FGFR gene aberrations are associated with tumor growth and survival. We explored the role of FGFR2 amplification in gastric cancer and the therapeutic potential of AZD4547, a potent and selective ...ATP-competitive receptor tyrosine kinase inhibitor of fibroblast growth factor receptor (FGFR)1-3, in patients with FGFR2-amplified gastric cancer.
Array-comparative genomic hybridization and FISH were used to identify FGFR2 amplification in gastric cancer patient tumor samples. The effects of FGFR2 modulation were investigated in gastric cancer cells with FGFR2 amplification and in patient-derived gastric cancer xenograft (PDGCX) models using two approaches: inhibition with AZD4547 and short hairpin RNA (shRNA) knockdown of FGFR2.
Amplification of the FGFR2 gene was identified in a subset of Chinese and Caucasian patients with gastric cancer. Gastric cancer cell lines SNU-16 and KATOIII, carrying the amplified FGFR2 gene, were extremely sensitive to AZD4547 in vitro with GI50 values of 3 and 5 nmol/L, respectively. AZD4547 effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules and induced apoptosis in SNU-16 cells. Furthermore, inhibition of FGFR2 signaling by AZD4547 resulted in significant dose-dependent tumor growth inhibition in FGFR2-amplified xenograft (SNU-16) and PDGCX models (SGC083) but not in nonamplified models. shRNA knockdown of FGFR2 similarly inhibited tumor growth in vitro and in vivo. Finally, compared with monotherapy, we showed enhancement of in vivo antitumor efficacy using AZD4547 in combination with chemotherapeutic agents.
FGFR2 pathway activation is required for driving growth and survival of gastric cancer carrying FGFR2 gene amplification both in vitro and in vivo. Our data support therapeutic intervention with FGFR inhibitors, such as AZD4547, in patients with gastric cancer carrying FGFR2 gene amplification.
To investigate the incidence of FGFR1 amplification in Chinese non-small cell lung cancer (NSCLC) and to preclinically test the hypothesis that the novel, potent, and selective fibroblast growth ...factor receptor (FGFR) small-molecule inhibitor AZD4547 will deliver potent antitumor activity in NSCLC FGFR1-amplified patient-derived tumor xenograft (PDTX) models.
A range of assays was used to assess the translational relevance of FGFR1 amplification and AZD4547 treatment including in vitro lung cell line panel screening and pharmacodynamic (PD) analysis, FGFR1 FISH tissue microarray (TMA) analysis of Chinese NSCLC (n = 127), and, importantly, antitumor efficacy testing and PD analysis of lung PDTX models using AZD4547.
The incidence of FGFR1 amplification within Chinese patient NSCLC tumors was 12.5% of squamous origin (6 of 48) and 7% of adenocarcinoma (5 of 76). AZD4547 displayed a highly selective profile across a lung cell line panel, potently inhibiting cell growth only in those lines harboring amplified FGFR1 (GI(50) = 0.003-0.111 μmol/L). AZD4547 induced potent tumor stasis or regressive effects in four of five FGFR1-amplified squamous NSCLC PDTX models. Pharmacodynamic modulation was observed in vivo, and antitumor efficacy correlated well with FGFR1 FISH score and protein expression level.
This study provides novel epidemiologic data through identification of FGFR1 gene amplification in Chinese NSCLC specimens (particularly squamous) and, importantly, extends the clinical significance of this finding by using multiple FGFR1-amplified squamous lung cancer PDTX models to show tumor stasis or regression effects using a specific FGFR inhibitor (AZD4547). Thus, the translational science presented here provides a strong rationale for investigation of AZD4547 as a therapeutic option for patients with squamous NSCLC tumors harboring amplification of FGFR1.
Coal-based graphite obtained from catalytic graphitization has raised great interests in many industrial areas including adsorbent, electrodes, hydrogen storage and many more. In this paper, residual ...carbon (RC), acquired from gasification fine slag (GFS) after flotation and acid leaching, was used as carbon precursor in graphitization process due to its high carbon content and graphitization tendency. Ferric chloride (FeCl3) was added as catalyst to facilitate graphitization process. The microstructure of the graphite samples obtained with and without FeCl3 was determined by X-ray diffraction (XRD), high-resolution transmission electron microscopy (HRTEM), scanning electron microscope - energy dispersive spectroscopy (SEM-EDS) and Raman spectroscopy, so that the structural differences can be studied and catalytic mechanism can be analyzed. The results revealed that with the increase of temperature and presence of FeCl3, the layer spacing (d002) gradually decreased. Accordingly, the graphitization degree (g), crystallite size (La) and stacking height (Lc) presented an increase trend, which illustrated that the graphite domain gradually became larger. And the g value of graphite sample derived from RC at 2800 °C with FeCl3 was even higher than that of sample obtained with anthracite at 3000 °C. Besides, the better-defined XRD diffractions peaks and Raman spectra also indicated better ordered graphite structures. The possible catalytic mechanism could involve the formation of an intermediate eutectic carbide (FexCy), which appeared as spherical droplets at 2400 °C and could significantly facilitate the graphite process. The result was confirmed by the kinetic analysis results, as the reaction activation energy of the graphitization process with FeCl3 in the temperature range of 2000–2400 °C was significantly lower than that without FeCl3 or in other temperature ranges. With the analysis of the microstructures, one possible catalytic mechanism appropriate for the graphitization of residual carbon with FeCl3 was proposed.
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Retinoic acid receptor alpha (RARα) has been considered as one of the most important targets for the treatment of acute promyelocytic leukemia. To discover more novel lead compounds, ligand-based ...pharmacophore modeling of a series of structurally diverse RARα agonists was applied to acquire the binding model (KI pharmacophore model) and the efficacy model (EC
50
pharmacophore model) of RARα. In this paper, a three-dimensional quantitative structure–activity relationship (3D-QSAR) in Discovery Studio 2.5 was used to generate pharmacophore models. Via Fischer’s randomization validation and maximum unbiased validation, the best pharmacophore model for KI pharmacophore model was Hypo1K and for EC
50
pharmacophore model was Hypo7E. Virtual screening of National Cancer Institute database using Hypo1K and Hypo7E was performed, respectively. Six potent compounds in the retrieved hits with a CAS number were confirmed to be effective on leukemia cell lines and other tumors in the literatures. As evident from the validation and the biological screening results, it can be concluded that the Hypo1K and Hypo7E were reliable and useful tools for lead optimization of novel RARα agonists.
A reconfigurable neural network vision sensor is proposed by using gate-tunable photoresponse of van der Waals heterostructures.
Early processing of visual information takes place in the human ...retina. Mimicking neurobiological structures and functionalities of the retina provides a promising pathway to achieving vision sensor with highly efficient image processing. Here, we demonstrate a prototype vision sensor that operates via the gate-tunable positive and negative photoresponses of the van der Waals (vdW) vertical heterostructures. The sensor emulates not only the neurobiological functionalities of bipolar cells and photoreceptors but also the unique connectivity between bipolar cells and photoreceptors. By tuning gate voltage for each pixel, we achieve reconfigurable vision sensor for simultaneous image sensing and processing. Furthermore, our prototype vision sensor itself can be trained to classify the input images by updating the gate voltages applied individually to each pixel in the sensor. Our work indicates that vdW vertical heterostructures offer a promising platform for the development of neural network vision sensor.
Seeking high‐capacity, high‐rate, and durable anode materials for lithium‐ion batteries (LIBs) has been a crucial aspect to promote the use of electric vehicles and other portable electronics. Here, ...a novel alloy‐forming approach to convert amorphous Si (a‐Si)‐coated copper oxide (CuO) core–shell nanowires (NWs) into hollow and highly interconnected Si–Cu alloy (mixture) nanotubes is reported. Upon a simple H2 annealing, the CuO cores are reduced and diffused out to alloy with the a‐Si shell, producing highly interconnected hollow Si–Cu alloy nanotubes, which can serve as high‐capacity and self‐conductive anode structures with robust mechanical support. A high specific capacity of 1010 mAh g−1 (or 780 mAh g−1) has been achieved after 1000 cycles at 3.4 A g−1 (or 20 A g−1), with a capacity retention rate of ≈84% (≈88%), without the use of any binder or conductive agent. Remarkably, they can survive an extremely fast charging rate at 70 A g−1 for 35 runs (corresponding to one full cycle in 30 s) and recover 88% capacity. This novel alloy‐nanotube structure could represent an ideal candidate to fulfill the true potential of Si‐loaded LIB applications.
A novel highly interconnected Si–Cu alloy (mixture) nanotube anode structure is fabricated from amorphous Si‐coated copper‐oxide core–shell nanowires in a simple H2 reduction process. The anode materials show a high specific capacity of 780 mAh g−1 after 1000 cycles at 20 A g−1, without the use of any binder or conductive agent.
Flexible near‐infrared (NIR) photodetectors (PDs) are desired for accurate heart rate monitoring, based directly on arterial‐blood‐volume‐change detection, instead of indirect oximetry technology. In ...this work, a robust 3D construction of flexible a‐SiGe:H p‐i‐n radial junction (RJ) PDs is explored directly upon soft Al foils, working at NIR wavelength 800 nm, which has the highest skin transparency and the least absorption difference from oxyhemoglobin and deoxyhemoglobin variation. The 3D a‐SiGe:H RJ‐PDs demonstrate excellent flexibility and mechanical stability that can undergo 1000‐times bending to 10 mm radius, with a high responsivity of ≈140 mA W−1@800 nm and rise/fall time scales of 5.4 µs/17.6 µs (3.6 µs/13.2 µs before bending). Successful photoplethysmography (PPG) detection of sphygmic signals is achieved at the wrist with significant arterial blood volume changes, working in reflectance mode and using a single NIR source @800 nm. These unique capabilities, enabled by the a‐SiGe:H RJ, have a promising potential to establish a reliable and convenient PPG detection technology, which can help to extract the heartbeat via solely arterial blood volume change, as a complementary and potentially very useful new diagnostic dimension for efficient and accurate real‐time health monitoring.
Flexible and robust near‐infrared (NIR) a‐SiGe:H p‐i‐n radial junction photodetectors, built upon silicon nanowires grown directly upon soft Al foils, demonstrate a successful photoplethysmography detection of sphygmic signals, working in a reflectance mode with a single NIR probing light @800 nm, which are promising to enable a new rapid diagnostic dimension for efficient and accurate real‐time health monitoring.
Stretchable electronics are finding widespread applications in bio‐sensing, skin‐mimetic electronics, and flexible displays, where high‐density integration of elastic and durable interconnections is ...a key capability. Instead of forming a randomly crossed nanowire (NW) network, here, a large‐scale and precise integration of highly conductive nickel silicide nanospring (SiNix‐NS) arrays are demonstrated, which are fabricated out of an in‐plane solid–liquid–solid guided growth of planar Si nanowires (SiNWs), and subsequent alloy‐forming process that boosts the channel conductivity over 4 orders of magnitude (to 2 × 104 S cm−1). Thanks to the narrow diameter of the serpentine SiNix‐NS channels, the elastic geometry engineering can be accomplished within a very short interconnection distance (down to ≈3 µm), which is crucial for integrating high‐density displays or logic units in a rigid‐island and elastic‐interconnection configuration. Deployed over soft polydimethylsiloxane thin film substrate, the SiNix‐NS array demonstrates an excellent stretchability that can sustain up to 50% stretching and for 10 000 cycles (at 15%). This approach paves the way to integrate high‐density inorganic electronics and interconnections for high‐performance health monitoring, displays, and on‐skin electronic applications, based on the mature and rather reliable Si thin film technology.
A large‐scale integration of highly conductive (>2 × 104 S cm−1) nickel silicide nanospring arrays, fabricated out of a guided growth of planar silicon nanowires and alloy‐forming process, is demonstrated, with narrow diameter <160 nm and elastic design that can sustain up to 50% stretching and for 10 000 cycles (at 15%). It is ideal for interconnecting high‐density displays or logic units on elastomer substrates.
Compared to human vision, conventional machine vision composed of an image sensor and processor suffers from high latency and large power consumption due to physically separated image sensing and ...processing. A neuromorphic vision system with brain-inspired visual perception provides a promising solution to the problem. Here we propose and demonstrate a prototype neuromorphic vision system by networking a retinomorphic sensor with a memristive crossbar. We fabricate the retinomorphic sensor by using WSe
/h-BN/Al
O
van der Waals heterostructures with gate-tunable photoresponses, to closely mimic the human retinal capabilities in simultaneously sensing and processing images. We then network the sensor with a large-scale Pt/Ta/HfO
/Ta one-transistor-one-resistor (1T1R) memristive crossbar, which plays a similar role to the visual cortex in the human brain. The realized neuromorphic vision system allows for fast letter recognition and object tracking, indicating the capabilities of image sensing, processing and recognition in the full analog regime. Our work suggests that such a neuromorphic vision system may open up unprecedented opportunities in future visual perception applications.
Geometry and doping control in silicon nanowires (SiNWs) are both crucial aspects in fabricating three-dimensional (3D) radial junction thin film solar cells, while the coupling between them remains ...a peculiar aspect to be better understood. In this work, we focus on the geometry evolution and the doping effects realized in tin-catalyzed SiNWs grown via a plasma-enhanced vapor-liquid-solid procedure by using different diborane (B
H
) dopant flows. It is shown that with the increase of B
H
flow rate from 0.3 to 2.1 SCCM, the radial growth of SiNWs is greatly accelerated by more than 30%, while the length is shortened to 50%. This can be related to the enhanced chemisorption probability of SiH
radicals, with the addition of B
H
, on the SiNW sidewall during silane (SiH
) plasma deposition in PECVD system, which leads to easier nucleation directly on the sidewalls and faster radial expansion of the SiNWs. A trade-off has to be sought between seeking a strong light trapping and ensuring a sufficient doping for high-quality PIN junction with the increase of B
H
doping flow. These new understandings lay a critical basis for understanding and searching for an optimal growth control for constructing high-performance 3D radial junction thin-film solar cells.
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