Although first-line crizotinib treatment leads to clinical benefit in
lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R (ROS1
) mutation and progression in the central nervous system ...(CNS) represents a therapeutic challenge. Here, we investigated the antitumor activity of repotrectinib, a novel next-generation ROS1/TRK/ALK-tyrosine kinase inhibitor (TKI) in
patient-derived preclinical models.
Antitumor activity of repotrectinib was evaluated in
patient-derived preclinical models including treatment-naïve and ROS1
models and was further demonstrated in patients enrolled in an on-going phase I/II clinical trial (NCT03093116). Intracranial antitumor activity of repotrectinib was evaluated in a brain-metastasis mouse model.
Repotrectinib potently inhibited
and
tumor growth and ROS1 downstream signal in treatment-naïve YU1078 compared with clinically available crizotinib, ceritinib, and entrectinib. Despite comparable tumor regression between repotrectinib and lorlatinib in YU1078-derived xenograft model, repotrectinib markedly delayed the onset of tumor recurrence following drug withdrawal. Moreover, repotrectinib induced profound antitumor activity in the CNS with efficient blood-brain barrier penetrating properties. Notably, repotrectinib showed selective and potent
and
activity against ROS1
. These findings were supported by systemic and intracranial activity of repotrectinib observed in patients enrolled in the on-going clinical trial.
Repotrectinib is a novel next-generation ROS1-TKI with improved potency and selectivity against treatment-naïve and ROS1
with efficient CNS penetration. Our findings suggest that repotrectinib can be effective both as first-line and after progression to prior ROS1-TKI.
Solid‐state conversion of single crystals from polycrystalline materials has the advantages of cost‐effectiveness, chemical homogeneity, and versatility over the conventional melt growth and solution ...growth methods, particularly for systems with high melting points, incongruent melting, high reactivity (volatility), and phase transformations at high temperature. Nevertheless, for commercial production, this technique has only been successful in a few limited systems, in particular ferroelectric systems. This is mostly because of the difficulty in controlling the microstructure, particularly suppressing grain growth in the polycrystal during its conversion. This article describes the principle and the current status of the solid‐state conversion of single crystals. We first introduce the recently developed principle of microstructural evolution to explain the basis of the microstructure control in polycrystals for solid‐state conversion. We then report recent technical developments in fabricating single crystals by the solid‐state single crystal growth (SSCG) method and their physical properties. The SSCG method is expected to be studied and utilized more widely in fabricating single crystals with complex compositions as a strong alternative to the melt growth and solution growth methods.
The development of high performance gas sensors that operate at room temperature has attracted considerable attention. Unfortunately, the conventional mechanism of chemiresistive sensors is ...restricted at room temperature by insufficient reaction energy with target molecules. Herein, novel strategy for room temperature gas sensors is reported using an ionic‐activated sensing mechanism. The investigation reveals that a hydroxide layer is developed by the applied voltages on the SnO2 surface in the presence of humidity, leading to increased electrical conductivity. Surprisingly, the experimental results indicate ideal sensing behavior at room temperature for NO2 detection with sub‐parts‐per‐trillion (132.3 ppt) detection and fast recovery (25.7 s) to 5 ppm NO2 under humid conditions. The ionic‐activated sensing mechanism is proposed as a cascade process involving the formation of ionic conduction, reaction with a target gas, and demonstrates the novelty of the approach. It is believed that the results presented will open new pathways as a promising method for room temperature gas sensors.
An ionic‐activated chemiresistive sensing mechanism is suggested to realize ideal gas sensors for room temperature operation. The investigation reveals that an ionic‐activated layer is developed by the applied voltages on the SnO2 surface in the presence of humidity. The ionic‐activated layer enables surprisingly ideal gas sensing at room temperature. The mechanism is demonstrated stepwise, showing the novelty of the approach.
Summary
Background
Data relating to the association between inflammatory bowel disease (IBD) and pregnancy outcomes are lacking in Korea.
Aims
To determine the incidence rates of pregnancy outcomes ...in women with IBD.
Methods
A nationwide population study was performed using the Korean National Health Insurance claims database. A total of 2058 women with IBD consisting of ulcerative colitis (UC, n = 1469) and Crohn's disease (CD, n = 589) were pregnant between 2007 and 2016. We compared their incidence of pregnancy outcomes with 20 580 age‐matched controls without IBD. We also stratified the patients into those with quiescent to mild and moderate to severe IBD and compared the outcomes between them.
Results
The pregnancy rate of women with IBD was lower than that of women without (25.7% vs 32.3%, P < 0.001). Caesarean section (46.5% vs 38.8%, odds ratio OR 1.43, 95% confidence interval CI: 1.17‐1.75), and intrauterine growth retardation (IUGR) (3.0% vs 1.0%, OR 2.89, 95% CI: 1.59‐5.26) were increased in CD patients than the controls. In regards to disease severity, there were no significant differences in pregnancy outcomes between patients with quiescent to mild IBD and the controls. However, the live birth rate of patients with moderate to severe IBD was lower than that of the controls (65.0% vs 69.9%, OR 0.79, 95%CI: 0.66‐0.94). In addition, moderate to severe IBD was significantly associated with spontaneous abortion (14.9% vs 11.9%, OR 1.33, 95% CI: 1.04‐1.68), caesarean section (46.4% vs 38.8%, OR 1.41, 95% CI: 1.14‐1.74) and IUGR (3.4% vs 1.0%, OR 3.20, 95% CI: 1.75‐5.84).
Conclusions
With the exception of moderate to severe disease, the incidences of adverse pregnancy outcomes in women with IBD are similar to that of the general population.
Glioblastoma (GBM) is a devastating and incurable brain tumour, with a median overall survival of fifteen months
. Identifying the cell of origin that harbours mutations that drive GBM could provide ...a fundamental basis for understanding disease progression and developing new treatments. Given that the accumulation of somatic mutations has been implicated in gliomagenesis, studies have suggested that neural stem cells (NSCs), with their self-renewal and proliferative capacities, in the subventricular zone (SVZ) of the adult human brain may be the cells from which GBM originates
. However, there is a lack of direct genetic evidence from human patients with GBM
. Here we describe direct molecular genetic evidence from patient brain tissue and genome-edited mouse models that show astrocyte-like NSCs in the SVZ to be the cell of origin that contains the driver mutations of human GBM. First, we performed deep sequencing of triple-matched tissues, consisting of (i) normal SVZ tissue away from the tumour mass, (ii) tumour tissue, and (iii) normal cortical tissue (or blood), from 28 patients with isocitrate dehydrogenase (IDH) wild-type GBM or other types of brain tumour. We found that normal SVZ tissue away from the tumour in 56.3% of patients with wild-type IDH GBM contained low-level GBM driver mutations (down to approximately 1% of the mutational burden) that were observed at high levels in their matching tumours. Moreover, by single-cell sequencing and laser microdissection analysis of patient brain tissue and genome editing of a mouse model, we found that astrocyte-like NSCs that carry driver mutations migrate from the SVZ and lead to the development of high-grade malignant gliomas in distant brain regions. Together, our results show that NSCs in human SVZ tissue are the cells of origin that contain the driver mutations of GBM.
Detection of gas-phase chemicals finds a wide variety of applications, including food and beverages, fragrances, environmental monitoring, chemical and biochemical processing, medical diagnostics, ...and transportation. One approach for these tasks is to use arrays of highly sensitive and selective sensors as an electronic nose. Here, we present a high performance chemiresistive electronic nose (CEN) based on an array of metal oxide thin films, metal-catalyzed thin films, and nanostructured thin films. The gas sensing properties of the CEN show enhanced sensitive detection of H2S, NH3, and NO in an 80% relative humidity (RH) atmosphere similar to the composition of exhaled breath. The detection limits of the sensor elements we fabricated are in the following ranges: 534 ppt to 2.87 ppb for H2S, 4.45 to 42.29 ppb for NH3, and 206 ppt to 2.06 ppb for NO. The enhanced sensitivity is attributed to the spillover effect by Au nanoparticles and the high porosity of villi-like nanostructures, providing a large surface-to-volume ratio. The remarkable selectivity based on the collection of sensor responses manifests itself in the principal component analysis (PCA). The excellent sensing performance indicates that the CEN can detect the biomarkers of H2S, NH3, and NO in exhaled breath and even distinguish them clearly in the PCA. Our results show high potential of the CEN as an inexpensive and noninvasive diagnostic tool for halitosis, kidney disorder, and asthma.
Reduced graphene oxide (rGO) is one of the promising sensing elements for high-performance chemoresistive sensors because of its remarkable advantages such as high surface-to-volume ratio, ...outstanding transparency, and flexibility. In addition, the defects on the surface of rGO, including oxygen functional groups, can act as active sites for interaction with gaseous molecules. However, the major drawback of rGO-based sensors is the extremely sluggish and irreversible recovery to the initial state after a sensing event, which makes them incapable of producing repeatable and reliable sensing signals. Here, we show that pristine GO can be used as the active sensing material with reversible and high response to NO2 at room temperature. First-principles calculations, in conjunction with experimental results, reveal the critical role of hydroxyl groups rather than epoxy groups in changing metallic graphene to the semiconducting GO. We show that the adaptive motions of the hydroxyl groups, that is, the rotation of these groups for the adsorption of NO2 molecules and relaxation to the original states during the desorption of NO2 molecules, are responsible for the fast and reversible NO2 sensing behavior of GO. Our work paves the way for realizing high-response, reversible graphene-based room-temperature chemoresistive sensors for further functional convergence.
The use of heterojunctions based on Rh-decorated WO3 nanorods is an effective strategy for achieving high-performance gas sensors for volatile organic compounds (VOCs), especially acetone (CH3COCH3). ...Herein, we successfully fabricated Rh-decorated WO3 nanorods with one-dimensional (1D) structures by glancing angle deposition (GLAD). Interestingly, morphological changes characterized by anomalous surfaces with numerous regions of negative curvature were observed upon decoration of the bare WO3 nanorods with Rh, which were systematically investigated on the basis of impeded surface diffusion and trapping effects. The improvements of gas sensing properties were stepwisely demonstrated by synergistic effects involving transition of Rh, high chemical potential of the negative curvature, primary decomposition at the top side, and highly ordered nanostructures. We are confident that the results provide new insight into the synthesis of effective nanostructures and contribute to a variety of applications including battery, solar water splitting, and sensor devices.
Background
Although great advances in artificial intelligence for interpreting small bowel capsule endoscopy (SBCE) images have been made in recent years, its practical use is still limited. The aim ...of this study was to develop a more practical convolutional neural network (CNN) algorithm for the automatic detection of various small bowel lesions.
Methods
A total of 7556 images were collected for the training dataset from 526 SBCE videos. Abnormal images were classified into two categories: hemorrhagic lesions (red spot/angioectasia/active bleeding) and ulcerative lesions (erosion/ulcer/stricture). A CNN algorithm based on VGGNet was trained in two different ways: the combined model (hemorrhagic and ulcerative lesions trained separately) and the binary model (all abnormal images trained without discrimination). The detected lesions were visualized using a gradient class activation map (Grad‐CAM). The two models were validated using 5,760 independent images taken at two other academic hospitals.
Results
Both the combined and binary models acquired high accuracy for lesion detection, and the difference between the two models was not significant (96.83% vs 96.62%, P = 0.122). However, the combined model showed higher sensitivity (97.61% vs 95.07%, P < 0.001) and higher accuracy for individual lesions from the hemorrhagic and ulcerative categories than the binary model. The combined model also revealed more accurate localization of the culprit area on images evaluated by the Grad‐CAM.
Conclusions
Diagnostic sensitivity and classification of small bowel lesions using a convolutional neural network are improved by the independent training for hemorrhagic and ulcerative lesions. Grad‐CAM is highly effective in localizing the lesions.
A (040)‐crystal facet engineered BiVO4 ((040)‐BVO) photoanode is investigated for solar fuel production. The (040)‐BVO photoanode is favorable for improved charge carrier mobility and high ...photocatalytic active sites for solar light energy conversion. This crystal facet design of the (040)‐BVO photoanode leads to an increase in the energy conversion efficiency for solar fuel production and an enhancement of the oxygen evolution rate. The photocurrent density of the (040)‐BVO photoanode is determined to be 0.94 mA cm−2 under AM 1.5 G illumination and produces 42.1% of the absorbed photon‐to‐current conversion efficiency at 1.23 V (vs RHE, reversible hydrogen electrode). The enhanced charge separation efficiency and improved charge injection efficiency driven by (040) facet can produce hydrogen with 0.02 mmol h−1 at 1.23 V. The correlation between the (040)‐BVO photoanode and the solar fuel production is investigated. The results provide a promising approach for the development of solar fuel production using a BiVO4 photoanode.
A facile strategy for improving solar fuel production of BiVO4 photoanodes is investigated. A (040)‐crystal facet engineered BiVO4 is hydrothermally synthesized with a structure directing agent and seed layer approach. Its photocurrent density is determined to be 0.94 mA cm−2 under 1‐sun and produces 42.1% of the absorbed photon‐to‐current conversion efficiency at 1.23 V (vs RHE, reversible hydrogen electrode). The photoelectrochemical hydrogen production can reach 0.2 mmol in 10 h.
