Irradiation-induced localization of IL-12-expressing mesenchymal stem cells to enhance the curative effect in murine metastatic hepatoma

Irradiation in conjunction with gene therapy is considered for efficient cancer treatment. Mesenchymal stem cells (MSCs), due to their irradiation-promotable tumor tropism, are ideal delivery vehicles for gene therapy. In this study, we investigated whether treatment with radiation and interleukin (IL)-12-expressing MSCs (MSCs/IL-12) exerts improved antitumor effects on murine metastatic hepatoma. HCa-I and Hepa 1-6 cells were utilized to generate heterotopic murine hepatoma models. Tumor-bearing mice were treated with irradiation or MSCs/IL-12 alone, or a combination. Monocyte chemoattractant protein-1 (MCP-1/CCL2) expression was assessed in irradiated hepatoma tissues to confirm a chemotactic effect. Combination treatment strategies were established and their therapeutic efficacies were evaluated by monitoring tumor growth, metastasis and survival rate. IL-12 expression was assessed and the apoptotic activity and immunological alterations in the tumor microenvironment were examined. MCP-1/CCL2 expression and localization of MSCs/IL-12 increased in the irradiated murine hepatoma cells. The antitumor effects, including suppression of pulmonary metastasis and survival rate improvements, were increased by the combination treatment with irradiation and MSCs/IL-12. IL-12 expression was increased in tumor cells, causing proliferation of cluster of differentiation 8(+) T-lymphocytes and natural killer cells. The apoptotic activity increased, indicating that the cytotoxicity of immune cells was involved in the antitumor effect of the combined treatment. Treatment with irradiation and MSCs/IL-12 showed effectiveness in treating murine metastatic hepatoma. IL-12-induced proliferation of immune cells played an important role in apoptosis of tumor cells. Our results suggest that treatment with irradiation and MSCs/IL-12 may be a useful strategy for enhancing antitumor activity in metastatic hepatoma. What's new? Mesenchymal stem cells (MSCs) are promising gene-delivery vehicles, with the potential to improve antitumor effects when used in combination with existing therapies. In the present study, the combined use of interleukin (IL)-12-expressing MSCs (MSCs/IL-12) and radiation therapy increased antitumor activity in murine metastatic hepatoma, a model that is representative of human metastatic hepatocellular carcinoma (HCC), which affects nearly half of HCC patients. Treatment with MSCs/IL-12 resulted in increased IL-12 expression in tumor cells and immune cell proliferation. Immune cell cytotoxicity, evidenced by increased apoptotic activity, appeared to play a role in MSCs/IL-12 augmentation of antitumor effects.1178Ysciescopu

Finite element analysis for normal pressure hydrocephalus: The effects of the integration of sulci.

Finite element analysis (FEA) is increasingly used to investigate the brain under various pathological changes. Although FEA has been used to study hydrocephalus for decades, previous studies have primarily focused on ventriculomegaly. The present study aimed to investigate the pathologic changes regarding sulcal deformation in normal pressure hydrocephalus (NPH). Two finite element (FE) models-an anatomical brain geometric (ABG) model and the conventional simplified brain geometric (SBG) model-of NPH were constructed. The models were constructed with identical boundary conditions but with different geometries. The ABG model contained details of the sulci geometry, whereas these details were omitted from the SBG model. The resulting pathologic changes were assessed via four biomechanical parameters: pore pressure, von Mises stress, pressure, and void ratio. NPH was induced by increasing the transmantle pressure gradient (TPG) from 0 to a maximum of 2.0 mmHg. Both models successfully simulated the major features of NPH (i.e., ventriculomegaly and periventricular lucency). The changes in the biomechanical parameters with increasing TPG were similar between the models. However, the SBG model underestimated the degree of stress across the cerebral mantle by 150% compared with the ABG model. The SBG model also overestimates the degree of ventriculomegaly (increases of 194.5% and 154.1% at TPG = 2.0 mmHg for the SBG and ABG models, respectively). Including the sulci geometry in a FEA for NPH clearly affects the overall results. The conventional SBG model is inferior to the ABG model, which accurately simulated sulcal deformation and the consequent effects on cortical or subcortical structures. The inclusion of sulci in future FEA for the brain is strongly advised, especially for models used to investigate space-occupying lesions.This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2013R1A1A1004827).This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.media.2015.05.00

Direct Observation of Localized Spin Antiferromagnetic Transition in PdCrO2 by Angle-Resolved Photoemission Spectroscopy

We report the first case of the successful measurements of a localized spin antiferromagnetic transition in delafossite-type PdCrO2 by angle-resolved photoemission spectroscopy (ARPES). This demonstrates how to circumvent the shortcomings of ARPES for investigation of magnetism involved with localized spins in limited size of two-dimensional crystals or multi-layer thin films that neutron scattering can hardly study due to lack of bulk compared to surface. Also, our observations give direct evidence for the spin ordering pattern of Cr3+ ions in PdCrO2 suggested by neutron diffraction and quantum oscillation measurements, and provide a strong constraint that has to be satisfied by a microscopic mechanism for the unconventional anomalous Hall effect recently reported in this system.X1118sciescopu

Light Higgsino from Axion Dark Radiation

The recent observations imply that there is an extra relativistic degree of freedom coined dark radiation. We argue that the QCD axion is a plausible candidate for the dark radiation, not only because of its extremely small mass, but also because in the supersymmetric extension of the Peccei-Quinn mechanism the saxion tends to dominate the Universe and decays into axions with a sizable branching fraction. We show that the Higgsino mixing parameter mu is bounded from above when the axions produced at the saxion decays constitute the dark radiation: mu \lesssim 300 GeV for a saxion lighter than 2m_W, and mu less than the saxion mass otherwise. Interestingly, the Higgsino can be light enough to be within the reach of LHC and/or ILC even when the other superparticles are heavy with mass about 1 TeV or higher. We also estimate the abundance of axino produced by the decays of Higgsino and saxion.Comment: 18 pages, 1 figure; published in JHE

Centralized Modularity of N-Linked Glycosylation Pathways in Mammalian Cells

Glycosylation is a highly complex process to produce a diverse repertoire of cellular glycans that are attached to proteins and lipids. Glycans are involved in fundamental biological processes, including protein folding and clearance, cell proliferation and apoptosis, development, immune responses, and pathogenesis. One of the major types of glycans, N-linked glycans, is formed by sequential attachments of monosaccharides to proteins by a limited number of enzymes. Many of these enzymes can accept multiple N-linked glycans as substrates, thereby generating a large number of glycan intermediates and their intermingled pathways. Motivated by the quantitative methods developed in complex network research, we investigated the large-scale organization of such N-linked glycosylation pathways in mammalian cells. The N-linked glycosylation pathways are extremely modular, and are composed of cohesive topological modules that directly branch from a common upstream pathway of glycan synthesis. This unique structural property allows the glycan production between modules to be controlled by the upstream region. Although the enzymes act on multiple glycan substrates, indicating cross-talk between modules, the impact of the cross-talk on the module-specific enhancement of glycan synthesis may be confined within a moderate range by transcription-level control. The findings of the present study provide experimentally-testable predictions for glycosylation processes, and may be applicable to therapeutic glycoprotein engineering

The mu problem and sneutrino inflation

We consider sneutrino inflation and post-inflation cosmology in the singlet extension of the MSSM with approximate Peccei-Quinn(PQ) symmetry, assuming that supersymmetry breaking is mediated by gauge interaction. The PQ symmetry is broken by the intermediate-scale VEVs of two flaton fields, which are determined by the interplay between radiative flaton soft masses and higher order terms. Then, from the flaton VEVs, we obtain the correct mu term and the right-handed(RH) neutrino masses for see-saw mechanism. We show that the RH sneutrino with non-minimal gravity coupling drives inflation, thanks to the same flaton coupling giving rise to the RH neutrino mass. After inflation, extra vector-like states, that are responsible for the radiative breaking of the PQ symmetry, results in thermal inflation with the flaton field, solving the gravitino problem caused by high reheating temperature. Our model predicts the spectral index to be n_s\simeq 0.96 due to the additional efoldings from thermal inflation. We show that a right dark matter abundance comes from the gravitino of 100 keV mass and a successful baryogenesis is possible via Affleck-Dine leptogenesis.Comment: 27 pages, no figures, To appear in JHE

Controlling the evolution of two-dimensional electron gas states at a metal/Bi2Se3 interface

We demonstrate that the evolution of a two-dimensional electron gas system at an interface of a metal and the model topological insulator (TI) Bi2Se3 can be controlled by choosing an appropriate kind of metal element and by applying a low temperature evaporation procedure. In particular, we find that only topological surface states (TSSs) can exist at a Mn/Bi2Se3 interface, which would be useful for implementing a TI-based device with surface current channels only. The existence of TSSs alone at the interface is confirmed by angle-resolved photoemission spectroscopy (ARPES). Based on the ARPES and core-level x-ray photoemission spectroscopy measurements, we propose a cation intercalation model to explain our findings.open1156sciescopu

Scale and Translation Invariant Methods for Enhanced Time-Frequency Pattern Recognition

Time-frequency (t-f) analysis has clearly reached a certain maturity. One can now often provide striking visual representations of the joint time-frequency energy representation of signals. However, it has been difficult to take advantage of this rich source of information concerning the signal, especially for multidimensional signals. Properly constructed time-frequency distributions enjoy many desirable properties. Attempts to incorporate t-f analysis results into pattern recognition schemes have not been notably successful to date. Aided by Cohen's scale transform one may construct representations from the t-f results which are highly useful in pattern classification. Such methods can produce two dimensional representations which are invariant to time-shift, frequency-shift and scale changes. In addition, two dimensional objects such as images can be represented in a like manner in a four dimensional form. Even so, remaining extraneous variations often defeat the pattern classification approach. This paper presents a method based on noise subspace concepts. The noise subspace enhancement allows one to separate the desired invariant forms from extraneous variations, yielding much improved classification results. Examples from sound classification are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47350/1/11045_2004_Article_181150.pd

Intrathecal injection of human umbilical cord blood-derived mesenchymal stem cells for the treatment of basilar artery dissection: a case report

<p>Abstract</p> <p>Introduction</p> <p>Basilar artery dissection is a rare occurrence, and is significantly associated with morbidity and mortality. To the best of our knowledge, we report the first case of basilar artery dissection treated with mesenchymal stem cells.</p> <p>Case presentation</p> <p>We present the case of a 17-year-old Korean man who was diagnosed with basilar artery dissection. Infarction of the bilateral pons, midbrain and right superior cerebellum due to his basilar artery dissection was partially recanalized by intrathecal injection of human umbilical cord blood-derived mesenchymal stem cells. No immunosuppressants were given to our patient, and human leukocyte antigen alloantibodies were not detected after cell therapy.</p> <p>Conclusions</p> <p>This case indicates that intrathecal injections of mesenchymal stem cells can be used in the treatment of basilar artery dissection.</p

The role of the RACK1 ortholog Cpc2p in modulating pheromone-induced cell cycle arrest in fission yeast

The detection and amplification of extracellular signals requires the involvement of multiple protein components. In mammalian cells the receptor of activated C kinase (RACK1) is an important scaffolding protein for signal transduction networks. Further, it also performs a critical function in regulating the cell cycle by modulating the G1/S transition. Many eukaryotic cells express RACK1 orthologs, with one example being Cpc2p in the fission yeast Schizosaccharomyces pombe. In contrast to RACK1, Cpc2p has been described to positively regulate, at the ribosomal level, cells entry into M phase. In addition, Cpc2p controls the stress response pathways through an interaction with Msa2p, and sexual development by modulating Ran1p/Pat1p. Here we describe investigations into the role, which Cpc2p performs in controlling the G protein-mediated mating response pathway. Despite structural similarity to Gβ-like subunits, Cpc2p appears not to function at the G protein level. However, upon pheromone stimulation, cells overexpressing Cpc2p display substantial cell morphology defects, disorientation of septum formation and a significantly protracted G1 arrest. Cpc2p has the potential to function at multiple positions within the pheromone response pathway. We provide a mechanistic interpretation of this novel data by linking Cpc2p function, during the mating response, with its previous described interactions with Ran1p/Pat1p. We suggest that overexpressing Cpc2p prolongs the stimulated state of pheromone-induced cells by increasing ste11 gene expression. These data indicate that Cpc2p regulates the pheromone-induced cell cycle arrest in fission yeast by delaying cells entry into S phase