ALBERT

Description: Introduction: A better understanding in the role of the B-cell receptor-signaling pathway in lymphomagenesis led to the clinical development of ibrutinib is an orally bioavailable Bruton's tyrosine kinase inhibitor (BTKi). Ibrutinib has clinical activity in several subtypes of B-cell lymphoma (follicular lymphoma, mantle cell lymphoma and certain diffuse large B-cell lymphoma [DLBCL] subtypes). Recently, an increasing number of ibrutinib-treated patients are developing disease progression, stressing the need to optimize its therapeutic potential. To this end, we evaluated the biological effects and interactions of ibrutinib and CFZ, a non-reversible proteasome inhibitor in several lymphoma pre-clinical models including primary tumor cells isolated from lymphoma patients. Methods: A panel of rituximab-sensitive (RSCL) and rituximab-resistant (RRCL) cell lines as well as primary tumor cells isolated from B-cell lymphoma patients (N=20) were exposed to ibrutinib and/or CFZ. Changes in cell viability were evaluated by Presto Blue and Titer Glo assays respectively. Coefficient of synergy was determined using the CalcuSyn software. To further study the mechanisms responsible for the biological effects of ibrutinib and CFZ, RSCL and RRCL were exposed to Ibrutinib+/- CFZ for 48hr. Changes in apoptosis, mitochondrial potential, and cell cycle distribution were evaluated by flow cytometry by AnnexinV-PI, DiOC6 or PI staining respectively. Subsequently, protein lysates were isolated from ibrutinib+/- CFZ exposed RSCL or RRCL and changes in downstream targets (PKCδ a member of diacylglycerol-dependent, calcium-independent serine/threonine-specific protein kinases PKC isoform know to be a substrate of caspase 3 and able to mediate apoptosis), Bcl-2 family members and cell cycle regulatory proteins were evaluated by Western blotting. Results: In vitro exposure of RSCL, RRCL, and primary tumor cells to ibrutinib and CFZ resulted in synergistic anti-tumor activity. In addition, the combination of ibrutinib and CFZ resulted in a more pronounced decrease in the mitochondrial potential, higher degree of apoptosis (as demonstrated by flow cytometry and caspase 3 or PARP cleavage) and increase in G1 cell cycle arrest when compared to single agent ibrutinib or CFZ. Perhaps related to these findings, we found that exposure of lymphoma cells to Ibrutinib and CFZ resulted in an increase in caspase 3, the active form of PKCδ and BAX levels. Using caspase inhibitor Q-VD-OPh rescued the combination killing effect of ibrutinib and CFZ, as well as abrogated induction of the active form of PKCδ. In addition, Ibrutinib in combination with CFZ decreased cyclin E and CDK2 levels. Conclusions: Together our data suggests that ibrutinib and CFZ had a strong synergistic anti-tumor activity against rituximab-chemotherapy sensitive and resistant lymphoma cells and patient samples. At the molecular level, the combination of ibrutinib and CFZ affects the balance of the apoptotic machinery and key regulatory proteins of the cell cycle that could play an important role in the synergistic effects observed. Further signaling and in vivo studies are necessary to evaluate the therapeutic role of ibrutinib in combination with carfilzomib in B-cell lymphoma (Research, in part, supported by a NIH grant R01 CA136907-01A1 awarded to Roswell Park Cancer Institute and The Eugene and Connie Corasanti Lymphoma Research Funds). Disclosures Czuczman: MorphoSys: Consultancy; Celgene: Employment; Immunogen: Other: Advisory board; Boehringer-Ingelheim: Other: Advisory Board.

Description: Windows are a significant path for structure-borne and air-borne noise transmission in general aviation aircraft. In this paper, numerical and experimental results are used to evaluate damped plexiglas windows for the reduction of structure-borne and air-borne noise transmitted into the interior of an aircraft. In contrast to conventional homogeneous windows, the damped plexiglas windows were fabricated using two or three layers of plexiglas with transparent viscoelastic damping material sandwiched between the layers. Transmission loss and radiated sound power measurements were used to compare different layups of the damped plexiglas windows with uniform windows of the same nominal thickness. This vibro-acoustic test data was also used for the verification and validation of finite element and boundary element models of the damped plexiglas windows. Numerical models are presented for the prediction of radiated sound power for a point force excitation and transmission loss for diffuse acoustic excitation. Radiated sound power and transmission loss predictions are in good agreement with experimental data. Once validated, the numerical models were used to perform a parametric study to determine the optimum configuration of the damped plexiglas windows for reducing the radiated sound power for a point force excitation.

Description: Windows are a significant path for structure-borne and air-borne noise transmission into aircraft. To improve the acoustical performance, damped windows were fabricated using two or three layers of plexiglas with transparent viscoelastic damping material sandwiched between the layers. In this paper, numerical and experimental results are used to evaluate the acoustic benefits of damped windows. Tests were performed in the Structural Acoustic Loads and Transmission Facility at NASA Langley Research Center to measure the transmission loss for diffuse acoustic excitation and radiated sound power for point force excitation. Comparisons between uniform and damped plexiglas windows showed increased transmission loss of 6 dB at the first natural frequency, 6 dB at coincidence, and 4.5 dB over a 50 to 4k Hz range. Radiated sound power was reduced up to 7 dB at the lower natural frequencies and 3.7 dB over a 1000 Hz bandwidth. Numerical models are presented for the prediction of radiated sound power for point force excitation and transmission loss for diffuse acoustic excitation. Radiated sound power and transmission loss predictions are in good agreement with experimental data. A parametric study is presented that evaluates the optimum configuration of the damped plexiglas windows for reducing the radiated sound power.

Description: The validation of finite element and boundary element model for the vibro-acoustic response of a curved honeycomb core composite aircraft panel is completed. The finite element and boundary element models were previously validated separately. This validation process was hampered significantly by the method in which the panel was installed in the test facility. The fixture used was made primarily of fiberboard and the panel was held in a groove in the fiberboard by a compression fitting made of plastic tubing. The validated model is intended to be used to evaluate noise reduction concepts from both an experimental and analytic basis simultaneously. An initial parametric study of the influence of core thickness on the radiated sound power from this panel, using this numerical model was subsequently conducted. This study was significantly influenced by the presence of strong boundary condition effects but indicated that the radiated sound power from this panel was insensitive to core thickness primarily due to the offsetting effects of added mass and added stiffness in the frequency range investigated.

Description: A method to intended for measurement of the insertion loss of an acoustic treatment applied to an aircraft fuselage in-situ is documented in this paper. Using this method, the performance of a treatment applied to a limited portion of an aircraft fuselage can be assessed even though the untreated fuselage also radiates into the cabin, corrupting the intensity measurement. This corrupting noise in the intensity measurement incoherent with the panel vibration of interest is removed by correlating the intensity to reference transducers such as accelerometers. Insertion loss of the acoustic treatments is estimated from the ratio of correlated intensity measurements with and without a treatment applied. In the case of turbulent boundary layer excitation of the fuselage, this technique can be used to assess the performance of noise control methods without requiring treatment of the entire fuselage. Several experimental studies and numerical simulations have been conducted, and results from three case studies are documented in this paper. Conclusions are drawn about the use of this method to study aircraft sidewall treatments.

Description: A sonic boom simulator at NASA Langley Research Center has been constructed for research on human response to low-amplitude sonic booms heard indoors. Research in this facility will ultimately lead to development of a psychoacoustic model for single indoor booms. The first subjective test was designed to explore indoor human response to variations in sonic boom rise time and amplitude. Another goal was to identify loudness level variability across listener locations within the facility. Finally, the test also served to evaluate the facility as a laboratory research tool for studying indoor human response to sonic booms. Subjects listened to test sounds and were asked to rate their annoyance relative to a reference boom. Measurements of test signals were conducted for objective analysis and correlation with subjective responses. Results confirm the functionality of the facility and effectiveness of the test methods and indicate that loudness level does not fully describe indoor annoyance to the selected sonic boom signals.

Description: A facility has been constructed at NASA Langley Research Center to simulate the soundscape inside residential houses that are exposed to environmental noise from aircraft. This controllable indoor listening environment, the Interior Effects Room, enables systematic study of parameters that affect psychoacoustic response. The single-room facility, built using typical residential construction methods and materials, is surrounded on adjacent sides by two arrays of loudspeakers in close proximity to the exterior walls. The arrays, containing 52 subwoofers and 52 mid-range speakers, have a usable bandwidth of 3 Hz to 5 kHz and sufficient output to allow study of sonic boom noise. In addition to these exterior arrays, satellite speakers placed inside the room are used to augment the transmitted sound with rattle and other audible contact ]induced noise that can result from low frequency excitation of a residential house. The layout of the facility, operational characteristics, acoustic characteristics and equalization approaches are summarized.

Description: A sonic-boom simulator at NASA Langley Research Center has been constructed to research the indoor human response to low-amplitude sonic booms. The research goal is the development of a psychoacoustic model for individual sonic booms to be validated by future community studies. The study in this report assessed the suitability of existing noise metrics for predicting indoor human annoyance. The test signals included a wide range of synthesized and recorded sonic-boom waveforms. Results indicated that no noise metric predicts indoor annoyance to sonic-boom sounds better than Perceived Level, PL. During the study it became apparent that structural vibrations induced by the test signals were contributing to annoyance, so the relationship between sound and vibration at levels of equivalent annoyance has been quantified.

Description: Human response to sonic booms heard indoors is affected by the generation of contact-induced rattle noise. The annoyance caused by sonic boom-induced rattle noise was studied in a series of psychoacoustics tests. Stimuli were divided into three categories and presented in three different studies: isolated rattles at the same calculated Perceived Level (PL), sonic booms combined with rattles with the mixed sound at a single PL, and sonic booms combined with rattles with the mixed sound at three different PL. Subjects listened to sounds over headphones and were asked to report their annoyance. Annoyance to different rattles was shown to vary significantly according to rattle object size. In addition, the combination of low-amplitude sonic booms and rattles can be more annoying than the sonic boom alone. Correlations and regression analyses for the combined sonic boom and rattle sounds identified the Moore and Glasberg Stationary Loudness (MGSL) metric as a primary predictor of annoyance for the tested sounds. Multiple linear regression models were developed to describe annoyance to the tested sounds, and simplifications for applicability to a wider range of sounds are presented.

Description: Sandwich honeycomb composite panels are lightweight and strong, and, therefore, provide a reasonable alternative to the aluminum ring framelstringer architecture currently used for most aircraft airframes. The drawback to honeycomb panels is that they radiate noise into the aircraft cabin very efficiently provoking the need for additional sound treatment which adds weight and reduces the material's cost advantage. A series of honeycomb panels were made which incorporated different design strategies aimed at reducing the honeycomb panels' radiation efficiency while at the same time maintaining its strength. The majority of the desi gns were centered around the concept of creatin g areas of reduced stiffness in the panel by adding voids and recesses to the core. The effort culminated with a reinforced./recessed panel which had 6 dB higher transmission loss than the baseline solid core panel while maintaining comparable strength.