME: STATICS AND DYNAMICS." Engineering Structures and Technologies 2, no. 3 (September 30, 2010): 101–5. http://dx.doi.org/10.3846/skt.2010.14.
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When all deformations of a column are elastic, transverse deflections of the column depend on transverse force and axial displacements depend on axial force only. These classical dependences are unsuitable for elastic-plastic deformations. Plastic deformations develop in columns when steel frame is influenced by extreme action. When a steel column is in the elastic-plastic state, the distribution of elastic and plastic deformations in the cross-section depends on both the bending moment and compressing force. The ideal elastic-plastic material is assumed in this investigation (Prandtl stress – strain diagram). If the shape of the column section is double tee, flange width is neglected with respect to web height, but the area of the flange cross-section is assumed a constant. Single-sided or double-sided yield depends on the moment and force, and therefore curvature and the axial strain of the column can be calculated when yielding dependences are determined. Transverse and axial displacements of the highest point of the column are deduced by integration and depend on two arguments: bending force and axial force. These dependences are essentially non-linear, so linear approximations can be assessed for some vicinity of axial force and bending moment values. When axial force is a constant and transverse force increases, both axial and transverse displacements tend to increase. If transverse force is a constant and axial force increases, both displacements increases but dependence lines remain different and depend on cross-section shape parameter equal to the ratio of the flange area and the area of the whole cross-section. A distinguished feature of plastic deformations is dependence on the history of loading a frame of which can be selected in an arbitrary way by an investigator if a quasi-static solution is under examination. The loading of a frame and inertia forces have to be deduced if dynamic analysis is studied. Not only the ultimate result but also the way of approaching a plastic piston – plastic hinge is important. The bended and compressed column is the structure when inelastic dynamic analysis is really important.
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Teh, Selina Shiqing K., Eitan Halper-Stromberg, Laura Morsberger, Kirsten Bowland, Alexis Bennett, Robert B. Scharpf, Ying S. Zou, and James R. Eshleman. "Abstract 6103: Genomic instability delays cell death in PDAC after simultaneous double strand breaks." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6103. http://dx.doi.org/10.1158/1538-7445.am2023-6103.
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Abstract Apoptosis, the main cell death mechanism triggered by double strand breaks (DSBs), occurs as quickly as 2-3 hours, or 6-24 hours in vivo. However, when we transduced Cas9-expressing pancreatic cancer (PC) cell lines with multi-target sgRNAs, in which each sgRNA contains 2-16 target sites in the human genome, we found that most of the reduction in sgRNA tag counts did not occur in the first 7 days post transduction, but rather occurred between days 7 and 21. We demonstrated that CRISPR-Cas9 scission occurs over the course of days in our PC cells and peaked at days 3-5, consistent with another recent observation. Thus, we hypothesized that the mechanism of cell death was likely not due to DNA damage response pathways that were immediately and directly triggered by the multiple scission events, but rather was caused by a slower process. To test this, we treated the Cas9-expressing TS0111 PC cell line with a 14-target sgRNA and performed cytogenetic analysis on cells harvested from 0-21 days after transduction at 3-4 day intervals using a chromosome breakage assay. We observed various karyotypic abnormalities, such as formations of ring, dicentric, and tricentric chromosomes. These abnormalities accumulated over time and peaked at day 14, except for the chromatid and chromosome breaks in which the frequency was maintained through day 21, suggesting ongoing occurrence of breakage events. Analysis of breakpoints on dicentric and tricentric chromosomes showed that although breakpoints at sgRNA targeted regions predominated at early time points and decreased over time, non-targeted regions increased and peaked at day 14. A break-apart FISH assay was also implemented to confirm that these structural variants (SVs) were a direct result of CRISPR-Cas9 cuts, in which the number of cells with abnormal FISH patterns increased over time and also peaked at day 14. Additionally, we performed bioinformatics analyses on the whole genome sequencing data of surviving colonies post treatment of multi-target sgRNAs to identify novel SVs. We found that novel SVs increased as a function of the number of sgRNA target sites, and majority of the SVs were found at non-targeted sites, consistent with ongoing genomic instability. Interestingly, we found that cells responded to the 14-cutter by becoming polyploid, manifesting as extremely large nuclei or multinucleated giant cells. XY FISH showed that polyploidy peaked at day 10 and decreased by day 21. Finally, we assayed for apoptosis, which increased on days 7 and 14 but decreased by day 21. We concluded that cytotoxicity occurred following the induction of multiple DSBs that resulted in ongoing chromosomal rearrangements and polyploidization, ultimately leading to cell death via apoptosis and possibly other mechanisms. Citation Format: Selina Shiqing K. Teh, Eitan Halper-Stromberg, Laura Morsberger, Kirsten Bowland, Alexis Bennett, Robert B. Scharpf, Ying S. Zou, James R. Eshleman. Genomic instability delays cell death in PDAC after simultaneous double strand breaks. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6103.
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Shimizu, Nobutaka, Takeharu Mori, Hiromasa Ohta, Yasuko Nagatani, Shinya Saijyo, Hideaki Takagi, Ai Kamijyo, Takashi Kosuge, and Noriyuki Igarashi. "Improvement and Upgrade of Small-Angle X-ray Scattering Beamlines at the Photon Factory." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1757. http://dx.doi.org/10.1107/s2053273314082424.
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Three small-angle X-ray scattering (SAXS) beamlines, BL-6A, BL-10C and new BL-15A2 are available at the Japanese synchrotron facility, Photon Factory (PF). We are recently improving and upgrading the SAXS beamlines at the PF in order to support new measurements and construct a high-throughput experimental system. BL-6A is a bending magnet beamline and the wavelength is fixed at 1.5 angstrom. This beamline had two detectors, PILAUS 300K (Dectris) for SAXS/GI-SAXS and PILATUS 100K (Dectris) for WAXD experiment, respectively, and the simultaneous measurement using these detectors are available. We installed a new experimental stage and replaced PILATUS 300K with PILATUS3 1M in this March. Therefore, the range of an applicable camera length spread to 0.25 ~ 2.5 m, and the detectable angle area expanded in the small-angle region. BL-10A is also a bending magnet beamline and the wavelength has been fixed at 1.488 angstrom. We replaced almost all the optical and experimental components of this beamline with new ones in this March. A fixed-exit double-crystal monochromator, a focusing mirror and a mirror bender were newly installed in this beamline. We will be able to change the energy from 6 to 14 keV. Although the photon flux at the sample position will not change after this upgrade, the area of the beam at the focal point will decrease to 40 % on the basis of the raytracing calculation. The camera length spread from 2 m to 3m in a new experimental stage with the camera tube. PILATUS3 2M and 200K (Dectris) were also installed as a detector. The commissioning will be started from this May, and the beamline will be re-opened from this June. In order to control all new devices and make the user-operation easier, we newly developed GUI software for the beamline control and the experiment. We are also developing the solution sample mixer and changer at BL-15A2 for the high-throughput Bio-SAXS measurement. We will present the current status of these beamline refurbishment.
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Pazolli, Ermira, Randy Kipp, Alessandro Boezio, Hakan Gunaydin, Amanda Iskandar, Matthew Zubrowski, Bret Williams, et al. "Abstract P5-16-10: RLY-2608: The first allosteric mutant- and isoform-selective inhibitor of PI3Kα, is efficacious as a single agent and drives regressions in combination with standard of care therapies in PIK3CA mutant breast cancer models." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–16–10—P5–16–10. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-16-10.
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Abstract Inhibition of CDK4/6 combined with the estrogen receptor (ER) degrader fulvestrant significantly improves progression free survival and overall survival in advanced hormone receptor positive (HR+) breast cancer patients and is now the standard of care (SOC) in this disease. Up to 40% of HR+ breast cancers harbor PIK3CA mutations leading to activation of phosphoinositide 3-kinase alpha (PI3Kα), which has been associated with resistance to CDK4/6 inhibitors and fulvestrant. Therefore, PI3Kα inhibitor combinations with CDK4/6 inhibitors and/or fulvestrant are of high interest in HR+, PIK3CA mutant breast cancer. The therapeutic index of active site (orthosteric) inhibitors of PI3Kα has been limited by the dual issues of no clinically meaningful selectivity for mutant versus wild-type (WT) PI3Kα and off-isoform inhibitory activity. Alpelisib, the only approved orthosteric PI3Kα inhibitor, is emblematic of the class with toxicity related to inhibition of wild type PI3Kα and other PI3K isoforms resulting in sub-optimal inhibition of mutant PI3Kα, frequent discontinuation, and challenges in combining with CDK4/6 inhibitors. To overcome these limitations, we designed RLY-2608, the first allosteric, mutant, and isoform-selective inhibitor of PI3Kα. We solved the full-length cryo-EM structure of PI3Kα, performed long time-scale molecular dynamic simulations to elucidate conformational differences between WT and mutant PI3Kα, and leveraged these insights to enable the design of RLY-2608. RLY-2608 does not compete with orthosteric inhibitors for binding and associates 8x faster with mutant PI3Kα relative to WT PI3Kα. In biochemical assays, RLY-2608 inhibits kinase domain (H1047R) and helical domain (E542K, and E545K) mutant PI3Kα activity, demonstrating <10nM potency with 8-12x selectivity relative to WT. RLY-2608 is > 1000-fold selective over the β, δ, and γ PI3K isoforms in biochemical assays and demonstrates exquisite selectivity across a panel of 322 kinases, with no other kinases showing >50% inhibition. We performed in vitro combinations in two HR+ PIK3CA mutant cell lines (MCF7: E545K; T47D: H1047R) and observed synergy between RLY-2608 and fulvestrant or CDK4/6 inhibitors. In vivo, we tested combinations of RLY-2608 with fulvestrant and/or the CDK4/6 inhibitor abemaciclib in the MCF7 xenograft model. Oral administration of RLY-2608 in combination with fulvestrant led to improved efficacy compared to either agent alone in a dose-dependent manner, with regressions observed in the combination arms at all doses. Furthermore, the triple combination of RLY-2608, fulvestrant, and abemaciclib resulted in superior efficacy compared to either the RLY-2608 + fulvestrant or RLY-2608 + abemaciclib doublets, with deep regressions observed in the triple combination arm. In addition, in vivo combination efficacy with fulvestrant and CDK4/6 inhibitors (palbociclib or abemaciclib) was assessed in patient-derived xenografts harboring the PIK3CA H1047R or E545K mutation along with a second site PIK3CA minor mutation. In these studies, combination benefit was observed with doses of RLY-2608 significantly lower than the dose required for maximum efficacy as a single agent. RLY-2608 synergizes in vitro with both anti-estrogen and CDK4/6 inhibitors in cell models of HR+/PIK3CA mutant breast cancer. RLY-2608 can be combined with fulvestrant and CDK4/6 inhibitors in vivo with tumor regressions observed in both cell- and patient-derived xenograft models. The pre-clinical profile of RLY-2608 supports the clinical development of RLY-2608 both in single agent and combination clinical trials in patients with PIK3CA mutant tumors, including HR+/PIK3CA mutant breast cancer. Citation Format: Ermira Pazolli, Randy Kipp, Alessandro Boezio, Hakan Gunaydin, Amanda Iskandar, Matthew Zubrowski, Bret Williams, Kelley Shortsleeves, Alexandre Larivee, Tom McLean, Klaus Michelsen, Hongtao Zeng, Jonathan LaRochelle, Joe Manna, Lucian DiPietro, Andre Lescarbeau, Mary Mader, Bindu Bennet, Jeremy Wilbur, Qi Wang, Levi Pierce, Iain Martin, James Watters, Pascal Fortin, Donald Bergstrom. RLY-2608: The first allosteric mutant- and isoform-selective inhibitor of PI3Kα, is efficacious as a single agent and drives regressions in combination with standard of care therapies in PIK3CA mutant breast cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-10.
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Bussel, James B., Gregory Cheng, Mansoor N. Saleh, Bhabita Mayer, Sandra Y. Vasey, and Andres Brainsky. "Incidence of Thromboembolic Events Across Eltrombopag Clinical Trials In Chronic Immune Thrombocytopenia (ITP)." Blood 116, no. 21 (November 19, 2010): 70. http://dx.doi.org/10.1182/blood.v116.21.70.70.
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Abstract Abstract 70 Introduction: Chronic ITP is characterized by decreased platelet counts resulting from autoantibody-mediated peripheral platelet destruction and suboptimal platelet production. Eltrombopag is an oral, thrombopoietin receptor agonist approved for the treatment of ITP in the USA and elsewhere. Thromboembolic events (TEEs) can occur in patients with ITP; it has been speculated that ITP has prothrombotic characteristics and that low platelet counts may prevent a higher incidence of TEEs (Sarpatwari, 2010; Aledort, 2004; Zelcer, 2003). In the UK General Practice Research Database, incidence rates for TEEs were 1.35/100 patient years (PYs) (95% CI [0.99, 1.79]) for patients with ITP vs 1.16/100 PYs (95% CI [0.99, 1.35]) in patients without ITP (Sarpatwari, 2010). Similar results were found in a US claims database study (Bennett, 2008) and in romiplostim studies (Bussel, 2009). In this study we evaluated the incidence of TEEs in patients with chronic ITP treated with eltrombopag. Methods: Data from 446 patients with chronic ITP exposed to eltrombopag were analyzed from 5 eltrombopag clinical trials: two 6-week, randomized, double-blind, phase 2 and 3 studies, with patients on eltrombopag (n=164) or placebo (n=67) (Bussel, 2007; Bussel, 2009); RAISE, a 6-month, randomized, double-blind, phase 3 study, with 135 patients on eltrombopag and 62 on placebo (Cheng, 2010); REPEAT, a phase 2 study with 66 patients on eltrombopag for 3 cycles of 6 weeks on-therapy followed by up to 4 weeks off therapy (Psaila, 2008); and EXTEND, an ongoing extension study with 299 of the same patients on eltrombopag for at least 2 years (Cheng, 2008). The first occurrence of a TEE was used in the calculation of the incidence rates across the ITP program. Confirmed or suspected cases of TEEs were either reported by investigators or identified after sponsor evaluation based on symptoms reported as adverse events (AEs) that were potentially compatible with a TEE. In an additional analysis, the odds ratio for a TEE at different platelet thresholds was investigated to assess if a direct relationship could be established. Results: Across the ITP program, 20 patients (4.5%, 20/446) exposed to eltrombopag have experienced 27 TEEs. The TEEs were DVT (12), pulmonary embolism (6), MI (4), ischemic stroke (3), suspected prolonged reversible ischemic neurologic deficit (1), and transient ischemic attack (1). No placebo-treated patient experienced a TEE. The PYs of exposure to study medication was approximately 17 times greater than PYs of exposure to placebo (eltrombopag 584.4 PYs; placebo 35.4 PYs). Despite the increased exposure to eltrombopag in the EXTEND study, the incidence of TEEs (3.14/100 PYs, 95% CI [1.92, 4.85]) decreased compared to previously reported data (4.04/100 PYs, 95% CI [2.35, 6.46], Bussel, 2009). There was no clear pattern observed with regard to time to TEE onset; events were reported as early as day 1 and up to day 981 (median time to onset 229 days). The platelet counts most proximal to the events ranged between 14,000/μ L and 482,000/μ L (median 143,000/μ L). The majority of patients (55%, 11) had platelet counts below the normal range at the time of the TEE (<150,000/μ L). 4/20 patients experienced the TEE closest to their maximum platelet count achieved on study, whereas the majority (80%, 16/20) experienced the TEE at a lower platelet count than their maximum platelet count during treatment with eltrombopag. As seen in the Table, no changes in the odds ratio for a TEE at different platelet thresholds were observed. All patients experiencing a TEE had at least one risk factor for TEE; analysis did not reveal any one risk factor that was associated with the majority of cases. Two of 15 patients with TEEs tested had positive results for heterozygous Factor V Leiden mutation. Conclusions: There is no increase in the incidence rate of TEEs across the ITP program despite longer duration of eltrombopag treatment. The data presented here confirm previous observations that there is no evidence of a correlation between platelet count increases and the occurrence of TEEs in patients with chronic ITP on eltrombopag. Disclosures: Bussel: GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cheng:GlaxoSmithKline: Consultancy, Honoraria, Speakers Bureau. Saleh:GlaxoSmithKline, Novartis, Imcoline, Celgene: Honoraria, Speakers Bureau. Mayer:GlaxoSmithKline: Employment, Equity Ownership. Vasey:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment.
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Bagherzadeh, Azadeh, Jennifer Baker, Charlotte Bennett, Mi-Young Lee, Natalia Pacheco, Bhavisha Patel, Kevin Stewart, et al. "Abstract 2803: Pharmacokinetics and pharmacodynamics of the novel OMA1 activator BTM 3566 in a mouse model of diffuse large B-cell lymphoma." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2803. http://dx.doi.org/10.1158/1538-7445.am2023-2803.
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Abstract We have previously described a novel compound, BTM-3566, that exhibits robust single agent activity in xenograft and PDX models of DLBCL. BTM-3566 is effective on all types of DLBCL, independent of cell of origin (COO) or genotype. Drug activity depends on activation of the mitochondrial protease OMA1 followed by activation of HRI and induction of the ATF4 ISR. To ascertain whether ATF4 ISR induction occurs in vivo, we determined the pharmacokinetics (PK) and pharmacodynamic (PD) responses of BTM-3566 in mouse xenograft models of DLBCL using the double hit lymphoma SU-DHL-10. To establish PK parameters, tumor bearing mice were dosed orally for 1 or 5 consecutive days with 20 mg/kg BTM-3566 and blood sampled over 28 hours. Plasma levels of BTM-3566 were determined and analyzed using a non-compartment model. Half-life in blood plasma was 5.4 and 4.5 hours on days 1 and 5 respectively. Total exposure (AUCinf) was 524164 and 429485 hr*nM on day 1 and day 5 respectively. Drug AUCinf in tumor after a single oral dose of BTM-3566 was 151260 hr*nM. Free drug was estimated to be above the free IC90 for approximately 16 hours post-dose in both plasma and tumor. PD responses to BTM-3566 treatment were determined by measuring biomarkers of the therapeutic cascade: OPA1 cleavage is used as a surrogate for target engagement and activation of OMA1; increased phosphorylation of eIF2α represents pathway activation; induction of ATF4 regulated transcripts and the decrease in the anti-apoptotic protein MCL1 represent pathway effect. A single 20/mg/kg dose of BTM-3566 on day 1 resulted in cleavage of OPA1 by 0.5 hour, with maximal cleavage seen by 12 hours. Phosho-eIF2α was observed by 0.5 hours, peaking at 6 hours. Induction of the ATF4 transcripts ATF4, DDIT3, TRIB3, and CDKN1A was observed within 2 hours with a maximum at 6-12 hours followed by a reduction in transcript levels. MCL1 protein levels were reduced consistent with suppression of translation and protein turnover. By day 5, repeat dosing shows evidence of cumulative pathway effects: OPA1 is extensively cleaved; despite generally depressed levels, phosphorylation of eIF2α remains dynamic and MCL1 levels are markedly suppressed. Induction of ATF4 transcripts, however, follow largely the same kinetics as seen on day 1. The data suggests that in vivo anti-tumor activity of BTM-3566 is associated with activation of the mitochondrial protease OMA1 and induction of the ATF4 ISR. Robust tumor regression is correlated with both blood plasma levels of BTM-3566 and induction of the ATF4 ISR pathway. The data support the use of both ATF4 transcripts and OPA1 cleavage as robust PD markers of target engagement and pathway effect in human clinical trials. An Investigational New Drug application for BTM3566 in B-cell malignancies has been approved with initiation of first in human clinical trials planned for spring 2023. Citation Format: Azadeh Bagherzadeh, Jennifer Baker, Charlotte Bennett, Mi-Young Lee, Natalia Pacheco, Bhavisha Patel, Kevin Stewart, Jon Travers, Michael Stocum, Todd Hembrough, Matthew Kostura. Pharmacokinetics and pharmacodynamics of the novel OMA1 activator BTM 3566 in a mouse model of diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2803.
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Morand, E. F., A. Bender, A. Deshpande, B. Vaidyanathan, C. Vazquez Mateo, M. Przetak, F. Moreau, M. Khursheed, S. Roy, and D. Pearson. "AB0444 ENPATORAN: PRECLINICAL EVIDENCE SUPPORTING GLUCOCORTICOID DOSE REDUCTION AND PHASE II STUDY DESIGN IN PATIENTS WITH SLE AND/OR CLE (WILLOW)." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1350.2–1351. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4386.
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BackgroundEnpatoran is a potent selective dual inhibitor of toll-like receptor (TLR) 7 and TLR8, aberrant activation of which may be involved in systemic lupus erythematosus (SLE) pathogenesis and glucocorticoid resistance.1,2,3 Enpatoran suppressed disease development in lupus mouse models, improving survival and reducing proteinuria, autoantibodies, and the interferon (IFN) gene signature.1 In healthy participants and patients hospitalized with COVID-19 pneumonia, enpatoran was well tolerated and demonstrated effective TLR7/8 engagement.4 Enpatoran is potentially glucocorticoid sparing and may help avoid the detrimental effects of long-term corticosteroid use in SLE management.5,6ObjectivesTo evaluate the glucocorticoid-sparing effect of enpatoran and design a basket trial to assess its efficacy and safety in patients with SLE and/or cutaneous lupus erythematosus (CLE).MethodsCytokine concentrations and gene expression changes were measured in stimulated human peripheral blood mononuclear cells (PBMCs) from healthy donors after treatment with dexamethasone, TLR7/8 inhibitor, or both. A Phase II, basket design proof-of-concept, dose-finding study in patients with SLE and/or CLE (WILLOW) was designed.ResultsIn healthy donor PBMCs, synergy was observed between TLR7/8 inhibitor and dexamethasone. Combination treatment inhibited cytokine release (IL-6) with greater potency than either treatment alone and reduced the expression of nuclear factor-kappa B and IFN-regulated genes. WILLOW is a Phase II, basket proof-of-concept, dose-finding, randomized, double-blind, placebo (PBO)-controlled 24-week study with two cohorts (NCT05162586, Figure 1). The primary objectives of WILLOW are to evaluate the dose–response relationship of enpatoran in reducing disease activity based on Cutaneous Lupus Erythematosus Disease Area and Severity Index-A (CLASI-A) or BILAG-Based Composite Lupus Assessment (BICLA) response rate. The secondary objectives are to investigate effects on both BICLA response and clinically meaningful corticosteroid reduction and evaluate disease control (including clinically meaningful corticosteroid reduction) in patients with predominantly active CLE or SLE. Cohort A will enroll patients with CLE (active subacute CLE and/or discoid LE) or SLE with predominantly active lupus rash. Cohort B, in two parts, will enroll SLE patients with moderate to severe systemic disease activity. Part 1 will assess clinical signal and Part 2 may be adapted to improve dose finding. Glucocorticoid-sparing will be evaluated by mandatory tapering to a prednisone-equivalent dose of ≤5 mg/day.Figure 1.WILLOW study design.Cohort A and Cohort B Part 1 will start in parallel.*Part 2 will be initiated after a pre-specified number of patients are enrolled in Part 1; enpatoran doses in Part 2 may be adapted to improve dose finding (dashed boxes).BILAG, British Isles Lupus Assessment Group; CLASI-A, Cutaneous Lupus Erythematosus Disease Area and Severity Index-A; CLE, cutaneous lupus erythematosus; CS, corticosteroid; DBPC, double-blind placebo-controlled; DLE, discoid lupus erythematosus; PBO, placebo; SCLE, Subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index.ConclusionEnpatoran is a novel TLR7/8 inhibitor and may enable glucocorticoid dose reduction in patients with SLE and CLE. The WILLOW study incorporates multiple novel elements including a basket design and evaluation of glucocorticoid-sparing.References[1]Vlach, et al. J Pharmacol Exp Ther. 2021;376:397–409;[2]Northcott, et al. Lancet Rheumatol. 2021;5:e357–e370;[3]Guiducci, et al. Nature. 2010;465:937–941;[4]Port, et al. Pharmacol Res Perspect. 2021;9:e00842;[5]Thamer, et al. J Rheumatol. 2009;36:560–564;[6]Ruiz-Irastorza, et al. Rheumatology. 2012;51:1145–1153.AcknowledgementsThis study was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945), who funded medical writing support by Bioscript Stirling Ltd.Disclosure of InterestsEric F. Morand: None declared, Andrew Bender Shareholder of: Shares in Merck KGaA, Employee of: EMD Serono Research & Development institute (an affiliate of Merck KGaA), Aditee Deshpande Employee of: EMD Serono Research & Development institute (an affiliate of Merck KGaA), Bharat Vaidyanathan Employee of: EMD Serono Research & Development institute (an affiliate of Merck KGaA), cristina vazquez mateo Employee of: EMD Serono Research & Development institute (an affiliate of Merck KGaA), Melinda Przetak Employee of: EMD Serono Research & Development institute (an affiliate of Merck KGaA), Flavie Moreau Employee of: EMD Serono Research & Development institute (an affiliate of Merck KGaA), Mukhy Khursheed Employee of: Merck Serono Ltd (an affiliate of Merck KGaA), Sanjeev Roy Employee of: Ares Trading SA (an affiliate of Merck KGaA), David Pearson Consultant of: Biogen Inc.
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Dougados, M., D. Van der Heijde, C. Bingham, P. C. Taylor, L. Fallon, J. Woolcott, Y. Brault, L. Wang, and M. Kessouri. "FRI0335 THE EFFECT OF TOFACITINIB ON RESIDUAL PAIN IN PATIENTS WITH PSORIATIC ARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 760–61. http://dx.doi.org/10.1136/annrheumdis-2020-eular.949.
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Background:Current treatments for PsA have proven effective in reducing patient (pt)-reported pain;1,2however, residual pain often remains. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA.Objectives:This descriptive analysis evaluated the effect of tofacitinib, adalimumab and placebo on residual pain in pts with PsA whose inflammation was attenuated after 3 months of therapy.Methods:Data were included from OPAL Broaden (NCT01877668), a randomised, double-blind, placebo-controlled Phase 3 trial of 12 months’ duration in pts with PsA.3Pts were randomised to receive tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, adalimumab 40 mg subcutaneous injection once every 2 weeks or placebo. This analysis assessed pts with ‘residual pain’ at Month (M)3. Residual pain was considered as pain in pts with complete attenuation of inflammation at M3, defined by a swollen joint count (SJC) of 0 and CRP levels <6 mg/L. Pain was measured by a visual analogue scale (VAS; 0 [“no pain”] – 100 mm [“most severe pain”]). Changes in pain from baseline to M3 and residual pain (VAS pain reported at M3) were assessed.Results:Demographics and baseline disease characteristics have previously been reported in the primary study, and were generally similar between treatment groups.3At M3, 100/422 (23.7%) pts with PsA had achieved SJC of 0 and CRP <6 mg/L. At M3, more tofacitinib-treated (tofacitinib 5 mg BID, n=23/107 [21.5%]; tofacitinib 10 mg BID, n=33/104 [31.7%]) and adalimumab-treated pts (n=31/106 [29.2%]) achieved SJC of 0 and CRP <6 mg/L vs placebo (PsA: n=13/105 [12.4%]). Baseline pain appeared numerically higher in tofacitinib-treated pts (tofacitinib 5 mg BID, 54.7 mm; tofacitinib 10 mg BID, 58.4 mm) vs adalimumab-treated pts (47.7 mm) and placebo (50.4 mm). In pts who achieved SJC of 0 and CRP <6 mg/L at M3, improvements in pain from baseline to M3 appeared numerically greater in pts receiving tofacitinib vs those receiving placebo (Figure 1a). When considering absolute (residual) pain at M3, mean residual pain was similar across treatment groups (ranging from 22.7–29.2 mm; Figure 1b), despite a higher baseline pain in tofacitinib treatment groups.Conclusion:Changes from baseline in pain and absolute pain at M3 suggest that in pts with PsA whose inflammation has been completely attenuated, tofacitinib might have an effect on residual pain not obviously attributable to inflammation. However, the sample population was small, and there were large standard deviations. To confirm these results and to understand the mechanisms by which tofacitinib may improve residual pain, a meta-analysis will be performed using individual participant data from pts with rheumatic disease who have participated in tofacitinib randomised controlled trials.References:[1]Gladman et al. Ann Rheum Dis 2007;66:163-68.[2]Gladman et al. Arthritis Care Res 2014;66:1085-92.[3]Mease et al. NEJM 2017;377:1537-50.Acknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Mark Bennett of CMC Connect and funded by Pfizer Inc.Disclosure of Interests:Maxime Dougados Grant/research support from: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Speakers bureau: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Clifton Bingham Grant/research support from: Bristol-Myers Squibb, Consultant of: Bristol-Myers Squibb, Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Lara Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, John Woolcott Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Yves Brault Shareholder of: Pfizer France, Employee of: Pfizer France, Lisy Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Meriem Kessouri Shareholder of: Pfizer France, Employee of: Pfizer France
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Ritchlin, C. T., A. Ogdie, J. T. Giles, J. J. Gomez-Reino, P. Helliwell, L. Stockert, P. Young, et al. "AB0827 IMPACT OF BASELINE BODY MASS INDEX ON THE EFFICACY AND SAFETY OF TOFACITINIB IN PATIENTS WITH PSORIATIC ARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1717.2–1718. http://dx.doi.org/10.1136/annrheumdis-2020-eular.993.
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Background:Obesity is highly prevalent in PsA (~45%)1and is associated with a reduced response to TNF inhibitors.2Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA.Objectives:This post hoc analysis assessed tofacitinib efficacy and safety in patients (pts) with PsA by baseline (BL) body mass index (BMI) category.Methods:Data were pooled from two placebo (PBO)-controlled, double-blind, Phase 3 studies in pts with active PsA and an inadequate response to ≥1 conventional synthetic DMARD (OPAL Broaden [12 months;NCT01877668]) or to ≥1 TNF inhibitor (OPAL Beyond [6 months;NCT01882439]).3,4This analysis included pts randomised to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID or PBO, stratified by BL BMI: <25 kg/m2, ≥25–<30 kg/m2, ≥30–<35 kg/m2, or ≥35 kg/m2. Efficacy and safety were reported to Month (M)3. M3 efficacy outcomes included ACR20/50/70 and HAQ-DI responses, dactylitis and enthesitis resolution rates and changes from BL in HAQ-DI, Short Form-36 Version 2 (SF-36v2) Physical (PCS) and Mental Component Summary (MCS) scores, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores. Safety outcomes included adverse events (AEs), such as cardiovascular (CV) events and changes in lipid levels and liver function tests (LFTs).Results:This analysis included 710 pts; 43.8% were obese (BMI ≥30). At BL, 161 (22.7%) pts had a BMI <25, 238 (33.5%) had a BMI ≥25–<30, 186 (26.2%) had a BMI ≥30–<35 and 125 (17.6%) had a BMI ≥35. Most pts were white (92.5–96.8%), middle-aged (mean: 44.5–51.2 yrs) and female (49.5–65.6%). Greater proportions of obese pts were from Russia/Eastern Europe (35.0%) and USA/Canada (31.8%), vs the rest of world. At BL, higher BMI correlated with an increased prevalence of metabolic syndrome (4.3% in BMI <25 to 76.0% in BMI ≥35) and CRP levels >2.87 mg/L (49.1% in BMI <25 to 84.0% in BMI ≥35). Higher proportions of pts (42.5–47.9%) in BL BMI categories <35 reported no prior biologic DMARD use, vs pts with a BL BMI ≥35 (33.6%). At M3, efficacy improvements were greater in tofacitinib-treated pts vs PBO-treated pts (Figure 1). In pts with a BL BMI ≥35, a trend towards fewer pts responding was observed (Figure 1) and mean changes from baseline in SF-36v2 PCS and MCS and FACIT-F generally appeared lower (Figure 2) vs pts in lower BL BMI categories. Up to M3, the proportions of pts with AEs, and percentage change from BL in lipid levels and LFTs, were generally similar across all BL BMI categories. Three CV events were reported: non-fatal cerebrovascular accident, transient ischemic attack (both tofacitinib 5 mg BID, BMI ≥30–<35) and coronary artery revascularisation (PBO; BMI ≥35). Limitations include the 3-month observation time, particularly for safety findings, thus longer observation times are warranted.Conclusion:Regardless of BL BMI, tofacitinib demonstrated greater efficacy than PBO at M3 in pts with PsA. Similar to other advanced therapies,2reduced efficacy was generally observed in tofacitinib and PBO pts with a BL BMI ≥35. Tofacitinib safety appeared consistent across all BL BMI categories.References:[1]Labitigan et al. Arthritis Care Res (Hoboken) 2014;66:600-07.[2]Singh et al. PLoS One 2018;13:e0195123.[3]Mease et al. NEJM 2017;377:1537-50.[4]Gladman et al. NEJM 2017;377:1525-36.Acknowledgments:Medical writing support was provided by Mark Bennett of CMC Connect, McCann Health Medical Communications, and funded by Pfizer Inc.Disclosure of Interests:Christopher T. Ritchlin Grant/research support from: UCB Pharma, AbbVie, Amgen, Consultant of: UCB Pharma, Amgen, AbbVie, Lilly, Pfizer, Novartis, Gilead, Janssen, Alexis Ogdie Shareholder of: Amgen, Novartis, Pfizer Inc, Grant/research support from: Novartis, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Corrona, Eli Lilly, Novartis, Pfizer Inc, Jon T Giles Grant/research support from: Pfizer Inc, Juan Jesus Gomez-Reino Grant/research support from: AbbVie, Novartis, Pfizer Inc, Roche, UCB, Consultant of: Pfizer Inc, Speakers bureau: AbbVie, Bristol-Myers Squibb, Janssen, MSD, Pfizer Inc, Roche, UCB, Philip Helliwell: None declared, Lori Stockert Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Pamela Young Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Wael Joseph Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Rajiv Mundayat Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Daniela Graham Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, John Woolcott Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ana Belen Romero Shareholder of: Pfizer Inc, Employee of: Pfizer Inc
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Arnaout, Angel, Susan Robertson, Kianoosh Keyhanian, Megan Hopkins, Linda Liao, Vida Talebian, Arif Awan, et al. "Abstract PD11-02: PD11-02 A Phase II Randomized Window of Opportunity Trial Evaluating Cytotoxic and Immunomodulatory effects of Intratumoral INT230-6 in Early Stage Breast Cancer: the INVINCIBLE Trial." Cancer Research 83, no. 5_Supplement (March 1, 2023): PD11–02—PD11–02. http://dx.doi.org/10.1158/1538-7445.sabcs22-pd11-02.
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Abstract Background: The majority of breast cancers outside of the triple negative subtype are considered immunological quiescent and are therefore minimally responsive to immunotherapies. One potential method to combat this is through local therapies that induce cell death, thereby exposing tumor antigens, providing adjuvants for anti-tumor immune priming, and potentially increasing responsiveness to immunotherapies. We have conducted a randomized, Phase 2 presurgical Window-Of-Opportunity trial for intratumoral (IT) INT230-6 (comprising VINblastine (VIN) Cisplatin (VIN)) evaluating clinical and BioLogical Effects in patients with early-stage operable Breast Cancer (the INVINCIBLE trial- https://clinicaltrials.gov/ct2/show/NCT04781725). INT230-6 contains a dispersion enhancer molecule (SHAO) with the cytotoxic agents and is designed to cause tumor necrosis by dispersion throughout the tumor and diffusion into cancer cells. Previous in vitro studies have demonstrated that INT230-6 halts cancer cell replication and induces cell death recruiting dendritic cells and T-cells to the tumor microenvironment. In this trial, IT injections of INT230-6 are conducted to 1) exploit the potential of regional cytotoxic chemotherapy on breast cancer in vivo and 2) assess the immune response within the tumor, microenvironment and systemically in the host blood prior to surgical resection. Methods: Women with newly diagnosed and awaiting surgery for early-stage intermediate or high-grade T1-T2 invasive breast cancers were recruited to the trial. The study has two parts. Part I was a randomized (2:1) open label trial comparing 1-3 doses of INT230-6 injected weekly versus no treatment prior to surgery to evaluate safety, feasibility, and optimal drug dosing. Part II was a double-blinded randomized (2:1) trial where patients received one IT dose of INT230-6 vs saline injection. The primary objective was to estimate the proportion of patients with tumor necrosis and complete cell cycle arrest (CCCA) at the time of surgery compared to control. In addition, we performed targeted sequencing and proteomic profiling in tumour samples from the INT230-6 clinical trial. Results: The study recruited 90 patients with age ranges of 40-77 yrs (mean = 60 yrs) with tumors ranging from 1.5-4.3 cm (mean = 2.4cm). No surgeries were delayed or altered as a result of trial participation and the most common (>10%) AEs were injection site pain, injection site reaction and nausea/vomiting. Compared to the control group, up to 95% tumor necrosis was present in varying biologic subtypes and histologies, including invasive lobular carcinoma. Preliminary gene expression analysis showed significant differential gene expression between the baseline biopsy and surgical specimens. Pathway analysis identified genes associated with TCR signaling, B cells, T cells, chemokine signaling and NF-κB signaling were significantly changed in the post treatment samples. There was a relative increase in CD4 and CD8 T cells and B and NK cells within the tumor and in the tumour microenvironment. Conclusion: Preliminary evidence shows that a single dose of INT230-6 can cause substantial tumor necrosis and stimulate an immune response in breast cancers prior to surgery with minimal adverse effects and good tolerability. This window of opportunity clinical trial demonstrates that INT230-6 injection is a novel and simple method to convert traditionally immune quiescent breast cancers into immunogenic tumors. This can open the door to future potential immunotherapeutic options in early stage breast cancer. Citation Format: Angel Arnaout, Susan Robertson, Kianoosh Keyhanian, Megan Hopkins, Linda Liao, Vida Talebian, Arif Awan, John MS Bartlett, Gregory R. Pond, Lazlo Radvanyi, Lewis H. Bender, Ian B. Walters, Vanessa Lopez Ozuna, Melanie Spears. PD11-02 A Phase II Randomized Window of Opportunity Trial Evaluating Cytotoxic and Immunomodulatory effects of Intratumoral INT230-6 in Early Stage Breast Cancer: the INVINCIBLE Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-02.
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Deshmukh, A., A. Pereira, N. Geraci, E. Tzvetkov, M. Przetak, M. Catalina, E. F. Morand, A. Bender, and B. Vaidyanathan. "POS1413 PRECLINICAL EVIDENCE FOR THE GLUCOCORTICOID-SPARING POTENTIAL OF A DUAL TLR7/8 INHIBITOR IN AUTOIMMUNE DISEASES." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 1060–61. http://dx.doi.org/10.1136/annrheumdis-2023-eular.2555.
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BackgroundToll-like receptor 7 (TLR7) and TLR8 are single-stranded RNA-sensing endosomal pattern recognition receptors that evolved to defend against viral infections, however their dysregulation and activation by endogenous ligands has been implicated in autoimmune diseases including lupus. While glucocorticoids (GC) are effective, they have many undesirable effects that limit their use. In addition, resistance to GC, which was recently shown to be imparted by TLR activation and Type I interferon (IFN), is a major challenge for the treatment of patients with autoimmune diseases including lupus. New treatment approaches that allow for the use of lower doses of GC would be highly beneficial.ObjectivesTo evaluate the GC-sparing effects of a dual TLR7 and TLR8 inhibitor (TLR7/8i).MethodsHuman peripheral blood mononuclear cells (PBMC) from healthy donors were treated with TLR7/8i, dexamethasone, or both. Cytokine production was measured using an AlphaLISA immunoassay, gene expression was analyzed by NanoString and single-cell RNA sequencing, and effects on protein markers were evaluated by flow cytometry. In addition, the efficacy of combined TLR7/8i and dexamethasone treatment was evaluated in the MRL/lprmouse model of lupus.ResultsStudies in human PBMCs revealed synergistic effects of TLR7/8i and GC on inflammatory cytokine production resulting in increased GC potency in the presence of TLR7/8i (Figure 1A), an effect that was most pronounced in myeloid cells, especially monocytes (Figure 1B). Gene expression analysis revealed that the combination of TLR7/8i plus GC substantially impacted myeloid cell clusters, particularly modules for IFN and GC response genes, as well as nuclear factor-kappa B-regulated cytokines. Treatment with TLR7/8i and GCin vivowas more efficacious then either agent alone, as evidenced by reduced proteinuria (Figure 1C) and improved survival.ConclusionThese results demonstrate that TLR7/8 inhibition increases the potency of GC by alleviating TLR activation-dependent GC resistance in a cell type-specific manner. Our findings suggest a GC-sparing potential for TLR7/8i compounds and indicate that TLR7/8 inhibition may offer a new therapeutic strategy for the treatment of autoimmune diseases. The safety, efficacy and GC-sparing effect of the TLR7/8i enpatoran is being evaluated in patients with systemic and/or cutaneous lupus erythematosus in the randomized, double-blind, placebo-controlled Phase II WILLOW study (NCT05162586), which has a mandatory GC tapering schedule.Figure 1.Dexamethasone and TLR7/8i have synergistic effects on (A) IL-6 production in R848-stimulated PBMCs, (B) TNFα production in monocytes, and (C) proteinuria in a mouse model of lupus.AcknowledgementsThis study was sponsored by EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. Medical writing support was provided by Bioscript Group Ltd, Macclesfield, UK, and funded by Merck Healthcare KGaA, Darmstadt, Germany.Disclosure of InterestsAnkita Deshmukh Employee of: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Albertina Pereira Employee of: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Nicholas Geraci Employee of: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Evgeni Tzvetkov Employee of: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Melinda Przetak Employee of: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Michelle Catalina Employee of: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Eric F. Morand Consultant of: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Grant/research support from: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Andrew Bender Shareholder of: Merck KGaA, Darmstadt, Germany, Employee of: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Bharat Vaidyanathan Employee of: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA.
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Lee, Oukseub, Xinlei Mi, Yanfei Xu, Luis Blanco, Azza M. Akasha, Kelly Benante, Shanshan Zhang, et al. "Abstract PD15-12: PD15-12 A pre-surgical window trial of oral tamoxifen versus transdermal 4-hydroxytamoxifen gel in women with estrogen receptor positive duct carcinoma in situ (DCIS)." Cancer Research 83, no. 5_Supplement (March 1, 2023): PD15–12—PD15–12. http://dx.doi.org/10.1158/1538-7445.sabcs22-pd15-12.
Full textAbstract:
Abstract Background: Adjuvant oral tamoxifen (TAM) benefits women with DCIS, but toxicity concerns have limited its acceptance. Transdermal therapy with 4-hydroxy tamoxifen (4-OHT) gel applied to the breast skin is a possible solution. Previous pilot data suggest equivalent anti-proliferative efficacy of TAM and 4-OHT gel, but minimal systemic exposure with transdermal therapy. We report a prospective double blinded randomized phase 2 trial comparing TAM to 4-OHT gel in women with DCIS. Methods: 107 women with estrogen receptor positive (≥10%) DCIS were randomized to TAM (20 mg/day + placebo gel) or 4-OHT gel (2mg 4-OHT gel/breast, bilaterally + oral placebo), for 4-10 weeks prior to surgery. The primary endpoint was reduction in DCIS Ki67 labeling index (LI). Secondary endpoints included the 12-gene DCIS Score assay (Exact Sciences), breast tissue and plasma concentrations of 4-OHT and endoxifen, TAM-responsive circulating proteins, and patient reported symptoms (Breast Eight Symptom Scale). We estimated that 80 evaluable participants would provide 80.5% power to establish non-inferiority of 4-OHT, defined as relative Ki67-LI decline >35% and absolute decline >2.6%, with one-sided 𝛼=0.10. Non-inferiority of 4-OHT gel for Ki67-LI reduction was tested using an ANCOVA model. Statistical comparisons within- and between-arms were calculated with paired t-test and Welch Two Sample t-test, respectively. Results: 72 of 87 women adhered to the protocol, and were evaluable for the primary endpoint (39 TAM and 33 4-OHT gel). Mean treatment duration was 47 days for TAM and 44 days for 4-OHT gel (p=0.2). The median absolute decline in Ki67 labeling index was significant in the oral TAM (-3.7%, p< 0.001) but not in 4-OHT gel arm (-1.3%, p=0.2) (p=0.002). Ki67 results following menopausal stratification also favored the TAM arm: (-1.3%; p=0.06 in 37 premenopausal women and -3.7%; p=0.02 in 35 postmenopausal women). Similarly, DCIS score showed a significantly greater reduction in the TAM (-14, p< 0.001) but not in the 4-OHT gel arm (-4, p=0.1). Tissue 4-OHT concentrations were non-significantly higher in the TAM arm and were similar between superficial and deep sampling locations (superficial 6.1 and 4.2 ng/g for TAM and 4-OHT gel, respectively, p= 0.55; deep 5.7 and 3.8 ng/g, respectively, p= 0.06), whereas plasma 4-OHT concentration was markedly lower in the gel group (2 ng/mL and 0.24 ng/mL for TAM and 4-OHT gel, respectively, P < 0.001). Endoxifen was abundant in plasma (11 ng/mL) and deep tissue (13 ng/g) of the TAM arm, but present in trace amounts in the 4-OHT gel arm (undetectable in plasma and 0.31 ng/g in tissue; p < 0.001). Circulating TAM responsive markers (insulin like growth factor 1, sex hormone binding globulin, von Willebrand factor, and protein S total) and vasomotor symptoms were significantly and unfavorably modulated by TAM, but not by 4-OHT gel therapy. Conclusions: The non-inferiority of transdermal 4-OHT gel to Tam in terms of anti-proliferative effect in DCIS lesions was not demonstrated at the doses used for this study. DCIS Score analysis gave similar results. Tissue 4-OHT concentration in 4-OHT gel and Tam-treated subjects was roughly similar. However, endoxifen exposure was higher with oral TAM therapy and may partially explain the observed differences in major endpoints. In future studies, use of higher 4-OHT gel doses, longer duration of treatment, or different formulation may overcome these. Citation Format: Oukseub Lee, Xinlei Mi, Yanfei Xu, Luis Blanco, Azza M. Akasha, Kelly Benante, Shanshan Zhang, Carissa LaBoy, Thomas Helland, Melissa Pilewskie, Amy Degnim, Zahraa Al-Hilli, Amanda L. Amin, E Shelley Hwang, Joseph M. Guenther, Simon Steinar Hustad, Demirkan B. Gursel, Masha Kocherginsky, Gunnar Mellgren, Eileen Dimond, Marjorie Perloff, Brandy M. Heckman-Stoddard, Seema Khan. PD15-12 A pre-surgical window trial of oral tamoxifen versus transdermal 4-hydroxytamoxifen gel in women with estrogen receptor positive duct carcinoma in situ (DCIS) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD15-12.