<i>KMT2C</i> Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition

Cho, Soo-Jeong,Yoon, Changhwan,Lee, Jun Ho,Chang, Kevin K.,Lin, Jian-xian,Kim, Young-Ho,Kook, Myeong-Cherl,Aksoy, Bu¨lent Arman,Park, Do Joong,Ashktorab, Hassan,Smoot, Duane T.,Schultz, Nikolaus,Yoon, American Association for Cancer Research 2018 Clinical Cancer Research Vol.24 No.24

<P><B>Purpose:</B></P><P>Lauren diffuse-type gastric adenocarcinomas (DGAs) are generally genomically stable. We identified lysine (K)-specific methyltransferase 2C (<I>KMT2C</I>) as a frequently mutated gene and examined its role in DGA progression.</P><P><B>Experimental Design:</B></P><P>We performed whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy. Lysine (K)-specific methyltransferase 2C (<I>KMT2C</I>) was analyzed in DGA cell lines and in patient tumors.</P><P><B>Results:</B></P><P><I>KMT2C</I> was the most frequently mutated gene (11 of 27 tumors [41%]). KMT2C expression by immunohistochemistry in tumors from 135 patients with DGA undergoing gastrectomy inversely correlated with more advanced tumor stage (<I>P</I> = 0.023) and worse overall survival (<I>P</I> = 0.017). KMT2C shRNA knockdown in non-transformed HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47- to 88-fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52% to 60%, and reduced cell invasion by 50% to 74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared with wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77% to 78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis.</P><P><B>Conclusions:</B></P><P><I>KMT2C</I> is frequently mutated in certain populations with DGA. KMT2C loss in DGA promotes EMT and is associated with worse overall survival.</P>

Structure and Magnetic Entropy Change in Melt-spun MnFePGe

A. Yan,K.-H. Muller,L. Schultz,O. Gutfleisch,Artikel I 한국자기학회 2007 한국자기학회 학술연구발표회 논문개요집 Vol.- No.-

Arc-length and explicit methods for static analysis of prestressed concrete members

Bulent Mercan,Henryk K. Stolarski,Arturo E. Schultz 사단법인 한국계산역학회 2016 Computers and Concrete, An International Journal Vol.18 No.1

This paper compares the arc-length and explicit dynamic solution methods for nonlinear finite element analysis of prestressed concrete members subjected to monotonically increasing loads. The investigations have been conducted using an L-shaped, prestressed concrete spandrel beam, selected as a highly nonlinear problem from the literature to give insight into the advantages and disadvantages of these two solution methods. Convergence problems, computational effort, and quality of the results were investigated using the commercial finite element package ABAQUS. The work in this paper demonstrates that a static analysis procedure, based on the arc-length method, provides more accurate results if it is able to converge on the solution. However, it experiences convergence problems depending upon the choice of mesh configuration and the selection of concrete post-cracking response parameters. The explicit dynamic solution procedure appears to be more robust than the arc-length method in the sense that it provides acceptable solutions in cases when the arc-length approach fails, however solution accuracy may be slightly lower and computational effort may be significantly larger. Furthermore, prestressing forces must be introduced into the finite element model in different ways for the explicit dynamic and arc-length solution procedures.

On the Superposition of Strengthening Mechanisms in Dispersion Strengthened Alloys and Metal-Matrix Nanocomposites: Considerations of Stress and Energy

J. B. Ferguson,Benjamin F. Schultz,Dev Venugopalan,Hugo F. Lopez,Pradeep K. Rohatgi,Kyu Cho,Chang-Soo Kim 대한금속·재료학회 2014 METALS AND MATERIALS International Vol.20 No.2

Yield strength improvement in dispersion strengthened alloys and nano particle-reinforced composites bywell-known strengthening mechanisms such as solid solution, grain refinement, coherent and incoherentdispersed particles, and increased dislocation density resulting from work-hardening can all be describedindividually. However, there is no agreed upon description of how these mechanisms combine to determinethe yield strength. In this work, we propose an analytical yield strength prediction model combiningarithmetic and quadratic addition approaches based on the consideration of two types of yielding mechanisms;stress-activated and energy-activated. Using data available in the literature for materials of differinggrain sizes, we consider the cases of solid solutions and coherent precipitates to show that they followstress-activated behavior. Then, we applied our model with some empirical parameters to precipitationhardenablematerials of various grain sizes in both coherent and incoherent precipitate conditions, whichdemonstrated that grain boundary and Orowan-strengthening can be treated as energy-activated mechanisms.

Impact of Brownian Motion on the Particle Settling in Molten Metals

J. B. Ferguson,Benjamin F. Schultz,Pradeep K. Rohatgi,Chang-Soo Kim 대한금속·재료학회 2014 METALS AND MATERIALS International Vol.20 No.4

Understanding the settling behavior of nanoparticles in molten metals/alloys is important as it will aid inachieving uniform dispersions of reinforcement particles in metal matrix nanocomposites. Uniform dispersionsare necessary to activate the Orowan strengthening mechanism, which can increase yield strengthwithout significant diminishment of ductility. In this work, an analytical model of particle size effects onsettling is described that takes into account both deterministic Stokes' law and stochastic Brownian motion. The model shows a clear transitional behavior where settling velocity follows Stokes' law for large particlesand then drops to zero for small particles implying that Brownian motion predominates. It indicatedthat, in the Brownian motion regime, where the discrete nature of the liquid must be considered, the randommotion imparted by unbalanced collisions can overwhelm the motions normally imposed by forces such asgravity, viscous drag, and thermal/concentration gradients.

Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia

Laborda, Eduardo,Mazagova, Magdalena,Shao, Sida,Wang, Xinxin,Quirino, Herlinda,Woods, Ashley K.,Hampton, Eric N.,Rodgers, David T.,Kim, Chan Hyuk,Schultz, Peter G.,Young, Travis S. MDPI 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.11

<P>The treatment of patients with acute myeloid leukemia (AML) with targeted immunotherapy is challenged by the heterogeneity of the disease and a lack of tumor-exclusive antigens. Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric antigen receptor (CAR)-engineered T-cells (CAR-T-cells), a therapy that has been highly successful in the treatment of B-cell leukemia and lymphoma. However, CD33 and CD123 are present on hematopoietic stem cells, and targeting with CAR-T-cells has the potential to elicit long-term myelosuppression. C-type lectin-like molecule-1 (CLL1 or CLEC12A) is a myeloid lineage antigen that is expressed by malignant cells in more than 90% of AML patients. CLL1 is not expressed by healthy Hematopoietic Stem Cells (HSCs), and is therefore a promising target for CAR-T-cell therapy. Here, we describe the development and optimization of an anti-CLL1 CAR-T-cell with potent activity on both AML cell lines and primary patient-derived AML blasts in vitro while sparing healthy HSCs. Furthermore, in a disseminated mouse xenograft model using the CLL1-positive HL60 cell line, these CAR-T-cells completely eradicated tumor, thus supporting CLL1 as a promising target for CAR-T-cells to treat AML while limiting myelosuppressive toxicity.</P>

Two-Dimensional IR Spectroscopy of Protein Dynamics Using Two Vibrational Labels: A Site-Specific Genetically Encoded Unnatural Amino Acid and an Active Site Ligand

Thielges, Megan C.,Axup, Jun Y.,Wong, Daryl,Lee, Hyun Soo,Chung, Jean K.,Schultz, Peter G.,Fayer, Michael D. American Chemical Society 2011 The journal of physical chemistry. B, Condensed ma Vol.115 No.38

<P>Protein dynamics and interactions in myoglobin (Mb) were characterized via two vibrational dynamics labels (VDLs): a genetically incorporated site-specific azide (Az) bearing unnatural amino acid (AzPhe43) and an active site CO ligand. The Az-labeled protein was studied using ultrafast two-dimensional infrared (2D IR) vibrational echo spectroscopy. CO bound at the active site of the heme serves as a second VDL located nearby. Therefore, it was possible to use Fourier transform infrared (FT-IR) and 2D IR spectroscopic experiments on the Az in unligated Mb and in Mb bound to CO (MbAzCO) and on the CO in MbCO and MbAzCO to investigate the environment and motions of different states of one protein from the perspective of two spectrally resolved VDLs. A very broad bandwidth 2D IR spectrum, encompassing both the Az and CO spectral regions, found no evidence of direct coupling between the two VDLs. In MbAzCO, both VDLs reported similar time scale motions: very fast homogeneous dynamics, fast, ∼1 ps dynamics, and dynamics on a much slower time scale. Therefore, each VDL reports independently on the protein dynamics and interactions, and the measured dynamics are reflective of the protein motions rather than intrinsic to the chemical nature of the VDL. The AzPhe VDL also permitted study of oxidized Mb dynamics, which could not be accessed previously with 2D IR spectroscopy. The experiments demonstrate that the combined application of 2D IR spectroscopy and site-specific incorporation of VDLs can provide information on dynamics, structure, and interactions at virtually any site throughout any protein.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jpcbfk/2011/jpcbfk.2011.115.issue-38/jp206986v/production/images/medium/jp-2011-06986v_0004.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jp206986v'>ACS Electronic Supporting Info</A></P>

Probing the energy barriers and magnetization reversal processes of nanoperforated membrane based percolated media

Neu, V,Schulze, C,Faustini, M,Lee, J,Makarov, D,Suess, D,Kim, S-K,Grosso, D,Schultz, L,Albrecht, M IOP Pub 2013 Nanotechnology Vol.24 No.14

<P>Magnetization reversal processes in Co/Pt multilayers prepared on nanoperforated templates are probed by magnetization relaxation measurements. The signature of pinning controlled domain wall movement as expected for percolated media is identified. This contrasts with the nucleation-type reversal mechanism of a Co/Pt reference film prepared on a smooth substrate. A zero field energy barrier of 93<I>k</I><SUB>B</SUB><I>T</I> is determined by fluctuation field measurements and is elucidated by micromagnetic calculations using the nudged elastic band method. This value is sufficiently large to qualify the material as a promising percolated medium.</P>