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Su, Lin Bo, Jian Hua Chen, and Ying Peng Hu. "The Study of Coded CPM Schemes." Applied Mechanics and Materials 198-199 (September 2012): 1408–12. http://dx.doi.org/10.4028/www.scientific.net/amm.198-199.1408.
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Continuous Phase Modulation (CPM) schemes belong to a class of constant-envelope digital modulation schemes, the constant-envelope nature of the CPM signals makes them robust for the nonlinear and fading channels, and very useful for the satellite and/or the mobile radio channels. Comparing to PSK modulation, CPM modulation can not only provide spectral economy, but also exhibit a “coding gain”. CPM can be decomposed into a Continuous Phase Encoder (CPE) followed by a Memoryless Modulator (MM), this allows many new coded modulation schemes of combination of convolutional encoder and CPM modulator to be possible, such as serially-concatenated CPM (SC-CPM), SC-CPM with Convolutional Codes over Rings, pragmatic CPM (P-CPM), Concatenation of convolutional endocder and extended CE（CCEC）, etc. Some simulations show that these new CPM schemes can offer superior performance.
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Zhang, Lei, Man Ping Tong, and Hong Bo Wang. "Rate-Compatible Punctured Ring Convolutional Coded Continuous Phase Modulation." Applied Mechanics and Materials 195-196 (August 2012): 217–20. http://dx.doi.org/10.4028/www.scientific.net/amm.195-196.217.
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In this paper, continuous phase modulation (CPM) with rate-compatible punctured ring convolutional codes is investigated. Some typical schemes with maximum normalized minimum squared euclidean distance (NMSED) are searched and given. The performance of bit error rate for rate-compatible punctured ring convolutional coded CPM on AWGN channel is simulated, and simulation results show that this system can provide good performance of bit error rate and variable-rate capabilities. Furthermore, simulation results also prove that the transmission efficiency increases when code rate is decreasing.
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Weikert, O., and U. Zölzer. "A wireless MIMO CPM system with blind signal separation for incoherent demodulation." Advances in Radio Science 6 (May 26, 2008): 101–5. http://dx.doi.org/10.5194/ars-6-101-2008.
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Abstract. A multiple-input multiple-output (MIMO) wireless transmission system with continuous phase modulation (CPM) is considered. A novel MIMO CPM receiver with incoherent modulation is presented. The incoherent demodulation of CPM allows an uncomplicated handling of a frequency offset compared to coherent approaches requiring exact knowledge of the carrier frequency. Blind signal separation (BSS) is applied in the proposed MIMO CPM receiver to separate the signals without any knowledge of the MIMO channel. The BSS permits the demodulation of each separated signal by an incoherent CPM demodulator. For bandwidth efficient transmission partial response CPM and non-binary modulation is applied. The applicability of the proposed system is verified by simulation results.
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Shang, Wen Jing, Sheng Guo Zhou, Nan Wang, and Victor Rublev. "Research on the Method of CPM Signal Phase Smoothing Based on Different Power Sine Function." Advanced Materials Research 981 (July 2014): 417–21. http://dx.doi.org/10.4028/www.scientific.net/amr.981.417.
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Continuous phase modulation (CPM) signal has the advantages of high bandwidth efficiency, continuous phase, faster decay speed of power spectrum, constant envelope and so on, which is widely used in communication systems. The degree of the phase smoothing is one of main factors that affect the decay speed of CPM signal power spectrum. One method of smoothing CPM signal phase based on different power sine function as the frequency modulation function is proposed. We draw the phase trajectory of baseband signal and the normalized power spectrum by using the MATLAB software. The spectrum characteristics of the signal generated have great improvement compared with MSK signal, which reach the desired goal.
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Qi, Junwei, Sergey B. Makarov, Mingxin Liu, Beiming Li, and Wei Xue. "Research on an Optimization Method for a Partially Responsive Continuous Phase Modulated (CPM) Signal Based on an Optimal Generic Function." Symmetry 11, no. 9 (September 3, 2019): 1114. http://dx.doi.org/10.3390/sym11091114.
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This paper establishes an optimal generic function model in order to obtain a continuous phase modulated (CPM) signal with a smoother phase modulation function. This is achieved by finding the solution to the symbol signals at different lengths of the CPM function. In the solution process, the unknown amount that needs to be solved is reduced by using the even function symmetry characteristic of the signal to be solved. For each different form of the signal, the time domain form of the CPM function and the corresponding normalized energy spectral density are compared under the influence of the phase modulation signal length and the generic function parameter n. The data transmission rate is improved by introducing inter-symbol interference, and the modulation process is realized using six-way parallel transmission when the CPM function is 6T. The simulation results show that the CPM function obtained by establishing an optimal generic function model has high-quality time-frequency characteristics. The real-time phase trajectory and the high-order derivative are both continuous, and the modulated signal has constant envelope characteristics. The CPM function has a fast rolling-off in the frequency domain and small out-of-band radiation, which greatly improves the characteristics of the frequency band utilization.
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Tasadduq, Imran A. "CPM-GFDM: A Novel Combination of Continuous Phase Modulation and Generalized Frequency Division Multiplexing for Wireless Communication." Applied Sciences 13, no. 2 (January 7, 2023): 854. http://dx.doi.org/10.3390/app13020854.
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In this paper, continuous phase modulation-generalized frequency division multiplexing (CPM-GFDM) is proposed. The performance of CPM-GFDM is evaluated over Gaussian and frequency selective fading channels. In the proposed technique, the mapper in the transmitter and the de-mapper in the receiver of traditional GFDM are replaced by a CPM mapper and de-mapper, respectively. Using Monte-Carlo simulations, the bit error rate performance is evaluated for several rational values of the modulation index. We establish the superiority of CPM-GFDM over traditional GFDM using error performance plots through extensive simulations. We demonstrate that there are several values of the modulation index that give a performance superior to the conventional GFDM, with giving the best performance for additive white Gaussian noise (AWGN) channels, while for the frequency-selective channels the best performance is observed when .
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YANG, Richard Hsin-Hsyong, Chia-Kun LEE, and Shiunn-Jang CHERN. "Continuous Phase Modulation (CPM) Revisited: Using Time-Limited Phase Shaping Pulses." IEICE Transactions on Communications E96.B, no. 11 (2013): 2828–39. http://dx.doi.org/10.1587/transcom.e96.b.2828.
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Dvornikov, Sergey, and Sergey Dvornikov. "Empirical Approach to the Estimating the Immunity of Phase Modulation Signals with Continuous Phase." Informatics and Automation 19, no. 6 (December 11, 2020): 1280–306. http://dx.doi.org/10.15622/ia.2020.19.6.6.
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The high spectral efficiency of signals with continuous phase modulation (CPM) has determined their popularity and active use in various radio engineering projects. The uniqueness of the properties of CPM signals is associated with the preservation of the continuity of their phase when changing information messages for the duration of a symbol. At the same time, until recently, of the entire wide class of signals with continuous phase modulation, the most widespread were various variations, the so-called Minimum Shift Keying (MSK) signals. However, these are far from the only representatives of the class of CPM signals with the property of high spectral compactness. This article examines no less interesting signals of this class, formed by means of Dual Phase Modulation (DPM). In particular, analytical expressions of their synthesis are presented, their belonging to the class of CPM signals is substantiated. In addition, the article investigates the temporal properties of the phase function recommended by ITU-R SM.328-11 for the synthesis of signals with continuous phase modulation, presents the time and frequency fragments of MSK signals in comparison with signals with Binary Phase Shift Keying (BPSK). The stages of the analytical derivation of the model of noise immunity of PCM signals in terms of the probability of a bit error based on an empirical approach are presented. The generality of the obtained model with the known expression for MSK signals is shown by studying the difference function of the approximation error (error of the order of 10-3), which made it possible to obtain a more compact representation of the developed model in relation to DPM signals. It has been proven that DPM signals have higher noise immunity properties in relation to MSK signals (about 0.5 dB at an error level of 10-5), using the results of studying the difference functions determined by the difference between the signal symbols corresponding to the information values "1" and "0". The directions of further research are determined.
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Jarrett, Monica E., Robert J. Shulman, Kevin C. Cain, Wimon Deechakawan, Lynne T. Smith, Philippe Richebé, Margaret Eugenio, and Margaret M. Heitkemper. "Conditioned Pain Modulation in Women With Irritable Bowel Syndrome." Biological Research For Nursing 16, no. 4 (January 24, 2014): 368–77. http://dx.doi.org/10.1177/1099800413520486.
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Evidence suggests that patients with irritable bowel syndrome (IBS) are more vigilant to pain-associated stimuli. The aims of this study were to compare women with IBS ( n = 20) to healthy control (HC, n = 20) women on pain sensitivity, conditioned pain modulation (CPM) efficiency, and salivary cortisol levels before and after the CPM test and to examine the relationship of CPM efficiency with gastrointestinal pain, somatic pain, psychological distress symptoms, and salivary cortisol levels in each group. Women, aged 20–42 years, gave consent, completed questionnaires, and kept a symptom diary for 2 weeks. CPM efficiency was tested with a heat test stimulus and cold water condition stimulus in a laboratory between 8 and 10 a.m. on a follicular phase day. Salivary cortisol samples were collected just before and after the experimental testing. Compared to the HC group, women with IBS reported more days with gastrointestinal and somatic pain/discomfort, psychological distress, fatigue, and feeling stressed. During the CPM baseline testing, women with IBS reported greater pain sensitivity compared to the HC group. There was no significant group difference in salivary cortisol levels nor in CPM efficiency, though a post-hoc analysis showed a higher prevalence of impaired CPM efficiency among IBS subjects with more severe lower-GI symptoms. In the IBS group, reduced CPM efficiency was associated with daily abdominal pain/discomfort and psychological distress. Overall, women with IBS exhibited an increased sensitivity to thermal stimuli. Impaired CPM was present in a subset of women with IBS.
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Zhang, Lei, Bin Hu, Jun Wu, and Zhong Hua Liu. "Complexity Constrained Detection of Continuous Phase Modulation Based on Breadth-First Method." Applied Mechanics and Materials 263-266 (December 2012): 331–34. http://dx.doi.org/10.4028/www.scientific.net/amm.263-266.331.
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This paper solves the problem of high detection complexity of continuous phase modulation (CPM) signals over additive white Gaussian noise (AWGN) channel. A complexity constrained sequence detection method for CPM is provided using breadth-first maximum-likelihood sequence detection. The derived result is to reserve only those states which are closest to the received signal in the Euclidean distance after retain one best path for every state. Compared with the maximum-likelihood detector based on Viterbi Algorithm (VA), a significant reduction in complexity is obtained by the suggested detector while maintaining good performances.
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Trachtman, A., I. Kalet, and S. Shamai. "Limiter-discriminator detection of continuous phase modulation (CPM) Tomlinson filtering." IEEE Transactions on Communications 42, no. 2/3/4 (February 1994): 819–25. http://dx.doi.org/10.1109/tcomm.1994.580181.
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Chiu, Po-Sheng, Kurt Vonmetz, Federico Canini, and H. Paul Urbach. "Investigation of extended depth-of-field f/8 camera with optimized cubic phase mask and digital restoration." EPJ Web of Conferences 238 (2020): 03008. http://dx.doi.org/10.1051/epjconf/202023803008.
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An investigation of extended depth-of-field camera with optimized phase mask and digital restoration is presented. The goal of this paper is to implement the wavefront coding technique without affecting much of the original design, and the design has taken the complexity of imaging system into consideration. The optimized strength of cubic phase mask (CPM) is based on the analytical optimal solution for the task-based imaging system [J. Opt. Soc. Am. A 25, 1064 (2008)]. The noisy intermediate images of CPM system with highest spatial frequency of interest can be effectively restored by vector-based Richardson-Lucy algorithm. Restoration from the system with generalized CPM produces precise image position than the system with CPM does. In general, the CPM system procures modulation transfer function higher than 0.195 in the whole depth-of-field, and the mean squared error of the restored images are less than 5 %.
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Huang, Lian Fen, Tian Li Hu, Zhi Yan Wang, and Wei Ming Lin. "Design and Analysis of a Low Complexity CPM Receiver Based on Differential Soft Decision." Advanced Materials Research 171-172 (December 2010): 495–99. http://dx.doi.org/10.4028/www.scientific.net/amr.171-172.495.
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In this paper, based on the research of the Continuous Phase Modulation (CPM) receiver, we conclude that the coherent demodulation can achieve better frequency efficiency than the non-coherent demodulation, at the cost of higher design complexity. Hence, this paper proposes a novel differential soft decision scheme to reduce the complexity of the CPM receiver. Simulation results show that the proposed scheme can reduce the complexity of the CPM receiver significantly, while causes a slight performance loss
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Tasadduq, Imran A., Mohsin Murad, and Pablo Otero. "CPM-OFDM Performance over Underwater Acoustic Channels." Journal of Marine Science and Engineering 9, no. 10 (October 11, 2021): 1104. http://dx.doi.org/10.3390/jmse9101104.
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We propose and evaluate the performance of a continuous phase modulation based orthogonal frequency division multiplexing (CPM-OFDM) transceiver for underwater acoustic communication (UAC). In the proposed technique, the mapper in traditional OFDM is replaced by CPM while a realistic model of underwater channel is employed. Bit error rate (BER) as well as peak to average power ratio (PAPR) performance of the proposed scheme is evaluated using Monte-Carlo simulations. The error performance observed clearly establishes the superiority of CPM-OFDM over traditional OFDM schemes. Specifically, a value of 7/16 or 9/16 for the modulation index gives the best error performance. Furthermore, the error performance of the proposed scheme is within acceptable values up to a transmitter–receiver distance of 1.5 km. Additionally, the PAPR performance of the proposed scheme suggests that like other OFDM schemes, a PAPR reduction scheme is mandatory for acceptable PAPR performance of CPM-OFDM.
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Haddix, Pryce L. "Associations between cellular levels of ATP and prodigiosin pigment throughout the growth cycle of Serratia marcescens." Canadian Journal of Microbiology 67, no. 9 (September 2021): 639–50. http://dx.doi.org/10.1139/cjm-2020-0619.
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Serratia marcescens is a prolific producer of the red, membrane-associated pigment prodigiosin. Earlier work has established both a positive role for prodigiosin in ATP production during the population lag phase and a negative role during high-rate, low cell density growth. This study uses the growth rate and growth phase modulation afforded by chemostat culture to extend prodigiosin functional analysis to the high-density and stationary phases. Cellular levels of prodigiosin were positively associated with cellular levels of ATP during high-density growth, and artificial pigment induction during this phase increased cellular ATP levels. Following peak high-density ATP per cell, the early stationary phase enabled significant population growth, while prodigiosin levels remained high and ATP declined. During the late stationary phase, ATP per cell was positively associated with prodigiosin per cell, while both declined during continued growth. These results provide correlational evidence for the multiple effects of prodigiosin pigment on ATP production throughout the growth cycle. Earlier work and the data presented here enable the formulation of a working model for the oscillating relationships between cellular levels of ATP and prodigiosin during batch culture.
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Zhou, Ke, Shilian Wang, and Eryang Zhang. "Coherent RAKE Receiver for CPM-Based Direct Sequence Spread Spectrum." Mathematical Problems in Engineering 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/6971083.
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Direct sequence spread spectrum (DSSS) using continuous phase modulation (CPM) inherits the techniques’ benefits, constant envelope, anti-interference, and spectral efficiency. To get diversity gains over a Rayleigh-fading multipath channel as in conventional direct sequence spread-spectrum binary phase shift keying (DSSS-BPSK) system, a new class of coherent RAKE receivers is proposed in this work. By introducing chip branch metric to the receiver scheme, despreading and data detection can be done meanwhile based on Maximum Likelihood Sequence Detection (MLSD). Compared to the conventional RAKE receiver which sums decision metrics symbol-by-symbol, the proposed DSSS-CPM RAKE receiver accumulates symbol branch metric increments over every phase state of multiple paths after chip phase synchronization. Numerical results show that DSSS-CPM using the synchronous despreading and demodulation algorithm has no performance loss compared to CPM system that employs MLSD algorithm under the same test conditions. Moreover, the proposed RAKE receiver outperforms conventional RAKE receiver and achieves a remarkable diversity gain of bit error rate (BER) under the Rayleigh-fading multipath channel.
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Wu, Feiyu, Qianwu Zhang, Qian Xiang, Huihui Yin, and Xiyan Zhang. "Multi-user detection for CPM spread system with turbo in VDES." Journal of Physics: Conference Series 2387, no. 1 (November 1, 2022): 012009. http://dx.doi.org/10.1088/1742-6596/2387/1/012009.
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Abstract The multi-user detection technology uses the spread sequence, delay, amplitude and phase information of each user to jointly detect users, which can effectively suppress multiple access interference, It is one of the key technologies in satellite communication system to make full use of uplink spectrum resources and improve system performance and capacity. Continuous phase modulation spread signal can adapt to multi-user communication due to the random variation of spread sequence, which is gradually applied to satellite communication. QPSK-CPM spread modulation scheme is adopted in the random access channel of VHF data exchange system. Aiming at the multi-user detection problem of QPSK-CPM spread system, proposing a multi-user detection algorithm based on interference elimination joint Turbo iterative detection based on the characteristics of CPM spread sequence. Compared with the traditional serial interference cancellation algorithm, the algorithm can effectively eliminate the multiple access interference problem caused by user aliasing by using the characteristics of Turbo codes. The theoretical simulation shows that the algorithm has a good detection effect on multi-user aliased signals.
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Remlein, Piotr. "Multiuser cpm transmission for mimo systems." Image Processing & Communications 18, no. 4 (December 1, 2013): 59–65. http://dx.doi.org/10.2478/v10248-012-0093-0.
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Abstract Frequency-Division Multiplexed Continuous Phase Modulation (FDM-CPM) systems with Multiple Input Multiple Output (MIMO) transmission are investigated. In this paper, a multiuser reception scheme for CPM MIMO transmission is presented. The analyzed system is designed to achieve high spectral efficiency by exploiting the multiplexing gain of MIMO techniques. To take advantage of the multiplexing gain of MIMO systems, a Zero Forcing (ZF) MIMO detector and a low-complexity iterative algorithm for Inter- Carrier Interference (ICI) cancellation are considered. Numerical simulations have been performed to assess the performance improvement achieved with the proposed frequency-division multiplexed CPM multiuser MIMO system
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Lei, Guo Wei, Yuan An Liu, and Xue Fang Xiao. "Threaded Space Time Code Design for CPM with Joint Decoding." Applied Mechanics and Materials 631-632 (September 2014): 847–50. http://dx.doi.org/10.4028/www.scientific.net/amm.631-632.847.
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In the letter, a system of continuous phase modulation (CPM) with threaded space time codes (TSTC) is proposed for multiple-input multiple-output systems. In the system, source bits are coded via outer coder of Reed Solomon (RS). The codeword of which is suitable for TSTC design. Then inner coder mainly converts binary symbols into M-ary symbols for purpose of CPM. At receiver, Joint soft decoding approach is considered. Finally simulation results are provided for VBLAST, DBLAST, and TSTC as comparison.
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Bing, Li, and Baoming Bai. "Design of Simplified Maximum-Likelihood Receivers for Multiuser CPM Systems." Scientific World Journal 2014 (2014): 1–6. http://dx.doi.org/10.1155/2014/174294.
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A class of simplified maximum-likelihood receivers designed for continuous phase modulation based multiuser systems is proposed. The presented receiver is built upon a front end employing mismatched filters and a maximum-likelihood detector defined in a low-dimensional signal space. The performance of the proposed receivers is analyzed and compared to some existing receivers. Some schemes are designed to implement the proposed receivers and to reveal the roles of different system parameters. Analysis and numerical results show that the proposed receivers can approach the optimum multiuser receivers with significantly (even exponentially in some cases) reduced complexity and marginal performance degradation.
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Azarov, Andrey I., and Evgenyi V. Budarin. "ESTIMATION THE NOISE IMMUNITY OF CONTINUOUS PHASE MODULATION SIGNALS WITH FULL RESPONSE BASED SIMULATION MODEL." T-Comm 15, no. 1 (2021): 52–56. http://dx.doi.org/10.36724/2072-8735-2021-15-1-52-56.
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The problem of spectral load of communication channels is now becoming urgent, which determines the efforts of the world’s leading tech communication companies to search for perspective signals. These signals must ensure compliance with international standards governing the use of frequency bands and the permissible level of out-of-band emissions and the required noise immunity of information transmission. The article deals with the noise immunity of continuous phase modulation signals research. A preliminary estimation is carried out by calculating the Euclidean distances between signals. The estimates of the noise immunity were obtained experimentally. The results of simulation are presented for fixed value of the signal to noise ratio for signals. Modulation indices and phase pulse were taken into account. The results of the study make it possible to emphasize the modulation indices for CPM FR signals, having more noise immunity then the known BPSK and MSK signals. Increasing the noise immunity becomes possible due to intersymbol phase communication. These signals are received according to the Viterbi algorithm. The results of the study show the values of the modulation indices to be of practical interest.
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Xue, Rui, Tong Wang, Yanbo Sun, and Huaiyu Tang. "Optimized Design for NB-LDPC-Coded High-Order CPM: Power and Iterative Efficiencies." Symmetry 12, no. 8 (August 13, 2020): 1353. http://dx.doi.org/10.3390/sym12081353.
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In this paper, a non-binary low-density parity-check (NB-LDPC) coded high-order continuous phase modulation (CPM) system is designed and optimized to improve power and iterative efficiencies. Firstly, the minimum squared normalized Euclidean distance and the 99% double-sided power bandwidth are introduced to design a competitive CPM, improving its power efficiency under a given code rate and spectral efficiency. Secondly, a three-step method based on extrinsic information transfer (EXIT) and entropy theory is used to design NB-LDPC codes, which reduces the convergence threshold approximately 0.42 and 0.58 dB compared with the candidate schemes. Thirdly, an extrinsic information operation is proposed to address the positive feedback issue in iterative detection and decoding and the value of bit error rate (BER) can approximately be reduced by 5×10−3. Finally, iteration optimization employing the EXIT chart and mutual information between demodulation and decoding is performed to achieve a suitable tradeoff for the communication reliability and iterative decoding delay. Simulation results show that the resulting scheme provides an approximately 3.95 dB coding gain compared to the uncoded CPM and achieves approximately 0.5 and 0.7 dB advantages compared with the candidate schemes. The resulting NB-LDPC-coded high-order CPM for a given code rate and spectral efficiency converges earlier into a turbo cliff region compared with other competitors and significantly improves power and iterative efficiencies.
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Xue, Rui, Qing-ming Cao, and Qiang Wei. "A Flexible Modulation Scheme Design for C-Band GNSS Signals." Mathematical Problems in Engineering 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/165097.
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Due to the spectrum congestion of current navigation signals in L-band, C-band has been taken into consideration as a candidate frequency band for global navigation satellite system (GNSS). As is known, modulation scheme is the core part of signal structure, and how to design a modulation waveform that could make full use of narrow bandwidth 20 MHz and satisfy the constraint condition of frequency compatibility in C-band is the main research content of this paper. In view of transmission characteristics and constraint condition of compatibility in C-band, multi-hcontinuous phase modulation (CPM) is proposed as a candidate modulation scheme. Then the classical channel capacity estimation and a comprehensive evaluation criterion for GNSS modulation signals are employed to assess the proposed scheme in the aspects of the capacity over additive white Gaussian noise (AWGN), tracking accuracy, multipath mitigation, antijamming, and so on. Simulation results reveal that, through optimizing the number and size of modulation indexes, the flexible scheme could offer better performance in terms of code tracking, multipath mitigation, and antijamming compared with other candidates such as MSK and GMSK while maintaining high band efficiency and moderate implementation complexity of receiver. Moreover, this paper also provides a reference for next generation modulation signals in C-band.
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Han, Ruigang, Ning Jia, Zhongyuan Guo, Jianchun Huang, Dong Xiao, and Shengming Guo. "Prefiltered Single-Carrier Frequency-Domain Equalization for Binary CPM over Shallow Water Acoustic Channel." Sensors 22, no. 10 (May 18, 2022): 3821. http://dx.doi.org/10.3390/s22103821.
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The continuous phase modulation (CPM) technique is an excellent solution for underwater acoustic (UWA) channels with limited bandwidth and high propagation attenuation. However, the severe intersymbol interference is a big problem for the algorithm applying in shallow water. To solve this problem, an algorithm for prefiltered single-carrier frequency-domain equalization (PF-SCFDE) is presented in this paper. The regular whitening filter is replaced by a prefilter in the proposed algorithm. The output information sequence of this prefilter contains the forward information. To improve the performance, the output of the equalizer, combined with the forward information, is used to make the maximum likelihood estimation. The simulation results with minimum-shift keying and Gaussian-filtered minimum-shift keying signals over shallow water acoustic channels with low root mean square delay spread demonstrate that PF-SCFDE outperformed the traditional single-carrier frequency-domain equalization (SCFDE) by approximately 1 dB under a bit error rate (BER) of 10−4. A shallow sea trial has demonstrated the effectiveness of PF-SCFDE; PF-SCFDE had a reduction in BER of 18.35% as compared to the traditional SCFDE.
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Allen, Christine, Arcadio Poveda, and A. Hernández-Alcántara. "Halo Wide Binaries and Moving Clusters as Probes of the Dynamical and Merger History of our Galaxy." Proceedings of the International Astronomical Union 2, S240 (August 2006): 405–13. http://dx.doi.org/10.1017/s174392130700436x.
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AbstractWide or fragile pairs are sensitive probes of the galactic potential, and they have been used to provide information about the galactic tidal field, the density of GMC and the masses of dark matter perturbers present in both the disk and the halo. Halo wide binaries and moving clusters, since they are likely to be the remains of past mergers or of dissolved clusters, can provide information on the dynamical and merger history of our Galaxy. Such remnants should continue to show similar motions over times of the order of their ages. We have looked for phase space groupings among the low-metallicity stars of Schuster et al (2006) and have identified a number of candidate moving clusters. In several of the moving clusters we found a wide CPM binary already identified in our catalogue of wide binaries among high-velocity and metal-poor stars (Allen et al 2000a). Spectroscopic follow-up studies of these stars would confirm the physical reality of the groups, as well as allow us to distinguish whether their progenitors are dissolved clusters or accreted extragalactic systems.
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Rahimzadegan, Aso, Dennis Arslan, David Dams, Achim Groner, Xavi Garcia-Santiago, Rasoul Alaee, Ivan Fernandez-Corbaton, Thomas Pertsch, Isabelle Staude, and Carsten Rockstuhl. "Beyond dipolar Huygens’ metasurfaces for full-phase coverage and unity transmittance." Nanophotonics 9, no. 1 (November 30, 2019): 75–82. http://dx.doi.org/10.1515/nanoph-2019-0239.
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AbstractMetasurfaces made from densely packed resonant wavelength-scale particles enable abrupt modulation of impinging electromagnetic radiation within an ultrathin surface. Combining duality symmetry of particles and rotational symmetry of their arrangement led to the development of Huygens’ metasurfaces with perfect transmission. However, so far, when identical particles are considered, only their dipolar multipolar contributions are engineered. There, the achievable phase coverage at a fixed wavelength when modifying the period is smaller than 2π, being a clear limitation for applications. To lift such limitation, we consider dipolar-quadrupolar Huygens’ metasurfaces. They consist of scatterers that require a dipolar and a quadrupolar term to capture their response. We show that such metasurfaces offer access to the desired 2π phase coverage while preserving the perfect efficiency when the conditions of duality and symmetry continue to be met. We also propose core-multishell and disk-multiring particles made from realistic materials to meet the requirements and that can be used to build such metasurfaces. Our results are important as a theoretical basis for large-scale fabrications in imaging and integrated optics.
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Mukherjee, Sarbajit, Patrick Boland, Medhavi Gupta, Melissa Grimm, Kristopher Attwood, and Pawel Kalinski. "334 Phase II study evaluating a chemokine-modulatory (CKM) regimen in patients with colorectal cancer (CRC) metastatic to the liver." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A360. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0334.
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BackgroundCRC remains the 2nd most common cause of cancer-related death in the US. Hepatic metastases develop in 20–50% of CRC patients.1 Median overall survival (OS) of patients with metastatic CRC is poor, even with the advent of biologics. A high density of CRC-infiltrating effector cytotoxic T lymphocytes (Teff; CTL) is known to predict long-term outcomes and the responsiveness of tumors to immune checkpoint inhibitors (ICI). In our ex vivo tumor explant models and CRC-bearing experimental animals, the combination of toll-like receptor-3 (TLR3) ligands with interferon (IFN)-α with cyclooxygenase (COX)-2 inhibitors resulted in increased production of Teff attracting chemokines CXCL10 and CCL5, along with suppression of regulatory T cells (Treg) attracting chemokine, CCL22 in the tumor microenvironment.2,3 A combination of all three factors was needed to uniformly elevate the desirable chemokines and counteract CCL22 induction. Based on these studies and on prior clinical safety data, we developed this phase IIa study combining IFNα2b, celecoxib (COX-2 inhibitor) and rintatolimod (selective TLR3 agonist) as a chemokine-modulating (CKM) regimen for CRC patients with unresectable liver-metastatic disease. We aim to study the immunological impact, potential clinical efficacy and safety of this CKM regimen in a non-randomized, single-arm prospective phase II trial.MethodsEligible patients have recurrent/metastatic unresectable CRC with hepatic metastases that are amenable to biopsy. Enrolled patients have prior treatment with or contra-indication to a fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF treatment, and an anti-EGFR targeted therapy (if RAS wt), as well as a PD-1 or PD-L1 targeted drug if MSI-H/dMMR. Patients receive celecoxib (200 mg orally PO BID), IFNα2b IV (20 million units/m2 IV QD), and rintatolimod (200 mg IV QD) on days 1, 2, 3, 8, 9, 10, 15, 16 and 17 in the absence of disease progression or unacceptable toxicity. Response assessment via liver biopsies (pre-treatment and on D20) and CT imaging (RECIST v1.1) on D46. If stable disease/response is demonstrated during repeat CT imaging, patients will continue to follow-up with CT imaging q8 weeks until progression, clinical deterioration, or withdrawal from the study. Primary endpoint assessment compares the change in CD8+ T-cells before treatment, with that seen post-treatment (measured by quantitative RT-PCR and expressed as a ratio of CD8α to a housekeeping gene). Secondary endpoints include objective response rate and safety profile. Subjects are monitored continuously for safety, based on Bayesian analysis. Exploratory endpoints include progression-free survival and overall survival. With a sample size of n=12 evaluable pts, the study design has a 90% power to detect a 0.77 standard deviation increase (pre- to post treatment) at a significance level of 0.1.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov Identifier: NCT03403634.Ethics ApprovalThe study was approved by Roswell Park Comprehensive Cancer Center‘s Institutional Review Board, approval number: MOD00006722/I-52917.ConsentN/AReferencesLahr C.J, et al., A multifactorial analysis of prognostic factors in patients with liver metastases from colorectal carcinoma. J Clin Oncol, 1983. 1(11): p. 720–6.Muthuswamy R, et al. NF-κB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells. Cancer Res. 2012;72(15):3735–3743.Obermajer N, et al. Promoting the accumulation of tumor-specific T cells in tumor tissues by dendritic cell vaccines and chemokine-modulating agents. Nat Protoc13, 335–357 ( 2018).
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Gullander, Maria, Stein Knardahl, and Dagfinn Matre. "Painful heat attenuates electrically induced muscle pain in men and women." Scandinavian Journal of Pain 4, no. 2 (April 1, 2013): 103–8. http://dx.doi.org/10.1016/j.sjpain.2012.04.006.
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AabstractBackground and purposeWomen exhibit higher prevalence of most painful disorders. Several explanations have been proposed for this discrepancy, one being that endogenous pain modulatory pathways, which affect incoming nociceptive signals, act differently in men and women. A less efficient pain inhibitory system has been proposed as a contributing factor to explain why women exhibit higher prevalence of most painful disorders. The present study determined whether muscle pain, induced experimentally by electrical stimulation, is inhibited by a painful heat stimulus. This conditioned pain modulation (CPM) paradigm was used to determine whether women show signs of reduced inhibition compared to men.MethodsForty self-reported healthy individuals (20 female, 20 male) participated in a cross-over design with painful and non-painful heat as a conditioning stimulus. Test stimuli were painful intramuscular electrical stimulation of the tibialis anterior muscle at two intensities; low (1.1 × pain threshold) and high (1.6 × pain threshold). Painful conditioning was contact heat (45–49 ° C) to the contralateral forearm. Nonpainful conditioning was contact heat at 35 °C. Ten test stimuli were delivered in three blocks (before, during and after conditioning) in two sessions (painful and non-painful conditioning). The women were tested during days 12-14 of the menstrual cycle. This interval corresponds to the ovulatory phase of the menstrual cycle, the interval during which women are reported to show the largest inhibitory effects.ResultsTest stimuli were rated significantly lower during painful conditioning, compared with before conditioning. This was found for both low and high test stimulus intensities. Anonspecific attenuation was seen during non-painful conditioning for the low test stimulus intensity. Test stimuli were rated significantly lower also 3 min after conditioning, compared with before conditioning. The inhibitory effects were not different between men and women. Similar findings were obtained also if six non-CPM-responders (subjects rating test stimuli higher during conditioning than before conditioning) were excluded.Conclusions and implicationsThe present findings indicate that painful contact heat inhibits electrically induced muscle pain and that inhibition was not different between men and women, when women were tested in the interval 12-14 days after their last menstruation. Some inhibition of muscle pain was seen during non-painful conditioning, indicating that nonspecific inhibitory effects were triggered. Also the nonspecific inhibitory effects were similar in men and women.
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Youn, Seul Ki, Baskar Pagadala Gopi, Kenneth B. K. Teo, and Hyung Gyu Park. "Role of Gas-phase Reactions and Thermal Gradient Control in Carbon Nanotube Synthesis." MRS Proceedings 1451 (2012): 91–96. http://dx.doi.org/10.1557/opl.2012.1331.
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ABSTRACTWe investigate the role of precursor thermal rearrangement and surface catalytic reactions in the synthesis of vertically aligned carbon nanotubes (VA-CNTs) by acetylene-based, chemical vapor deposition (CVD) and demonstrate a millimeter-long growth of single-walled CNT (SWNT) without water assistance. A substrate heater was used to create an ascending temperature gradient from gas injection to catalyst substrate. Whereas temperature of catalyst substrates primarily determines their catalytic activity, it is a thermal condition of a gaseous mixture in the CVD chamber that also influence growth yield and structural features of as-grown CNTs. Employing Egloff’s characterization, [1] we discuss the importance of various gas thermal zones in producing high-quality nanotubes with augmented growth efficiency. We continue to report production of millimeter-long, VA-SWNT having a mean diameter of 1.7 ± 0.7 nm, catalyzed by iron on an alumina support. Important finding is that a million of aspect ratio of SWNT arrays can be produced, without water assistance, via combined action of an ascending temperature gradient toward catalyst substrate and low partial pressures of acetylene carbon feedstock. Our results do not only emphasize the role of precursor thermal rearrangement in CNT synthesis, but also offer a practical route to the modulation of such complex phenomena for an ultrahigh-yield growth of narrow VA-SWNT.
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Abbas Omran, Khalida. "The Construct and Interpretation of Chelated Coordination Polymers and Their Use in Nanomaterials Research." Journal of Environmental and Public Health 2022 (August 10, 2022): 1–13. http://dx.doi.org/10.1155/2022/3937375.
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Presently, an important step from basic research to practical applications is synthesizing nanostructured materials. Metal-organic structures, as well as coordination polymers, are a diverse group of materials with a wide range of potential and properties applications. It has been difficult to get these materials into commercial use because of many drawbacks. Polymers containing chelated units are described and assessed for their advancements and problems in preparation, properties, and structure. Here, a proposed approach based on designing coordination polymeric materials with chelated units using the metal-ligand approach (CPM-CU-MA) has been introduced for a columnar-layered plan, supramolecular components, and building levels. Nanocomposite materials can be formed through the thermal transformation of coordination polymers based on donor atoms. The polymeric metal chelates (PMCs) are categorized according to luminescent coordination polymer (LCoP) development. It is classified as macrocyclic intracomplex, polynuclear, and molecular according to its macrostructure. Supramolecular networks (SMNs) can be transformed into a coordination polymer by introducing cyclo-dehydrogenation of natural building blocks on a surface. The structure-property connections of LCPs can influence a framework of liquid crystal display (LCP) that has been given based on LC phase modulators with a large modulation depth and has useful applications in LC lens. In the spatial organization of PMCs, the main focus is on the commonalities and contrasts between higher- and lower-molecular-weight chelates based on molecularly imprinted sensors (MISs) and nanomaterial sensors for a wide range of uses. New functional nanoparticles based on the molecular components have exciting potential, as demonstrated by these findings based on parameters risk factors for human health, hazards reduction in the environment, lack of cost-effectiveness, environmental sustainability, and bioavailability of polymers with an overall performance of 95.3%.
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van Vollenhoven, Ronald F., Edward Clark Keystone, Vibeke Strand, Cesar Pacheco-Tena, Jiří Vencovský, Frank Behrens, Arthur Racewicz, et al. "Efficacy and safety of tregalizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase IIb, randomised, placebo-controlled trial." Annals of the Rheumatic Diseases 77, no. 4 (January 17, 2018): 495–99. http://dx.doi.org/10.1136/annrheumdis-2017-212478.
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ObjectiveTo evaluate the efficacy, biological activity and safety of tregalizumab in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX).Methods321 patients were randomised (1:1:1:1) to placebo or tregalizumab 25, 100 or 200 mg once-weekly subcutaneously in addition to MTX treatment. Responders at week 12 continued the same treatment, and non-responders at week 12 were escalated to the next higher tregalizumab dose level or re-randomised from placebo to active treatment. After 24 weeks, patients could continue treatment with tregalizumab for 24 weeks (extension phase). The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Safety and biological activity were monitored through week 48.ResultsAt week 12, ACR20 response rates were not statistically significantly different between placebo and any of the tregalizumab doses. Tregalizumab injections were well tolerated; most adverse events were mild to moderate and comparable among treatment and placebo groups. Biological activity was shown by dose-dependent CD4 downmodulation.ConclusionTreatment with tregalizumab did not show significant clinical efficacy in patients with active RA compared with placebo but resulted in the expected biological effect on CD4 modulation. Tregalizumab was generally well tolerated, and no new safety findings were identified.Trial registration numberNCT01999192; Results.
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Luo, XianGang, Fei Zhang, MingBo Pu, YingHui Guo, Xiong Li, and XiaoLiang Ma. "Recent advances of wide-angle metalenses: principle, design, and applications." Nanophotonics 11, no. 1 (December 2, 2021): 1–20. http://dx.doi.org/10.1515/nanoph-2021-0583.
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Abstract Optical imaging systems, like microscopes, cameras, and telescopes, continue to expand the scope of human observation of the world. As one of the key indicators of imaging systems, the field-of-view (FOV) is often limited by coma aberration. Expanding it generally relies on a combination of complex lenses, leading to a bulky and cumbersome system. Recently, the emergency of meta-optics provides an alternative to constructing compact and lightweight large-FOV metalens through elaborated phase modulation within a flat surface, showing great potential in surveillance, unmanned vehicles, onboard planes or satellites, medical science, and other new applications. In this article, we review recent advances of wide-angle metalenses, including operation principles, design strategies, and application demos. Firstly, basic principles of wide-angle imaging using a single metalens are interpreted. Secondly, some advanced methods for designing subwavelength structures with high angle robustness and high efficiency are discussed. Thirdly, some representative functional devices and applications are surveyed. Finally, we conclude with an outlook on future potentials and challenges that need to be overcome.
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Bendell, Johanna C., Scott Kopetz, Mark R. Middleton, P. Taylor Eves, Viviana Bozon, Adam P. Boyd, and Jan H. M. Schellens. "Phase 1b/2 study of binimetinib (BINI) in combination with nivolumab (NIVO) or NIVO plus ipilimumab (IPI) in patients (pts) with previously treated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) with RAS mutation." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): TPS870. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.tps870.
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TPS870 Background: Approximately 96% of CRCs have an MSS phenotype, which results in more immunologically quiescent tumors for which immunotherapies are largely ineffective (Lee et al. 2015; Overman et al. 2016). Pts with MSS CRC and activating RAS mutation (35%–45% of CRCs) have treatment options limited still further because anti-EGFR monoclonal antibodies (eg, cetuximab) are ineffective owing to dominant activation of RAS in the MAPK pathway (Douillard et al. 2014). However, preclinical and preliminary clinical data suggest that MAPK pathway inhibition enhances antigen presentation and T-cell cytotoxicity to positively modulate the efficacy of checkpoint inhibitors (Brea et al. 2016; Bendell et al. 2014). The main objective of this open-label multicenter phase 1b/2 study is to evaluate whether the potential positive modulation of NIVO or NIVO plus IPI, when combined with BINI, translates into clinically meaningful overall response in pts with MSS mCRC and RAS mutation. Methods: The study will enroll ~90 previously treated pts (1 or 2 prior regimens), ~42 in phase 1b and ~48 in phase 2. The primary objective of phase 1b will be to determine the recommended phase 2 dose (RP2D) of BINI in combination with NIVO ± IPI. Dose finding in the doublet arm will begin with BINI 45 mg BID + NIVO 480 mg Q4W; the triplet arm will begin with the BINI RP2D from the doublet arm + NIVO 480 mg Q4W + IPI 1 mg/kg Q8W. In phase 2, pts will be randomized 1:1 to doublet or triplet arms, incorporating the BINI RP2Ds found in phase 1b; treatment will continue in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, loss to follow-up, or death. The primary objective for phase 2 will be to assess response by RECIST version 1.1. The study will also characterize safety and PK. CT.gov Identifier: Clinical trial information: NCT03271047.
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Cutler, Corey S., Daniel Shoemaker, Peter Westervelt, Daniel R. Couriel, Sumithra Vasu, Luis M. Isola, Chatchada Karanes, et al. "Ex Vivo Pharmacologic Modulation in a Nutrient-Rich Medium to Accelerate Engraftment of Human Umbilical Cord Blood." Blood 124, no. 21 (December 6, 2014): 3807. http://dx.doi.org/10.1182/blood.v124.21.3807.3807.
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Abstract Umbilical cord blood (UCB) offers many potential advantages as a source of hematopoietic stem cells (HSCs) for allogeneic transplantation, including ease of collection, rapid availability, flexibility of HLA-matching, lower rates of GvHD and potentially lower relapse rates. However, the low HSC content of UCB compared to other graft sources results in a prolonged time to engraftment, and higher rates of graft failure and early mortality. Pulse ex vivo exposure of HSCs to 16,16-dimethyl PGE2 (FT1050) has been demonstrated to enhance HSC engraftment potential, which could benefit clinical UCB transplant. FT1050 modulation promotes multiple mechanisms, including increased proliferation, reduced apoptosis, and improved migration and homing [North 2007&2009; Hoggatt 2009]. Improved HSC homing is mediated by induction of CXCR4 gene expression leading to increased cell surface CXCR4. Further optimization of the UCB modulation process demonstrated that incubation with 10µM FT1050 for 2 hrs at 37C resulted in a maximal biological response of the FT1050-UCB (ProHema®). A Phase 1 trial was performed to evaluate the safety of FT1050-UCB paired with an unmanipulated UCB unit in reduced-intensity double UCBT (dUCBT) [Cutler 2013]. We observed durable, multi-lineage engraftment of FT1050-UCB with acceptable safety. Earlier neutrophil engraftment was observed relative to historical controls (median 17.5 vs. 21 days (historical control), p=0.045), coupled with preferential engraftment of the FT1050-UCB unit in 10 of 12 subjects. A Phase 2 multi-center clinical trial of FT1050-UCB in adult patients undergoing dUCBT for hematologic malignancies was then initiated. Subjects are randomized 2:1 to FT1050-UCB-containing vs. standard dUCBT after high-dose conditioning. The primary endpoint is a categorical analysis of neutrophil engraftment using a pre-specified control median. Data on the initial 11 subjects, of which 8 were randomized to receive FT1050-UCB, continue to demonstrate acceptable safety with adverse events attributed to FT1050-UCB limited primarily to common infusion-related side effects. Of the 8 FT1050-UCB subjects, 1 died prior to neutrophil engraftment, with the remaining 7 subjects engrafting at a median of 28 days vs. 31 days for the 3 control subjects. With median overall follow-up of 16.1 months, 4 of 8 subjects on the FT1050-UCB arm are alive with a median survival not reached (> 11.0 months). 1 of 3 control subjects is alive with median survival of 6.0 months. During the clinical translation process, the media used during FT1050 modulation of UCB was identified as a key variable. Standard UCB washing media, consisting of a nutrient-free saline solution of low molecular weight dextran and human serum albumin (LMD/HSA), is used clinically to stabilize fragile cells post-thaw by reducing lysis. This media was used in the Phase 1 trial and to initiate Phase 2. Early during the Phase 2 trial, we identified a novel cell-stabilizing nutrient-rich formulation (NRM), containing glucose, amino acids and other HSC-supporting nutrients that promoted full FT1050 modulation of UCB and increased cell viability. The expression of key FT1050-pathway genes was significantly higher with NRM compared to intermediate levels observed with LMD/HSA. Modulation of human CD34+ (hCD34+) cells with FT1050 in NRM led to an 8-fold increase over LMD/HSA in induced CXCR4 gene expression (20-fold total), which translated to significantly increased surface CXCR4 protein. In vivo homing models demonstrated that UCB CD34+ cells modulated with FT1050 in NRM resulted in a 2.2-fold homing increase relative to vehicle (p < 0.001) compared to a 1.6-fold increase with LMD/HSA (p = 0.002), with a significant difference between the two media conditions (p = 0.04). A xenotransplantation study in NSG mice with hCD34+ cells modulated with FT1050 in either NRM or LMD/HSA demonstrated a 2-fold increase in circulating hCD45+ cells 12-weeks post-transplant with NRM (p = 0.007; unpaired t-test). These findings supported the incorporation of NRM into the FT1050-UCB manufacturing process in order to further improve its clinical engraftment potential. Enrollment of a 60-patient Phase 2 trial has been initiated that incorporates this manufacturing change. Disclosures Shoemaker: Fate Therapeutics: Employment, Equity Ownership. Rezner:Fate Therapeutics: Employment. Guerrettaz:Fate Therapeutics: Employment. Robbins:Fate Therapeutics: Employment. Medcalf:Fate Therapeutics: Employment. Wolchko:Fate Therapeutics: Employment, Equity Ownership. Ferraro:Fate Therapeutics: Employment. Multani:Fate Therapeutics: Employment.
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Bussiere, Luke D., and Cathy L. Miller. "Reovirus and the Host Integrated Stress Response: On the Frontlines of the Battle to Survive." Viruses 13, no. 2 (January 28, 2021): 200. http://dx.doi.org/10.3390/v13020200.
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Cells are continually exposed to stressful events, which are overcome by the activation of a number of genetic pathways. The integrated stress response (ISR) is a large component of the overall cellular response to stress, which ultimately functions through the phosphorylation of the alpha subunit of eukaryotic initiation factor-2 (eIF2α) to inhibit the energy-taxing process of translation. This response is instrumental in the inhibition of viral infection and contributes to evolution in viruses. Mammalian orthoreovirus (MRV), an oncolytic virus that has shown promise in over 30 phase I–III clinical trials, has been shown to induce multiple arms within the ISR pathway, but it successfully evades, modulates, or subverts each cellular attempt to inhibit viral translation. MRV has not yet received Food and Drug Administration (FDA) approval for general use in the clinic; therefore, researchers continue to study virus interactions with host cells to identify circumstances where MRV effectiveness in tumor killing can be improved. In this review, we will discuss the ISR, MRV modulation of the ISR, and discuss ways in which MRV interaction with the ISR may increase the effectiveness of cancer therapeutics whose modes of action are altered by the ISR.
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Bai, Zhihong, and Yifei Li. "Unified Strategy for Fault-Tolerant Operation of MMC with Multiple SMs Failure Based on SMs Grouping Management." Energies 15, no. 15 (August 5, 2022): 5694. http://dx.doi.org/10.3390/en15155694.
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Modular multilevel converter (MMC) is distinguished by its modularity. In order to improve its reliability and avoid unscheduled maintenance, it requires the MMC to continue operating even though some of its submodules (SMs) have failed. In this paper, a grouping management method of SMs in MMC is first presented where every six SMs are conceptually grouped into a virtual subunit (SU), and on this basis, a simplified space vector modulation (SVM) implementation is developed. Then, the fault-tolerant solutions are proposed by investigating the post-fault operation of the MMC based on the virtual SU concept. It is analyzed that the SU failures can be categorized into three basic types, according to the phase where the failed SMs are located, and also multiple SM failures can be decomposed into one or multiple basic fault types. In this way, the fault-tolerant solutions are unified regardless of the number of faulty SMs. Further, the sorting capacitor voltage control is combined into the proposed methods to balance all of the SM capacitor voltages. With the proposed fault-tolerant method, the amplitude and THD of the line voltages are almost unchanged under fault conditions when compared with normal operations. The simulation and experiment verify the propositions.
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Berry, Neil, Monja Stein, Deborah Ferguson, Claire Ham, Jo Hall, Elaine Giles, Sarah Kempster, Yemisi Adedeji, Neil Almond, and Carolina Herrera. "Mucosal Responses to Zika Virus Infection in Cynomolgus Macaques." Pathogens 11, no. 9 (September 12, 2022): 1033. http://dx.doi.org/10.3390/pathogens11091033.
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Zika virus (ZIKV) cases continue to be reported, and no vaccine or specific antiviral agent has been approved for the prevention or treatment of infection. Though ZIKV is primarily transmitted by mosquitos, cases of sexual transmission and prolonged viral RNA presence in semen have been reported. In this observational study, we report the mucosal responses to sub-cutaneous and mucosal ZIKV exposure in cynomolgus macaques during acute and late chronic infection. Subcutaneous challenge induced a decrease in the growth factor VEGF in colorectal and cervicovaginal tissues 100 days post-challenge, in contrast to the observed increase in these tissues following vaginal infection. This different pattern was not observed in the uterus, where VEGF was upregulated independently of the challenge route. Vaginal challenge induced a pro-inflammatory profile in all mucosal tissues during late chronic infection. Similar responses were already observed during acute infection in a vaginal tissue explant model of ex vivo challenge. Non-productive and productive infection 100 days post-in vivo vaginal challenge induced distinct proteomic profiles which were characterized by further VEGF increase and IL-10 decrease in non-infected animals. Ex vivo challenge of mucosal explants revealed tissue-specific modulation of cytokine levels during the acute phase of infection. Mucosal cytokine profiles could represent biosignatures of persistent ZIKV infection.
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Elks, Philip M., Fredericus J. van Eeden, Giles Dixon, Xingang Wang, Constantino Carlos Reyes-Aldasoro, Philip W. Ingham, Moira K. B. Whyte, Sarah R. Walmsley, and Stephen A. Renshaw. "Activation of hypoxia-inducible factor-1α (Hif-1α) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model." Blood 118, no. 3 (July 21, 2011): 712–22. http://dx.doi.org/10.1182/blood-2010-12-324186.
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Abstract The oxygen-sensing transcription factor hypoxia-inducible factor-1α (HIF-1α) plays a critical role in the regulation of myeloid cell function. The mechanisms of regulation are not well understood, nor are the phenotypic consequences of HIF modulation in the context of neutrophilic inflammation. Species conservation across higher metazoans enables the use of the genetically tractable and transparent zebrafish (Danio rerio) embryo to study in vivo resolution of the inflammatory response. Using both a pharmacologic approach known to lead to stabilization of HIF-1α, and selective genetic manipulation of zebrafish HIF-1α homologs, we sought to determine the roles of HIF-1α in inflammation resolution. Both approaches reveal that activated Hif-1α delays resolution of inflammation after tail transection in zebrafish larvae. This delay can be replicated by neutrophil-specific Hif activation and is a consequence of both reduced neutrophil apoptosis and increased retention of neutrophils at the site of tissue injury. Hif-activated neutrophils continue to patrol the injury site during the resolution phase, when neutrophils would normally migrate away. Site-directed mutagenesis of Hif in vivo reveals that hydroxylation of Hif-1α by prolyl hydroxylases critically regulates the Hif pathway in zebrafish neutrophils. Our data demonstrate that Hif-1α regulates neutrophil function in complex ways during inflammation resolution in vivo.
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Baljevic, Muhamed, and Sarah A. Holstein. "Present and Future of Immunotherapy in the Management of Multiple Myeloma." Journal of Oncology Practice 14, no. 7 (July 2018): 403–10. http://dx.doi.org/10.1200/jop.18.00111.
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Multiple myeloma (MM) is the second most common hematologic malignancy with an increasing incidence and prevalence. The wide array of effective antimyeloma agents have transformed MM into a chronic condition for some patients, requiring long-term management planning. Immunomodulatory drugs and proteasome inhibitors have played a pivotal role in defining the most effective regimens for both transplantation-eligible and transplantation-ineligible subgroups. Nevertheless, recent approvals of immunotherapies in MM such as daratumumab have added another important component to combination treatments for both relapsed or refractory and newly diagnosed disease. Evolving novel therapies such as chimeric antigen receptor T cells are poised to raise the bar even further, holding a promise of effective treatment option for patients who would otherwise have limited treatment alternatives. As we continue to therapeutically exploit the essential roles of cell-mediated immune surveillance, antigen presentation, and modulation of inhibitory surface signaling, we are rapidly establishing the cornerstone role of immunotherapies in the management of all phases of MM. In this review, we will cover the spectrum of available immunotherapies approved for clinical use in MM, as well as briefly describe those in early- and late-phase development, with the focus of raising the awareness of the expanding immuno-oncology armamentarium in MM.
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Linden, Hannah M., Brenda F. Kurland, Jeanne Link, Vijayakrishna K. Gadi, Jennifer M. Specht, Julie Gralow, Erin K. Schubert, Lanell Peterson, Janet F. Eary, and David A. Mankoff. "Vorinostat to restore sensitivity to aromatase inhibitor therapy in metastatic breast cancer: A phase II clinical trial with ER imaging correlates." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): TPS3109. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.tps3109.
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TPS3109 Background: Endocrine refractory,Indolent, soft tissue, and bone dominant metastatic breast cancer is a clinical problem, for which alternatives to chemotherapy are needed, Histone deacetylace inhibitors (HDACi) have shown pre-clinical promise in estrogen receptor-modulation and restoring sensitivity to endocrine manipulation, suggesting potential clinical benefit. HDACi restore ER expression in ER-negative cells which are then sensitive to AI treatment in xenografts (Sabnis 2011) and are toxic to ER-positive cell lines (Huang 2000). Vorinostat is an FDA approved HDACi for CTCL, and could have a beneficial role in restoring ER-signaling in endocrine-resistant tumors. We hypothesized that HDACi therapy could restore sensitivity to aromatase inhibitor (AI) therapy, in patients with prior progression on AI, and allow continued endocrine therapy. Recent data suggest clinical benefit of Tamoxifen and vorinostat given continuously (Munster 2011) as well as entinostat and an AI (Yardley 2011). Our prior work has shown the feasibility of monitoring regional ER expression and ER-estrogen binding in vivo using [F-18]fluoroestradiol (FES) PET imaging (Linden 2011) providing a biomarker to interrogate the molecular target. Methods: Patients with metastatic breast cancer with prior clinical benefit from endocrine manipulation who progressed on AI therapy are eligible. Patients must be off ER blocking therapies, and functionally postmenopausal. Baseline FES and FDG PET are performed and patients receive investigational vorinostat treatment at 400 mg po BID for 2 weeks followed by serial FES and FDG PET to assess the impact of vorinostat on ER expression and tumor metabolism. Patients are retreated on their prior AI as a single agent for 6 weeks, followed by paired FES and FDG and clinical assessment. Patients with clinical benefit may continue on treatment: 2 weeks of vorinostat followed by 6 weeks of AI in 8-week cycles until progressive disease or toxicity. We have enrolled 4 of a planned 20 patients.
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Alexeeva, Vera, Dmitry Borovikov, Mark W. Miller, Steven C. Rosen, and Elizabeth C. Cropper. "Effect of a Serotonergic Extrinsic Modulatory Neuron (MCC) on Radula Mechanoafferent Function in Aplysia." Journal of Neurophysiology 80, no. 4 (October 1, 1998): 1609–22. http://dx.doi.org/10.1152/jn.1998.80.4.1609.
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Alexeeva, Vera, Dmitry Borovikov, Mark W. Miller, Steven C. Rosen, and Elizabeth C. Cropper. Effect of a serotonergic extrinsic modulatory neuron (MCC) on radula mechanoafferent function in Aplysia. J. Neurophysiol. 80: 1609–1622, 1998. The serotonergic metacerebral cells (MCCs) and homologous neurons in related mollusks have been extensively investigated within the context of feeding. Although previous work has indicated that the MCCs exert widespread actions, MCC modulation of sensory neurons has not been identified. We characterized interactions between the MCCs and a cell that is part of a recently described group of buccal radula mechanoafferents. The cell, B21, has a peripheral process in the tissue underlying the chitinous radula [the subradula tissue (SRT)]. Previous studies have shown that B21 can fire phasically during ingestive motor programs and provide excitatory drive to the circuitry active during radula closing/retraction. We now show that activity of B21 can be modulated by serotonin (5-HT) and the MCCs. Centrally, although a slow depolarization is typically recorded in B21 as a result of MCC stimulation, this depolarization does not cause B21 to spike. It can, however, increase B21 excitability enabling a pulse that was previously subthreshold to elicit an action potential in B21. B21 is in fact rhythmically depolarized during the radula closing/retraction phase of ingestive motor programs. Thus central effects of the MCCs on radula mechanoafferent activity are only likely to be apparent while B21 is receiving input from the feeding central pattern generator. Peripherally, radula mechanoafferent neurons can be activated 1) when a mechanical stimulus is applied to the biting surface of the SRT and 2) when the SRT contracts. MCC stimulation and 5-HT modulate B21 responses to both types of stimuli. For example, MCC stimulation and low concentrations of 5-HT cause subthreshold mechanical stimuli applied to the SRT to become suprathreshold. 5-HT and MCC stimulation also enhance SRT contractility. Peripheral effects of MCC activity are also likely to be phase dependent. For example, MCC stimulation does not cause B21 to respond to peripheral stimuli with an afterdischarge. Consequently, radula mechanoafferents are likely to be activated when food is present between the radula halves during radula closing/retraction but are not likely to continue to fire as opening/protraction is initiated. In a similar vein, MCC effects on the contractility of the SRT will only be apparent when contractions are elicited by motor neuron activity. SRT motor neurons are rhythmically activated during ingestive motor programs. Thus we have shown that radula mechanoafferent activity can be modulated by the MCCs and that this modulation is likely to occur in a phase-dependent manner.
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Arthur, Connie M., Amanda Mener, Seema Patel, Lilian Cataldi Rodrigues, Carol Xue, Robert Sheppard Nickel, James C. Zimring, Jeanne E. Hendrickson, and Sean R. Stowell. "Reticuloendothelial Saturation Dictates the Development of RBC Resistance to Antibody-Mediated Clearance Following Incompatible Transfusion." Blood 124, no. 21 (December 6, 2014): 1559. http://dx.doi.org/10.1182/blood.v124.21.1559.1559.
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Abstract Background: Immune-mediated destruction of red blood cells (RBCs) normally occurs following incompatible transfusion, however some RBCs may remain in circulation after initial cellular clearance despite the presence of RBC specific antibodies. Recent studies suggest that antibody-induced “antigen-modulation” may in part be responsible for this cellular resistance to antibody-mediated removal following the initial phase of RBC clearance. However, the factors that dictate whether cells undergo clearance or antigen modulation immediately following incompatible RBC transfusion remain unknown. As previous studies suggest that reticuloendothelial phagocytic capacity is sometimes surpassed upon engagement and removal of antibody-opsonized cells, we hypothesized that rapid change in the phagocytic burden of reticuloendothelial cells may contribute to the development of RBC resistance following incompatible RBC transfusion. Methods: Anti-Fy3 immunized or non-immunizedC57BL/6 recipient mice were first transfused with HOD.FVB RBCs expressing the HEL, OVA and Duffy chimeric antigen (HOD), followed by a second HOD.FVB RBC transfusion at various time intervals following the initial transfusion. Following transfusion, mice were evaluated at 10 min, 1h, 2h and 4h post-transfusion for HOD.FVB RBC survival, detectable HOD antigen, and RBC bound antibody by flow cytometric analysis. To examine the potential impact of RBC age on the sensitivity of HOD.FVB to antibody-induced clearance, HOD.FVB mice were injected with N-hydroxysulfosuccinimide (NHS) biotin 35 days prior to RBC isolation, to aid in differentiation of older from younger transfused RBCs, and then likewise transfused into anti-Fy3 immunized or non-immunizedC57BL/6 recipients and similarly evaluated for clearance, bound antibody and detectable antigen on biotin positive or negative transfused cells using flow cytometric analysis. Results: While HOD.FVB RBCs transfused into anti-Fy3-immunized C57BL/6 recipients displayed a rapid clearance following the initial transfusion, the degree of HOD.FVB RBC clearance significantly decreased following secondary transfusions that occurred within 2 hours of the initial transfusion. However, 2 days following the initial transfusion, recipients cleared HOD.FVB RBCs at the same rate as immunized recipients not previously exposed to HOD.FVB RBCs. Examination of the HOD antigen and bound antibody demonstrated that antigen levels likewise displayed the most significant decreases during the same time period in which RBC clearance decreased. Removal of HOD RBCs during the initial clearance phase did not appear to reflect preferential clearance of older RBCs, as transfused biotinylated and non-biotinylated RBCs harvested 1 day or 35 days following biotinylation displayed equal levels of antibody-induced clearance. Conclusion: Alterations in recipient clearance capacity following incompatible RBC exposure suggests that rapid phagocytic removal of RBCs may temporarily staturate the reticuloendothelial system immediately following RBC transfusion. However, antigen modulation appears to continue even while congestion of the reticuloendothelial system has halted RBC clearance. RBCs that escape the initial wave of clearance appear to become protected from antibody-mediated removal once the phagocytic capability of the recipient is restored, as the level of detectable antigen has dropped below that required for triggering phagocytic removal. The initial phase of clearance does not appear to reflect preferential clearance of older RBCs within the transfused units, but instead likely reflects stochastic removal of antibody bound RBCs, as RBC clearance occurred independent of RBC age. Disclosures No relevant conflicts of interest to declare.
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Daud, A., M. Schmitt, D. Marchion, E. Bicaku, S. Minton, M. Egorin, J. Zwiebel, A. Chiappori, D. Sullivan, and P. Munster. "Phase I trial of a sequence-specific combination of the HDAC inhibitor, vorinostat (SAHA) followed by doxorubicin in advanced solid tumor malignancies." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 3502. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.3502.
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3502 Background: Preclinical cell culture and xenograft studies suggest that pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) may potentiate topoisomerase (topo) inhibitors. The HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. Methods: This Phase I trial explores the safety, tolerability and maximum tolerated dose (MTD) of a weekly schedule of escalating vorinostat doses (twice daily days 1–3) followed by doxorubicin (20 mg/m2) on day 3 (3 out of 4 weeks). Histone acetylation and topo II expression are evaluated in pre-and post-vorinostat peripheral blood mononuclear cells and in tumor cells of the 30 patients treated at the MTD. Results: To date, 15 patients [median age 54 (38–73)] have been treated in 4 vorinostat cohorts: 200, 300, 400, 500 mg bid. Tumor types included: breast (3), melanoma (3), pancreatic (2) and one each of SCLC, sarcoma, endometrial, colon, prostate, renal cell and bladder cancer. Dose-limiting toxicities included a grade 3 thrombocytopenia (1/6) at the 400 mg bid dose. Non-dose limiting Grade 3 and 4 toxicities include neutropenia, thrombocytopenia, fatigue, pulmonary embolus, and anemia (1 pt each). Currently, vorinostat doses of 500 mg bid are being evaluated. One confirmed partial response in a breast cancer patient, as well as minor responses in a melanoma and a prostate cancer patient were seen in 10 evaluable patients. Patients received a median number of 2 (1–9+) treatment cycles. Doxorubicin is stopped after 6 cycles and patients continue on vorinostat alone. H3 and H4 histone acetylation and topo II expression will be correlated with vorinostat dose, plasma concentration and response. Conclusion: A sequence-specific combination of vorinostat and doxorubicin is active without exacerbation of doxorubicin toxicity. The tolerated vorinostat dose exceeds the proposed single agent dose for vorinostat derived from patients with hematological malignancies. Histone hyperacetylation occurs in peripheral blood mononuclear cells at all levels. The anti-tumor activity in breast cancer and melanoma will be further explored. No significant financial relationships to disclose.
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Ingham, Matthew, Shing Mirn Lee, Sahil Doshi, Susana Hernandez, Shahnaz V. Singh-Kandah, Zoe Singer, Ovidiu C. Trifan, and Gary K. Schwartz. "A phase II trial with safety lead-in to evaluate the addition of APX005M, a CD40 agonistic monoclonal antibody, to standard-of-care doxorubicin chemotherapy for the treatment of advanced soft tissue sarcoma." Journal of Clinical Oncology 38, no. 5_suppl (February 10, 2020): TPS85. http://dx.doi.org/10.1200/jco.2020.38.5_suppl.tps85.
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TPS85 Background: Soft tissue sarcoma (STS) is a biologically heterogeneous disease for which existing immunotherapy approaches (e.g. anti-PD-1) have shown limited clinical activity. Cytotoxic chemotherapy with doxorubicin (D), an anthracycline, remains standard-of-care treatment for most advanced STS. Combining chemotherapy with immunomodulatory treatments may enhance antigen presentation and favorably impact the immune microenvironment (iME). APX005M (Apexigen; San Carlos, CA) is a novel CD40 agonistic antibody. Preclinically, CD40 ligation plus chemotherapy induced expression of costimulatory and major histocompatibility complex molecules on antigen presenting cells (APCs), shifted the myeloid compartment towards an M1 phenotype and expanded T-cell receptor clonality, which are characteristics in which the sarcoma iME is deficient (2,3). In phase 1, APX005M showed dose-dependent activation of APCs in peripheral blood and favorable tolerability. We designed a phase II study evaluating D+A as a novel combination for STS. Methods: This is a single-arm, open-label, Simon 2 stage phase II study with safety lead-in evaluating D+A among 27 patients with STS. Pts have advanced STS (excluding GIST and Kaposi sarcoma) for which doxorubicin is appropriate and any prior lines of therapy, including none. Pts receive D 75 mg/m2 and A 0.3 mg/m2 IV day 1 in 21 day cycles. Doxorubicin is stopped after cycle 8 but APX005M may continue. The primary endpoint is the objective response rate (ORR). The study design has power of 85% to show an improvement in ORR from 10% (inactive) to 30% (active) with α = 0.04. Secondary endpoints include PFS and safety. Pts undergo collection of stool specimens at baseline and cycle 3 to evaluate composition of the gut microbiome including effects on clinical outcomes and modulation of microbiome by treatment. Pts undergo paired tumor biopsies at baseline and cycle 2 which are evaluated with gene expression and multiplex immunohistochemistry to evaluate effects of D+A on iME. The study opened in 1/2019. Clinical trial information: NCT03719430.
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Reddy, Neha K., Niamh Coleman, and Vivek Subbiah. "Trends in early phase clinical trials: A tale of exponential economic growth and access." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e18504-e18504. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e18504.
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e18504 Background: There has been exponential economic growth in the BRIC (Brazil, Russia, India and China) nations in recent years, and outsourcing of clinical trials to these countries has occurred in tandem. Our study aimed to assess the current status of early phase oncology clinical trial recruitment in the BRIC countries, to assess the impact of these emerging economies and global markets in health care. Methods: We reviewed the open-access clinical trial registry, clinicaltrials.gov, for registered interventional recruiting early phase trials (Phase I/II) in the BRIC countries in adults and analyzed each country separately and collectively. We extracted descriptive data and established a database and proceeded to perform literature review and examine trends in early phase clinical trials. Results: We identified 888 recruiting early phase clinical trials in BRIC countries; China had 95% (842/888) of the trials, Brazil 1.5% (13/888), Russia 3.4% (30/888) and India 0.34% (3/888). For tumor specific studies, gastrointestinal (17%, 148/888), lung 11% (94/888) and breast (17%, 53/888) cancers were the most studied. Most trials were industry-sponsored (76%, 675/888); and most conducted in a single country (95%, 846). Industry-sponsored studies comprised 96% in China (635/842), 87% in Russia (26/30), 92% in Brazil (12/13), 67% (2/3) in India. Overall, immunotherapy agents in single and combination treatment strategies were the most common agent under investigation, with novel therapies such as CAR T-cell therapy (eg. CAR-T/TCR NK-CAR CAR-T/TCR-T Cell) being increasingly used in China (168 single agent trials, 30 trials in combination: 24% of trials in China). In contrast, CAR T-cell therapy trials were not yet in BRIC nations outside of China. Combination studies were frequent (33%, 293/888), and included a variety of combination strategies utilizing targeted therapies, immunotherapies, chemotherapies, antibody drug conjugates and novel biologics. Conclusions: Despite the economic explosion and shift of non-oncology clinical trials to BRIC nations, US and Europe continue to dominate in the design and conduct of early phase clinical trials in hematology and oncology. However, there has been exponential growth in early phase trial testing in China, which now accounts for 18.5% of the world’s population and has the majority (95%) of trials in BRIC nations. Contrastingly, India, which accounts for 17.7% of world’s population, has < 1% of BRIC nation trials. In keeping with trends in the US and Europe, there is a dominance of industry-sponsored studies in BRIC countries. Globally, early phase trials are increasing in their complexity with ongoing interest in immune modulation as a treatment strategy.
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Desantes, Kenneth, John M. Maris, Kimberly McDowell, Crystal Mackall, Sadhna Shankar, Jim Vasselli, Francine Chen, et al. "A phase 1, open-label, dose escalation study of enoblituzumab (MGA271) in pediatric patients with B7-H3-expressing relapsed or refractory solid tumors." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): TPS2596. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps2596.
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TPS2596 Background: Enoblituzumab, is an Fc optimized humanized IgG1 monoclonal antibody that binds to B7-H3 (CD276), a member of the B7 family. It is Fc-engineered to enhance effector function including antibody dependent cellular cytotoxicity (ADCC). IHC analyses with the parental anti-B7H3 mAb specificity incorporated in enoblituzmab revealed limited B7-H3 expression in normal tissues but high expression in many cancers (Loo et al., 2012). Among pediatric solid tumors, high expression of B7-H3 has been reported in neuroblastoma, rhabdomyosarcoma, osteosarcoma, Wilms tumor, Ewing’s sarcoma and desmoplastic small round cell tumor. B7-H3 overexpression correlates with poor prognosis in a broad range of cancers in adults suggesting a potential role in enabling tumor immune escape. ADCC and potential modulation of T cell function resulting in enhanced antitumor immune response are presumed mechanisms of action of enoblituzumab. Methods: This is an open-label, dose escalation / cohort expansion phase 1 study (NCT02982941) designed to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of enoblituzumab in children and young adults with B7-H3-expressing relapsed or refractory malignant solid tumors. A 3+3 design is used in escalating dose cohorts of weekly intravenous (IV) enoblituzumab starting at 10 mg/kg. Response is first determined at 8 weeks. irRECIST is used for response assessment for patient management. Enoblituzumab may continue up to 2 years based on response. Cohort expansion phase, to further define the safety and initial antitumor activity of enoblituzumab, will start after maximum tolerated dose is determined. The patients are assigned to 1 of 5 cohorts based on disease type as follows: 1) neuroblastoma - measurable disease, 2) neuroblastoma - non-measurable disease, 3) rhabdomyosarcoma, 4) osteosarcoma, and 5) Ewing’s sarcoma, Wilms’ tumor and desmoplastic small round cell tumors. Enrollment is ongoing. Ref : Development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent antitumor activity. Loo D, Alderson RF, Chen FZ, Huang L et al. Clin Cancer Res. 2012; 18:3834-45. Clinical trial information: NCT02982941.
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MILLER, R. S., and J. BELLAN. "Direct numerical simulation of a confined three-dimensional gas mixing layer with one evaporating hydrocarbon-droplet-laden stream." Journal of Fluid Mechanics 384 (April 10, 1999): 293–338. http://dx.doi.org/10.1017/s0022112098004042.
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Direct numerical simulations are performed of a confined three-dimensional, temporally developing, initially isothermal gas mixing layer with one stream laden with as many as 7.3×105 evaporating hydrocarbon droplets, at moderate gas temperature and subsonic Mach number. Complete two-way phase couplings of mass, momentum and energy are incorporated which are based on a thermodynamically self-consistent specification of the vapour enthalpy, internal energy and latent heat of vaporization. Effects of the initial liquid mass loading ratio (ML), initial Stokes number (St0), initial droplet temperature and flow three-dimensionality on the mixing layer growth and development are discussed. The dominant parameter governing flow modulation is found to be the liquid mass loading ratio. Variations in the initial Stokes number over the range 0.5[les ]St0[les ]2.0 do not cause significant modulations of either first- or second-order gas phase statistics. The mixing layer growth rate and kinetic energy are increasingly attenuated for increasing liquid loadings in the range 0[les ]ML[les ]0.35. The laden stream becomes saturated before evaporation is completed for all but the smallest liquid loadings owing to: (i) latent heat effects which reduce the gas temperature, and (ii) build up of the evaporated vapour mass fraction. However, droplets continue to be entrained into the layer where they evaporate owing to contact with the relatively higher-temperature vapour-free gas stream. The droplets within the layer are observed to be centrifuged out of high-vorticity regions and to migrate towards high-strain regions of the flow. This results in the formation of concentration streaks in spanwise braid regions which are wrapped around the periphery of secondary streamwise vortices. Persistent regions of positive and negative slip velocity and slip temperature are identified. The velocity component variances in both the streamwise and spanwise directions are found to be larger for the droplets than for the gas phase on the unladen stream side of the layer; however, the cross-stream velocity and temperature variances are larger for the gas. Finally, both the mean streamwise gas velocity and droplet number density profiles are observed to coincide for all ML when the cross-stream coordinate is normalized by the instantaneous vorticity thickness; however, first-order thermodynamic profiles do not coincide.
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Hashimoto, Yusuke, Makoto Ueno, Maki Tanaka, and Masafumi Ikeda. "Results from phase I study of the oncolytic viral immunotherapy agent canerpaturev (C-REV) in combination with gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 325. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.325.
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325 Background: Canerpaturev (C-REV, formerly HF10) is an oncolytic, spontaneous mutant Herpes Simplex Virus type 1, and is one of immunotherapies that combine direct tumor cell killing with immune modulation. The purpose of this study is to determine the recommended dose of C-REV in combination with chemotherapy (Gemcitabine + Nab-paclitaxel; G-nP) in Japanese patients with stage III or IV unresectable pancreatic cancer. We report the safety and antitumor activity data of this study. Methods: This study was a “3 + 3” design with a 2-dose escalation scheme evaluating 2 doses of C-REV. The subjects received C-REV at 1x106 or 1x107 TCID50/mL (up to 2mL, depending on tumor size) intratumorally by EUS-guidance at a 2-week interval in addition to 1000 mg/m2 gemcitabine and 125 mg/m2 nab-paclitaxel by intravenous infusion on days 1, 8, and 15 of a 4-week cycle. The study treatment could continue up to 1 year if eligible for injection. The primary endpoint was Dose Limiting Toxicity (DLT); the secondary endpoints were adverse events (AEs) assessed per NCI CTCAE v4.0, Best Overall Response Rate (BORR) at 16-week by RECIST and progression-free survival. Results: Six patients (pts) were enrolled and treated: 33% (2/6) men, age range 63 to 72 yrs, disease stage 33% III, 66% IV. Of 6 safety evaluable pts, no DLTs were reported. 16% (1/6) pt(s) had C-REV-related ≥ G3 AE, and it was acute pancreatitis (G3). G-nP-related ≥ G3 AEs observed in more than 2 pts were neutropenia (50%), and the majority of ≥ G3 AEs were similar as the AEs previously reported in G-nP therapy. As of 01 Sep 2018, of the 6 efficacy evaluable pts, BORR at 16-week was 66% (4 PR). Disease control rate was 100% (2 SD), and 1 of 2 SD pts continues the study treatment. We will present the updated data. Conclusions: The recommended dose was determined as 1x107 TCID50/mL. The combination of C-REV and the standard chemotherapy demonstrated a favorable benefit/risk profile and encouraging antitumor activity in Japanese patients with unresectable pancreatic cancer. Clinical trial information: NCT03252808.
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London, Cheryl, Luis feo Bernabe, Sandra Barnard, William Kisseberth, Antonella Borgatti, Michael Henson, Heather Wilson, et al. "Evaluation Of The Novel, Orally Bioavailable Selective Inhibitor Of Nuclear Export (SINE) Verdinexor (KPT-335) In Spontaneous Canine Cancer: Results Of Phase I and Phase II Clinical Trials." Blood 122, no. 21 (November 15, 2013): 5149. http://dx.doi.org/10.1182/blood.v122.21.5149.5149.
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Abstract SINE (Selective Inhibitors of Nuclear Export) block the activity of XPO1/CRM1, 1 of 7 nuclear export proteins in cells, forcing the nuclear retention of key tumor suppressor proteins (TSP), leading to selective apoptosis of tumor cells. The purpose of these studies was to evaluate the in vitro activity of SINE against canine tumor cell lines and investigate the biological activity of Verdinexor (KPT-335) in dogs with spontaneous cancers as proof of principle for human clinical studies with SINE. Several different canine tumor cell lines including those derived from Non-Hodgkin Lymphoma (NHL) exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE; NHL cells were particularly sensitive with IC50 concentrations ranging from 2-42 nM. A Phase I clinical trial of Verdinexor was performed in dogs with cancer with an emphasis on NHL given in vitro activity demonstrated against the tumor cell lines. The maximum tolerated dose (MTD) was 1.75 mg/kg twice per week although biological activity was observed at 1 mg/kg. Clinical benefit including Partial Response (PR) and Stable Disease (SD) for at least 4 weeks was observed in 9/14 dogs with NHL with a median time to progression of 66 days (range 35-256). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg Verdinexor on a Monday/Wednesday/Friday (MWF) regimen; clinical benefit (PR + SD) was observed in 4/6 dogs with a median time to progression of 83 days (range 35-250+). Toxicities were primarily gastrointestinal in nature consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care and dose modulation. A validated health related Quality of Life (QOL) form used to assess dogs during treatment demonstrated that the overall quality of life did not decrease in dogs in this study supporting the notion that clinical toxicities associated with Verdinexor are generally well tolerated. Based on these findings, a Phase IIb study was performed in 58 dogs with either newly diagnosed or relapsed NHL. Drug was administered initially at 1.5 mg/kg MWF, but this dosing regimen was changed to 1.25 mg/kg M/Th due to the high rate of anorexia and weight loss on the MWF regimen; dose escalation was permitted to 1.5 mg/kg on the M/Th regimen. The objective response rate was 34% (1 CR, 19 PR) with an additional 33 dogs experiencing SD for a minimum of 4 weeks, resulting in a of 91% disease control rate. While the median time to progression was approximately 5 weeks, 19 dogs (32%) remained on study drug for >8 weeks; several dogs continue to receive Verdinexor. Laboratory abnormalities were minimal and clinical toxicities were mild on the M/Th regimen. Together, these data provide robust evidence that the novel orally bioavailable XPO1 inhibitor Verdinexor exhibits single agent biological activity in a spontaneous large animal model of human NHL. Furthermore, Verdinexor was well tolerated even in the absence of supportive care, suggesting that SINE compounds could exhibit good long-term tolerability in people. Disclosures: London: Zoetis: Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; Abbott: Honoraria. Modiano:Karyopharm: Research Funding. Saint-Martin:Karyopharm: Employment. McCauley:Karyopharm : Employment, Equity Ownership, Patents & Royalties. Shacham:Karyopharm : Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc.: Employment.
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Myint, Han, Linjie Tian, Jahangheer Shaik, Emilia Barbu, Qinjie Zhou, Aaron Morawski, Hasan Abukharma, et al. "487 NC410, a fusion protein of LAIR-2 (Leukocyte Associated Immunoglobulin-like Receptor) with human IgG1 Fc, is safe & tolerable with evidence of immune modulation in subjects with advanced solid tumors." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A516—A517. http://dx.doi.org/10.1136/jitc-2021-sitc2021.487.
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BackgroundCollagen and C1q in the extracellular matrix (ECM), are the predominant ligands for LAIR-1, an inhibitory receptor expressed on the cell surface of several immune cell subsets that inhibits immune activation and migration. LAIR-2, a soluble homolog of LAIR-1, competes for binding to collagen and C1q and serves as a natural decoy to promote immune function under normal conditions. Dysregulation of the ECM and increased expression of collagen and C1q within the tumor microenvironment (TME) plays a critical role in promoting tumor progression. NC410 was engineered to overcome this highly immunosuppressive environment by blocking LAIR-1 function, reversing immune suppression, and inducing ECM remodeling to promote immune cell infiltration within the TME.MethodsThis is a first in human, phase 1/2, open-label, single-armed dose-escalation study to determine the safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose, preliminary efficacy and to explore pharmacodynamic biomarkers of NC410 (figure 1). Key eligibility criteria include subjects with advanced or metastatic solid tumors with measurable disease based on RECIST v1.1.ResultsAs of 07/22/2021, a total of 16 patients have been enrolled, treated, and completed the DLT period. NC410 (up to 60 mg), was well tolerated, with no safety concerns, infusion-related toxicities, or DLT reported. No anti-drug antibody (ADA) was detected post-NC410 up to 60 mg treatment. As expected, the C1Q level decreased immediately after the NC410 infusion and was replenished after two hours. Evaluation from samples to date available up to cycle 5 suggests that there was no reduction in the baseline C1Q level with subsequent dosing (figure 2). LAIR-2 levels continued to increase in a dose-dependent fashion post-NC410 dosing and marginal increase pre-dose (figure 3). Interestingly, we observed an increase in soluble LAIR-1 over time in a similar pattern to LAIR-2 (figure 4). Furthermore, immunophenotyping of patient whole blood suggests a trend towards an increase in CD4+ and CD8+ T cells including LAIR-1+ T cells in cohort 4, although overall expression levels of LAIR-1 did not appear to increase (ongoing analysis). Cytokines, chemokines, and collagen degradation products (CDP) will be evaluated as potential pharmacodynamic biomarkers as we continue through higher dose cohorts.Abstract 487 Figure 1NC410: study schemaAbstract 487 Figure 2C1Q levels show immediate reduction after NC410 dosing with no accumulated depletionAbstract 487 Figure 3LAIR-2 levels show an increase in dose-dependent fashion after NC410 dosing with marginal increase pre-doseAbstract 487 Figure 4Soluble LAIR-1 levels show a similar pattern to LAIR-2 levelsConclusionsPreliminary evaluation of NC410 in subjects with advanced or metastatic solid tumors appears to be safe and well-tolerated with evidence of immune modulation consistent with predictive PK/PD modeling in a Phase 1/2 open-label study. Further evaluation will be done with increasing doses to confirm these initial findings.Trial RegistrationNCT04408599Ethics ApprovalThis study has been approved by the IRB of all the participating institutions, and all participants have given informed consent before taking part in the study.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.