Biobased nanofibrous aerogels are one of the emerging topics in materials chemistry because of their unique properties and environmental friendliness, but their practical potential has not yet been ...fully clarified. For the first step of an industrial feasibility study of biobased nanofibrous aerogel as high-performance thermal insulators, this paper aims to establish a preparation protocol of decimeter-sized monoliths (∼120 × 120 mm2) of cross-linked chitosan aerogels and their thermal conductivity evaluation. In contrast to the well-studied silica aerogel, the chitosan gel has flexible polymeric network and shows a drastic change in volume during the process, which must be taken into consideration for the design of solvent exchange protocol. The obtained aerogel shows a remarkably low thermal conductivity of 16–17 mW m–1 K–1. This value shows that the chitosan aerogel is one of the promising candidates for superinsulation materials in the next-generation thermal energy management.
Targeted therapies have changed the landscape of treatments for non-small cell lung cancer (NSCLC). Specific targeted therapies have been approved for NSCLC patients harboring genetic alterations in ...four oncogenes, and agents targeting additional oncogenic drivers are under investigation. Standard first-line chemotherapy has been supplanted by these targeted therapies due to superior efficacy and lower toxicity. Despite excellent response rates and durable responses in some cases, most patients experience relapse within a few years due to the development of acquired drug resistance. Next generation targeted therapies are being developed to overcome drug resistance and extend the duration of therapy. In this review, we summarize the current treatment strategies for the major targetable oncogenic mutations/alterations in NSCLC and discuss the mechanisms leading to acquired drug resistance.
Random forest regression was applied to optimize the melt-blending process of polyphenylene sulfide (PPS) with poly(ethylene-glycidyl methacrylate-methyl acrylate) (E-GMA-MA) elastomer to improve the ...Charpy impact strength. A training dataset was constructed using four elastomers with different GMA and MA contents by varying the elastomer content up to 20 wt% and the screw rotation speed of the extruder up to 5000 rpm at a fixed barrel temperature of 300 °C. Besides the controlled parameters, the following measured parameters were incorporated into the descriptors for the regression: motor torque, polymer pressure, and polymer temperatures monitored by infrared-ray thermometers installed at four positions (T1 to T4) as well as the melt viscosity and elastomer particle diameter of the product. The regression without prior knowledge revealed that the polymer temperature T1 just after the first kneading block is an important parameter next to the elastomer content. High impact strength required high elastomer content and T1 below 320 °C. The polymer temperature T1 was much higher than the barrel temperature and increased with the screw speed due to the heat of shear. The overheating caused thermal degradation, leading to a decrease in the melt viscosity and an increase in the particle diameter at high screw speed. We thus reduced the barrel temperature to keep T1 around 310 °C. This increased the impact strength from 58.6 kJ m
as the maximum in the training dataset to 65.3 and 69.0 kJ m
at elastomer contents of 20 and 30 wt%, respectively.
Solubilities of two polymorphs of famotidine (A, B) and three polymorphs of sulfathiazole (I, II, and IV) were measured in various solvents at 298.15 K to clarify how the solubility ratios B/A, I/IV, ...and II/IV depend on the solvent. The famotidine solubility increased in the order of ethyl acetate < water < 2-propanol < acetonitrile < 1-propanol < ethanol < acetone < methanol for both polymorphs. The solubility ratio B/A varied from 1.09 to 1.32, having a positive correlation with the solvent polarity. In contrast, the sulfathiazole solubility increased in the order of water < ethyl acetate < 2-propanol < 1-propanol < ethanol < methanol. The solubility ratios I/IV and II/IV changed little within 1.62 ± 0.04 and 1.00 ± 0.03, respectively. The negligible solvent dependence indicates that the solubility ratios are determined only by the free energy difference between the polymorphs in the solid state. This enabled us to estimate the solubilities of metastable form I in water, methanol, and ethanol, which could not be measured due to solvent-mediated transformation. The solubility ratios were compared with those calculated using three types of thermodynamic equations from the transition temperature and enthalpy change measured by differential scanning calorimetry. The equation proposed by Hoffmann gave the values closest to the experimental results.
Purpose Advanced anaplastic lymphoma kinase ( ALK) fusion-positive non-small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes ...in these patients vary, and the benefit of TKIs is limited as a result of acquired resistance. Emerging data suggest that the ALK fusion variant may affect clinical outcome, but the molecular basis for this association is unknown. Patients and Methods We identified 129 patients with ALK-positive NSCLC with known ALK variants. ALK resistance mutations and clinical outcomes on ALK TKIs were retrospectively evaluated according to ALK variant. A Foundation Medicine data set of 577 patients with ALK-positive NSCLC was also examined. Results The most frequent ALK variants were EML4-ALK variant 1 in 55 patients (43%) and variant 3 in 51 patients (40%). We analyzed 77 tumor biopsy specimens from patients with variants 1 and 3 who had progressed on an ALK TKI. ALK resistance mutations were significantly more common in variant 3 than in variant 1 (57% v 30%; P = .023). In particular, ALK G1202R was more common in variant 3 than in variant 1 (32% v 0%; P < .001). Analysis of the Foundation Medicine database revealed similar associations of variant 3 with ALK resistance mutation and with G1202R ( P = .010 and .015, respectively). Among patients treated with the third-generation ALK TKI lorlatinib, variant 3 was associated with a significantly longer progression-free survival than variant 1 (hazard ratio, 0.31; 95% CI, 0.12 to 0.79; P = .011). Conclusion Specific ALK variants may be associated with the development of ALK resistance mutations, particularly G1202R, and provide a molecular link between variant and clinical outcome. ALK variant thus represents a potentially important factor in the selection of next-generation ALK inhibitors.
ROS1 gene rearrangement was observed in around 1-2 % of NSCLC patients and in several other cancers such as cholangiocarcinoma, glioblastoma, or colorectal cancer. Crizotinib, an ALK/ROS1/MET ...inhibitor, is highly effective against ROS1-rearranged lung cancer and is used in clinic. However, crizotinib resistance is an emerging issue, and several resistance mechanisms, such as secondary kinase-domain mutations (e.g., ROS1-G2032R) have been identified in crizotinib-refractory patients. Here we characterize a new selective ROS1/NTRK inhibitor, DS-6051b, in preclinical models of ROS1- or NTRK-rearranged cancers. DS-6051b induces dramatic growth inhibition of both wild type and G2032R mutant ROS1-rearranged cancers or NTRK-rearranged cancers in vitro and in vivo. Here we report that DS-6051b is effective in treating ROS1- or NTRK-rearranged cancer in preclinical models, including crizotinib-resistant ROS1 positive cancer with secondary kinase domain mutations especially G2032R mutation which is highly resistant to crizotinib as well as lorlatinib and entrectinib, next generation ROS1 inhibitors.
Most
-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors.
amplification has been described in patients progressing on ALK inhibitors, ...but frequency of this event has not been comprehensively assessed.
We performed FISH and/or next-generation sequencing on 207 posttreatment tissue (
= 101) or plasma (
= 106) specimens from patients with ALK-positive lung cancer to detect
genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with
alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance.
amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop
amplification than those who had received next-generation ALK inhibitors after crizotinib (
= 0.019). Two tumor specimens harbored an identical
rearrangement, one of which had concurrent
amplification. Expressing
in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both
and
amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired
alterations achieved rapid responses to ALK/MET combination therapy.
Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired
alterations may derive clinical benefit from therapies that target both ALK and MET.
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•Two-step foaming with high P (> 50 MPa) and rapid decompression (> 1.25 GP/s).•PMMA foams with a cell size of 42 nm–58 nm and a porosity of 27–58 %.•Smaller cells in polymer foams ...that cannot be observed by SEM.•Achievement of a high cell nucleation (1014 nuclei cm−3 - 1015 nuclei cm−3).•Effects of high saturation pressure for high cell uniformity and cell nucleation.
A two-step foaming process was developed that uses different temperatures in each step and combines ultra-high saturation pressure (Ps > 50 MPa) and rapid depressurization (> 1.25 GPa/s) for production of nanocellular polymer foams. The effect of process conditions were investigated using polymethylmethacrylate (PMMA) and carbon dioxide. Foams with small cells (< 100 nm) and a large cell nucleation density (N0 > 1015 nuclei cm−3) were obtained, which were of a finer structure than those made by previous one-step foaming process. N0 tended to increase even at Ps =100 MPa. A fine cell structure (30.5 nm ± 10.4 nm) was observed with scanning transmission electron microscopy (STEM), and was confirmed when two-step process conditions were used. The process and advantages of ultra-high pressure are discussed with regard to porosity, cell size and N0.
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