Molecular Subgroup Analysis of Clinical Outcomes in a Phase 3 Study of Gemcitabine and Oxaliplatin with or without Erlotinib in Advanced Biliary Tract Cancer

AbstractBACKGROUND: We previously reported that the addition of erlotinib to gemcitabine and oxaliplatin (GEMOX) resulted in greater antitumor activity and might be a treatment option for patients with biliary tract cancers (BTCs). Molecular subgroup analysis of treatment outcomes in patients who had specimens available for analysis was undertaken. METHODS: Epidermal growth factor receptor (EGFR), KRAS, and PIK3CA mutations were evaluated using peptide nucleic acid–locked nucleic acid polymerase chain reaction clamp reactions. Survival and response rates (RRs) were analyzed according to the mutational status. Sixty-four patients (48.1%) were available for mutational analysis in the chemotherapy alone group and 61 (45.1%) in the chemotherapy plus erlotinib group. RESULTS: 1.6% (2/116) harbored an EGFR mutation (2 patients; exon 20), 9.6% (12/121) harbored a KRAS mutation (12 patients; exon 2), and 9.6% (12/118) harbored a PIK3CA mutation (10 patients, exon 9 and 2 patients, exon 20). The addition of erlotinib to GEMOX in patients with KRAS wild-type disease (n = 109) resulted in significant improvements in overall response compared with GEMOX alone (30.2% vs 12.5%, P = .024). In 95 patients with both wild-type KRAS and PIK3CA, there was evidence of a benefit associated with the addition of erlotinib to GEMOX with respect to RR as compared with GEMOX alone (P = .04). CONCLUSION: This study demonstrates that KRAS mutational status might be considered a predictive biomarker for the response to erlotinib in BTCs. Additionally, the mutation status of PIK3CA may be a determinant for adding erlotinib to chemotherapy in KRAS wild-type BTCs

EC-18, a Synthetic Monoacetyldiacylglyceride, Inhibits Hematogenous Metastasis of KIGB-5 Biliary Cancer Cell in Hamster Model

EC-18 (monoacetyldiacylglyceride) stimulates T cell production of IL-2, IL-4, IL-12, IFN-γ, and GM-CSF in vitro. To study the effects of these cytokines stimulated by EC-18 on cancer cells, we applied hamster biliary cancer model, a difficult cancer to treat. Cancer (KIGB-5) cells were given intravenously to produce hematogenous metastatic lung lesions which were treated with EC-18 at 10, 25, and 50 mg/kg/day respectively. The fourth group was untreated control. At 4th, 8th, and 12th week the lungs were examined. EC-18 treated groups showed only a few microscopic lung lesions and no evidence of metastatic lesion with highest dose whereas widespread gross lung lesions were observed in untreated control. To investigate whether the anti-tumor effect of EC-18 is associated with suppression of tumor cell Toll-like receptor 4 (TLR-4) expression in addition to stimulation of the immune cells, KIGB-5 cells were exposed to LPS with or without EC-18. TLR-4 mRNA and protein expression, measured by reverse transcriptase PCR (RT-PCR), real-time quantitative PCR and western blot analysis, showed suppression of TLR-4 expression in KIGB-5 cells treated with EC-18 compared with control. In conclusion, EC-18 has a significant anti-tumor effect in this experimental model of biliary cancer suggesting potential for clinical application to this difficult cancer

Flaw-Containing Alumina Hollow Nanostructures Have Ultrahigh Fracture Strength To Be Incorporated into High-Efficiency GaN Light-Emitting Diodes

In the present study, we found that alpha-alumina hollow nanoshell structure can exhibit an ultrahigh fracture strength even though it contains a significant number of nanopores. By systematically performing in situ mechanical testing and finite element simulations, we could measure that the fracture strength of an alpha-alumina hollow nanoshell structure is about four times higher than that of the conventional bulk size alpha-alumina. The high fracture strength of the alpha-alumina hollow nanoshell structure can be explained in terms of conventional fracture mechanics, in that the position and size of the nanopores are the most critical factors determining the fracture strength, even at the nanoscales. More importantly, by deriving a fundamental understanding, we would be able to provide guidelines for the design of reliable ceramic nanostructures for advanced GaN light-emitting diodes (LEDs). To that end, we demonstrated how our ultrastrong alpha-alumina hollow nanoshell structures could be successfully incorporated into GaN LEDs, thereby greatly improving the luminous efficiency and output power of the LEDs by 2.2 times higher than that of conventional GaN LEDs

Phase transformation mechanism and hardness during ageing of an austenitic Fe-30Mn-10.5Al-1.1C-3Mo lightweight steel

The effects of an ageing treatment on the microstructural evolution and mechanical properties of austenite-based Fe-30Mn-10.5Al-1.1C-3Mo lightweight steel were investigated through a transmission electron microscopy (TEM) analyses and an atom probe tomography (APT) analyses. The solution-treated sample was aged at 675 °C for various holding periods up to 5 × 105 s. The initial microstructure of the solution-treated sample consisted of γ-austenite and ordered κ-(Fe,Mn)3AlC carbides, and it was found that the phase transformation sequence during ageing was as follows: γ + κ → γ + κ + D03 → γ + κ + D03 + β-Mn → γ + κ + (D03) + β-Mn + B2 → γ + κ + β-Mn + B2 → γ + κ + β-Mn + B2 + M6C. In the early stage of ageing, ordered D03 phases formed at the austenite grain boundaries (AGB), twin boundaries and austenite grain interior due to the decreased austenite stability caused by the precipitation of κ-carbides. After ageing for longer than 5000sec, β-Mn phases began to precipitate at the AGB and γ/D03 interphase, and then grew into the γ and D03 phases encroaching upon them. As the β-Mn phase grew, B2 phases newly formed in two ways. First, when the β-Mn phase grew into the D03 phase via the D03 to β-Mn transformation, the discontinuous precipitation of the B2 phase formed in the Al enriched zone caused by low solubility of Al in the β-Mn phase. Next, the B2 phase formed along the AGB inside the β-Mn phase regardless of the D03 phase, i.e., when the β-Mn phase nucleated at the AGB and grew into the austenite interior, the B2 phases precipitated in the Al enriched zone along the PAGB at the β-Mn interior. Finally, Mo-enriched M6C carbides formed around the B2 phases. Vickers hardness tests of solution-treated and aged samples were carried out. At the early stage of ageing, the Vickers hardness increased gradually due to the precipitation of the κ-carbides and D03 phases. With the formation of the β-Mn phase after ageing for more than 10000sec, the Vickers hardness increased dramatically. © 2019 Elsevier B.V.FALS

Investigations of the microstructure evolution and tensile deformation behavior of austenitic Fe-Mn-Al-C lightweight steels and the effect of Mo addition

A series of Fe-30 wt%Mn-10.5 wt%Al-1.1 wt%C steels with Mo addition from 0 to 5 wt% were prepared to investigate the effect of Mo on the microstructure and tensile deformation behavior of austenitic lightweight steel. When the Mo content was below 4 wt%, the microstructure of solution-treated samples consisted of austenite and kappa-carbide, while Mo-enriched M6C and M23C6 carbides were additionally precipitated in samples containing Mo more than 4 wt% during a solution treatment at 1050 degrees C. These carbides inhibited austenite grain growth during the solution treatment, resulting in significant grain refinement in the samples containing more that 4 wt% of Mo. Tensile test results showed that the yield strength gradually decreased with an increase in the Mo content up to 3 wt% due to the suppression of kappa-carbide precipitation, whereas it significantly increased when the Mo content exceeded 4 wt% due to grain refinement and precipitation strengthening caused by Mo-enriched carbides. During the tensile deformation, the strain hardening rates of all alloys increased and then the deformation mode subsequently changed with an increase in the Mo content from shearband-induced plasticity (SIP) to microband-induced plasticity (MBIP). Finally, the change in the kappa-carbide precipitation behavior upon the addition of Mo and its effect on the deformation behavior were carefully analyzed and discussed through nanoindentation experiments, first-principles calculations and atom probe tomography analyses. (C) 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.1

Atomistic investigations of kappa-carbide precipitation in austenitic Fe-Mn-Al-C lightweight steels and the effect of Mo addition

The effect of Mo addition on precipitation behavior of κ-(Fe,Mn)3AlC during aging in austenitic Fe-Mn-Al-C lightweight steels was investigated. First-principles calculations indicate that substitution of Fe or Mn by Mo in κ-carbide is energetically unfavorable in the respect to formation energy, and it, moreover, increases strain energy contribution to interfacial energy between austenite matrix and κ-carbide. Atom probe tomography (APT) and transmission electron microscopy (TEM) analysis showed the results consistent with the calculations, i.e., Mo didn't partition into κ-carbide and delayed κ-carbide precipitation. Finally, nanoindentation experiments presented that Mo addition changed the aging hardening behavior, corresponding to κ-carbide precipitation behavior. © 2016 Acta Materialia Inc.

Production of Flavonoids in Callus Cultures of Sophora flavescens Aiton

Flavonoids, including maackiain (Maac) from Sophora flavescens Aiton roots, have many pharmacological properties, such as antitumor, antimicrobial, and antifungal activities. This research aimed to develop an in vitro plant and callus culture system for S. flavescens for the purpose of generating an alternative production system for enhancing Maac production, as Maac is usually present in very small amounts in S. flavescens’ roots. We arranged the optimal conditions of different tissues of S. flavescens and supplemented the medium with various plant growth regulators (PGRs). The highest induction and proliferation rates of callus was shown in combination treatments of all concentrations of thidiazuron (TDZ) and picloram. In addition, calli induced with leaf explants cultured on 2.0 mg/L picloram and 0.5 mg/L 6-benzyladenine (BA) in Murashige and Skoog (MS) medium had the highest accumulation of the active metabolite Maac. In vitro shoots were regenerated on medium containing combinations of TDZ and α-Naphthalene acetic acid (NAA). A reliable protocol for the mass production of secondary metabolites using a callus culture of S. flavescens was successfully established

Characterization of microstructural evolution in austenitic Fe-Mn-Al-C lightweight steels with Cr content

The influence of Cr addition on the microstructures and tensile properties of Fe-20Mn-12Al-1.5C lightweight steels was investigated. Microstructural phases were thoroughly identified through scanning electron microscopy (SEM), transmission electron microscopy (TEM), electron backscatter diffraction (EBSD), and x-ray diffraction (XRD). Tensile behaviors were characterized using a tensile test and observation around fractured surface. Fe-20Mn-12Al-1.5C lightweight steel without Cr consisted of austenite with fine intragranular κ-carbides, coarse intergranular κ-carbides, and a small amount of ferrite. As Cr content increased to 5 wt%, coarse κ-carbides around grain boundaries disappeared and the fraction of ferrite slightly decreased, while the fraction of austenite slightly increased, leading to a homogenized microstructure consisting of mostly austenite with fine intragranular κ-carbides and a very small amount of ferrite and ordered phase DO3. This results from the addition of Cr, which is a carbide-forming element, which suppresses the formation of κ-carbides and consequently, austenite retains more stability due to an increase in the amount of carbon inside austenite. When Cr content exceeded 5 wt%, the fraction of DO3 increased drastically, the fraction of austenite reduced sharply, and Cr-rich M7C3 carbides precipitated. This is attributed to the role of Cr in steels, which is a carbide former as well as a ferrite stabilizer. As for tensile properties, tensile strength declined, and elongation improved with increasing Cr, up to 5 wt%. The decrease in tensile strength originates from the reduced κ-carbide fraction and growth in grain size, and the improvement in elongation is due to the reduction in coarse κ-carbides which act as crack initiation sites. As Cr content exceeded 5 wt%, the tensile strength increased, but the elongation decreased dramatically, owing to the precipitation of M7C3 carbides which are vulnerable to cracking. The steel containing 5 wt% of Cr showed the best tensile properties due to microstructural homogeneity, namely, a simple microstructure containing austenite with fine κ-carbides inside austenite and the low fraction of ordered phase DO3. © 2020 Elsevier Inc.FALS