Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated. We biologically characterized a novel ZNF767-BRAF fusion found in a vemurafenib-refractory respiratory tract PMM, from which cell line harboring ZNF767-BRAF fusion were established for further molecular analyses. In an independent data set, NFIC-BRAF fusion was identified in an oral PMM case and TMEM178B-BRAF fusion and DGKI-BRAF fusion were identified in two malignant melanomas with a low mutational burden (number of mutation per megabase, 0.8 and 4, respectively). Subsequent analyses revealed that the ZNF767-BRAF fusion protein promotes RAF dimerization and activation of the MAPK pathway. We next tested the in vitro and in vivo efficacy of vemurafenib, trametinib, BKM120 or LEE011 alone and in combination. Trametinib effectively inhibited tumor cell growth in vitro, but the combination of trametinib and BKM120 or LEE011 yielded more than additive anti-tumor effects both in vitro and in vivo in a melanoma cells harboring the BRAF fusion. In conclusion, BRAF fusions define a new molecular subset of PMM that can be targeted therapeutically by the combination of a MEK inhibitor with PI3K or cyclin-dependent kinase 4/6 inhibitors.

This paper describes an analytical and experimental investigation into the active control of harmonic sound transmission in a structural-acoustic coupled system. A rectangular enclosure is considered that has five acoustically rigid walls and a flexible plate on the remaining side through which a harmonic sound wave is transmitted into the enclosure. The control system is designed to globally reduce the sound field inside the enclosure, and the roles of structural and acoustic actuators are of particular interest. Three control configurations, classified by the type of actuators, are compared and discussed. They are: (i) use of a single point-force actuator, (ii) use of a single acoustic piston source, and (iii) simultaneous use of both a point-force actuator and an acoustic piston source. It is shown both analytically and experimentally that the point-force actuator is effective in controlling plate-dominated modes while the acoustic source is effective in controlling cavity-dominated modes. Since the transmitted sound field is governed by both plate- and cavity-dominated modes, the hybrid use of both types of actuators is shown to be a desirable configuration for the active control of sound transmission into a structural-acoustic coupled system.

In-head localization of sound images is a critical problem in headphone reproduction. The paper investigates the degree of externalization in terms of the distance of auditory images for various synthesis and reproduction cases. An effective binaural headphone system was constructed by way of binaural synthesis using head-related impulse responses and individual headphone equalization using Wiener filter theory. The headphone system designed had an average reproduction performance error of 2.4% for five subjects with a random noise input, and was used to perform some subjective tests with a set of virtual sources equally spaced and distanced from the center of each subject's head in the horizontal plane. The effects of individual and nonindividual binaural syntheses and those of equalized and nonequalized reproductions were separately investigated. In the tests, each subject was instructed to indicate the distance of auditory images. The results obtained demonstrate that individual equalization is important for externalization, and individual synthesis is important for consistent distance perception. Thus, a combined use of both individual equalization and individual synthesis resulted in externalized sound images of a consistent distance.

Two modal control techniques, negative position feedback (NPF) and positive position feedback (PPF), are applied to reduce multi-mode vibration of a lightly damped flexible beam using a piezoelectric sensor and piezoelectric actuators. The NPF and PPF controllers are constructed by respectively feeding back the generalized displacement response from the sensor in a negative and a positive sense to the actuators through second order high pass and low pass filters. PPF is well known while NPF is new for this application and is in fact an electrical realization of a dynamic vibration absorber. The choice of the parameters for controllers of both types is made easy by a robust modal control technique that offers an optimal performance for NPF control and a near-optimal performance for PPF control. Explicit forms of the controller parameters are presented. Experiments are conducted on a cantilever beam embedded with a matched pair of PZT (lead zirconate titanate) patch actuators and a collocated PVDF (polyvinylidene fluoride) patch sensor. The experiments demonstrate that it is possible to realize an electrical dynamic absorber using the generalized displacement sensor. It is further demonstrated that NPF can be a good alternative control strategy particularly when multiple modes are to be controlled.

Abstract-This paper describes a theoretical and experimental study to show how an electrical damper or an electrical dynamic absorber, implemented using an electromagnetic actuator and an accelerometer, can control vibration transmission through a vibration isolator. The electrical damper is realized by feeding back the equipment velocity to the actuator with constant gain. The electrical dynamic absorber is realized by feeding back the equipment acceleration through a second-order low-pass filter. Because it is found that the plant on a flexible base is asymptotically similar to that on a rigid base, the optimal parameters of the control filter are determined analytically, independent of the base dynamics. Experimental results show that the electrical dynamic absorber has a similar performance to the electrical damper. The maximum reduction in transmitted vibration achieved was about 38 dB for both methods. It is also shown that the electrical dynamic absorber is more robust to undesirable dynamics outside the control bandwidth. Another advantage of the electrical dynamic absorber is that it does not require an integrator to transform acceleration into velocity.Index Terms-Acceleration-position feedback (APF), direct velocity feedback (DVFB), electrical damper, electrical dynamic absorber, vibration control.