BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas

B-cell lymphoma; Cancer therapy; CNS cancerLimfoma de cèl·lules B; Teràpia del càncer; Càncer del SNCLinfoma de células B; Terapia del cáncer; Cáncer del SNCBromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] of ≥4 months’ duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion cohorts (parts B [N = 25] and C [N = 41]). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8–33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0–8.6) and a CBR of 31.7% (95% CI, 18.1–48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents.This study was sponsored by Celgene, a Bristol Myers Squibb Company. The study sponsor was involved in the study design, analysis of data, and writing the manuscript. Medical writing and editorial assistance were provided by Bernard Kerr, PGDipSci, and Agata Shodeke, of Spark, funded by Bristol Myers Squibb

Distributed event-triggered communication for angular speed synchronization of networked BLDC motors

[EN] This work presents the design and implementation of a collaborative and decentralized control for synchronizing the angular velocity of a group of spatially distributed brushless direct current (BLDC) motors. Via an Active Disturbance Rejection Control (ADRC), acting as an internal-loop, the dynamics of the BLDC can be assimilated to that of a first-order integrator, which is considered an agent. Then, a decentralized collaborative control strategy with event-triggered communication is proposed, which solves the problem of leader-follower consensus for the multi-agent system and thus speed synchronization. The communication topology between agents is modeled using an undirected and connected graph. The decentralized control law incorporates an event function, which indicates the instant at which the i-th agent transmits the angular velocity information to its neighbor. An experimental platform using two BLDC and a virtual leader was developed to validate the proposed approach. The experimental results show excellent performance for angular velocity consensus for regulation tasks, while the bandwidth usage is only 1.25 % regarding a periodic communication implementation.[ES] Este trabajo presenta el diseño e implementación de un control colaborativo descentralizado para la sincronización de velocidad angular de un conjunto de motores de corriente continua sin escobillas (BLDC) distribuidos espacialmente. Apoyándose de un control por rechazo activo de perturbaciones, actuando como un bucle interno, la dinámica del BLDC puede asimilarse a la de un integrador de primer orden y el cual será considerado un agente. Se propone entonces una estrategia de control colaborativo descentralizado con una comunicación activada por eventos, que resuelve el problema del consenso líder-seguidor del sistema multi-agente y, con ello, la sincronización de velocidades entre motores. La topología de comunicación entre agentes se modela usando un grafo conectado y no dirigido. La ley de control descentralizado incorpora una función de evento, que indica el instante en el que $i$-ésimo agente transmite la información de velocidad angular a su vecino. El intercambio asíncrono de información permite reducir el tráfico de datos en la red de comunicaciones, lo que permite aprovechar el ancho de banda. Al analizar la dinámica de la trayectoria del error del sistema, se establece que el vector de error del sistema multi-agente tiende de forma exponencial y permanece confinado a una vecindad del origen del espacio de estados de error. Aunque la estrategia está diseñada para n-agentes, se desarrolló una plataforma experimental compuesta por dos motores y un líder virtual, permitiendo validar la estrategia. Los resultados experimentales muestran un excelente desempeño del consenso de velocidad angular de ambos motores BLDC para tareas de regulación, mientras que el uso del ancho de banda es de solamente 1.25 % con respecto a una implementación de comunicación periódica.Hernández-Méndez, A.; Guerrero-Castellanos, J.; Orozco-Urbieta, T.; Linares-Flores, J.; Mino-Aguilar, G.; Curiel, G. (2021). Comunicación distribuida activada por eventos para la sincronización de velocidad angular de motores BLDC en red. Revista Iberoamericana de Automática e Informática industrial. 18(4):360-370. https://doi.org/10.4995/riai.2021.14989OJS360370184Ahmed, N., Cortes, J., Martinez, S., 2016. Distributed control and estimation of robotic vehicle networks: Overview of the special issue-part II. IEEE Control Systems 36 (4), 18-21. https://doi.org/10.1109/MCS.2016.2558398Aranda-Escolástico, E., Guinaldo, M., Heradio, R., Chacon, J., Vargas, H., Sánchez, J., Dormido, S., 2020. 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Power active filter control based on a resonant disturbance observer. IET Power Electronics 8 (4), 554-564. https://doi.org/10.1049/iet-pel.2014.0032Garcia, E., Cao, Y., Wang, X., Casbeer, D. W., July 2015. Decentralized eventtriggered consensus of linear multi-agent systems under directed graphs. In: 2015 American Control Conference (ACC). pp. 5764-5769. https://doi.org/10.1109/ACC.2015.7172242Guerrero-Castellanos, J., Rifaï, H., Arnez-Paniagua, V., Linares-Flores, J., Saynes-Torres, L., Mohammed, S., 2018. Robust active disturbance rejection control via control lyapunov functions: Application to actuated-ankle-footorthosis. Control Engineering Practice 80, 49 - 60. https://doi.org/10.1016/j.conengprac.2018.08.008Guerrero-Castellanos, J., Vega-Alonzo, A., Durand, S., Marchand, N., Gonzalez-Diaz, V., Casta˜neda-Camacho, J., Guerrero-Sánchez, W., 2019. Leader-following consensus and formation control of vtol-uavs with eventtriggered communications. Sensors 19 (24), 1-26. https://doi.org/10.3390/s19245498Guinaldo, M., Dimarogonas, D. V., Johansson, K. H., S'anchez, J., Dormido, S., 2013. Distributed event-based control strategies for interconnected linear systems. Control Theory & Applications, IET 7 (6), 877-886. https://doi.org/10.1049/iet-cta.2012.0525Guzey, H. M., Dumlu, A., Guzey, N., Alpay, A., April 2018. Optimal synchronizing speed control of multiple dc motors. In: 2018 4th International Conference on Optimization and Applications (ICOA). pp. 1-5. https://doi.org/10.1109/ICOA.2018.8370508Han, J., 2009. From pid to active disturbance rejection control. Transactions on Industry Electronics 56 (3), 900-906. https://doi.org/10.1109/TIE.2008.2011621Hebertt Sira-Ramírez, Alberto Luviano-Juárez, M. R.-N. E.-W. Z.-B., 2017. Active Disturbance Rejection Control of Dynamic Systems. Butterworth- Heinemann.Hernandez-Méndez, A., Linares-Flores, J., Sira-Ramírez, H., Guerrero-Castellanos, J., Mino-Aguilar, G., 2017. A backstepping approach to decentralized active disturbance rejection control of interacting boost converters. Transactions on Industry Applications 53 (4), 4063-4072. https://doi.org/10.1109/TIA.2017.2683441Lee, J., Bagheri, B., Kao, H.-A., 2015. A cyber-physical systems architecture for industry 4.0-based manufacturing systems. Manufacturing Letters 3, 18- 23. https://doi.org/10.1016/j.mfglet.2014.12.001Lewis, F. L., Zhang, H., Hengster-Movric, K., Das, A., 2013. Cooperative control of multi-agent systems: optimal and adaptive design approaches. Springer Science & Business Media. https://doi.org/10.1007/978-1-4471-5574-4Marchand, N., Durand, S., Guerrero-Castellanos, J. F., 2013. A general formula for event-based stabilization of nonlinear systems. Automatic Control, IEEE Transactions on 58 (5), 1332-1337. https://doi.org/10.1109/TAC.2012.2225493Miskowicz, M., 2015. Event-Based Control and Signal Processing. CRC Press.Neenu, T., Poongodi, P., 07 2009. Position control of dc motor using genetic algorithm based pid controller. Lecture Notes in Engineering and Computer Science 2177.Olfati-Saber, R., Murray, R. M., 2004a. Consensus problems in networks of agents with switching topology and time-delays. Automatic Control, IEEE Transactions on 49 (9), 1520-1533. https://doi.org/10.1109/TAC.2004.834113Olfati-Saber, R., Murray, R. M., Sep. 2004b. Consensus problems in networks of agents with switching topology and time-delays. IEEE Transactions on Automatic Control 49 (9), 1520-1533. https://doi.org/10.1109/TAC.2004.834113Ren, W., Beard, R. W., 2008. Distributed consensus in multi-vehicle cooperative control. Springer. https://doi.org/10.1007/978-1-84800-015-5Sánchez-Santana, J., Guerrero-Castellanos, J., Villarreal-Cervantes, M., Ramırez-Martınez, S., 2018. Control distribuido y disparado por eventos para la formación de robots m'oviles tipo (3, 0)?. In: Congreso Nacional de Control Automático.Seyboth, G. S., Dimarogonas, D. V., Johansson, K. H., 2013. Event-based broadcasting for multi-agent average consensus. Automatica 49 (1), 245-252. https://doi.org/10.1016/j.automatica.2012.08.042Shi, T., Liu, H., Geng, Q., Xia, C., 2016. Improved relative coupling control structure for multi-motor speed synchronous driving system. IET Electric Power Applications 10 (6), 451-457. https://doi.org/10.1049/iet-epa.2015.0515Sira-Ramírez, H., Hernández-Méndez, A., Linares-Flores, J., Luviano-Juarez, A., 2016. Robust flat filtering dsp based control of the boost converter. Control Theory and Technology 14 (3), 224-236. https://doi.org/10.1007/s11768-016-6025-6Sira-Ramírez, H., Linares-Flores, J., Luviano-Juárez, A., Cortés-Romero, J., 2015. Ultramodelos globales y el control por rechazo activo de perturbaciones en sistemas no lineales diferencialmente planos. Revista Iberoamericanade Automática e Informática Industrial RIAIg 12 (2), 133 - 144. https://doi.org/10.1016/j.riai.2015.02.001Song, H., Rawat, D. B., Jeschke, S., Brecher, C., 2017. Front matter. In: Cyber- Physical Systems. Intelligent Data-Centric Systems. Academic Press, Boston, pp. i - ii.Sun, J., Liu, R., Luo, Y., Sun, W., 2009. Research on multi-motor synchronization control for cutter head of shield machine based on the ring coupled control strategy. In: Xie, M., Xiong, Y., Xiong, C., Liu, H., Hu, Z. (Eds.), Intelligent Robotics and Applications. Springer Berlin Heidelberg, Berlin, Heidelberg, pp. 345-354. https://doi.org/10.1007/978-3-642-10817-4_34Tao, L., Chen, Q., Nan, Y., Dong, F., Jin, Y., 09 2018. Speed tracking and synchronization of a multimotor system based on fuzzy adrc and enhanced adjacent coupling scheme. Complexity 2018, 1-16. https://doi.org/10.1155/2018/5632939Torres, F. J., Guerrero, G. V., García, C. D., Gomez, J. F., Adam, M., Escobar, R. F., Sep. 2016. Master-slave synchronization of robot manipulators driven by induction motors. IEEE Latin America Transactions 14 (9), 3986-3991. https://doi.org/10.1109/TLA.2016.7785923Valenzuela, A., Lorenz, R., 02 2001. Electronic line-shafting control for paper machine drives. Industry Applications, IEEE Transactions on 37, 158 - 164. https://doi.org/10.1109/28.903141Xia, C. L., 2012. Permanent magnet brushless DC motor drives and controls. John Wiley & Sons. https://doi.org/10.1002/9781118188347Xie, D., Xu, S., Zhang, B., Li, Y., Chu, Y., 2016. Consensus for multi-agent systems with distributed adaptive control and an event-triggered communication strategy. IET Control Theory Applications 10 (13), 1547-1555. https://doi.org/10.1049/iet-cta.2015.1221Yang, D., Ren,W., Liu, X., Dec 2014. Decentralized consensus for linear multiagent systems under general directed graphs based on event-triggered/selftriggered strategy. In: 53rd IEEE Conference on Decision and Control. pp. 1983-1988. https://doi.org/10.1109/CDC.2014.7039689Yu, H., Xi, J.-Q., Zhang, F., Hu, Y.-h., 02 2014. 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Imaging neutron capture cross sections: i-TED proof-of-concept and future prospects based on Machine-Learning techniques

Babiano-Suárez, V., et al.i-TED is an innovative detection system which exploits Compton imaging techniques to achieve a superior signal-to-background ratio in (n, γ) cross-section measurements using time-of-flight technique. This work presents the first experimental validation of the i-TED apparatus for high-resolution time-of-flight experiments and demonstrates for the first time the concept proposed for background rejection. To this aim, the Au(n, γ) and Fe(n, γ) reactions were studied at CERN n_TOF using an i-TED demonstrator based on three position-sensitive detectors. Two CD detectors were also used to benchmark the performance of i-TED. The i-TED prototype built for this study shows a factor of ∼ 3 higher detection sensitivity than state-of-the-art CD detectors in the 10 keV neutron-energy region of astrophysical interest. This paper explores also the perspectives of further enhancement in performance attainable with the final i-TED array consisting of twenty position-sensitive detectors and new analysis methodologies based on Machine-Learning techniques.This work has been carried out in the framework of a project funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC Consolidator Grant project HYMNS, with grant agreement No. 681740). The authors acknowledge support from the Spanish Ministerio de Ciencia e Innovación under grants PID2019-104714GB-C21, FPA2017-83946-C2-1-P, FIS2015-71688-ERC, CSIC for funding PIE-201750I26, and the funding agencies of the participating institutes. We would like to thank the crew at the Electronics Laboratory of IFIC, in particular Manuel Lopez Redondo and Jorge Nácher Arándiga for their excellent and efficient work

Neutron cross-sections for advanced nuclear systems : The n-TOF project at CERN

© Owned by the authors, published by EDP Sciences, 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedThe study of neutron-induced reactions is of high relevance in a wide variety of fields, ranging from stellar nucleosynthesis and fundamental nuclear physics to applications of nuclear technology. In nuclear energy, high accuracy neutron data are needed for the development of Generation IV fast reactors and accelerator driven systems, these last aimed specifically at nuclear waste incineration, as well as for research on innovative fuel cycles. In this context, a high luminosity Neutron Time Of Flight facility, n-TOF, is operating at CERN since more than a decade, with the aim of providing new, high accuracy and high resolution neutron cross-sections. Thanks to the features of the neutron beam, a rich experimental program relevant to nuclear technology has been carried out so far. The program will be further expanded in the near future, thanks in particular to a new high-flux experimental area, now under construction.Peer reviewedFinal Published versio

Right Paraduodenal Hernia in an Adult Patient: Diagnostic Approach and Surgical Management

Paraduodenal hernia, a rare congenital anomaly which arises from an error of rotation of the midgut, is the most common type of intraabdominal hernia. There are two variants, right and left paraduodenal hernia, the right being less common. We report the case of a 41-year-old patient with a right paraduodenal hernia with a 6-month history of intermittent episodes of intestinal obstruction. Diagnosis was established by CT scan and upper gastrointestinal series with small bowel follow-through. In a planned laparotomy, herniation of the small bowel loops through the fossa of Waldeyer was found. Division of the lateral right attachments of the colon opened the hernia sac widely, replacing the pre- and postarterial segments of the intestine in the positions they would normally occupy at the end of the first stage of rotation during embryonic development. Six months after the surgery, after an uneventful recovery, the patient remains free of symptoms

238U(n, γ) reaction cross section measurement with C 6D6 detectors at the n-TOF CERN facility

This is an Open Access article distributed under the terms of the Creative Commons Attribution License 2.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedThe radiative capture cross section of 238U is very important for the developing of new reactor technologies and the safety of existing ones. Here the preliminary results of the 238U(n,γ) cross section measurement performed at n-TOF with C6D6 scintillation detectors are presented, paying particular attention to data reduction and background subtraction.Peer reviewe

Measurement of the 240Pu(n,f) cross-section at the CERN n-TOF facility : First results from experimental area II (EAR-2)

The accurate knowledge of the neutron-induced fission cross-sections of actinides and other isotopes involved in the nuclear fuel cycle is essential for the design of advanced nuclear systems, such as Generation-IV nuclear reactors. Such experimental data can also provide the necessary feedback for the adjustment of nuclear model parameters used in the evaluation process, resulting in the further development of nuclear fission models. In the present work, the 240Pu(n,f) cross-section was measured at CERN's n-TOF facility relative to the well-known 235U(n,f) cross section, over a wide range of neutron energies, from meV to almost MeV, using the time-of-flight technique and a set-up based on Micromegas detectors. This measurement was the first experiment to be performed at n-TOF's new experimental area (EAR-2), which offers a significantly higher neutron flux compared to the already existing experimental area (EAR-1). Preliminary results as well as the experimental procedure, including a description of the facility and the data handling and analysis, are presented

The nucleosynthesis of heavy elements in Stars : The key isotope 25Mg

This is an Open Access article distributed under the terms of the Creative Commons Attribution License 2.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedWe have measured the radiative neutron-capture cross section and the total neutron-induced cross section of one of the most important isotopes for the s process, the 25Mg. The measurements have been carried out at the neutron time-of-flight facilities n-TOF at CERN (Switzerland) and GELINA installed at the EC-JRC-IRMM (Belgium). The cross sections as a function of neutron energy have been measured up to approximately 300 keV, covering the energy region of interest to the s process. The data analysis is ongoing and preliminary results show the potential relevance for the s process.Peer reviewe

High-accuracy determination of the neutron flux in the new experimental area n_TOF-EAR2 at CERN

A new high flux experimental area has recently become operational at the n_TOF facility at CERN. This new measuring station, n_TOF-EAR2, is placed at the end of a vertical beam line at a distance of approximately 20m from the spallation target. The characterization of the neutron beam, in terms of flux, spatial profile and resolution function, is of crucial importance for the feasibility study and data analysis of all measurements to be performed in the new area. In this paper, the measurement of the neutron flux, performed with different solid-state and gaseous detection systems, and using three neutron-converting reactions considered standard in different energy regions is reported. The results of the various measurements have been combined, yielding an evaluated neutron energy distribution in a wide energy range, from 2meV to 100MeV, with an accuracy ranging from 2%, at low energy, to 6% in the high-energy region. In addition, an absolute normalization of the n_TOF-EAR2 neutron flux has been obtained by means of an activation measurement performed with 197Au foils in the beam.Peer reviewe

Measurement of 73 Ge(n,γ) cross sections and implications for stellar nucleosynthesis

© 2019 The Author(s). Published by Elsevier B.V.73 Ge(n,γ) cross sections were measured at the neutron time-of-flight facility n_TOF at CERN up to neutron energies of 300 keV, providing for the first time experimental data above 8 keV. Results indicate that the stellar cross section at kT=30 keV is 1.5 to 1.7 times higher than most theoretical predictions. The new cross sections result in a substantial decrease of 73 Ge produced in stars, which would explain the low isotopic abundance of 73 Ge in the solar system.Peer reviewe