Valproic Acid Downregulates the Expression of MGMT and Sensitizes Temozolomide-Resistant Glioma Cells

Temozolomide (TMZ) has become a key therapeutic agent in patients with malignant gliomas; however, its survival benefit remains unsatisfactory. Valproic acid (VPA) has emerged as an anticancer drug via inhibition of histone deacetylases (HDACs), but the therapeutic advantages of a combination with VPA and TMZ remain poorly understood. The main aim of the present study was to determine whether an antitumor effect could be potentiated by a combination of VPA and TMZ, especially in TMZ-resistant cell lines. A combination of VPA and TMZ had a significantly enhanced antitumor effect in TMZ-resistant malignant glioma cells (T98 and U138). This enhanced antitumor effect correlated with VPA-mediated reduced O6-methylguanine-DNA methyltransferase (MGMT) expression, which plays an important role in cellular resistance to alkylating agents. In vitro, the combination of these drugs enhanced the apoptotic and autophagic cell death, as well as suppressed the migratory activities in TMZ-resistant cell lines. Furthermore, in vivo efficacy experiment showed that treatment of combination of VPA and TMZ significantly inhibited tumor growth compared with the monotherapy groups of mice. These results suggest that the clinical efficacy of TMZ chemotherapy in TMZ-resistant malignant glioma may be improved by combination with VPA

Variation of lithium isotope geochemistry during basalt weathering and secondary mineral transformations in Hawaii

Lithium isotopes are a potential tracer of silicate weathering but the relationship between lithium isotope compositions and weathering state still need to be established with precision. Here, we report Li concentrations and Li isotope compositions of soils developed along a 4 million year humid-environment chronosequence in the Hawaiian Islands. Li concentrations are variable with depth and age, ranging from 0.24 to 21.3 ppm, and significant Li depletions (up to 92%) relative to parent basalts are systematically enhanced towards the surface. Our calculations show that the relative contribution from atmospheric deposits to the Li soil budget remains small, with a maximum contribution from dust Li of 20% at the oldest site. This is explained by the capacity of the weathering products to retain, within the profiles, the Li coming from basalt alteration, and allows us to explore more specifically the role of alteration processes on soil Li isotope signatures. The delta Li-7 values display a large range between -2.5 parts per thousand and + 13.9 parts per thousand. The youngest soils (0.3 ka) display the same delta Li-7 value as fresh basalt, regardless of depth, despite similar to 30% Li loss by leaching, indicating that there is little Li isotope fractionation during the incipient stage of weathering. delta Li-7 values for the older soils (>= 20 ka) vary non-linearly as a function of time and can be explained by progressive mineral transformations starting with the synthesis of metastable short-range order (nano-crystalline) minerals and followed by their transformation into relatively inert secondary minerals. Results highlight significant Li isotope fractionation during secondary mineral formation and in particular during Li uptake by kaolinite. Finally, we suggest that the non-monotonous evolution of the regolith delta Li-7 value over the last 4 Ma is consistent with climatic variations, where congruent release of Li isotopes occurs during warmer periods. (C) 2014 Elsevier Ltd. All rights reserved

Experimental investigation of Mg isotope fractionation during mineral dissolution and clay formation

International audienceSilicate minerals are a major Mg source to seawater through rivers and therefore it is important to determine the impact of dissolution and formation of Mg-rich primary and secondary minerals on the Mg isotope signature of natural waters. We dissolved biotite mineral in a plug flow reactor at controlled pH and T =25[degrees]C and synthesized TO- and TOT-phyllosilicates (lizardite and kerolite, respectively) at T =90, 150, and 250[degrees]C. All leaching solutions during biotite dissolution are enriched in light isotopes compared to the biotite sample, with a 1.1a[degrees] range of [DELTA].sup.26Mg.sub.biotite-solution. At pH=1, Mg isotopic steady-state between the solution and biotite is established after 600h, while at pH=5, it is never reached, even after 4months. A sequential leaching suggests that the solution [delta].sup.26Mg values depend mostly on a balance between the relative proportions of labile and structural Mg with different [delta].sup.26Mg values. Ca concentrations and elementary ratios measured in output solutions during the incipient stage of dissolution indicate non-negligible Mg contribution from small amount of disseminated carbonate phases present within the biotite sample. During synthetic clay formation, both TO and TOT clays are significantly enriched in heavy isotopes and follow Rayleigh fractionation equations for specific values of isotope fractionation factors. At T =250[degrees]C, a single isotope fractionation factor of 1.00059[+ or -]0.00014 can explain the Mg isotope evolution of both TO and TOT clays. A similar isotope fractionation factor of 1.00054[+ or -]0.00014 can be inferred from all TOT synthesized at T =90-250[degrees]C. A compilation of Mg isotope fractionation factors during secondary phase formation highlights a difference between field and experimental investigations at low temperature. More experiments are now necessary to determine the role of clay crystallochemistry at temperatures below 50[degrees]

Radiogenic and stable isotope measurement using a MC-ICP-MS

In this study, we presented newly developed analytical methods for radioactive, radiogenic, and stable isotopes using a multi-collector inductively coupled plasma mass spectrometer (MC-ICP-MS), where the elemental purification, and precision and accuracy were highlighted

Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells

Sphingosine kinase (SK) is involved in the growth of cells, including cancer cells. However, which of its two isotypes—SK1 and SK2—is more favorable for cancer growth remains unclear. Although PF-543 strongly and selectively inhibits SK1, its anticancer effect is not high, and the underlying reason remains difficult to explain. We previously determined that the tail group of PF-543 is responsible for its low metabolic stability (MS). In this study, compounds containing aromatic or aliphatic tails in the triazole group were synthesized, and changes in the SK-inhibitory effect and anticancer activity of PF-543 were assessed using pancreatic cancer cells. The compounds with aliphatic tails showed high inhibitory effects on pancreatic cancer cells but slightly lower selectivity for SK1. A compound with an introduced aliphatic tail activated protein phosphatase 2A (PP2A), showing an effect similar to that of FTY720. Molecular docking analysis revealed that the PP2A-binding form of this newly synthesized compound was different from that noted in the case of FTY720. This compound also improved the MS of PF-543. These results indicate that the tail structure of PF-543 influences MS

Control of magnetoelectric coupling in the Co2Y-type hexaferrites

We comprehensively investigated the magnetic, ferroelectric, and ME properties of Ba2-xSrxCo2(Fe1-yAly)(12)O-22 single crystals in broad doping ranges of Sr (1.0 <= x <= 1.8) and Al (0.00 <= y <= 0.08). Most of the investigated compounds exhibit an intriguing coexistence of two apparently competing magnetic phases: a transverse conical (TC) and alternating longitudinal conical (ALC) spin structure. The magnetic properties show that the Ba0.2Sr1.8Co2(Fe0.96Al0.04)(12)O-22 crystal has the highest ordering temperature and largest volume fraction of the ALC phase at zero H; further, after the application of an in-plane H, it exhibits a maximized volume fraction of the metastable TC phase, resulting in the highest ME susceptibility and electric polarization at all temperatures below 300 K. Our findings demonstrate that securing the thermal stability of the ALC phase is a crucial prerequisite to achieve optimized ME coupling in Co2Y-type hexaferrites, pointing to a general strategy applicable to other hexaferrites as well

Repair of Cranial Bone Defects Using rhBMP2 and Submicron Particle of Biphasic Calcium Phosphate Ceramics with Through-Hole

Recently a submicron particle of biphasic calcium phosphate ceramic (BCP) with through-hole (donut-shaped BCP (d-BCP)) was developed for improving the osteoconductivity. This study was performed to examine the usefulness of d-BCP for the delivery of osteoinductive rhBMP2 and the effectiveness on cranial bone regeneration. The d-BCP was soaked in rhBMP2 solution and then freeze-dried. Scanning electron microscope (SEM), energy dispersive spectroscopy (EDS), and Raman spectroscopy analyses confirmed that rhBMP2 was well delivered onto the d-BCP surface and the through-hole. The bioactivity of the rhBMP2/d-BCP composite was validated in MC3T3-E1 cells as an in vitro model and in critical-sized cranial defects in C57BL/6 mice. When freeze-dried d-BCPs with rhBMP2 were placed in transwell inserts and suspended above MC3T3-E1, alkaline phosphatase activity and osteoblast-specific gene expression were increased compared to non-rhBMP2-containing d-BCPs. For evaluating in vivo effectiveness, freeze-dried d-BCPs with or without rhBMP2 were implanted into critical-sized cranial defects. Microcomputed tomography and histologic analysis showed that rhBMP2-containing d-BCPs significantly enhanced cranial bone regeneration compared to non-rhBMP2-containing control. These results suggest that a combination of d-BCP and rhBMP2 can accelerate bone regeneration, and this could be used to develop therapeutic strategies in hard tissue healing

Continuous Patterning of Copper Nanowire-Based Transparent Conducting Electrodes for Use in Flexible Electronic Applications

Simple, low-cost and scalable patterning methods for Cu nanowire (NW)-based flexible transparent conducting electrodes (FTCEs) are essential for the widespread use of Cu NW FTCEs in numerous flexible optoelectronic devices, wearable devices, and electronic skins. In this paper, continuous patterning for Cu NW FTCEs <i>via</i> a combination of selective intense pulsed light (IPL) and roll-to-roll (R2R) wiping process was explored. The development of continuous R2R patterning could be achieved because there was significant difference in adhesion properties between NWs and substrates depending on whether Cu NW coated area was irradiated by IPL or not. Using a custom-built, R2R-based wiping apparatus, it was confirmed that nonirradiated NWs could be clearly removed out without any damage on irradiated NWs strongly adhered to the substrate, resulting in continuous production of low-cost Cu NW FTCE patterns. In addition, the variations in microscale pattern size by varying IPL process parameters/the mask aperture sizes were investigated, and possible factors affecting on developed pattern size were meticulously examined. Finally, the successful implementation of the patterned Cu NW FTCEs into a phosphorescent organic light-emitting diode (PhOLED) and a flexible transparent conductive heater (TCH) were demonstrated, verifying the applicability of the patterned FTCEs. It is believed that our study is the key step toward realizing the practical use of NW FTCEs in various flexible electronic devices