EGFR is frequently mutated and amplified in lung adenocarcinomas sensitive to EGFR inhibitors gefitinib and erlotinib. A secondary mutation, T790M, has been associated with acquired resistance but ...has not been shown to be sufficient to render EGFR mutant/amplified lung cancers resistant to EGFR inhibitors. We created a model for studying acquired resistance to gefitinib by prolonged exposure of a gefitinib-sensitive lung carcinoma cell line (H3255; EGFR mutated and amplified) to gefitinib in vitro. The resulting resistant cell line acquired a T790M mutation in a small fraction of the amplified alleles that was undetected by direct sequencing and identified only by a highly sensitive HPLC-based technique. In gefitinib-sensitive lung cancer cells with EGFR mutations and amplifications, exogenous introduction of EGFR T790M effectively conferred resistance to gefitinib and continued ErbB-3/PI3K/Akt signaling when in cis to an activating mutation. Moreover, continued activation of PI3K signaling by the PIK3CA oncogenic mutant, p110alpha E545K, was sufficient to abrogate gefitinib-induced apoptosis. These findings suggest that allelic dilution of biologically significant resistance mutations may go undetected by direct sequencing in cancers with amplified oncogenes and that restoration of PI3K activation via either a T790M mutation or other mechanisms can provide resistance to gefitinib.
•Bacterial cellulose/graphene oxide (BC/GO) aerogels were prepared by solvent mixing.•A small amount of DMSO addition during hydrogel formation allow pores orientation.•BC/GO reduced with NH3 ...(gas-phase) show enhanced mechanical and thermal performance.•The reduced BC/GO aerogels present notable values of electric conductivity.
We present a novel method for processing bacterial cellulose/graphene oxide (BC/GO) aerogels with multifunctional properties. The addition of a small amount of dimethyl sulfoxide (DMSO) to the aqueous dispersion of the nanomaterials during the gelification process affected the water freezing temperature of the system and thereby affecting the porous structure of the aerogel obtained after liophilization. The possibility to obtain small and elongated pore with axial orientation allowed a significant improvement of the structural stability of the aerogels. Moreover, the aerogels reduction by thermal treatment with ammonia gas induced crosslinking between the different nanophases, thus given an incremental factor for the mechanical performance of the aerogels under harsh conditions. The resulting aerogels also showed significant improvements in terms of thermal stability and electrical conductivity. These multifunctional BC/GO aerogels present high potential as sustainable and ecological alternative materials for lightweight packaging, filters for atmosphere and water treatment, or energy applications.
This is a phase II, multicenter, open-label study of chemotherapy-naïve patients with non-small-cell lung cancer (NSCLC) and age > or = 70 years who were treated with erlotinib and evaluated to ...determine the median, 1-year, and 2-year survival. The secondary end points include radiographic response rate, time to progression (TTP), toxicity, and symptom improvement.
Eligible patients with NSCLC were treated with erlotinib 150 mg/d until disease progression or significant toxicity. Tumor response was assessed every 8 weeks by computed tomography scan using Response Evaluation Criteria in Solid Tumors. Tumor samples were analyzed for the presence of somatic mutations in EGFR and KRAS.
Eighty eligible patients initiated erlotinib therapy between March 2003 and May 2005. There were eight partial responses (10%), and an additional 33 patients (41%) had stable disease for 2 months or longer. The median TTP was 3.5 months (95% CI, 2.0 to 5.5 months). The median survival time was 10.9 months (95% CI, 7.8 to 14.6 months). The 1- and 2- year survival rates were 46% and 19%, respectively. The most common toxicities were acneiform rash (79%) and diarrhea (69%). Four patients developed interstitial lung disease of grade 3 or higher, with one treatment-related death. EGFR mutations were detected in nine of 43 patients studied. The presence of an EGFR mutation was strongly correlated with disease control, prolonged TTP, and survival.
Erlotinib monotherapy is active and relatively well tolerated in chemotherapy-naïve elderly patients with advanced NSCLC. Erlotinib merits consideration for further investigation as a first-line therapeutic option in elderly patients.
The supercritical carbon dioxide (scCO2) synthesis of non‐reduced graphene oxide (GO) aerogels from dispersions of GO in ethanol is here reported as a low‐cost, efficient, and environmentally ...friendly process. The preparation is carried out under the mild conditions of 333 K and 20 MPa. The high aspect ratio of the used GO sheets (ca. 30 μm lateral dimensions) allowed the preparation of aerogel monoliths by simultaneous scCO2 gelation and drying. Solid‐state characterization results indicate that a thermally‐stable mesoporous non‐reduced GO aerogel was obtained by using the supercritical procedure, keeping most of the surface oxygenated groups on the GO sheets, thus, facilitating further functionalization. Moreover, the monoliths have a very low density, high specific surface area, and excellent mechanical integrity; characteristics which rival those of most light‐weight reduced graphene aerogels reported in the literature.
Critical condition: The supercritical carbon dioxide synthesis of non‐reduced graphene oxide (GO) aerogels from dispersions of GO in ethanol is here reported as a low‐cost, efficient, and environmentally friendly process. Moreover, the monoliths have a very low density, high specific surface area, and excellent mechanical integrity; characteristics which rival those of most light‐weight reduced graphene aerogels reported in the literature.
Purpose: Mutations in the epidermal growth factor receptor (EGFR) are associated with clinical and radiographic responses to EGFR
tyrosine kinase inhibitors gefitinib and erlotinib. Currently ...available methods of EGFR mutation detection rely on direct
DNA sequencing, which requires isolation of DNA from a relatively pure population of tumor cells, cannot be done on small
diagnostic specimens, and lack sensitivity. Here we describe the use of a sensitive screening method that overcomes many of
these limitations.
Experimental Design: We screened 178 non–small cell lung cancer specimens for mutations in exons 18 to 21 of EGFR using a DNA endonuclease, SURVEYOR,
which cleaves mismatched heteroduplexed DNA. Samples were analyzed by high-performance liquid chromatography on the Transgenomic
WAVE HS system. Selected specimens that produced digestion products using SURVEYOR were subsequently reanalyzed by size separation
or under partially denaturing conditions, followed by fractionation and sequencing. The specimens included DNA isolated from
frozen tumor specimens, dissected formalin-fixed, paraffin-embedded tumor specimens undergoing clinical sequencing, and undissected
formalin-fixed, paraffin-embedded specimens. One hundred sixty specimens were independently analyzed using direct DNA sequencing
in a blinded fashion.
Results: EGFR mutations were detected in 16 of 61 fresh frozen tumor specimens, 24 of 91 dissected formalin-fixed, paraffin-embedded
tumor specimens, and 11 of 26 undissected formalin-fixed, paraffin-embedded tumor specimens. Compared with sequencing, the
sensitivity and specificity of the present method were 100% and 87%. The positive and negative predictive values were 74%
and 100%, respectively. SURVEYOR analysis detected 7 (4%) mutations that were not previously detected by direct sequencing.
Conclusions: SURVEYOR analysis provides a rapid method for EGFR mutation screening with 100% sensitivity and negative predictive value.
This unbiased scanning technique is superior to direct sequencing when used with undissected formalin-fixed, paraffin-embedded
specimens.
The increasing complexity in composition and structure of modern porous nanocomposite materials requires the development of advanced technologies that allow the simultaneous treatment of dissimilar ...compounds, not only with unlike composition but also involving different classes of pores, e.g., micro and mesopores. This work shows that supercritical CO2 (scCO2) technology can be used as generic processing aid to obtain composites involving non-reduced graphene oxide (GO) and metal organic frameworks (MOFs) in the form of aerogels with hierarchical porosity. Hybrid aerogels are formed by either depositing (ex situ) or growing (in situ) MOF nanocrystals onto the surface of 2D GO nanosheets. The archetypal hydrophilic HKUST-1 and UiO-66 and hydrophobic ZIF-8 microporous MOFs are chosen to exemplify the method possibilities. The ex situ route was adequate to prepare hydrophilic MOFs@GO homogeneous composites, while the in situ approach must be used to prepare hydrophobic MOFs@GO aerogels. Moreover, the scCO2 methodology should be adjusted for each studied MOF in regard of the organic solvent used to disperse the nanoentities constituting the composite. The end-products are obtained in the form of aerogels mimicking the shape of the recipient in which they are contained. The products are characterized in regard of structure by X-ray diffraction, textural properties by low temperature N2 adsorption/desorption and morphology by electronic microscopy.
Display omitted
•scCO2 as a synthetic platform for fabrication of meso/microporous MOF@GO aerogels.•MOF hydrophobic/hydrophilic nature defines the choice of ex situ/in situ scCO2 method.•The ex situ route can be applied to a large number of MOFs with hydrophilic nature.•The in situ method can be also applied to hydrophobic MOFs to reduce time/resources.•MOF@GO composites were homogenous with hierarchical micro/meso porosity.
A novel CuZnO multicomponent catalyst, involving reduced graphene oxide (rGO) as a support, was synthesized to be applied in the catalytic hydrogenation of CO2 to methanol. The CuZnO@rGO composite ...was prepared as a 3D aerogel by a two‐step process involving supercritical CO2 for macrostructuration and H2 treatment for reduction. Electron microscopy was applied to visualize the meso/macroporous morphology formed by the supercritical drying. The elemental mapping depicted a homogenous distribution of CuZnO nanoparticles deposited on the rGO flakes. It was demonstrated that methanol production increases for the CuZnO@rGO composite in comparison to unsupported similar CuZnO nanoparticles. This behavior was ascribed to a different interaction established between the Cu0 and ZnO nanoparticles used as synthetized or deposited on rGO. It is shown that the highly reduced rGO component stimulates H2O desorption produced during the hydrogenation reaction, thus it serves as a support hindering the sintering of Cu0 nanoparticles. The formation of a diluted surface alloy of Zn into Cu0 was determined for the unsupported CuZnO NPs, while for the CuZnO@rGO aerogel composite, the absence of any additional phase, e. g., a surface alloy or reduced ZnO, was confirmed. The composite aerogels show excellent MeOH selectivity at high temperature (up to 260 °C) and low pressure (10 bar).
CO2 hydrogenation: A novel graphene‐oxide aerogel supported CuZnO catalyst was synthesized for the selective CO2 hydrogenation to methanol. The graphene‐oxide support played a crucial role in the immobilization of the active nanoparticles, as well as in hindering the formation of diluted Cu−Zn surface alloy, which resulted in superior activity and methanol selectivity in comparison to unsupported CuZnO catalyst.
Soft crystallization routes for the controlled growth of one- and two-dimensional Cu(II)-coordination polymers of the type (Cu(hfa)2) x (3-tpt) n (hfa = hexafluoroacetylacetonate, 3-tpt = ...2,4,6-tris(3-pyridyl)-1,3,5-triazine) are described. Three volatile solvents with different protic/aprotic characteristics were chosen as the reaction media, e.g., supercritical CO2, chloroform, and ethanol. Five (1–5) new compounds were crystallized, with different structures and Cu(II)/3-tpt ratios. The structures of 3-tpt and five new coordination polymers were elucidated by single-crystal synchrotron X-ray diffraction. A description of the crystallization pathways followed for the synthesis of the individual compounds is given based on the protic or aprotic character of the used solvents and reagents’ solubility constraints. The main novelty of the work relies in establishing the foundations of 3-tpt isomeric control during crystallization through solvent selection. From the five precipitated new compounds, 3 displays a significant framework flexibility, associated with N2 adsorption at low temperature, presenting a stepwise adsorption isotherm. The N2 adsorption process was followed by in situ synchrotron X-ray powder diffraction.
PDF
