Rubber Toughened and Nanoparticle Reinforced Epoxy Composites

Epoxy resins have achieved acceptance as adhesives, coatings, and potting compounds, but their main application is as matrix to produce reinforced composites. However, their usefulness in this field still limited due to their brittle nature. Some studies have been done to increase the toughness of epoxy composites, of which the most successful one is the modification of the polymer matrix with a second toughening phase. Resin Transfer Molding (RTM) is one of the most important technologies to manufacture fiber reinforced composites. In the last decade it has experimented new impulse, due to its favorable application to produce large surface composites with good technical properties and at relative low cost. This research work focuses on the development of novel modified epoxy matrices, with enhanced mechanical and thermal properties, suitable to be processed by resin transfer molding technology, to manufacture Glass Fiber Reinforced Composites (GFRC’s) with improved performance in comparison to the commercially available ones. In the first stage of the project, a neat epoxy resin (EP) was modified using two different nano-sized ceramics: silicium dioxide (SiO2) and zirconium dioxide (ZrO2); and micro-sized particles of silicone rubber (SR) as second filler. Series of nanocomposites and hybrid modified epoxy resins were obtained by systematic variation of filler contents. The rheology and curing process of the modified epoxy resins were determined in order to define their aptness to be processed by RTM. The resulting matrices were extensively characterized qualitatively and quantitatively to precise the effect of each filler on the polymer properties. It was shown that the nanoparticles confer better mechanical properties to the epoxy resin, including modulus and toughness. It was possible to improve simultaneously the tensile modulus and toughness of the epoxy matrix in more than 30 % and 50 % respectively, only by using 8 vol.-% nano-SiO2 as filler. A similar performance was obtained by nanocomposites containing zirconia. The epoxy matrix modified with 8 vol.-% ZrO2 recorded tensile modulus and toughness improved up to 36% and 45% respectively regarding EP. On the other hand, the addition of silicone rubber to EP and nanocomposites results in a superior toughness but has a slightly negative effect on modulus and strength. The addition of 3 vol.-% SR to the neat epoxy and nanocomposites increases their toughness between 1.5 and 2.5 fold; but implies also a reduction in their tensile modulus and strength in range 5-10%. Therefore, when the right proportion of nanoceramic and rubber were added to the epoxy resin, hybrid epoxy matrices with fracture toughness 3 fold higher than EP but also with up to 20% improved modulus were obtained. Widespread investigations were carried out to define the structural mechanisms responsible for these improvements. It was stated, that each type of filler induces specific energy dissipating mechanisms during the mechanical loading and fracture processes, which are closely related to their nature, morphology and of course to their bonding with the epoxy matrix. When both nanoceramic and silicone rubber are involved in the epoxy formulation, a superposition of their corresponding energy release mechanisms is generated, which provides the matrix with an unusual properties balance. From the modified matrices glass fiber reinforced RTM-plates were produced. The structure of the obtained composites was microscopically analyzed to determine their impregnation quality. In all cases composites with no structural defects (i.e. voids, delaminations) and good superficial finish were reached. The composites were also properly characterized. As expected the final performance of the GFRCs is strongly determined by the matrix properties. Thus, the enhancement reached by epoxy matrices is translated into better GFRC´s macroscopical properties. Composites with up to 15% enhanced strength and toughness improved up to 50%, were obtained from the modified epoxy matrices

Antitumor Effects of a Novel Chromosome Region Maintenance 1 (CRM1) Inhibitor on Non-Small Cell Lung Cancer Cells In Vitro and in Mouse Tumor Xenografts

<div><p>Background</p><p>Chromosome Region Maintenance 1 (CRM1) is a nuclear exporter and its inhibitor has anti-tumor activity in various cancers. This study assessed the therapeutic efficiency of the novel CRM1 inhibitor KPT-185 on non-small cell lung cancer (NSCLC).</p><p>Methods</p><p>NSCLC cell lines were treated with KPT-185 to assess changes in cell viability, cell cycle, apoptosis, and protein expression. NOD-SCID mice carrying NSCLC cell xenografts were orally treated with KPT-276, a clinical analog of KPT-185, to examine the efficacy and side effects of KPT-276 in vivo.</p><p>Results</p><p>KPT-185 significantly reduced the viability of six NSCLC cell lines in a time- and dose-dependent manner, including epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant H1975 and H1650GR cell lines. In addition, KPT-185 induced these NSCLC cells to arrest at G1 phase of the cell cycle and caused apoptosis in a dose-dependent manner. KPT-185 treatment also reduced CRM1 protein levels in six NSCLC cell lines, and the reduction could be completely abolished by the proteasome inhibitor bortezomib. KPT-185 activated caspase 3, 8, and 9, but inhibited survivin expression in NSCLC cells. In a mouse H1975 cell xenograft model, tumor growth was significantly inhibited by oral KPT-276 administration, and there was no significant mouse body weight loss or other side effects.</p><p>Conclusions</p><p>The current study demonstrated the anti-tumor effects of KPT-185 in NSCLC cells, including EGFR-TKI-resistant NSCLC cell lines. Further studies will assess anti-tumor activity of KPT-185 in a clinical trial for NSCLC patients.</p></div

Effects of KPT-276 on mouse H1975 cell xenograft growth inhibition.

<p>NSCLC H1975 cells were transplanted into NOD-SCID mice. Mice with an established NSCLC cell xenograft were orally administered with vehicle, gefitinib, or KPT-276. Tumor cell xenograft growth was assessed for 30 days. Tumor growth curves showed a statistically significant suppression of H1975 cell growth in vivo when compared to vehicle or gefitinib treatment (<i>P</i><0.05; A). Mice administered oral KPT-276 (100 mg/kg, three times a week for three weeks) tolerated the treatment well (B). The protein level of CRM1was detected in xenograft tumors by immunohistochemistry (C, 400×).</p

Effect of KPT-185 on the regulation of protein expression in NSCLC cells.

<p>The six NSCLC cell lines were treated with KPT-185 for 48 h. The expression of CRM1 protein was down-regulated (A & E), while the CRM1 mRNA levels were up-regulated (B, N = 3). In the presence of the proteasome inhibitor bortezomib, the reduction of CRM1 protein following KPT-185 treatment was almost blocked in H1975, HCC827, and H1650GR cells (C). EGFR expression was downregulated following KPT-185 treatment. The NF-κB and IκB-α proteins levels were not significantly affected. KPT-185 upregulated wild type p53 in A549 cells, downregulated mutant p53 in H1975 cell, and there was no effect in HCC827 and H2228 cell. In addition, p53 was not detected in H1650 and H1650GR cells (D&E, 400×).</p

Effect of KPT-185 on the regulation of NSCLC cell cycle.

<p>Cells were arrested at the G1 phase of the cell cycle in KPT-185 sensitive cells. (N = 3).</p

Effect of KPT185 on cell viability in NSCLC cells.

<p>Six NSCLC cell lines were treated with KPT-185 for 48 h or 72 h. Cell viability was suppressed by KPT-185 in a dose- and time-dependent manner (A∼F). KPT-185 inhibited cell viability in H1975 (G) and HCC827 (H) cells when compared to the effect of EGFR-TKI gefitinib treatment. (N = 3).</p

Effect of KPT-185 on the regulation of apoptosis related protein expression in NSCLC cells.

<p>The six NSCLC cell lines were treated with KPT-185 for 48 h. Caspases-8, -9 and -3 and PARP were activated or cleaved, but survivin was down-regulated (A). In the presence of the pan-caspase inhibitor Z-VAD-FMK, KPT-185-induced apoptosis was completely blocked in H1975 cells (B, N = 3).</p

Multivariate logistic regression in CRC patients between gene mutations and clinicopathological characteristics.

<p>LRT: likelihood ratio test; 95% CI: 95% confidence interval.</p

Frequency of the various KRAS and BRAFmutations.

<p>Panel A: KRAS mutations (codons12 & 13: n = 674; codon61: n = 672). Panel B: BRAF mutations (exon11: n = 676; exon15: n = 675). The data are presented as percentages (number of total samples).</p

Frequency of the various PIK3CA and NRAS mutations.

<p>Panel A: PIK3CA mutations (exon9: n = 643; exon20: n = 636). Panel B: NRAS mutations (codons12 & 13: n = 630; codon61: n = 643). The data are presented as percentages (number of total samples).</p