ORCID Profile
0000-0002-5031-1929
Current Organisations
Gachon University - Medical Campus
,
Ajou University
,
Asan Medical Center
,
University of Melbourne
,
University of Queensland
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Publisher: Scientific Research Publishing, Inc.
Date: 2012
Publisher: Oxford University Press (OUP)
Date: 11-01-2018
Publisher: MDPI AG
Date: 04-06-2019
DOI: 10.3390/CELLS8060536
Abstract: Hepatocellular carcinoma (HCC) is the sixth most common type of cancer, with an increasing mortality rate. Aberrant expression of fibroblast growth factor 19–fibroblast growth factor receptor 4 (FGF19–FGFR4) is reported to be an oncogenic-driver pathway for HCC patients. Thus, the FGF19–FGFR4 signaling pathway is a promising target for the treatment of HCC. Several pan-FGFR (1–4) and FGFR4-specific inhibitors are in different phases of clinical trials. In this review, we summarize the information, recent developments, binding modes, selectivity, and clinical trial phases of different available FGFR4 an-FGF inhibitors. We also discuss future perspectives and highlight the points that should be addressed to improve the efficacy of these inhibitors.
Publisher: Elsevier BV
Date: 09-2016
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.BBRC.2012.07.142
Abstract: Human peroxiredoxin 1 (hPrx1), a member of the peroxiredoxin family, detoxifies peroxide substrates and has been implicated in numerous biological processes, including cell growth, proliferation, differentiation, apoptosis, and redox signaling. To date, Prx1 has not been implicated in RNA metabolism. Here, we investigated the ability of hPrx1 to bind RNA and act as an RNA chaperone. In vitro, hPrx1 bound to RNA and DNA, and unwound nucleic acid duplexes. hPrx1 also acted as a transcription anti-terminator in an assay using an Escherichia coli strain containing a stem-loop structure upstream of the chlor henicol resistance gene. The overall cellular level of hPrx1 expression was not increased at low temperatures, but the nuclear level of hPrx1 was increased. In addition, hPrx1 overexpression enhanced the survival of cells exposed to cold stress, whereas hPrx1 knockdown significantly reduced cell survival under the same conditions. These findings suggest that hPrx1 may perform biological functions as a RNA-binding protein, which are distinctive from known functions of hPrx1 as a reactive oxygen species scavenger.
Publisher: Elsevier BV
Date: 08-2015
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.GENE.2010.06.007
Abstract: The human genome contains genes encoding for over 40 different types of kinesin and kinesin-like proteins. Of these, the functions of 13 kinesins remain uncharacterized. In this study, we constructed a plasmid containing the ORF of KIF18B and revealed that the KIF18B message of approximately 3kb is expressed in a tissue- and cell type-specific manners. A polypeptide of 842 amino acids was deduced from the ORF sequence. We identified another form of 873 amino acids which arises from alternative splicing at the C-terminal end. We also generated an anti-KIF18B antibody which detects a protein band of 120kDa. Western analyses showed that the protein level of KIF18B is elevated at late G(2) through metaphase, very similar to cyclin B1. Immunocytochemical staining revealed that the KIF18B protein is present predominantly in the nucleus and to a lesser extent in the cytoplasm of interphase cells. During mitosis, most KIF18B was found to be closely associated with astral microtubules emanating from the spindle pole during prometaphase and metaphase. Meanwhile, KIF18B was not detected at anaphase and telophase, consistent with the Western blotting data. The nuclear localization signal was roughly determined by using several EGFP-tagged deletion mutants of KIF18B. Together, the expression of KIF18B is regulated in a cell cycle-dependent manner and therefore may play an important role(s) in cell ision.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2013
Publisher: MDPI AG
Date: 22-02-2019
Abstract: : (1) Motivation: The exponential increase in multilayered data, including omics, pathways, chemicals, and experimental models, requires innovative strategies to identify new linkages between drug response information and omics features. Despite the availability of databases such as the Cancer Cell Line Encyclopedia (CCLE), the Cancer Therapeutics Response Portal (CTRP), and The Cancer Genome Atlas (TCGA), it is still challenging for biologists to explore the relationship between drug response and underlying genomic features due to the heterogeneity of the data. In light of this, the Integrated Pharmacogenomic Database of Cancer Cell Lines and Tissues (IPCT) has been developed as a user-friendly way to identify new linkages between drug responses and genomic features, as these findings can lead not only to new biological discoveries but also to new clinical trials. (2) Results: The IPCT allows biologists to compare the genomic features of sensitive cell lines or small molecules with the genomic features of tumor tissues by integrating the CTRP and CCLE databases with the REACTOME, cBioPortal, and Expression Atlas databases. The input consists of a list of small molecules, cell lines, or genes, and the output is a graph containing data entities connected with the queried input. Users can apply filters to the databases, pathways, and genes as well as select computed sensitivity values and mutation frequency scores to generate a relevant graph. Different objects are differentiated based on the background color of the nodes. Moreover, when multiple small molecules, cell lines, or genes are input, users can see their shared connections to explore the data entities common between them. Finally, users can view the resulting graphs in the online interface or download them in multiple image or graph formats. (3) Availability and Implementation: The IPCT is available as a web application with an integrated MySQL database. The web application was developed using Java and deployed on the Tomcat server. The user interface was developed using HTML5, JQuery v.3.1.0 , and the Cytoscape Graph API v.1.0.4. The IPCT can be accessed at ipct.ewostech.net. The source code is available at uhammadshoaib/ipct.
Publisher: Wiley
Date: 09-2007
Abstract: Many diseases are caused by perturbations of cellular signaling pathways and related pathway networks as a result of genetic aberrations. These perturbations are manifested by altered cellular protein profiles in the fluids bathing tissue/organs (i.e., the tissue interstitial fluid, TIF). A major challenge of clinical chemistry is to quantitatively map these perturbed protein profiles - the so-called "signatures of disease" - using modern proteomic technologies. This information can be utilized to design protein biomarkers for the early detection of disease, monitoring disease progression and efficacy of drug action. Here, we discuss the use of body fluids in the context of prospective biomarker discovery, and the marked 1000-1500-fold dilution of body fluid proteins, during their passage from TIF to the circulatory system. Further, we discuss proteomics strategies aimed at depleting major serum proteins, especially albumin, in order to focus on low-abundance protein eptides in plasma. A major limitation of depletion strategies is the removal of low-molecular weight protein eptides which specifically bind major plasma proteins. We present a prototype model, using albumin, for understanding the multifaceted nature of biomarker research, highlighting the involvement of albumin in Alzheimer's disease. This model underscores the need for a system-level understanding for biomarker research and personalized medicine.
Publisher: Public Library of Science (PLoS)
Date: 05-03-2014
Publisher: Korean Academy of Medical Sciences
Date: 2013
Publisher: Oxford University Press (OUP)
Date: 25-09-2016
DOI: 10.1093/BIOINFORMATICS/BTW612
Abstract: In this era of biological big data, data integration has become a common task and a challenge for biologists. The Resource Description Framework (RDF) was developed to enable interoperability of heterogeneous datasets. The EBI-RDF platform enables an efficient data integration of six independent biological databases using RDF technologies and shared ontologies. However, to take advantage of this platform, biologists need to be familiar with RDF technologies and SPARQL query language. To overcome this practical limitation of the EBI-RDF platform, we developed cMapper, a web-based tool that enables biologists to search the EBI-RDF databases in a gene-centric manner without a thorough knowledge of RDF and SPARQL. cMapper allows biologists to search data entities in the EBI-RDF platform that are connected to genes or small molecules of interest in multiple biological contexts. The input to cMapper consists of a set of genes or small molecules, and the output are data entities in six independent EBI-RDF databases connected with the given genes or small molecules in the user's query. cMapper provides output to users in the form of a graph in which nodes represent data entities and the edges represent connections between data entities and inputted set of genes or small molecules. Furthermore, users can apply filters based on database, taxonomy, organ and pathways in order to focus on a core connectivity graph of their interest. Data entities from multiple databases are differentiated based on background colors. cMapper also enables users to investigate shared connections between genes or small molecules of interest. Users can view the output graph on a web browser or download it in either GraphML or JSON formats. cMapper is available as a web application with an integrated MySQL database. The web application was developed using Java and deployed on Tomcat server. We developed the user interface using HTML5, JQuery and the Cytoscape Graph API. cMapper can be accessed at cmapper.ewostech.net. Readers can download the development manual from the website ocs/cMapperDocumentation.pdf. Source Code is available at uhammadshoaib/cmapper. Supplementary data are available at Bioinformatics online.
Publisher: Korean College of Helicobacter and Upper Gastrointestinal Research
Date: 10-03-2020
Abstract: Background/Aims: Although proton pump inhibitors (PPIs) remain a mainstay for the suppression of gastric acid secretion, long-term PPI use is associated with side effects. However, the genotoxicity associated with long-term PPI use is unclear.Materials and Methods: This prospective observational pilot study enrolled patients who had been on PPIs for year and healthy controls from July 2015 to August 2016. The subjects completed self-report questionnaires pertaining to their drug and medical history, and only those with no medical history and a ≥2-year wash-out period (for drugs other than PPIs) were included. We collected peripheral-blood lymphocytes from long-term PPI users and healthy controls and analyzed the genotoxicity by using the cytokinesis-block micronucleus cytome assay we also determined the fasting serum levels of pyridoxine, folate, cobalamin, and homocysteine.Results: Ten long-term PPI users and 40 healthy control subjects were enrolled. The median serum pyridoxine, folate, cobalamin, and homocysteine levels were not significantly different between the groups. The median frequencies of micronuclei (MNi), nucleoplasmic bridges (NPBs), and nuclear buds (Nbuds) per 1,000 binucleated cells, in long-term PPI users and healthy controls, were 30.3 and 16.3 ( i P /i .005), 2.5 and 1.8 ( i P /i .005), and 9.3 and 5.0 ( i P /i .005), respectively. Even after adjustment for confounding factors, the OR of the MNi, NPBs, and Nbuds for long-term PPI users compared with healthy control subjects were 14.1 ( i P /i .001), 2.0 ( i P /i =0.001), and 1.3 ( i P /i =0.3), respectively.Conclusions: Long-term PPI use was significantly associated with an increased risk of genotoxicity after adjustment for age, sex, body mass index, medical history, drug history, and the serum levels of vitamins.
Publisher: Research Square Platform LLC
Date: 23-12-2020
DOI: 10.21203/RS.3.RS-133311/V1
Abstract: Background Hepatocytes usually express fibroblast growth factor receptor 4 (FGFR4), but not its ligand, fibroblast growth factor 19 (FGF19). A subtype of hepatocellular carcinoma (HCC) expresses FGF19, which activates the FGFR4 signaling pathway that induces cell proliferation. FGFR4 inhibitors that target this mechanism are under clinical development for the treatment of HCCs with FGF19 lification or FGFR4 overexpression. Src plays an essential role in the FGFR1 and FGFR2 signaling pathways. However, it is yet to be understood whether Src has any role in the FGF19-FGFR4 pathway in HCCs. In this study, we aimed to elucidate the role of Src in the FGF19-FGFR4 axis in HCC. Methods 3 HCC cell lines expressing both FGF19 and FGFR4 were selected. The expression of each protein was suppressed by siRNA treatment, and the activity-regulating relationship between FGFR4 and Src was investigated by westernblot. Co-immunoprecipitation was performed using the FGFR4 antibody to identify the endosomal complex formation and receptor endocytosis. The intracellular migration pathways of the endosomal complex were observed by immuno-fluorescence and nuclear co-immunoprecipitation. Dasatinib and BLU9931 were used for cytotoxicity comparison. Results FGFR4 modulates the activity of Src and Src modulates the expression of FGFR4, showing a mutual regulatory relationship. FGFR4 activated by FGF19 formed an endosomal complex with Src and STAT3 and moved to the nucleus. However, when Src was suppressed, the formation of the endosomal complex was not observed. FGFR4 was released from the complex transferred into the nucleus and the binding of Src and STAT3 was maintained. Dasatinib showed cytotoxic results comparable to BLU9931. The results of our study demonstrated that Src is essential for the nuclear transport of STAT3, as it induces the endosomal delivery of FGFR4 in FGF19-expressing HCC cell lines. Conclusions We found that Src is essential for the endosomal delivery of the FGFR4 signaling complex in HCC. Our findings provide a scientific rationale for repurposing Src inhibitors for the treatment of HCCs in which the FGFR4 pathway is activated.
Publisher: Impact Journals, LLC
Date: 06-09-2014
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.PEP.2012.08.021
Abstract: Amyloid-β peptide 1-42 (Aβ(1-42)), the predominant form in senile plaques, plays important roles in the pathogenesis of Alzheimer's disease. Because Aβ(1-42) has aggregation-prone nature, it has been difficult to produce in a soluble state in bacterial expression systems. In this study, we modified our expression system to increase the soluble fraction of Aβ(1-42) in Escherichia coli (E. coli) cells. The expression level and solubility of recombinant Aβ(1-42) induced at the low temperature (16°C) is highly increased compared to that induced at 37°C. To optimize expression temperature, the coding region of Aβ(1-42) was constructed in a pCold vector, pCold-TF, which has a hexahistidine-tagged trigger factor (TF). Recombinant Aβ(1-42) was expressed primarily as a soluble protein using pCold vector system and purified with a nickel-chelating resin. When the toxic effect of recombinant Aβ(1-42) examined on human neuroblastoma SH-SY5Y cells, the purified Aβ(1-42) induced cell toxicity on SH-SY5Y cells. In conclusion, the system developed in this study will provide a useful method for the production of aggregation prone-peptide such as Aβ(1-42).
Publisher: Springer Science and Business Media LLC
Date: 30-03-2013
DOI: 10.1007/S00335-013-9449-Z
Abstract: Hanwoo, Korean native cattle, is indigenous to the Korean peninsula. They have been used mainly as draft animals for about 5,000 years however, in the last 30 years, their main role has been changed to meat production by selective breeding which has led to substantial increases in their productivity. Massively parallel sequencing technology has recently made possible the systematic identification of structural variations in cattle genomes. In particular, copy number variation (CNV) has been recognized as an important genetic variation complementary to single-nucleotide polymorphisms that can be used to account for variations of economically important traits in cattle. Here we report genome-wide copy number variation regions (CNVRs) in Hanwoo cattle obtained by comparing the whole genome sequence of Hanwoo with Black Angus and Holstein sequence datasets. We identified 1,173 and 963 putative CNVRs representing 16.7 and 7.8 Mbp from comparisons between Black Angus and Hanwoo and between Holstein and Hanwoo, respectively. The potential functional roles of the CNVRs were assessed by Gene Ontology enrichment analysis. The results showed that response to stimulus, immune system process, and cellular component organization were highly enriched in the genic-CNVRs that overlapped with annotated cattle genes. Of the 11 CNVRs that were selected for validation by quantitative real-time PCR, 9 exhibited the expected copy number differences. The results reported in this study show that genome-wide CNVs were detected successfully using massively parallel sequencing technology. The CNVs may be a valuable resource for further studies to correlate CNVs and economically important traits in cattle.
Publisher: Humana Press
Date: 2007
Publisher: S. Karger AG
Date: 22-05-2018
DOI: 10.1159/000488541
Abstract: b i Background: /i /b i FGF19 /i lification is a relatively novel type of genetic aberration that has been proposed to be a driver of hepatocarcinogenesis. Selective inhibitors of i FGFR4 /i , a receptor of i FGF19 /i , have been developed as targeted therapies for hepatocellular carcinoma (HCC). Despite the role of i FGF19 /i in mediating HCC progression, the clinicopathological characterization of patients exhibiting i FGF19 /i lification remains unclear. Immunohistochemical staining is the simplest and most widely used method of identifying aberrations in the i FGF19 /i gene, although its specificity is very low. b i Methods: /i /b This study investigated the prognostic significance of i FGF19 /i lification in a large cohort of 989 HCC patients using fluorescence in situ hybridization (FISH), which has a high degree of specificity. In addition, FISH data from formalin-fixed, paraffin-embedded sections were compared with copy number variation (CNV) data obtained from fresh frozen sections to validate the use of FISH as a diagnostic tool. b i Results: /i /b i FGF19 /i lifications were detected by FISH in 51 (5.15%) of the 989 patients, and were independently associated with poor survival and a higher risk of tumor recurrence, as well as with poor prognostic factors such as a high α-fetoprotein level, hepatitis B or C virus infection, a large tumor size, microvascular invasion, and necrosis. In addition, i FGF19 /i lification was associated with i TP53 /i mutation, and was mutually exclusive with i CTNNB1 /i mutation. The results of the FISH and CNV analyses exhibited a significant concordance rate of 96% (κ = 0.618, i /i & #x3c 0.001). b i Conclusions: /i /b These data indicate that i FGF19 /i lification represents a unique molecular subtype associated with poor prognostic characteristics, which supports the hypothesis that the i FGF19-FGFR4 /i signaling pathway plays an important role in hepatocarcinogenesis. We have also demonstrated that FISH is a viable alternative to CNV analysis, offering a number of advantages in the clinical setting.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2018
DOI: 10.1200/CCI.17.00109
Abstract: IBM Watson for Oncology (WFO) is a clinical decision-support computing system that provides oncologists with evidence-based treatment recommendations for a variety of cancer diagnoses. The evidence-based supported treatment recommendations are presented in three categories: Recommended, representing the Memorial Sloan Kettering Cancer Center (MSKCC) preferred approach For Consideration, evidence-based alternative treatments and Not Recommended, alternative therapies that may be unacceptable. We examined the absolute concordance of treatment options with that of the recommendations of a multidisciplinary team of oncologists from Gachon University, Gil Medical Centre, Incheon, South Korea. We enrolled 656 patients with stage II, III, and IV colon cancer between 2009 and 2016. Cases were processed using WFO and, using retrospective clinical data, outputs were compared with the actual treatment the patient received. Absolute concordance was defined as an alignment of recommendation in the Recommended MSKCC preferred-approach category. Treatment recommendations that were represented in the For Consideration category were not the focus of this study. The absolute concordance between the WFO-derived MSKCC preferred approach and Gil Medical Centre treatment recommendations was 48.9%. The percentage of cases found to be acceptable was 65.8% (432 of 656) and the stage-specific concordance rate was 32.5% for patients with stage II disease who had risk factors and 58.8% for patients with stage III disease. Patients 70 years of age and older had a concordance rate of only 20.2%, whereas younger patients had a concordance rate of 63.8% ( P = .0001). The main reasons attributed to the low concordance rate were age, reimbursement plan, omitting chemotherapy after liver resection, and not recommending biologic agents (ie, cetuximab and bevacizumab).
Publisher: American Scientific Publishers
Date: 11-2013
Abstract: Sensitive and accurate DNA quantification is an essential step in most DNA analyses, especially in analysis of a small amount of DNA. Instead of typical DNA quantification methods (i.e., UV spectrometry, fluorometry, and quantitative polymerase chain reaction), electrical impedance spectroscopy has recently been investigated for label-free and efficient quantification of DNA. In this study, quantification of DNA in solution was investigated using electrical impedance spectroscopy without pre-processing, including the modification of the electrode surface and immobilization of DNA onto the electrode. The results showed that the measured impedance spectra were in agreement with a designed equivalent circuit model, and that the extrapolated parameters of interfacial electrode impedance were dependent on DNA concentration. The impedance measured at 1 and 10 kHz showed good correlation with DNA concentration (R2 > 0.95), with a dynamic range of detection from 0.01 pg/microl to 100 ng/microl. Based on the results, it is expected to utilize impedance spectroscopy for the real-time and label-free characterization of DNA concentration with high sensitivity and low operation cost.
Publisher: Wiley
Date: 12-2008
Abstract: Stem cells (SCs) are defined by their combined abilities to both self‐renew indefinitely in vitro and differentiate into adult cell types. One of the major driving forces of SC research is that SCs may provide a potentially unlimited source for cell‐replacement therapies in regenerative medicine. However, the identification of SCs and their progenies at different stages, and the success of cell‐replacement therapies, which form the basis of SC engineering, will depend on the ability to characterize and ultimately isolate homogeneous primary stem or progenitor cell populations to a large degree. Furthermore, the recent identification of cancer stem cells (CSCs) opens a new avenue for developing novel therapeutic strategies by targeting a specific subset of cancer cells with self‐renewal and proliferation capacity. Crucial to these tasks will be the discovery of novel plasma membrane‐associated SC markers. In this review, we focus on the seminal contribution that membrane proteomics could make to further clinical applications of SCs by providing tools for purification and identification of SCs and their progenies at each stage of differentiation, as well as, to understand the underlying mechanisms of SC differentiation. The need to standardize biological SC models before embarking on international SC proteomics efforts is discussed.
Publisher: American Chemical Society (ACS)
Date: 21-06-2008
DOI: 10.1021/PR800225Z
Abstract: Exosomes, small membrane vesicles secreted by a multitude of cell types, are involved in a wide range of physiological roles such as intercellular communication, membrane exchange between cells, and degradation as an alternative to lysosomes. Because of the small size of exosomes (30-100 nm) and the limitations of common separation procedures including ultracentrifugation and flow cytometry, size-based fractionation of exosomes has been challenging. In this study, we used flow field-flow fractionation (FlFFF) to fractionate exosomes according to differences in hydrodynamic diameter. The exosome fractions collected from FlFFF runs were examined by transmission electron microscopy (TEM) to morphologically confirm their identification as exosomes. Exosomal lysates of each fraction were digested and analyzed using nanoflow LC-ESI-MS-MS for protein identification. FIFFF, coupled with mass spectrometry, allows nanoscale size-based fractionation of exosomes and is more applicable to primary cells and stem cells since it requires much less starting material than conventional gel-based separation, in-gel digestion and the MS-MS method.
Publisher: Wiley
Date: 26-10-2014
DOI: 10.1002/ART.38787
Publisher: Springer Science and Business Media LLC
Date: 24-10-2011
DOI: 10.1038/ONC.2011.484
Abstract: To identify potential microRNA (miRNA) links between Smad3, a mediator of TGF-β (transforming growth factor-β) signaling, and E-cadherin, we characterized the miRNA profiles of two gastric cancer cell lines: SNU484-LPCX, which does not express Smad3, and SNU484-Smad3, in which Smad3 is overexpressed. We found that among differentially expressed miRNAs, miR-200 family members are overexpressed in SNU484-Smad3 cells. Subsequent studies, including analysis of the effects of silencing Smad3 in SNU484-Smad3 cells and a luciferase reporter assay, revealed that Smad3 directly binds to a Smad-binding element located in the promoter region of miR-200b/a, where it functions as a transcriptional activator. TGF-β did not affect the regulatory role of Smad3 in transcription of miR-200 and expression of epithelial-mesenchymal transition markers. We conclude that Smad3 regulates, at the transcriptional level, miR-200 family members, which themselves regulate ZEB1 and ZEB2, known transcriptional repressors of E-cadherin, at the posttranscriptional level in a TGF-β-independent manner. This represents a novel link between Smad3 and posttranscriptional regulation by miRNAs in epithelial-mesenchymal transition in gastric cancer cells.
Publisher: Frontiers Media SA
Date: 18-12-2017
Publisher: Wiley
Date: 05-2007
Abstract: Asymmetrical flow field-flow fractionation (AFlFFF) has been carried out in a miniaturized channel by reducing the channel dimensions. Performance of the miniaturized AFlFFF (mAFlFFF) channel was evaluated with standard proteins and polystyrene latex spheres from nanometer to micrometer size. By reducing the channel dimension, proteins or particulate materials can be separated within a few minutes without a significant loss in resolution. The mAFlFFF channel was applied for the separation of exosomes harvested from immortalized human mesenchymal stem cell line. It shows a potential to fractionate exosome vesicles according to sizes which can be useful for proteomic studies in relation to immunotherapeutic applications.
Publisher: Korean Association of Anatomists
Date: 2010
Publisher: Springer Science and Business Media LLC
Date: 04-2021
DOI: 10.1186/S12967-021-02807-4
Abstract: Hepatocytes usually express fibroblast growth factor receptor 4 (FGFR4), but not its ligand, fibroblast growth factor 19 (FGF19). A subtype of hepatocellular carcinoma (HCC) expresses FGF19, which activates the FGFR4 signaling pathway that induces cell proliferation. FGFR4 inhibitors that target this mechanism are under clinical development for the treatment of HCCs with FGF19 lification or FGFR4 overexpression. Src plays an essential role in the FGFR1 and FGFR2 signaling pathways. However, it is yet to be understood whether Src has any role in the FGF19-FGFR4 pathway in HCCs. In this study, we aimed to elucidate the role of Src in the FGF19-FGFR4 axis in HCC. 3 HCC cell lines expressing both FGF19 and FGFR4 were selected. The expression of each protein was suppressed by siRNA treatment, and the activity-regulating relationship between FGFR4 and Src was investigated by westernblot. Co-immunoprecipitation was performed using the FGFR4 antibody to identify the endosomal complex formation and receptor endocytosis. The intracellular migration pathways of the endosomal complex were observed by immuno-fluorescence and nuclear co-immunoprecipitation. Dasatinib and BLU9931 were used for cytotoxicity comparison. FGFR4 modulates the activity of Src and Src modulates the expression of FGFR4, showing a mutual regulatory relationship. FGFR4 activated by FGF19 formed an endosomal complex with Src and STAT3 and moved to the nucleus. However, when Src was suppressed, the formation of the endosomal complex was not observed. FGFR4 was released from the complex transferred into the nucleus and the binding of Src and STAT3 was maintained. Dasatinib showed cytotoxic results comparable to BLU9931. The results of our study demonstrated that Src is essential for the nuclear transport of STAT3, as it induces the endosomal delivery of FGFR4 in FGF19-expressing HCC cell lines. We found that Src is essential for the endosomal delivery of the FGFR4 signaling complex in HCC. Our findings provide a scientific rationale for repurposing Src inhibitors for the treatment of HCCs in which the FGFR4 pathway is activated.
Publisher: Springer Science and Business Media LLC
Date: 30-07-2013
Abstract: Hanwoo (Korean cattle), which originated from natural crossbreeding between taurine and zebu cattle, migrated to the Korean peninsula through North China. Hanwoo were raised as draft animals until the 1970s without the introduction of foreign germplasm. Since 1979, Hanwoo has been bred as beef cattle. Genetic variation was analyzed by whole-genome deep resequencing of a Hanwoo bull. The Hanwoo genome was compared to that of two other breeds, Black Angus and Holstein, and genes within regions of homozygosity were investigated to elucidate the genetic and genomic characteristics of Hanwoo. The Hanwoo bull genome was sequenced to 45.6-fold coverage using the ABI SOLiD system. In total, 4.7 million single-nucleotide polymorphisms and 0.4 million small indels were identified by comparison with the Btau4.0 reference assembly. Of the total number of SNPs and indels, 58% and 87%, respectively, were novel. The overall genotype concordance between the SNPs and BovineSNP50 BeadChip data was 96.4%. Of 1.6 million genetic differences in Hanwoo, approximately 25,000 non-synonymous SNPs, splice-site variants, and coding indels (NS/SS/Is) were detected in 8,360 genes. Among 1,045 genes containing reliable specific NS/SS/Is in Hanwoo, 109 genes contained more than one novel damaging NS/SS/I. Of the genes containing NS/SS/Is, 610 genes were assigned as trait-associated genes. Moreover, 16, 78, and 51 regions of homozygosity (ROHs) were detected in Hanwoo, Black Angus, and Holstein, respectively. ‘Regulation of actin filament length’ was revealed as a significant gene ontology term and 25 trait-associated genes for meat quality and disease resistance were found in 753 genes that resided in the ROHs of Hanwoo. In Hanwoo, 43 genes were located in common ROHs between whole-genome resequencing and SNP chips in BTA2, 10, and 13 coincided with quantitative trait loci for meat fat traits. In addition, the common ROHs in BTA2 and 16 were in agreement between Hanwoo and Black Angus. We identified 4.7 million SNPs and 0.4 million small indels by whole-genome resequencing of a Hanwoo bull. Approximately 25,000 non-synonymous SNPs, splice-site variants, and coding indels (NS/SS/Is) were detected in 8,360 genes. Additionally, we found 25 trait-associated genes for meat quality and disease resistance among 753 genes that resided in the ROHs of Hanwoo. These findings will provide useful genomic information for identifying genes or casual mutations associated with economically important traits in cattle.
Publisher: Elsevier BV
Date: 04-2002
DOI: 10.1016/S0167-4781(01)00373-6
Abstract: The high-mobility-group (HMG) proteins are chromatin-associated proteins that are common to all higher organisms. They bind DNA in a sequence-specific or non-sequence-specific way to induce DNA bending, and regulate chromatin function and gene expression. Here we report the characterization of an HMG box-containing gene, designated human Smarce1r gene. It contained an open reading frame (ORF) encoding 317 amino acids and had 86% and 94% identity with the murine Smarce1r ORF at the nucleic acid and amino acid level, respectively. A putative nuclear localization signal, one HMG domain, and a coiled-coil domain were localized. A single transcript of 1.6 kb was ubiquitously expressed in various human tissues except for the fetal brain in which the transcript was barely detected. Western blot analysis revealed that human SMARCE1r was expressed in specific tissues such as colon and placenta. Subcellular fractionation, DNA-affinity column chromatography, and electrophoretic mobility shift assays showed that human SMARCE1r was associated with the nuclear matrix and that it possessed DNA binding activity, as expected.
Publisher: Public Library of Science (PLoS)
Date: 18-12-2008
Publisher: Springer Science and Business Media LLC
Date: 03-10-2018
Publisher: Hindawi Limited
Date: 03-02-2019
DOI: 10.1155/2019/8072928
Abstract: Backgrounds/Aims . Watson for Oncology (WFO) is a cognitive technology that processes medical information by analyzing the latest evidence and guidelines. However, studies of the concordance rate between WFO and clinicians for advanced gastric cancer (AGC) are lacking. Methods . We retrospectively reviewed 65 patients with AGC who consulted WFO and the Gachon Gil Medical Center multidisciplinary team (GMDT) in 2016 and 2017. The recommendations of WFO were compared with the opinions of the GMDT. WFO provided three treatment options: recommended (first treatment option), for consideration (second treatment option), and not recommended. Results . In total, 65 patients (mean age 61.0 years 44 males and 21 females) were included in the study. The concordance rate between WFO and the GMDT was 41.5% (27/65) at the recommended level and 87.7% (57/65) at the for consideration level. The main causes of discordance between WFO and the GMDT were as follows. First, WFO did not consider the medical history. Second, WFO recommended the use of agents that are considered outdated in Korea. Third, some patients wanted to be involved in a clinical trial. Fourth, some patients refused to use the biologic agents recommended by WFO for financial reasons as they were not covered by medical insurance. Conclusions . The concordance rate at the recommended level was relatively low but was higher at the for consideration level. Discordances arose mainly from the different medical circumstances at the Gachon Gil Medical Center (GMC) and the Memorial Sloan Kettering Cancer Center (MSKCC), the main WFO consulting center. The utility of WFO as a tool for supporting clinical decision making could be further improved by incorporating regional guidelines.
Publisher: Impact Journals, LLC
Date: 11-09-2017
Publisher: Korean Endocrine Society
Date: 2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-04-2015
DOI: 10.1002/HEP.27740
Publisher: Springer Science and Business Media LLC
Date: 02-05-2016
DOI: 10.1038/NATURE17676
Publisher: Cold Spring Harbor Laboratory
Date: 26-05-2009
Abstract: We present the first Korean in idual genome sequence (SJK) and analysis results. The diploid genome of a Korean male was sequenced to 28.95-fold redundancy using the Illumina paired-end sequencing method. SJK covered 99.9% of the NCBI human reference genome. We identified 420,083 novel single nucleotide polymorphisms (SNPs) that are not in the dbSNP database. Despite a close similarity, significant differences were observed between the Chinese genome (YH), the only other Asian genome available, and SJK: (1) 39.87% (1,371,239 out of 3,439,107) SNPs were SJK-specific (49.51% against Venter's, 46.94% against Watson's, and 44.17% against the Yoruba genomes) (2) 99.5% (22,495 out of 22,605) of short indels ( 4 bp) discovered on the same loci had the same size and type as YH and (3) 11.3% (331 out of 2920) deletion structural variants were SJK-specific. Even after attempting to map unmapped reads of SJK to unanchored NCBI scaffolds, HGSV, and available personal genomes, there were still 5.77% SJK reads that could not be mapped. All these findings indicate that the overall genetic differences among in iduals from closely related ethnic groups may be significant. Hence, constructing reference genomes for minor socio-ethnic groups will be useful for massive in idual genome sequencing.
Publisher: Elsevier BV
Date: 2019
Publisher: Springer Science and Business Media LLC
Date: 12-2009
Publisher: American Association for Cancer Research (AACR)
Date: 06-2015
DOI: 10.1158/1541-7786.MCR-14-0703
Abstract: Hepatocellular carcinoma (HCC) remains a significant clinical challenge with few therapeutic options available to cancer patients. MicroRNA 21-5p (miR-21) has been shown to be upregulated in HCC, but the contribution of this oncomiR to the maintenance of tumorigenic phenotype in liver cancer remains poorly understood. We have developed potent and specific single-stranded oligonucleotide inhibitors of miR-21 (anti-miRNAs) and used them to interrogate dependency on miR-21 in a panel of liver cancer cell lines. Treatment with anti–miR-21, but not with a mismatch control anti-miRNA, resulted in significant derepression of direct targets of miR-21 and led to loss of viability in the majority of HCC cell lines tested. Robust induction of caspase activity, apoptosis, and necrosis was noted in anti–miR-21-treated HCC cells. Furthermore, ablation of miR-21 activity resulted in inhibition of HCC cell migration and suppression of clonogenic growth. To better understand the consequences of miR-21 suppression, global gene expression profiling was performed on anti–miR-21-treated liver cancer cells, which revealed striking enrichment in miR-21 target genes and deregulation of multiple growth-promoting pathways. Finally, in vivo dependency on miR-21 was observed in two separate HCC tumor xenograft models. In summary, these data establish a clear role for miR-21 in the maintenance of tumorigenic phenotype in HCC in vitro and in vivo. Implications: miR-21 is important for the maintenance of the tumorigenic phenotype of HCC and represents a target for pharmacologic intervention. Mol Cancer Res 13(6) 1009–21. ©2015 AACR.
Publisher: Elsevier BV
Date: 09-2016
Publisher: Elsevier BV
Date: 09-2019
Publisher: Springer Science and Business Media LLC
Date: 12-2018
Publisher: Elsevier BV
Date: 08-2005
DOI: 10.1016/J.DIABRES.2004.12.010
Abstract: In vivo and in vitro experimental findings indicate that the hyperglycemic diabetic milieu can induce altered expression of the matrix metalloproteinase (MMP) genes and contribute to imbalances in vascular matrix homeostasis. We examined the plasma levels of enzymes and inhibitors involved in extracellular matrix turnover. We measured the plasma concentrations of MMP-2, MMP-9, and tissue inhibitor of metalloproteinase 1 (TIMP-1) in 80 type-2 diabetic subjects without uremia and in 80 age-matched controls. In addition, we determined the plasma levels of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and high sensitive(hs) C-reactive protein (CRP) in both groups. Plasma MMP-2, TIMP-1, and hs-CRP concentrations were significantly elevated in diabetic patients as compared to the control subjects (p<0.05). Plasma levels of MMP-2, MMP-9, TIMP-1, VCAM-1, ICAM-1, and hs-CRP were found not to be significantly associated with age, duration of diabetes, blood pressure, or serum lipid concentrations. Plasma MMP-2, TIMP-1 and hs-CRP concentrations were significantly increased in type-2 diabetic patients.
Publisher: Public Library of Science (PLoS)
Date: 21-07-2011
Publisher: Korean Cancer Association
Date: 15-01-2016
DOI: 10.4143/CRT.2015.490
Publisher: American Association for Cancer Research (AACR)
Date: 31-05-2015
DOI: 10.1158/1078-0432.CCR-14-0519
Abstract: Purpose: To better understand the complete genomic architecture of lung adenocarcinoma. Experimental Design: We used array experiments to determine copy number variations and sequenced the complete exomes of the 247 lung adenocarcinoma tumor s les along with matched normal cells obtained from the same patients. Fully annotated clinical data were also available, providing an unprecedented opportunity to assess the impact of genomic alterations on clinical outcomes. Results: We discovered that genomic alternations in the RB pathway are associated with significantly shorter disease-free survival in early-stage lung adenocarcinoma patients. This association was also observed in our independent validation cohort. The current treatment guidelines for early-stage lung adenocarcinoma patients recommend follow-up without adjuvant therapy after complete resection, except for high-risk patients. However, our findings raise the interesting possibility that additional clinical interventions might provide medical benefits to early-stage lung adenocarcinoma patients with genomic alterations in the RB pathway. When examining the association between genomic mutation and histologic subtype, we uncovered the characteristic genomic signatures of various histologic subtypes. Notably, the solid and the micropapillary subtypes demonstrated great ersity in the mutated genes, while the mucinous subtype exhibited the most unique landscape. This suggests that a more tailored therapeutic approach should be used to treat patients with lung adenocarcinoma. Conclusions: Our analysis of the genomic and clinical data for 247 lung adenocarcinomas should help provide a more comprehensive genomic portrait of lung adenocarcinoma, define molecular signatures of lung adenocarcinoma subtypes, and lead to the discovery of useful prognostic markers that could be used in personalized treatments for early-stage lung adenocarcinoma patients. Clin Cancer Res 21(11) 2613–23. ©2014 AACR. See related commentary by Collisson, p. 2418
Publisher: Springer Science and Business Media LLC
Date: 30-09-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-09-2014
DOI: 10.1002/HEP.27198
Abstract: Hepatic resection is the most curative treatment option for early-stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early-stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in nine genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high-copy lifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodeling pathways. RB1 mutations were significantly associated with cancer-specific and recurrence-free survival after resection (multivariate P = 0.038 and P = 0.012, respectively). FGF19 lifications, known to activate Wnt signaling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (P = 0.017). RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 lification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti-FGF19 treatment in these patients.
Publisher: Wiley
Date: 05-10-2021
Abstract: Human leukocyte antigen (HLA) class I has more than 18,000 alleles, each of which binds to a set of unique peptides from the cellular degradome. Deciphering the interaction between antigenic peptides and HLA proteins is crucial for understanding immune responses in autoimmune diseases and cancer. In this study, we aimed to characterize the peptidome that binds to HLA‐A*33:03, which is one of the most prevalent HLA‐A alleles in the Northeast Asian population, but poorly studied. For this purpose, we analyzed the HLA‐A*33:03 monoallelic B cell line using immunoprecipitation of HLA‐A and peptide complexes, followed by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). In this study, we identified 5731 unique peptides that were associated with HLA A*33:03, and experimentally validated the affinity of 40 peptides for HLA‐A*33:03 and their stability in HLA A*33:03‐peptides complexes. To our knowledge, this study represents the largest dataset of peptides associated with HLA‐A*33:03. Also, this is the first study in which HLA A*33:03‐associated peptides were experimentally validated.
Publisher: Public Library of Science (PLoS)
Date: 08-04-2013
Publisher: Public Library of Science (PLoS)
Date: 02-01-2014
Publisher: Public Library of Science (PLoS)
Date: 30-07-2008
Publisher: SAGE Publications
Date: 2011
DOI: 10.4137/EBO.S6618
Abstract: Next-generation sequencing (NGS) methods pose computational challenges of handling large volumes of data. Although cloud computing offers a potential solution to these challenges, transferring a large data set across the internet is the biggest obstacle, which may be overcome by efficient encoding methods. When encoding is used to facilitate data transfer to the cloud, the time factor is equally as important as the encoding efficiency. Moreover, to take advantage of parallel processing in cloud computing, a parallel technique to decode and split compressed data in the cloud is essential. Hence in this review, we present SOLiDzipper, a new encoding method for NGS data. The basic strategy of SOLiDzipper is to ide and encode. NGS data files contain both the sequence and non-sequence information whose encoding efficiencies are different. In SOLiDzipper, encoded data are stored in binary data block that does not contain the characteristic information of a specific sequence platform, which means that data can be decoded according to a desired platform even in cases of Illumina, Solexa or Roche 454 data. The main calculation time using Crossbow was 173 minutes when 40 EC2 nodes were involved. In that case, an analysis preparation time of 464 minutes is required to encode data in the latest DNA compression method like G-SQZ and transmit it on a 183 Mbit/s bandwidth. However, it takes 194 minutes to encode and transmit data with SOLiDzipper under the same bandwidth conditions. These results indicate that the entire processing time can be reduced according to the encoding methods used, under the same network bandwidth conditions. Considering the limited network bandwidth, high-speed, high-efficiency encoding methods such as SOLiDzipper can make a significant contribution to higher productivity in labs seeking to take advantage of the cloud as an alternative to local computing. szipper.dinfree.com . Academic/non-profit: Binary available for direct download at no cost. For-profit: Submit request for for-profit license from the web-site.
No related grants have been discovered for Sung-Min Ahn.