Mutant-Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug-Resistant Mutations

Targeting epidermal growth factor receptor (EGFR) through an allosteric mechanism provides a potential therapeutic strategy to overcome drug-resistant EGFR mutations that emerge within the ATP binding site. Here, we develop an allosteric EGFR degrader, DDC-01-163, which can selectively inhibit the proliferation of L858R/T790M (L/T) mutant Ba/F3 cells while leaving wildtype EGFR Ba/F3 cells unaffected. DDC-01-163 is also effective against osimertinib-resistant cells with L/T/C797S and L/T/L718Q EGFR mutations. When combined with an ATP-site EGFR inhibitor, osimertinib, the anti-proliferative activity of DDC-01-163 against L858R/T790M EGFR-Ba/F3 cells is enhanced. Collectively, DDC-01-163 is a promising allosteric EGFR degrader with selective activity against various clinically relevant EGFR mutants as a single agent and when combined with an ATP-site inhibitor. Our data suggests that targeted protein degradation is a promising drug development approach for mutant EGFR.     

Nanoscale retention‐loss dynamics of polycrystalline PbTiO3 nanotubes

We observed the nanoscale retention dynamics of polycrystalline PbTiO₃ nanotubes using piezoresponse force microscopy. We found that the retention loss of the nanodot domains on the nanotubes showed the stretched exponential relaxation behaviors with stretched exponential factor n being less than 1 (0.523 and 0.692), which are similar to the thin films. In addition, the nanodot domains showed a diverse relaxation time constant τ due to different remnant polarization of each dot domains. (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Observation of mechanical fracture and corresponding domain structure changes of polycrystalline PbTiO3 nanotubes

PbTiO₃ (PTO) nanotubes (NTs) were synthesized at various temperatures by gas phase reaction between PbO gas and anatase TiO₂ NTs and characterized by piezoresponse force microscopy (PFM). PTO ferroelectric phase was synthesized at as low as 400 °C as evidenced by PFM domain images and piezoresponse hysteresis loop measurement. Furthermore, the PTO NTs fabricated at above 500 °C underwent mechanical fracture through development of nanocracks due to grain growth, leading to ferroelectric domains with larger size and lower aspect ratio. (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Evaluation of the dosimetric characteristics of a radiophotoluminescent glass dosimeter for high-energy photon and electron beams in the field of radiotherapy

We aimed to evaluate the suitability of a glass dosimeter (GD) for high-energy photon and electron beams in experimental and clinical use, especially for radiation therapy. We examined the expanded dosimetric characteristics of GDs including dose linearity up to 500 Gy, uniformity among GD lots and for individual GDs, the angular dependence, and energy dependence of 4 therapeutic x-ray qualities. In addition, we measured the dosimetric features (dose linearity, uniformity, angular dependence, and energy dependence) of the GD for electron beams of 10 different electron energy qualities. All measurements with the exception of dose linearity for photon beam were performed in a water phantom. For high-energy photon beams, dose linearity has a linear relationship for a dose ranging from 1 to 500 Gy with the coefficient of determination; R² of 0.998. The uniformity of each GD of dose measurements was within ±0.5% for four GD lots and within ±1.2% for 80 GDs. In terms of the effects of photon beam angle, lower absorbed doses of within 1.0% were observed between 60° and 105° than at 90°. The GD energy dependence of 4 photon beam energy qualities was within ±2.0%. On the other hand, the result of the dose linearity for high-energy electron beams showed well fitted regression line with the coefficient of determination; R² of 0.999 between 6 and 20 MeV. The uniformity of GDs exposed to the nominal electron energies 6, 9, 12, 16, and 20 MeV was ±1.2%. In terms of the angular dependence to electron beams, absorbed doses were within 2.0% between 60° and 105° than at 90°. In evaluation of the energy dependence of the GD at nominal electron energies between 5 and 20 MeV, we obtained responses between 1.1% and 3.5% lower than that for a cobalt-60 beam. Our results show that GDs can be used as a detector for determining doses when a high-energy photon beam is used, and that it also has considerable potential for dose measurement of high-energy electron beam.     

Prediction error criterion for selecting variables in a linear regression model

Several criteria, such as CV, C _p , AIC, CAIC, and MAIC, are used for selecting variables in linear regression models. It might be noted that C _p has been proposed as an estimator of the expected standardized prediction error, although the target risk function of CV might be regarded as the expected prediction error R _PE. On the other hand, the target risk function of AIC, CAIC, and MAIC is the expected log-predictive likelihood. In this paper, we propose a prediction error criterion, PE, which is an estimator of the expected prediction error R _PE. Consequently, it is also a competitor of CV. Results of this study show that PE is an unbiased estimator when the true model is contained in the full model. The property is shown without the assumption of normality. In fact, PE is demonstrated as more faithful for its risk function than CV. The prediction error criterion PE is extended to the multivariate case. Furthermore, using simulations, we examine some peculiarities of all these criteria.     

Strong convergence theorems for strongly continuous semigroups of pseudocontractions

In this work, strongly continuous semigroups of pseudocontractions are studied based on an implicit iterative algorithm. Strong convergence theorems of fixed points are obtained in an arbitrary Banach space.     

Approximation of M/M/c retrial queue with PH-retrial times

We consider the M/M/c retrial queues with PH-retrial times. Approximation formulae for the distribution of the number of customers in service facility and the mean number of customers in orbit are presented. Some numerical results are presented.     

Long distance laser ultrasonic propagation imaging system for damage visualization

Wind turbine blade failure is the most prominent and common type of damage occurring in operating wind turbine systems. Conventional nondestructive testing systems are not available for in situ wind turbine blades. We propose a portable long distance ultrasonic propagation imaging (LUPI) system that uses a laser beam targeting and scanning system to excite, from a long distance, acoustic emission sensors installed in the blade. An examination of the beam collimation effect using geometric parameters of a commercial 2 MW wind turbine provided Lamb wave amplitude increases of 41.5 and 23.1 dB at a distance of 40 m for symmetrical and asymmetrical modes, respectively, in a 2 mm-thick stainless steel plate. With this improvement in signal-to-noise ratio, a feasibility study of damage detection was conducted with a 5 mm-thick composite leading edge specimen. To develop a reliable damage evaluation system, the excitation/sensing technology and the associated damage visualization algorithm are equally important. Hence, our results provide a new platform based on anomalous wave propagation imaging (AWPI) methods with adjacent wave subtraction, reference wave subtraction, reference image subtraction, and the variable time window amplitude mapping method. The advantages and disadvantages of AWPI algorithms are reported in terms of reference data requirements, signal-to-noise ratios, and damage evaluation accuracy. The compactness and portability of the proposed UPI system are also important for in-field applications at wind farms.     

Nephrotoxicity assessments of benzo(a)pyrene during zebrafish embryogenesis

Benzo(a)pyrene is a chemical produced during the process of making fried, roasted, and smoked foods. It remains unclear whether benzo(a)pyrene affects the early development of human organs. In this study, we used the transgenic zebrafish line Tg(wt1b:GFP) as a model to assess benzo(a)pyrene-induced kidney malformation. By soaking zebrafish embryos in benzo(a)pyrene at various doses (2, 20, and 200 ppb), only a minor effect on the survival rate was detected (0 ppb: 97.8 ± 1.9 %; 2–200 ppb: 89.1 ± 5.8–91.5 ± 8.3 %). However, benzo(a)pyrene significantly affected the development of the kidney (malformation rates ranges from 50.0 ± 3.5 to 77.4 ± 5.3 %). Various abnormalities, such as unusual curving of pronephric tubes, swollen glomerulus, and incomplete development of pronephric ducts, were observed. This study provides a rapid and effective protocol for the evaluation of the notable effects of benzo(a)pyrene on embryonic kidney development.