Establishment of a Novel PDX Mouse Model and Evaluation of the Tumor Suppression Efficacy of Bortezomib Against Liposarcoma

The patient-derived xenograft (PDX) model has been adopted as a major tool for studying tumorigenesis and differentiation in various carcinomas. In addition, it has been used in the development of anticancer agents. PDX models have been among the most meaningful tools used to understand the role of stromal cells and vascular cells in the body, which are major factors in cancer development and the application of therapeutic agents. Also, the establishment of PDX models from liposarcoma patients is considered to be important for understanding lipomagenesis and following drugs development. For these reasons, we developed patient-derived cell (PDC) and PDX models derived from 20 liposarcoma patients. The tissues of these patients were obtained in accordance with the principles of the Samsung Medical Center's ethics policy, and cell culture and xenografting onto the mice were performed under these principles. High-throughput drug screening (HTS) was carried out using established PDCs to select candidate drugs. Among the different candidate anticancer drugs, we tested the effect of bortezomib, which was expected to inhibit MDM2 amplification. First, we confirmed that the PDCs maintained the characteristics of liposarcoma cells by assessing MDM2 amplification and CDK4 overexpression using fluorescence in situ hybridization. Analysis of short tandem repeats and an array using comparative genomic hybridization confirmed that the PDX model exhibited the same genomic profile as that of the patient. Immunohistochemistry for MDM2 and CDK4 showed that the overexpression patterns of both proteins were similar in the PDX models and the PDCs. Specifically, MDM2 amplification was observed to be significantly correlated with the successful establishment of PDX mouse models. However, CDK4 expression did not show such a correlation. Of the anticancer drugs selected through HTS, bortezomib showed a strong anticancer effect against PDC. In addition, we observed that bortezomib suppressed MDM2 expression in a dose-dependent manner. In contrast, p21 tended to elicit an increase in PDC expression. Treatment of the PDX model with bortezomib resulted in an anticancer effect similar to that seen in the PDCs. These results support that PDCs and PDX models are among the most powerful tools for the development and clinical application of anticancer drugs for the treatment of liposarcoma patients

Engineering electrical property of Dirac semimetal perovskite SrIrO3 thin films by subtle changes in lattice structure

We synthesized orthorhombic SrIrO3 thin films on SrTiO3(001) substrates by employing pulsed laser deposition with systematic variation of the growth temperature and laser fluence. Despite of the different growth conditions, the low temperature resistivity only varies in the m Omega cm range. However, the characteristic temperature dependence varies with the growth condition, and displays the so-called "insulator-like", "intermediate", or "metal-like" behavior. We found that the alternative of metal-like or insulator-like electrical property is relevant to subtle changes in the lattice structure of semi-metallic SrIrO3 likely caused by small rotations of the IrO6 octahedrons. (C) 2019 The Japan Society of Applied Physics11Nsciescopu

Strong Rashba parameter of two-dimensional electron gas at CaZrO3/SrTiO3 heterointerface

Abstract We synthesized a CaZrO3/SrTiO3 oxide heterostructure, which can serve as an alternative to LaAlO3/SrTiO3, and confirmed the generation of 2-dimensional electron gas (2-DEG) at the heterointerface. We analyzed the electrical-transport properties of the 2-DEG to elucidate its intrinsic characteristics. Based on the magnetic field dependence of resistance at 2 K, which exhibited Weak Anti-localization (WAL) behaviors, the fitted Rashba parameter values were found to be about 12–15 × 10–12 eV*m. These values are stronger than the previous reported Rashba parameters obtained from the 2-DEGs in other heterostructure systems and several layered 2D materials. The observed strong spin–orbit coupling (SOC) is attributed to the strong internal electric field generated by the lattice mismatch between the CaZrO3 layer and SrTiO3 substrate. This pioneering strong SOC of the 2-DEG at the CaZrO3/SrTiO3 heterointerface may play a pivotal role in the developing future metal oxide-based quantum nanoelectronics devices

Thickness driven spin reorientation transition of epitaxial LaCrO3 films

We grew fully strained epitaxial LaCrO3 (LCO) films on SrTiO3(001) under layer-by-layer control up to the film thickness of t = 130 nm using a pulsed laser deposition method. The spin axis of the antiferromagnetic LCO film was systematically examined as a function of t by using Cr L-2,L-3-edge x-ray magnetic linear dichroism (XMLD). The XMLD results manifest a spin reorientation transition (SRT) across a transition thickness of t(T) similar to 60 nm. This SRT is well explained in terms of two competing magnetic anisotropy energies of the surface/interface (K-S) and the LCO film itself (K-V). Published by AIP Publishing.11Nsciescopu

Overexpression of Replication-Dependent Histone Signifies a Subset of Dedifferentiated Liposarcoma with Increased Aggressiveness

Liposarcoma (LPS) is an adult soft tissue malignancy that arises from fat tissue, where well-differentiated (WD) and dedifferentiated (DD) forms are the most common. DDLPS represents the progression of WDLPS into a more aggressive high-grade and metastatic form. Although a few DNA copy-number amplifications are known to be specifically found in WD- or DDLPS, systematic genetic differences that signify subtype determination between WDLPS and DDLPS remain unclear. Here, we profiled the genome and transcriptome of 38 LPS tumors to uncover the genetic signatures of subtype differences. Replication-dependent histone (RD-HIST) mRNAs were highly elevated and their regulation was disrupted in a subset of DDLPS, increasing cellular histone molecule levels, as measured using RNA-seq (the averaged fold change of 53 RD-HIST genes between the DD and WD samples was 10.9) and immunohistochemistry. The change was not observed in normal tissues. Integrated whole-exome sequencing, RNA-seq, and methylation analyses revealed that the overexpressed HMGA2 (the fold change between DD and WD samples was 7.3) was responsible for the increased RD-HIST level, leading to aberrant cell proliferation. Therefore, HMGA2-mediated elevation of RD-HISTs were crucial events in determining the aggressiveness of DDLPS, which may serve as a biomarker for prognosis prediction for liposarcoma patients

Therapeutic strategies for locally recurrent and metastatic de-differentiated liposarcoma with herpes simplex virus-thymidine kinase-expressing mesenchymal stromal cells

Background aims. Major challenges in de-differentiated liposarcoma (DDLPS) therapy are the high rate of sequential recurrence (>80%) and metastasis (20-30%) following surgical removal. However, well-defined therapeutic strategies for this rare malignancy are lacking and are critically needed. Methods. We investigated a new approach to DDLPS therapy with mesenchymal stromal cells expressing herpes simplex virus thymidine kinase (MSC-TK). In an effort to evaluate this efficacy, in vitro cytotoxicity of MSC-TK against DDLPS cells was analyzed using an apoptosis assay. For pre-clinical study, the MSC-TK induced reduction in recurrence and metastasis was validated in a recurrent DDLPS model after the macroscopic complete resection and lung metastasis DDLPS model. Results. MSC-TK induced apoptosis in DDLPS cells by bystander effects via gap junction intracellular communication (GJIC) of toxic ganciclovir (GCV). Recurrent DDLPS models following no residual tumor/microscopic tumor resection and lung metastasis DDLPS models were established, which suggested clinical relevance. MSC-TK markedly reduced locoregional recurrence rates and prolonged recurrence-free survival, thus increasing overall survival in the recurrent DDLPS model. MSC-TK followed by GCV treatment yielded a statistically significant reduction in early and advanced-stage lung metastasis. Discussion. This therapeutic strategy may serve as an alternative or additional strategy by applying MSC-TK to target residual tumors following surgical resection, thus reducing local relapse and metastasis in these patients.112sciescopu

Octave-band Directional Decompositions

To my parents