Publications by authors named "KyuKwang Kim"

15 Publications

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3DIV update for 2021: a comprehensive resource of 3D genome and 3D cancer genome.

Nucleic Acids Res 2021 01;49(D1):D38-D46

Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.

Three-dimensional (3D) genome organization is tightly coupled with gene regulation in various biological processes and diseases. In cancer, various types of large-scale genomic rearrangements can disrupt the 3D genome, leading to oncogenic gene expression. However, unraveling the pathogenicity of the 3D cancer genome remains a challenge since closer examinations have been greatly limited due to the lack of appropriate tools specialized for disorganized higher-order chromatin structure. Here, we updated a 3D-genome Interaction Viewer and database named 3DIV by uniformly processing ∼230 billion raw Hi-C reads to expand our contents to the 3D cancer genome. The updates of 3DIV are listed as follows: (i) the collection of 401 samples including 220 cancer cell line/tumor Hi-C data, 153 normal cell line/tissue Hi-C data, and 28 promoter capture Hi-C data, (ii) the live interactive manipulation of the 3D cancer genome to simulate the impact of structural variations and (iii) the reconstruction of Hi-C contact maps by user-defined chromosome order to investigate the 3D genome of the complex genomic rearrangement. In summary, the updated 3DIV will be the most comprehensive resource to explore the gene regulatory effects of both the normal and cancer 3D genome. '3DIV' is freely available at http://3div.kr.
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http://dx.doi.org/10.1093/nar/gkaa1078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778885PMC
January 2021

Characterization of Structural Variations in the Context of 3D Chromatin Structure.

Mol Cells 2019 Jul;42(7):512-522

Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.

Chromosomes located in the nucleus form discrete units of genetic material composed of DNA and protein complexes. The genetic information is encoded in linear DNA sequences, but its interpretation requires an understanding of threedimensional (3D) structure of the chromosome, in which distant DNA sequences can be juxtaposed by highly condensed chromatin packing in the space of nucleus to precisely control gene expression. Recent technological innovations in exploring higher-order chromatin structure have uncovered organizational principles of the 3D genome and its various biological implications. Very recently, it has been reported that large-scale genomic variations may disrupt higher-order chromatin organization and as a consequence, greatly contribute to disease-specific gene regulation for a range of human diseases. Here, we review recent developments in studying the effect of structural variation in gene regulation, and the detection and the interpretation of structural variations in the context of 3D chromatin structure.
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http://dx.doi.org/10.14348/molcells.2019.0137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681866PMC
July 2019

A Deep Learning-Based Automatic Mosquito Sensing and Control System for Urban Mosquito Habitats.

Sensors (Basel) 2019 Jun 21;19(12). Epub 2019 Jun 21.

School of Electrical Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 34141, Korea.

Mosquito control is important as mosquitoes are extremely harmful pests that spread various infectious diseases. In this research, we present the preliminary results of an automated system that detects the presence of mosquitoes via image processing using multiple deep learning networks. The Fully Convolutional Network (FCN) and neural network-based regression demonstrated an accuracy of 84%. Meanwhile, the single image classifier demonstrated an accuracy of only 52%. The overall processing time also decreased from 4.64 to 2.47 s compared to the conventional classifying network. After detection, a larvicide made from toxic protein crystals of the serotype bacteria was injected into static water to stop the proliferation of mosquitoes. This system demonstrates a higher efficiency than hunting adult mosquitos while avoiding damage to other insects.
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http://dx.doi.org/10.3390/s19122785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631209PMC
June 2019

Septin-2 is overexpressed in epithelial ovarian cancer and mediates proliferation via regulation of cellular metabolic proteins.

Oncotarget 2019 Apr 26;10(31):2959-2972. Epub 2019 Apr 26.

Division of Gynecologic Oncology, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, RI, USA.

Epithelial Ovarian Cancer (EOC) is associated with dismal survival rates due to the fact that patients are frequently diagnosed at an advanced stage and eventually become resistant to traditional chemotherapeutics. Hence, there is a crucial need for new and innovative therapies. Septin-2, a member of the septin family of GTP binding proteins, has been characterized in EOC for the first time and represents a potential future target. Septin-2 was found to be overexpressed in serous and clear cell human patient tissue compared to benign disease. Stable septin-2 knockdown clones developed in an ovarian cancer cell line exhibited a significant decrease in proliferation rates. Comparative label-free proteomic analysis of septin-2 knockdown cells revealed differential protein expression of pathways associated with the TCA cycle, acetyl CoA, proteasome and spliceosome. Further validation of target proteins indicated that septin-2 plays a predominant role in post-transcriptional and translational modifications as well as cellular metabolism, and suggested the potential novel role of septin-2 in promoting EOC tumorigenesis through these mechanisms.
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http://dx.doi.org/10.18632/oncotarget.26836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508204PMC
April 2019

MineLoC: A Rapid Production of Lab-on-a-Chip Biosensors Using 3D Printer and the Sandbox Game, Minecraft.

Sensors (Basel) 2018 Jun 10;18(6). Epub 2018 Jun 10.

Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 34141, Korea.

Here, MineLoC is described as a pipeline developed to generate 3D printable models of master templates for Lab-on-a-Chip (LoC) by using a popular multi-player sandbox game “Minecraft”. The user can draw a simple diagram describing the channels and chambers of the Lab-on-a-Chip devices with pre-registered color codes which indicate the height of the generated structure. MineLoC converts the diagram into large chunks of blocks (equal sized cube units composing every object in the game) in the game world. The user and co-workers can simultaneously access the game and edit, modify, or review, which is a feature not generally supported by conventional design software. Once the review is complete, the resultant structure can be exported into a stereolithography (STL) file which can be used in additive manufacturing. Then, the Lab-on-a-Chip device can be fabricated by the standard protocol to produce a Lab-on-a-Chip. The simple polydimethylsiloxane (PDMS) device for the bacterial growth measurement used in the previous research was copied by the proposed method. The error calculation by a 3D model comparison showed an accuracy of 86%. It is anticipated that this work will facilitate more use of 3D printer-based Lab-on-a-Chip fabrication, which greatly lowers the entry barrier in the field of Lab-on-a-Chip research.
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http://dx.doi.org/10.3390/s18061896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021845PMC
June 2018

Visual Estimation of Bacterial Growth Level in Microfluidic Culture Systems.

Sensors (Basel) 2018 Feb 3;18(2). Epub 2018 Feb 3.

Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 34141, Korea.

Microfluidic devices are an emerging platform for a variety of experiments involving bacterial cell culture, and has advantages including cost and convenience. One inevitable step during bacterial cell culture is the measurement of cell concentration in the channel. The optical density measurement technique is generally used for bacterial growth estimation, but it is not applicable to microfluidic devices due to the small sample volumes in microfluidics. Alternately, cell counting or colony-forming unit methods may be applied, but these do not work in situ; nor do these methods show measurement results immediately. To this end, we present a new vision-based method to estimate the growth level of the bacteria in microfluidic channels. We use Fast Fourier transform (FFT) to detect the frequency level change of the microscopic image, focusing on the fact that the microscopic image becomes rough as the number of cells in the field of view increases, adding high frequencies to the spectrum of the image. Two types of microfluidic devices are used to culture bacteria in liquid and agar gel medium, and time-lapsed images are captured. The images obtained are analyzed using FFT, resulting in an increase in high-frequency noise proportional to the time passed. Furthermore, we apply the developed method in the microfluidic antibiotics susceptibility test by recognizing the regional concentration change of the bacteria that are cultured in the antibiotics gradient. Finally, a deep learning-based data regression is performed on the data obtained by the proposed vision-based method for robust reporting of data.
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http://dx.doi.org/10.3390/s18020447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855051PMC
February 2018

Light Emitting Marker for Robust Vision-Based On-The-Spot Bacterial Growth Detection.

Sensors (Basel) 2017 Jun 21;17(6). Epub 2017 Jun 21.

Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 34141, Korea.

Simple methods using the striped pattern paper marker and FFT (fast Fourier transformation) have been proposed as alternatives to measuring the optical density for determining the level of bacterial growth. The marker-based method can be easily automated, but due to image-processing-base of the method, the presence of light or the color of the culture broth can disturb the detection process. This paper proposes a modified version of marker-FFT-based growth detection that uses a light emitting diode (LED) array as a marker. Since the marker itself can emit the light, the measurements can be performed even when there is no light source or the bacteria are cultured in a large volume of darkly colored broth. In addition, an LED marker can function as a region of interest (ROI) indicator in the image. We expect that the proposed LED-based marker system will allow more robust growth detection compared to conventional methods.
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http://dx.doi.org/10.3390/s17061459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492430PMC
June 2017

Vision Marker-Based In Situ Examination of Bacterial Growth in Liquid Culture Media.

Sensors (Basel) 2016 Dec 18;16(12). Epub 2016 Dec 18.

Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 34141, Korea.

The detection of bacterial growth in liquid media is an essential process in determining antibiotic susceptibility or the level of bacterial presence for clinical or research purposes. We have developed a system, which enables simplified and automated detection using a camera and a striped pattern marker. The quantification of bacterial growth is possible as the bacterial growth in the culturing vessel blurs the marker image, which is placed on the back of the vessel, and the blurring results in a decrease in the high-frequency spectrum region of the marker image. The experiment results show that the FFT (fast Fourier transform)-based growth detection method is robust to the variations in the type of bacterial carrier and vessels ranging from the culture tubes to the microfluidic devices. Moreover, the automated incubator and image acquisition system are developed to be used as a comprehensive detection system. We expect that this result can be applied in the automation of biological experiments, such as the Antibiotics Susceptibility Test or toxicity measurement. Furthermore, the simple framework of the proposed growth measurement method may be further utilized as an effective and convenient method for building point-of-care devices for developing countries.
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http://dx.doi.org/10.3390/s16122179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5191158PMC
December 2016

A Low Cost/Low Power Open Source Sensor System for Automated Tuberculosis Drug Susceptibility Testing.

Sensors (Basel) 2016 Jun 22;16(6). Epub 2016 Jun 22.

Urban Robotics Laboratory, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 34141, Korea.

In this research an open source, low power sensor node was developed to check the growth of mycobacteria in a culture bottle with a nitrate reductase assay method for a drug susceptibility test. The sensor system reports the temperature and color sensor output frequency change of the culture bottle when the device is triggered. After the culture process is finished, a nitrite ion detecting solution based on a commercial nitrite ion detection kit is injected into the culture bottle by a syringe pump to check bacterial growth by the formation of a pigment by the reaction between the solution and the color sensor. Sensor status and NRA results are broadcasted via a Bluetooth low energy beacon. An Android application was developed to collect the broadcasted data, classify the status of cultured samples from multiple devices, and visualize the data for the end users, circumventing the need to examine each culture bottle manually during a long culture period. The authors expect that usage of the developed sensor will decrease the cost and required labor for handling large amounts of patient samples in local health centers in developing countries. All 3D-printerable hardware parts, a circuit diagram, and software are available online.
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http://dx.doi.org/10.3390/s16060942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4934367PMC
June 2016

Sensor node for remote monitoring of waterborne disease-causing bacteria.

Sensors (Basel) 2015 May 5;15(5):10569-79. Epub 2015 May 5.

Department of Civil and Environmental Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 305-338, Korea.

A sensor node for sampling water and checking for the presence of harmful bacteria such as E. coli in water sources was developed in this research. A chromogenic enzyme substrate assay method was used to easily detect coliform bacteria by monitoring the color change of the sampled water mixed with a reagent. Live webcam image streaming to the web browser of the end user with a Wi-Fi connected sensor node shows the water color changes in real time. The liquid can be manipulated on the web-based user interface, and also can be observed by webcam feeds. Image streaming and web console servers run on an embedded processor with an expansion board. The UART channel of the expansion board is connected to an external Arduino board and a motor driver to control self-priming water pumps to sample the water, mix the reagent, and remove the water sample after the test is completed. The sensor node can repeat water testing until the test reagent is depleted. The authors anticipate that the use of the sensor node developed in this research can decrease the cost and required labor for testing samples in a factory environment and checking the water quality of local water sources in developing countries.
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http://dx.doi.org/10.3390/s150510569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482013PMC
May 2015

HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation.

Sci Rep 2014 Jun 30;4:5500. Epub 2014 Jun 30.

Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Alpert Medical School at Brown University, Providence, RI, 02905, USA.

Antiestrogens including tamoxifen and fulvestrant have been evaluated as chemotherapeutics for ovarian cancer, particularly in cases of platinum resistant disease. Human epididymis protein 4 (HE4) is highly overexpressed in women with ovarian cancer and overexpression of HE4 has been found to correlate with platinum resistance. However, the role of HE4 in modulating responses to hormones and hormonal therapy has not been characterized in ovarian cancer. Here we demonstrate that 17β-estradiol, tamoxifen, and fulvestrant induce nuclear and nucleolar translocation of HE4 and that HE4 overexpression induces resistance to antiestrogens. HE4 was found to interact with estrogen receptor-α (ER-α), and HE4 overexpression resulted in ER-α downregulation in vitro and in human ovarian cancers. We identified a novel role for importin-4 in governing the nuclear transport of HE4. Treatment with ivermectin, an importin inhibitor, blocked HE4/importin-4 nuclear accumulation and sensitized HE4-overexpressing ovarian cancer cells to fulvestrant and tamoxifen.
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http://dx.doi.org/10.1038/srep05500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074789PMC
June 2014

HE4 (WFDC2) gene overexpression promotes ovarian tumor growth.

Sci Rep 2014 Jan 6;4:3574. Epub 2014 Jan 6.

Molecular Therapeutics Laboratory, Program in Women's Oncology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02903, USA.

Selective overexpression of Human epididymal secretory protein E4 (HE4) points to a role in ovarian cancer tumorigenesis but little is known about the role the HE4 gene or the gene product plays. Here we show that elevated HE4 serum levels correlate with chemoresistance and decreased survival rates in EOC patients. HE4 overexpression promoted xenograft tumor growth and chemoresistance against cisplatin in an animal model resulting in reduced survival rates. HE4 displayed responses to tumor microenvironment constituents and presented increased expression as well as nuclear translocation upon EGF, VEGF and Insulin treatment and nucleolar localization with Insulin treatment. HE4 interacts with EGFR, IGF1R, and transcription factor HIF1α. Constructs of antisense phosphorothio-oligonucleotides targeting HE4 arrested tumor growth in nude mice. Collectively these findings implicate increased HE4 expression as a molecular factor in ovarian cancer tumorigenesis. Selective targeting directed towards the HE4 protein demonstrates therapeutic benefits for the treatment of ovarian cancer.
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http://dx.doi.org/10.1038/srep03574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880958PMC
January 2014

7 Methyl indole ethyl isothiocyanate causes ROS mediated apoptosis and cell cycle arrest in endometrial cancer cells.

Gynecol Oncol 2012 Aug 2;126(2):252-8. Epub 2012 May 2.

Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02905, USA.

Objective: Chemotherapy options for advanced endometrial cancer are limited and newer therapeutic agents are urgently needed. This study describes the therapeutic potential of 7 Methyl-indole ethyl isothiocyanate (7Me-IEITC) in endometrial cancer cell lines.

Methods: 7Me-IEITC was synthesized in our laboratory. The cell viability of 7Me-IEITC treated ECC-1 and KLE endometrial cancer cell was determined by MTS assay. Morphology and apoptosis were further confirmed by DAPI-staining and TUNEL assay. The measurement of reactive oxygen species (ROS), mitochondrial transmembrane depolarization potential (ΔΨm) and cell cycle phase was determined by FACS analysis. Expression of proteins involved in apoptosis, survival and cell-cycle progression was analyzed by Western blotting.

Results: 7Me-IEITC reduced the viability of the ECC-1 and KLE cancer cell-lines (IC(50)~2.5-10 μM) in a dose dependent fashion. 7Me-IEITC treatment caused mitochondrial transmembrane potential reduction, elevated the production of ROS, leading to activation of apoptosis in endometrial cancer KLE and ECC-1 cells. 7Me-IEITC treatment activated Bad, suppressed Bcl2 phosphorylation followed by PARP-1 deactivation and caspase 3 and 7 activation. 7Me-IEITC treatment arrested the progression of KLE cells in S-phase and caused CDC25 and cyclin-D1 downregulation. Pre-treatment with ascorbic acid abrogated 7Me-IEITC induced apoptosis in ECC-1 and KLE cells, suggesting that 7Me-IEITC mediated cytotoxicity is primarily through ROS production.

Conclusion: 7Me-IEITC demonstrated promising cytotoxic effects in endometrial cancer cell line model.
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http://dx.doi.org/10.1016/j.ygyno.2012.04.041DOI Listing
August 2012

Antitumor activity of nifurtimox is enhanced with tetrathiomolybdate in medulloblastoma.

Int J Oncol 2011 May 10;38(5):1329-41. Epub 2011 Mar 10.

Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA.

Medulloblastoma, a neuroectodermal tumor arising in the cerebellum, is the most common brain tumor found in children. We recently showed that nifurtimox induces production of reactive oxygen species (ROS) and subsequent apoptosis in neuroblastoma cells both in vitro and in vivo. Tetrathiomolybdate (TM) has been shown to decrease cell proliferation by inhibition of superoxide dismutase-1 (SOD1). Since both nifurtimox and TM increase ROS levels in cells, we investigated whether the combination of nifurtimox and TM would act synergistically in medulloblastoma cell lines (D283, DAOY). Genome-wide transcriptional analysis, by hybridizing RNA isolated from nifurtimox and TM alone or in combination treated and control cells (D283) on Affymetrix exon array gene chips was carried out to further confirm synergy. We show that nifurtimox and TM alone and in combination decreased cell viability and increased ROS levels synergistically. Examination of cell morphology following drug treatment (nifurtimox + TM) and detection of caspase-3 activation via Western blotting indicated that cell death was primarily due to apoptosis. Microarray data from cells treated with nifurtimox and TM validated the induction of oxidative stress, as many Nrf2 target genes (HMOX1, GCLM, SLC7A11 and SRXN1) (p<10(-5)) were upregulated. Other genes related to apoptosis, oxidative stress, DNA damage, protein folding and nucleosome formation were differentially involved in cells following treatment with nifurtimox + TM. Taken together, our results suggest nifurtimox and TM act synergistically in medulloblastoma cells in vitro, and that this combination warrants further studies as a new treatment for medulloblastoma.
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http://dx.doi.org/10.3892/ijo.2011.971DOI Listing
May 2011

Effect of indole ethyl isothiocyanates on proliferation, apoptosis, and MAPK signaling in neuroblastoma cell lines.

Bioorg Med Chem Lett 2007 Nov 19;17(21):5846-52. Epub 2007 Aug 19.

Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, The Warren Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI 02905, USA.

Several indole ethyl isothiocyanate (IEITC) analogs were designed, synthesized, and screened to evaluate their cytotoxicity against neuroblastoma (NB) cells in-vitro. In NB, predominantly a tumor of early childhood, survival remains low despite aggressive treatments. Therefore, novel treatment strategies are greatly needed. The objective of the present study was to study the therapeutic potential of IEITC by analyzing the cytotoxic, anti-proliferative, and apoptotic effects on NB cell lines. 7-Methyl-indole-3-ethyl isothiocyanate (7Me-IEITC) proved to be cytotoxic to various NB cell lines (SMS-KCNR, SK-N-SH, SH-SY5Y, and IMR-32) with an IC(50) at 2.5-5.0 microM, while primary control cells (lung fibroblasts) were not affected. 7Me-IEITC led to the activation of apoptotic markers caspase-3, -8, and -9, caused activation of pro-apoptotic p38 MAPK and SAP/JNK, and down-regulated pro-survival factor AKT in SMS-KCNR cells. Moreover, 7Me-IEITC displayed anti-proliferative effects (IC(50) at 600 nM) and caused an arrest in cell cycle progression. This wide effect of 7Me-IEITC on NB cell signaling and survival suggests that it could be developed as a therapeutic agent against neuroblastoma.
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http://dx.doi.org/10.1016/j.bmcl.2007.08.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2093989PMC
November 2007