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Purpose: To characterize the expression patterns of HDAC7 in patients with gastric cancer and evaluate the prognostic value of HDAC7 in gastric cancer. Methods: The expression of histone deacetylase 7 (HDAC7) was detected in paraffin-embedded gastric cancer samples from 86 patients by immunohistochemistry, and the differences in the expression of HDAC7 between cancerous and corresponding adjacent noncancerous tissues were compared using the Wilcoxon matched-pairs signed rank test. The correlation between HDAC7 expression and Ki-67 expression or clinicopathologic characteristics was evaluated using a Spearman rank correlation test. Prognostic outcomes that correlated with HDAC7 were examined using a Kaplan-Meier analysis and Cox proportional hazards model. Moreover, the effects of HDAC7 on the proliferation, migration and invasion of gastric cancer cells were investigated in vitro using human gastric carcinoma AGS cells. Results: We found that HDAC7 was downregulated in cancerous gastric tissues ( P = 0.0019). However, the expression of HDAC7 in cancerous gastric tissues positively correlated with Ki-67 expression ( P = 0.0325) and distant metastasis ( P = 0.020). Moreover, overall survival was shorter for patients expressing higher levels of HDAC7 in cancerous tissues ( P = 0.042). Mechanistically, the disruption of the HDAC7 gene attenuated the capacity of cell growth, migration and invasion and induced G0/G1 arrest in AGS cells. Conversely, forced ovperexpression of HDAC7 promoted cell growth, migration and invasion and G1/S transition in AGS cells. Conclusions: These results indicate that high HDAC7 expression in cancerous gastric tissues correlates with distant metastasis and predicts a poor prognosis for patients with gastric cancer. [ABSTRACT FROM AUTHOR]

In the present study, the neuroprotective effect of melatonin on arsenite-induced neurotoxicity was investigated in rat primary cultured cortical neurons. Incubation of melatonin prevented arsenite-induced neuronal cell loss in a concentration-dependent manner. Furthermore, melatonin significantly attenuated arsenite-induced elevation in microtubule-associated protein light chain 3 (LC3)-II levels, a biomarker of autophagy. Our fluorescent staining assay showed that melatonin decreased arsenite-induced elevation of co-localized fluorescent puncta of monodansylcadaverine (a specific marker of autophagic vacuoles) and lysotracker red (a specific marker of lysosomes), indicating that melatonin is capable of inhibiting arsenite-induced autophagy and autolysosome formation. Because 3-methyladenine (an autophagic inhibitor) attenuated the arsenite-reduced α-synuclein levels (a protein essential for the neurite outgrowth and synaptic plasticity), melatonin via inhibiting autophagy attenuated the arsenite-reduced α-synuclein levels. At the same time, melatonin ameliorated the arsenite-induced reduction in growth associated protein 43 (a hallmark protein of neurite outgrowth) and discontinuous neurites of rat primary cultured cortical neurons. In addition, melatonin was found to prevent arsenite-induced decreases in cytochrome c oxidase levels (a biomarker of mitochondrial mass) and elevation in co-localized fluorescent puncta of autolysosomes and cytochrome c oxidase. Moreover, melatonin prevented arsenite-induced reduction in peroxisome proliferator-activated receptor gamma co-activator 1 α, a transcriptional co-activator of mitochondrial biosynthesis. Taken together, melatonin may exert its neuroprotective action via inhibiting arsenite-induced autophagy and enhancing mitochondrial biogenesis and thus restoring α-synuclein levels, neuronal integrity, and mitochondrial mass in rat primary cultured cortical neurons. [ABSTRACT FROM AUTHOR]

Histone deacetylase (HDAC) inhibitors have been extensively investigated as therapeutic agents in cancer. However, the biological role of class IIa HDACs (HDAC4, 5, 7 and 9) in cancer cells, including multiple myeloma (MM), remains unclear. Recent studies show HDAC4 interacts with activating transcription factor 4 (ATF4) and inhibits activation of endoplasmic reticulum (ER) stress-associated proapoptotic transcription factor C/EBP homologous protein (CHOP). In this study, we hypothesized that HDAC4 knockdown and/or inhibition could enhance apoptosis in MM cells under ER stress condition by upregulating ATF4, followed by CHOP. HDAC4 knockdown showed modest cell growth inhibition; however, it markedly enhanced cytotoxicity induced by either tunicamycin or carfilzomib (CFZ), associated with upregulating ATF4 and CHOP. For pharmacological inhibition of HDAC4, we employed a novel and selective class IIa HDAC inhibitor TMP269, alone and in combination with CFZ. As with HDAC4 knockdown, TMP269 significantly enhanced cytotoxicity induced by CFZ in MM cell lines, upregulating ATF4 and CHOP and inducing apoptosis. Conversely, enhanced cytotoxicity was abrogated by ATF4 knockdown, confirming that ATF4 has a pivotal role mediating cytotoxicity in this setting. These results provide the rationale for novel treatment strategies combining class IIa HDAC inhibitors with ER stressors, including proteasome inhibitors, to improve patient outcome in MM. [ABSTRACT FROM AUTHOR]

A description is given of a functional silicon micromachined device that permits non-invasive, bidirectional, highly specific communication with cultured mammalian neurons. The heart of the system is a well structure that holds the cell in close proximity to a metal extracellular electrode while permitting normal outgrowth of axons and dendrites. An iterative approach is used to create a design that allows normal growth of the neurons while preventing their escape. An array of 16 such neurowells makes it possible to perform studies of biological neural network development and function with unprecedented detail. [ABSTRACT FROM AUTHOR]

Homologous recombination (HR), a mechanism to accurately repair DNA in normal cells, is deregulated in cancer. Elevated/deregulated HR is implicated in genomic instability and telomere maintenance, which are critical lifelines of cancer cells. We have previously shown that HR activity is elevated and significantly contributes to genomic instability in Barrett's esophageal adenocarcinoma (BAC). The purpose of this study was to evaluate therapeutic potential of HR inhibition, alone and in combination with telomerase inhibition, in BAC. We demonstrate that telomerase inhibition in BAC cells increases HR activity, RAD51 expression, and association of RAD51 to telomeres. Suppression of HR leads to shorter telomeres as well as markedly reduced genomic instability in BAC cells over time. Combination of HR suppression (whether transgenic or chemical) with telomerase inhibition, causes a significant increase in telomere attrition and apoptotic death in all BAC cell lines tested, relative to either treatment alone. A subset of treated cells also stain positive for β-galactosidase, indicating senescence. The combined treatment is also associated with decline in S-phase and a strong G2/M arrest, indicating massive telomere attrition. In a subcutaneous tumor model, the combined treatment resulted in the smallest tumors, which were even smaller (P=0.001) than those that resulted from either treatment alone. Even the tumors removed from these mice had significantly reduced telomeres and evidence of apoptosis. We therefore conclude that although telomeres are elongated by telomerase, elevated RAD51/HR assist in their maintenance/stabilization in BAC cells. Telomerase inhibitor prevents telomere elongation but induces RAD51/HR, which contributes to telomere maintenance/stabilization and prevention of apoptosis, reducing the efficacy of treatment. Combining HR inhibition with telomerase renders telomeres more vulnerable to degradation and significantly increases/expedites their attrition, leading to apoptosis. We therefore demonstrate that a therapy targeting HR and telomerase has the potential to prevent both tumor growth and genomic evolution in BAC. [ABSTRACT FROM AUTHOR]

The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50<200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM. [ABSTRACT FROM AUTHOR]

In the present study, the role of heme oxygenase (HO)-1 in sodium arsenite (arsenite)-induced neurotoxicity was investigated using primary cultured cortical neurons. Incubation with arsenite was found to cause cell death of primary cultured cortical neurons in concentration- and time-dependent manners. Furthermore, arsenite induced caspase 3 activation and decreased procaspase 12 levels, indicating that apoptosis is involved in the arsenite-induced neurotoxicity. The oxidative mechanism underlying arsenite-induced neurotoxicity was investigated. Western blot assay showed that arsenite significantly increased HO-1 levels, a redox-regulated protein. Co-incubation with glutathione (10 mM) attenuated arsenite-induced HO-1 elevation and caspase 3 activation, suggesting that oxidative stress is involved in the arsenite-induced neurotoxicity. The neurotoxic effects of inorganic arsenics were compared; arsenite was more potent than arsenate in inducing HO-1 expression and caspase 3 activation. Moreover, the cell viabilities of arsenite and arsenate were 60 ± 2 and 99 ± 2 % of control, respectively. HO-1 siRNA transfection was employed to prevent arsenite-induced HO-1 elevation. At the same time, arsenite-induced caspase 3 activation and neuronal death were attenuated in the HO-1 siRNA-transfected cells. Taken together, HO-1 appears to be neuroprotective in the arsenite-induced neurotoxicity in primary cultured cortical neurons. In addition to antioxidants, HO-1 elevation may be a neuroprotective strategy for arsenite-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

The purpose of these studies was to identify human leukocyte antigen (HLA)-A2(+) immunogenic peptides derived from XBP1 antigens to induce a multiple myeloma (MM)-specific immune response. Six native peptides from non-spliced XBP1 antigen and three native peptides from spliced XBP1 antigen were selected and evaluated for their HLA-A2 specificity. Among them, XBP1(184-192), XBP1 SP(196-204) and XBP1 SP(367-375) peptides showed the highest level of binding affinity, but not stability to HLA-A2 molecules. Novel heteroclitic XBP1 peptides, YISPWILAV or YLFPQLISV, demonstrated a significant improvement in HLA-A2 stability from their native XBP1(184-192) or XBP1 SP(367-375) peptide, respectively. Cytotoxic T lymphocytes generated by repeated stimulation of CD3(+) T cells with each HLA-A2-specific heteroclitic peptide showed an increased percentage of CD8(+) (cytotoxic) and CD69(+)/CD45RO(+) (activated memory) T cells and a lower percentage of CD4(+) (helper) and CD45RA(+)/CCR7(+) (naïve) T cells, which were distinct from the control T cells. Functionally, the cytotoxic T lymphocytes (CTL) demonstrated MM-specific and HLA-A2-restricted proliferation, interferon-γ secretion and cytotoxic activity in response to MM cell lines and importantly, cytotoxicity against primary MM cells. These data demonstrate the distinct immunogenic characteristics of unique heteroclitic XBP1 peptides, which induce MM-specific CTLs and highlights their potential application for immunotherapy to treat the patients with MM or its pre-malignant condition. [ABSTRACT FROM AUTHOR]

LBH589 is a novel pan-histone deacetylase (HDAC) inhibitor that has potent antitumor activity in multiple myeloma and other hematological malignancies. However, its impact on the immune system has not been defined. We here evaluated the effects of LBH589 on human myeloid dendritic cells (DCs) at clinically relevant concentrations. Exposure to LBH589 affected the surface molecule expression on immature and mature DCs, which was associated with DC maturation (CD83↓), antigen presentation (human leukocyte antigen-ABC↓) and T-cell co-stimulation (CD40↓ and CD86↑). LBH589 decreased both protein and polysaccharide antigen uptake capacities by DCs. Importantly, LBH589 impaired DC function to stimulate antigen-specific immune responses, resulting in the significant reduction of invariant natural killer T-cell (CD1d-restricted) and T-cell (major histocompatibility complex-restricted) activation in innate and adaptive immunity. LBH589 also significantly repressed the production of interleukin (IL)-6, IL-10, IL-12p70, IL-23 and tumor necrosis factor-α by Toll-like receptor (TLR)3 and TLR4-induced DC activation, indicating an important role of HDAC activity in immune regulation and inflammation. RelB, a component of the nuclear factor-κ B signaling pathway, was the key component regulated by HDAC inhibition in DCs. Together, our preclinical study demonstrates that LBH589 significantly impairs the phenotype and function of DCs, indicating a need for monitoring the immune status in patients receiving HDAC inhibitor therapy. It also provides a rationale to evaluate LBH589 activity for the treatment of inflammation. [ABSTRACT FROM AUTHOR]

This paper presents a three-dimensional, two-layer model for shallow geophysical mass flows, such as debris flows, hydraulic sediment transport, or sub-aquatic turbidity currents down arbitrary natural topographic terrains. The bottom layer is a dense granular fluid which interacts with the stagnant basal topography through an erosion/deposition mechanism. Above this layer is a lighter fluid layer. There is no mass exchange at the layer interface and at the free upper surface, and the materials in both layers are treated as density preserving. The intrinsic modelling equations are written in non-dimensional form and then formulated relative to a topography-adjusted coordinate system. The mass balance equations and momentum balance equations parallel to the bottom topography are depth-averaged over the layers. The emerging governing system of equations is subsequently simplified on the basis of problem-adapted scales, in which a small parameter ε, the shallowness parameter, plays a central role. The proposed ordering scheme is motivated by an earlier analysis, [1], and depends on the rheological complexities of the stress parameterizations of the two fluids. The ensuing equations are complemented by constitutive assumptions in each layer, at the bottom topography and at the layer interface. [ABSTRACT FROM AUTHOR]

We use the non-Cartesian, topography-based equations of mass and momentum balance for gravity driven frictional flows of Luca et al. (Math. Mod. Meth. Appl. Sci. 19, 127–171 (2009)) to motivate a study on various approximations of avalanche models for single-phase granular materials. By introducing scaling approximations we develop a hierarchy of model equations which differ by degrees in shallowness, basal curvature, peculiarity of constitutive formulation (non-Newtonian viscous fluids, Savage–Hutter model) and velocity profile parametrization. An interesting result is that differences due to the constitutive behaviour are largely eliminated by scaling approximations. Emphasis is on avalanche flows; however, most equations presented here can be used in the dynamics of other thin films on arbitrary surfaces. [ABSTRACT FROM AUTHOR]

A fundamental issue for describing gravity-driven flows over general topography is the search for an “optimal” coordinate. Bouchut and Westdickenberg [1] proposed an arbitrary coordinate system (BW) for general topography. The unified coordinate (UC) system (e.g., [2], [3]), which was developed for computational fluid dynamics, combines the advantages of both Eulerian and Lagrangian systems, so that the coordinates can instantaneously move with some singular surface within the flows. By utilizing the benefit of the BW coordinates and UC system, a new model of gravity-driven flows over general topography is derived, in which the erosion and deposition processes at the bed are considered. The depth-integrated mass and momentum equations are presented in the time-dependent and terrain-following coordinate system, which coincides with the interface distinguishing between the static and flowing layers. A shock-capturing numerical scheme is implemented to solve the derived equation system. Simulation results present the new features of this model and reveal a new physical insight of the erosion/deposition processes. [ABSTRACT FROM AUTHOR]

Bortezomib is a proteasome inhibitor for the treatment of relapsed/refractory multiple myeloma (MM). Mechanisms of resistance to Bortezomib are undefined. Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic protein, which protects tumor cells against spontaneous and chemotherapy-induced apoptosis. In MM, specific downregulation of Mcl-1 induces apoptosis. Here, we examined the role of Mcl-1 in Bortezomib- and doxorubicin-induced apoptosis. We demonstrate that Bortezomib, but not doxorubicin, triggers caspase-dependent generation of a 28 kDa Mcl-1-fragment, in several MM cell lines, including MM.1S cells. Conversely, transient transfection of MM.1S cells with a previously reported 28 kDa Mcl-1128–350 fragment, but not with the Mcl-11–127 fragment, induces apoptosis. Therefore, both downregulation of full-length antiapoptotic Mcl-1, as well as Bortezomib-induced generation of Mcl-1128–350 cleaved protein, contribute to MM cell apoptosis. To verify further these findings, we next compared effects triggered by Bortezomib, doxorubicin and melphalan in Mcl-1wt/wt and Mcl-1Δ/null murine embryonic fibroblasts (MEFs). Our results show that Bortezomib, but not doxorubicin or melphalan, triggers Mcl-1 cleavage in Mcl-1wt/wt, but not Mcl-1Δ/null MEFs and induces sub-G1 phase cells; caspase-3 and -9, and PARP cleavage as well as morphological signs of apoptosis. Taken together, these results support an important role of Mcl-1 and a Mcl-1 fragment in Bortezomib-induced cell death in general, and in MM in particular. To prevent relapse of MM in patients treated with Bortezomib, we therefore recommend the combination of Bortezomib with agents that induce MM cell death independent of Mcl-1.Oncogene (2008) 27, 721–731; doi:10.1038/sj.onc.1210679; published online 23 July 2007 [ABSTRACT FROM AUTHOR]

Internal tandem duplications (ITDs) of fms-like tyrosine kinase 3 (FLT3) receptor play an important role in the pathogenesis of acute myeloid leukemia (AML) and represent an attractive therapeutic target. ABT-869 has demonstrated potent effects in AML cells with FLT3-ITDs. Here, we provide further evidence that ABT-869 treatment significantly downregulates cyclins D and E but increases the expression of p21 and p27. ABT-869 induces apoptosis through downregulation of Bcl-xL and upregulation of BAK, BID and BAD. We also evaluate the combinations of ABT-869 and chemotherapy. ABT-869 demonstrates significant sequence-dependent synergism with cytarabine and doxorubicin in cell lines and primary leukemia samples. The optimal combination was validated in MV4-11 xenografts. Low-density array analysis revealed the synergistic interaction involved in downregulation of cell cycle and mitogen-activated protein kinase pathway genes. CCND1 and c-Mos were the most significantly inhibited targets on both transcriptional and translational levels. Treatment with short hairpin RNAs targeting either CCND1 or c-Mos further sensitized MV4-11 cells to ABT-869. These findings suggest that specific pathway genes were further targeted by adding chemotherapy and support the rationale of combination therapy. Thus, a clinical trial using sequence-dependent combination therapy with ABT-869 in AML is warranted. [ABSTRACT FROM AUTHOR]

We analyzed 18F-dopa PET data from 11 members of kindreds with familial progressive supranuclear palsy (PSP) to characterize their cerebral dopaminergic dysfunction. Three clinically-affected PSP patients showed reduced 18F-dopa uptake in the striatum, orbitofrontal cortex and amygdala. One asymptomatic subject exhibited progressive putamen dopaminergic dysfunction. 60% of subjects with abnormal 18F-dopa scans developed PSP subsequently. This is the first in vivo documentation of cortical dopaminergic deficiency in PSP. Reduced striatal 18F-dopa uptake in susceptible relatives may predict later clinical disease. [ABSTRACT FROM AUTHOR]

We have previously reported the fabrication of a nanocomposite from dodecanethiol-capped Au nanoparticles (average diameter 2.6 nm) and a silica aerogel. It was found that the Au particles were efficiently adsorbed on a silica wet-gel in organic solvents. In this paper, surface analysis of the silica surface and evaluation of adsorption rates for various solvents, performed to elucidate the nature of the interaction between the capped nanoparticles and the silica gel, are described. These observations indicate that dipole-induced dipole interaction between OH groups on the silica surface and metal cores of the nanoparticles is probably important for the adsorption. It was demonstrated that, by changing the solvent polarity, spatial distribution of the nanoparticles inside the gel can be controlled. [ABSTRACT FROM AUTHOR]

We have prepared titania aerogel and titania-coated silica aerogel incorporating thiol-capped Au nanoparticles. Both composite materials showed high CO oxidation activity after they were calcined at 673 K. Compositional and morphological changes driven by calcination were evaluated with thermogravimetry and X-ray diffractometry. From the results, it was suggested that the nanoparticles transformed from a faulted to a near-regular FCC structure presumably in concert with the formation of firm contacts between the nanoparticles and the gel substrates. While the diameters of the Au particles in the titania aerogel considerably increased upon calcination, those in the titania-coated silica aerogel were almost unchanged. As a consequence, the latter composite aerogel showed higher activity for oxidation of CO. [ABSTRACT FROM AUTHOR]

Fragmentation of germanium and tin cluster ions (Gex+, Snx+ : x = 4∼20) in the low-energy collisions with a Si surface has been investigated by means of a tandem time-of-flight mass spectrometer. At low incident energies, smaller clusters fragmented by an atom loss process, whereas larger clusters decayed by fission. The favored fragmentation paths for both cluster ions were similar to those for Si cluster ions. The results support the structural similarities among Si, Ge, and Sn clusters in the present size range. For tin cluster ions, low-energy fragmentation patterns were compared with those obtained from theoretical calculations using generalized gradient approximation (GGA) and the B3PW91 exchange-correlation functional. It has been found that the B3PW91 hybrid functional results are consistent with the experimental observations. [ABSTRACT FROM AUTHOR]

Prothrombin, a protein involved in blood coagulation, is a plasma glycoprotein composed of the Gla domain, two adjacent kringle domains, and a serine protease domain. Kringles are triple-disulfide-loop folding domains, which are found in several other blood proteins. In this study, we showed that recombinant human prothrombin kringle-1, -2, and -1-2 (rk-1, -2, -1-2) all have potent anti-angiogenic activities, which inhibit Lewis lung carcinoma (LLC) tumor growth and metastases. Recombinant human prothrombin kringles were expressed by an E. coli expression system and purified to apparent homogeneity from crude E. coli extracts. Purified rk-1, -2, -1-2 migrated with a molecular mass of 14, 19, and 31 kDa, respectively, on sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions. rk-1, -2, -1-2 exhibited potent inhibitory effects on bFGF-stimulated bovine capillary endothelial cell growth with half-maximal concentrations (ED50) of approximately 41, 55, and 156 nM, respectively. All of the recombinant human prothrombin kringles also inhibited angiogenesis in the chorioallantoic membrane (CAM) of chick embryos at a dose of 20 μg. Systemic administration of rk-1, -2, -1-2 at a dose of 0.5 mg/kg/day suppressed the growth of primary LLC and at dose of 0.5 and 1.0 mg/kg/day inhibited LLC metastases in C57BL6/J mice lungs through their anti-angiogenic effects. [ABSTRACT FROM AUTHOR]

Increased angiogenesis has recently been recognized in active multiple myeloma (MM). Since vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are two key mediators of angiogenesis, we characterized the production of VEGF, b-FGF and interleukin-6 (IL-6) (a MM growth and survival factor) in MM cell lines and Epstein-Barr virus (EBV) transformed B cell lines from MM patients, patient MM cells, as well as bone marrow stromal cells (BMSCs) from normal healthy donors and MM patients. We detected secretion of VEGF, but no bFGF and IL-6, in MM cell lines (MM.1S, RPMI 8226 and U266); EBV transformed B cell lines from MM patients (IM-9, HS-Sultan and ARH77); MM cell lines resistant to doxorubicin (RPMI-DOX40), mitoxantrone (RPMI-MR20), melphalan (RPMI-LR5) and dexamethasone (MM.1R); and patient MM cells (MM1 and MM2). BMSCs from MM patients and normal donors secreted VEGF, b-FGF and IL-6. Importantly, when MM cells were adhered to BMSCs, there was a significant increase in VEGF (1.5- to 3.1-fold) and IL-6 (1.9- to 56-fold) secretion. In contrast, the bFGF decreased in co-cultures of BMSCs and MM cells. Paraformaldehyde fixation of BMSCs or MM cells prior to adhesion revealed that VEGF was produced both from BMSCs and MM cells, though it may come primarily from BMSCs in some cultures. IL-6 was produced exclusively in BMSCs, rather than MM cells. Moreover, when MM cells were placed in Transwell insert chambers to allow their juxtaposition to BMSCs without cell to cell contact, induction of VEGF and IL-6 secretion persisted, suggesting the importance of humoral factors. Addition of exogenous IL-6 (10 ng/ml) increased VEGF secretion by BMSCs. Conversely, VEGF (100 ng/ml) significantly increased IL-6 secretion by BMSCs. Moreover, anti-human VEGF (1 microg/ml) and anti-human IL-6 (10 microg/ml) neutralizing antibodies reduced IL-6 and VEGF secretion, respectively, in cultures of BMSCs alone and co-cultures of BMSCs and MM cells. Finally, thalidomide (100 microM) and its immunomodulatory analog IMiD1-CC4047 (1 microM) decreased the upregulation of IL-6 and VEGF secretion in cultures of BMSCs, MM cells and co-cultures of BMSCs with MM cells. These data demonstrate the importance of stromal-MM cell interactions in regulating VEGF and IL-6 secretion, and suggest additional mechanisms whereby thalidomide and IMiD1-CC4047 act against MM cells in the BM millieu. [ABSTRACT FROM AUTHOR]

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The fluorescence detected ESR (ODESR) spectrum and X-induced and UV-excited fluorescence spectra were successfully obtained for ethylene propylene rubber doped with pyrene under various conditions. From the analysis of the ODESR intensity and its line-width, it was found that charge hopping between the solute pyrenes is the main mechanism for geminate recombination at the pyrene content larger than 0.3 wt%. At elevated temperatures, the excimer fluorescence relative to the monomer fluorescence induced by X-ray excitation is considerably stronger than that by UV-excitation, especially at high concentrations. On the other hand, at lower temperatures below ca. 280 K this difference could not be observed even at high concentration of 3.0 wt%. These observations indicate that the dimer cation formation, from which the excimer fluorescence is efficiently emitted, is accelerated by the hopping of cation-radical center to the clustering pyrenes at high temperatures and high concentrations. While only the electron hopping takes place at low temperatures, thus whether a charge recombination results in excimer formation or not is determined by the cationic trapping site, i.e. if several pyrenes are clustering there, excimer may be formed regardless of the excitation source. Although rapid translational motion is restricted in ethylene propylene rubber, the effective formation of excimer or dimer cation at high temperatures indicates that rotational diffusion and small distance translational diffusion are allowed within the fluorescence lifetime at those temperatures. [ABSTRACT FROM AUTHOR]

The alumina particles have been generated by a magnetron sputtering - gas aggregation method. The analyses of transmission electron microscope (TEM) images and electron diffraction patterns revealed some of the particles are tiny crystals of θ-alumina. The dependence of the particle size on the geometry and the temperature of the source exit has been studied. [ABSTRACT FROM AUTHOR]

Elevation in intracellular Ca2+ acting via protein kinase C (PKC) is shown to regulate tight junction resistance in T84 cells, a human colon cancer line and a model Cl- secretory epithelial cell. The Ca2+ ionophore A23187, which was used to increase the intracellular Ca2+ concentration, caused a decrease in tight junction resistance in a concentration- and time-dependent manner. Dual Na+/mannitol serosal-to-mucosal flux analysis performed across the T84 monolayers treated with 2 microM A23187 revealed that A23187 increased both fluxes and that in the presence of ionophore there was a linear relationship between the Na+ and mannitol fluxes with a slope of 56.4, indicating that the decrease in transepithelial resistance was due to a decrease in tight junction resistance. Whereas there was no effect of 0.1 microM A23187, 1 or 2 microM produced a 55% decrease in baseline resistance in 1 hr and 10 microM decreased resistance more than 80%. The A23187-induced decrease in tight junction resistance was partially reversible by washing 3 times with a Ringer's-HCO3 solution containing 1% BSA. The A23187 effect on resistance was dependent on intracellular Ca2+; loading the T84 cells with the intracellular Ca2+ chelator BAPTA significantly reduced the decrease in tight junction resistance caused by A23187. This intracellular Ca2+ effect was mediated by protein kinase C and not calmodulin. While the protein kinase C antagonist H-7 totally prevented the action of A23187 on tight junction resistance, the Ca2+/calmodulin inhibitor W13 did not have any effect. Sphingosine, another inhibitor of PKC, partially reduced the A23187-induced decline in tight junction resistance. The PKC agonist PMA mimicked the A23187 effect on resistance, although the effect was delayed up to 1 hr after exposure. In addition, however, PMA also caused an earlier increase in resistance, indicating it had an additional effect in addition to mimicking the effect of elevating Ca2+. The effects of a phospholipase inhibitor (mepacrine) and of inhibitors of arachidonic acid metabolism (indomethacin for the cyclooxygenase pathway, NDGA for the lipoxygenase pathway, and SKF 525A for the epoxygenase pathway) on the A23187 action were also examined. None of these agents altered the A23187-induced decrease in resistance. Monolayers exposed to 2 microM A23187 for 1 hr were stained with fluorescein conjugated phalloidin, revealing that neighboring cells did not part one from another and that A23187 did not have a detectable effect on distribution of F-actin in the perijunctional actomyosin ring. The results indicate that elevation in intracellular Ca2+ decreases tight junction resistance in the T84 monolayer, acting through protein kinase C by a mechanism which does not involve visible changes in the perijunctional actomyosin ring. [ABSTRACT FROM AUTHOR]

The relationships among ion current, membrane potential difference, and resistance of an epithelium are studied. The short-circuit technique introduced by Ussing and Zerahn does not completely short circuit the epithelium if the series resistance parallel to the cell layer between the voltage electrodes is not properly compensated. The residual potential difference across the epithelial cell layer in the 'short-circuit state' is proportional to both the measured short-circuit current and the resistance of the diffusion barriers not compensated. In the conventionally short-circuited small intestinal mucosa the villus and crypt areas are hypo-polarized to different degrees rather than simultaneously hyper- and hypo-polarized. Short-circuiting the whole tissue reduces but does not abolish the passive net ion movement across the tissue. Measurements of the electrical properties of the whole and denuded rat distal small intestine in HCO-Ringer solution containing 10 mm glucose reveal that the measured short-circuit current has under-estimated approximately 33% of the true short-circuit current and that the passive net Na flux from serosa to mucosa and Cl flux from mucosa to serosa are not negligible in the 'short-circuit state'. [ABSTRACT FROM AUTHOR]

In order to enhance the electrogenerative leaching rate of sphalerite reasonably, the basic principle of generative process was applied to the simultaneous leaching of sphalerite in the presence of MnO2. It was confirmed by experimental results that both mental ions and electric energy could be obtained in the simultaneous electrogenerative leaching process. The leaching cell had the open circuit potential about 1.0 V, about 2000 C of electric quantity was obtained, the optimal leaching ratio of Zn2+ and Mn2+ was 48.5, 39.6% respectively, after electrogenerative leaching for 11 h. [ABSTRACT FROM AUTHOR]

Plasma desorption mass spectrometry has been applied to characterization of dodecanthiol-passivated gold nanoparticles. An overview of the experimental set-up and mass analyses for the nanoparticles prepared in different conditions are shown. Mass distributions were found to shift to higher mass regions with increasing reaction temperature and reaction period. The results are consistent with those of transmission electron microscopy observations, UV-visible absorption spectra and also with a reported laser desorption mass spectrometry. [ABSTRACT FROM AUTHOR]

The structure of silica acrogel, a porous low density material having small particle size prepared from TMOS has been investigated by DSC, SAXS, and Raman spectroscopy. The predominant particle size of the aerogel were determined to be near 3 nm by SAXS analysis. The Raman spectra are qualitatively similar to those from fused silica, although the sample before heat treatment had typical Raman peaks assigned to organic groups contained in TMOS. The observed relatively intense peaks at near 490 and 606 cm suggest the existence of small rings, e.g., six(3-SiO) or eight(4-SiO) membered, in the aerogel. The structure change of the aerogel with temperature was also studied by Raman spectroscopy. [ABSTRACT FROM AUTHOR]

A 20-year-old male who sustained a severe avulsion injury of his left scalp and face together with a cranial bone fracture on his right temple six years previously, presented with extensive alopecia over the left temporal scalp. There was also a depression in the right temple with complex scarring caused by previous operations. A simultaneous complete reconstruction of the scalp defect and the depression was obtained by expansion of the left temporoparietal scalp, followed by free-flap transfer of the expanded tissue and augmentation with a free scapular flap. The end result was very satisfactory. [ABSTRACT FROM AUTHOR]

The article discusses the concepts of a routine laparoscopic single-stitch omental patch repair for perforated peptic ulcer. Experts believed that stringent selection and conversion criteria are paramount to ensure safety and satisfactory outcome with the technique. Further randomized controlled trials are required to establish its role as treatment of choice in the management of perforated peptic ulcer disease.

In order to enhance the electrogenerative leaching rate of sphalerite reasonably, the basic principle of generative process was applied to the simultaneous leaching of sphalerite in the presence of MnO2. It was confirmed by experimental results that both mental ions and electric energy could be obtained in the simultaneous electrogenerative leaching process. The leaching cell had the open circuit potential about 1.0 V, about 2000 C of electric quantity was obtained, the optimal leaching ratio of Zn2+ and Mn2+ was 48.5, 39.6% respectively, after electrogenerative leaching for 11 h. [ABSTRACT FROM AUTHOR]

Enzymatic compartments, inspired by cell compartmentalization, which bring enzymes and substrates together in confined environments, are of particular interest in ensuring the enhanced catalytic efficiency and increased lifetime of encapsulated enzymes. Herein, we constructed bioinspired enzymatic compartments (TPE-Q18H@GPs) with semi-permeability by spatiotemporally controllable self-assembly of catalytic peptide TPE-Q18H in hollow porous glucan particles (GPs), allowing substrates and products to pass in/out freely, while enzymatic aggregations were retained. Due to the enrichment of substrates and synergistic effect of catalytic nanofibers formed in the confined environment, the enzymatic compartments exhibited stronger substrate binding affinity and over two-fold enhancement of second-order kinetic constant (k cat /K m ) compared to TPE-Q18H nanofibers in disperse system. Moreover, GPs enabled the compartments sufficient stability against perturbation conditions, such as high temperature and degradation. This work opens an intriguing avenue to construct enzymatic compartments using porous biomass materials and has fundamental implications for constructing artificial organelles and even artificial cells., (© 2022. The Author(s).)