The use of optically tunable gold nanoparticles (GNPs) in conjunction with near-infrared (NIR) laser has emerged as an attractive option for laser-induced thermal therapy (LITT), as it capitalizes on plasmonic heating of GNPs tuned to absorb light strongly in the NIR region. Previously, the authors developed a multisource model to predict the temperature change in a GNP-laden tissue-like medium illuminated by NIR laser and implemented it by a linear superposition (LS) method combining analytic and finite element method (FEM) solutions. While it is intuitive and straightforward, the LS approach might be somewhat cumbersome to implement for realistic LITT cases because it requires separate calculations of the temperature change due to individual GNP heat sources and the laser heat source. Therefore, the current investigation aimed to develop a simpler yet mathematically more elegant and computationally more efficient method solely based on FEM to implement the authors multisource model.
Cavitation is an intricate multiphase phenomenon that interplays with turbulence in fluid flows. It exhibits clear duality in characteristics, being both destructive and beneficial in our daily lives and industrial processes. Despite the multitude of occurrences of this phenomenon, highly dynamic and multiphase cavitating flows have not been fundamentally well understood in guiding the effort to harness the transient and localized power generated by this process. In a microscale, multiphase flow liquid injection system, we synergistically combined experiments using time-resolved x-radiography and a novel simulation method to reveal the relationship between the injector geometry and the in-nozzle cavitation quantitatively. We demonstrate that a slight alteration of the geometry on the micrometer scale can induce distinct laminar-like or cavitating flows, validating the multiphase computational fluid dynamics simulation. Furthermore, the simulation identifies a critical geometric parameter with which the high-speed flow undergoes an intriguing transition from non-cavitating to cavitating.
Glioblastoma multiforme (GBM) is the most common and prognostically unfavorable form of brain tumor. The aggressive and highly invasive phenotype of these tumors makes them among the most anatomically damaging human cancers with a median survival of less than 1 year. Although canonical Wnt pathway activation in cancers has been historically linked to the presence of mutations involving key components of the pathway (APC, ?-catenin, or Axin proteins), an increasing number of studies suggest that elevated Wnt signaling in GBM is initiated by several alternative mechanisms that are involved in different steps of the disease. Therefore, inhibition of Wnt signaling may represent a therapeutically relevant approach for GBM treatment. After the selection of a GBM cell model responsive to Wnt inhibition, we set out to develop a screening approach for the identification of compounds capable of modulating canonical Wnt signaling and associated proliferative responses in GBM cells. Here, we show that the small molecule SEN461 inhibits the canonical Wnt signaling pathway in GBM cells, with relevant effects at both molecular and phenotypic levels in vitro and in vivo. These include SEN461-induced Axin stabilization, increased ?-catenin phosphorylation/degradation, and inhibition of anchorage-independent growth of human GBM cell lines and patient-derived primary tumor cells in vitro. Moreover, in vivo administration of SEN461 antagonized Wnt signaling in Xenopus embryos and reduced tumor growth in a GBM xenograft model. These data represent the first demonstration that small-molecule-mediated inhibition of Wnt signaling may be a potential approach for GBM therapeutics.
Retrospective analysis to compare the effect and complication of epidural patient-controlled analgesia (epidural PCA) with intravenous patient-controlled analgesia (IV PCA) for the treatment of the post-operative pain after posterior lumbar instrumented fusion.
A conventional x-ray fluorescence computed tomography (XFCT) technique requires monochromatic synchrotron x-rays to simultaneously determine the spatial distribution and concentration of various elements such as metals in a sample. However, the synchrotron-based XFCT technique appears to be unsuitable for in vivo imaging under a typical laboratory setting. In this study we demonstrated, for the first time to our knowledge, the possibility of performing XFCT imaging of a small animal-sized object containing gold nanoparticles (GNPs) at relatively low concentrations using polychromatic diagnostic energy range x-rays. Specifically, we created a phantom made of polymethyl methacrylate plastic containing two cylindrical columns filled with saline solution at 1 and 2 wt% GNPs, respectively, mimicking tumors/organs within a small animal. XFCT scanning of the phantom was then performed using microfocus 110 kVp x-ray beam and cadmium telluride (CdTe) x-ray detector under a pencil beam geometry after proper filtering of the x-ray beam and collimation of the detector. The reconstructed images clearly identified the locations of the two GNP-filled columns with different contrast levels directly proportional to gold concentration levels. On the other hand, the current pencil-beam implementation of XFCT is not yet practical for routine in vivo imaging tasks with GNPs, especially in terms of scanning time. Nevertheless, with the use of multiple detectors and a limited number of projections, it may still be used to image some objects smaller than the current phantom size. The current investigation suggests several modification strategies of the current XFCT setup, such as the adoption of the quasi-monochromatic cone/fan x-ray beam and XFCT-specific spatial filters or pinhole detector collimators, in order to establish the ultimate feasibility of a bench-top XFCT system for GNP-based preclinical molecular imaging applications.
Gold nanoparticles can be engineered to target cancerous cells and at the same time designed to absorb specific wavelengths of light. Consequently, with the presence of optically tunable gold nanoparticles such as gold nanoshells, light can be effectively converted to heat via photothermal effect well enough to raise the temperature of medium surrounding gold nanoshells for thermal ablation or hyperthermia treatments of cancers. In this study, the authors proposed a new computational method to estimate thermal response of gold nanoshells embedded in a tissue-like medium when illuminated by a near-infrared (NIR) laser. Specifically, the light transport theory with diffusion approximation was initially applied to model the temperature rise within a medium without gold nanoshells as a result of the dissipation of the NIR laser power throughout the medium. After then, the heat generated by individual gold nanoshells due to photothermal effect was calculated and combined with the results for the medium without gold nanoshells to estimate the global elevation of temperature within the gold nanoshell-laden medium. The current computational model was tested for its validity using two different phantom examples, one of which was similar to a previously reported phantom experiment. The test demonstrated the capability of the current model in terms of producing qualitatively reasonable results, while it also revealed a number of potential differences in the assumptions for the current model and previous experiment. After an adjustment in the model parameters to properly take into account such differences, the computational results and the experimental data matched reasonably well within the average percentage difference of 10%.
Phosphotyrosine binding (PTB) domains, which are found in a large number of proteins, have been implicated in signal transduction mediated by growth factor receptors. However, the in vivo roles of these PTB-containing proteins remain to be investigated. Here, we show that Xdpcp (Xenopus dok-PTB containing protein) has a pivotal role in regulating mesendoderm formation in Xenopus, and negatively regulates the activin/nodal signaling pathway. We isolated cDNA for xdpcp and examined its potential role in Xenopus embryogenesis. We found that Xdpcp is strongly expressed in the animal hemisphere at the cleavage and blastula stages. The overexpression of xdpcp RNA affects activin/nodal signaling, which causes defects in mesendoderm formation. In addition, loss of Xdpcp function by injection of morpholino oligonucleotides leads to the expansion of the mesodermal territory. Moreover, we found that axis duplication by ventrally forced expression of activin is recovered by coexpression with Xdpcp. In addition, Xdpcp inhibits the phosphorylation and nuclear translocation of Smad2. Furthermore, we also found that Xdpcp interacts with Alk4, a type I activin receptor, and inhibits activin/nodal signaling by disturbing the interaction between Smad2 and Alk4. Taken together, these results indicate that Xdpcp regulates activin/nodal signaling that is essential for mesendoderm specification.
A series of new fine-tunable monodentate phosphite and phosphoramidite ligands based on carboranes have been synthesized and used for asymmetric Rh-catalyzed hydrogenation of prochiral olefins with the result of up to 99.8% ee. Dependence of the enantioselectivity on the electron-withdrawing or electron-donating properties of the carboranyl substituent has been studied.
We used ultrafast x radiography and developed a novel multiphase numerical simulation to reveal the origin and the unique dynamics of the liquid-jet-generated shock waves and their interactions with the jets. Liquid-jet-generated shock waves are transiently correlated to the structural evolution of the disintegrating jets. The multiphase simulation revealed that the aerodynamic interaction between the liquid jet and the shock waves results in an intriguing ambient gas distribution in the vicinity of the shock front, as validated by the ultrafast x-radiography measurements. The excellent agreement between the data and the simulation suggests the combined experimental and computational approach should find broader applications in predicting and understanding dynamics of highly transient multiphase flows.
Wnt signaling is implicated in a variety of developmental and pathological processes. The molecular mechanisms governing the secretion of Wnt ligands remain to be elucidated. Wntless, an evolutionarily conserved multipass transmembrane protein, is a dedicated secretion factor of Wnt proteins that participates in Drosophila melanogaster embryogenesis. In this study, we show that Xenopus laevis Wntless (XWntless) regulates the secretion of a specific Wnt ligand, XWnt4, and that this regulation is specifically required for eye development in Xenopus. Moreover, the Retromer complex is required for XWntless recycling to regulate the XWnt4-mediated eye development. Inhibition of Retromer function by Vps35 morpholino (MO) resulted in various Wnt deficiency phenotypes, affecting mesoderm induction, gastrulation cell movements, neural induction, neural tube closure, and eye development. Overexpression of XWntless led to the rescue of Vps35 MO-mediated eye defects but not other deficiencies. These results collectively suggest that XWntless and the Retromer complex are required for the efficient secretion of XWnt4, facilitating its role in Xenopus eye development.
Secreted Wnt morphogens are signaling molecules essential for embryogenesis, pathogenesis, and regeneration and require distinct modifications for secretion, gradient formation, and activity. Whether Wnt proteins can be posttranslationally inactivated during development and homeostasis is unknown. Here we identify, through functional cDNA screening, a transmembrane protein Tiki1 that is expressed specifically in the dorsal Spemann-Mangold Organizer and is required for anterior development during Xenopus embryogenesis. Tiki1 antagonizes Wnt function in embryos and human cells via a TIKI homology domain that is conserved from bacteria to mammals and acts likely as a protease to cleave eight amino-terminal residues of a Wnt protein, resulting in oxidized Wnt oligomers that exhibit normal secretion but minimized receptor-binding capability. Our findings identify a Wnt-specific protease that controls head formation, reveal a mechanism for morphogen inactivation through proteolysis-induced oxidation-oligomerization, and suggest a role of the Wnt amino terminus in evasion of oxidizing inactivation. TIKI proteins may represent potential therapeutic targets.
Although angiogenesis is crucial for tumor growth and metastasis, the molecular mechanisms controlling this process are not clearly understood. Here, we explore the role of Dab2 in tumor angiogenesis. We found that Dab2 is expressed in several cancer cells, including A549 lung cancer cells, but it is hardly detectable in SW480 colon cancer cells. Migration and Erk phosphorylation were enhanced in human umbilical vein endothelial cells (HUVECs) treated with the conditioned medium obtained from Dab2-overexpressing SW480 stable cells. In addition, vascular endothelial growth factor (VEGF) protein was strongly detected in conditioned medium derived from Dab2-overexpressing SW480 cells, and Erk phosphorylation enhanced by Dab2(+) CM was restored by VEGF inhibition. Moreover, Dab2 depletion in A549 cells led to a decrease in HUVEC migration and Erk phosphorylation. Furthermore, we show that Dab2 is required for the TGF?-induced gene expression of angiogenic factors such as VEGF and FGF2. Taken together, these results suggest that Dab2, which is expressed in cancer cells, is pivotal for endothelial cell migration by affecting VEGF expression.
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