Publications by authors named "Dong Chul Kim"

77 Publications

Increased Extracellular Adenosine in Radiotherapy-Resistant Breast Cancer Cells Enhances Tumor Progression through A2AR-Akt-β-Catenin Signaling.

Cancers (Basel) 2021 Apr 27;13(9). Epub 2021 Apr 27.

Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Korea.

Recently, we found that the expressions of adenosine (ADO) receptors A2AR and A2BR and the ectonucleotidase CD73 which is needed for the conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and the extracellular ADO level are increased in TNBC MDA-MB-231 cells and RT-R-MDA-MB-231 cells compared to normal cells or non-TNBC cells. The expression of A2AR, but not A2BR, is significantly upregulated in breast cancer tissues, especially TNBC tissues, compared to normal epithelial tissues. Therefore, we further investigated the role of ADO-activated A2AR and its signaling pathway in the progression of RT-R-TNBC. ADO treatment induced MDA-MB-231 cell proliferation, colony formation, and invasion, which were enhanced in RT-R-MDA-MB-231 cells in an A2AR-dependent manner. A2AR activation by ADO induced AKT phosphorylation and then β-catenin, Snail, and vimentin expression, and these effects were abolished by A2AR-siRNA transfection. In an in vivo animal study, compared to 4T1-injected mice, RT-R-4T1-injected mice exhibited significantly increased tumor growth and lung metastasis, which were decreased by A2AR-knockdown. The upregulation of phospho-AKT, β-catenin, Snail, and vimentin expression in mice injected with RT-R-4T1 cells was also attenuated in mice injected with RT-R-4T1-A2AR-shRNA cells. These results suggest that A2AR is significantly upregulated in BC tissues, especially TNBC tissues, and ADO-mediated A2AR activation is involved in RT-R-TNBC invasion and metastasis through the AKT-β-catenin pathway.
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http://dx.doi.org/10.3390/cancers13092105DOI Listing
April 2021

Combination of Niraparib, Cisplatin and Twist Knockdown in Cisplatin-Resistant Ovarian Cancer Cells Potentially Enhances Synthetic Lethality through ER-Stress Mediated Mitochondrial Apoptosis Pathway.

Int J Mol Sci 2021 Apr 10;22(8). Epub 2021 Apr 10.

College of Pharmacy, Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, Korea.

Poly (ADP-ribose) polymerase 1 inhibitors (PARPi) are used to treat recurrent ovarian cancer (OC) patients due to greater survival benefits and minimal side effects, especially in those patients with complete or partial response to platinum-based chemotherapy. However, acquired resistance of platinum-based chemotherapy leads to the limited efficacy of PARPi monotherapy in most patients. Twist is recognized as a possible oncogene and contributes to acquired cisplatin resistance in OC cells. In this study, we show how Twist knockdown cisplatin-resistant (CisR) OC cells blocked DNA damage response (DDR) to sensitize these cells to a concurrent treatment of cisplatin as a platinum-based chemotherapy agent and niraparib as a PARPi on in vitro two-dimensional (2D) and three-dimensional (3D) cell culture. To investigate the lethality of PARPi and cisplatin on Twist knockdown CisR OC cells, two CisR cell lines (OV90 and SKOV3) were established using step-wise dose escalation method. In addition, in vitro 3D spheroidal cell model was generated using modified hanging drop and hydrogel scaffolds techniques on poly-2-hydroxylethly methacrylate (poly-HEMA) coated plates. Twist expression was strongly correlated with the expression of DDR proteins, PARP1 and XRCC1 and overexpression of both proteins was associated with cisplatin resistance in OC cells. Moreover, combination of cisplatin (Cis) and niraparib (Nira) produced lethality on Twist-knockdown CisR OC cells, according to combination index (CI). We found that Cis alone, Nira alone, or a combination of Cis+Nira therapy increased cell death by suppressing DDR proteins in 2D monolayer cell culture. Notably, the combination of Nira and Cis was considerably effective against 3D-cultures of Twist knockdown CisR OC cells in which Endoplasmic reticulum (ER) stress is upregulated, leading to initiation of mitochondrial-mediated cell death. In addition, immunohistochemically, Cis alone, Nira alone or Cis+Nira showed lower ki-67 (cell proliferative marker) expression and higher cleaved caspase-3 (apoptotic marker) immuno-reactivity. Hence, lethality of PARPi with the combination of Cis on Twist knockdown CisR OC cells may provide an effective way to expand the therapeutic potential to overcome platinum-based chemotherapy resistance and PARPi cross resistance in OC.
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http://dx.doi.org/10.3390/ijms22083916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070209PMC
April 2021

PD-1 Expression and its Correlation With Prognosis in Clear Cell Renal Cell Carcinoma.

In Vivo 2021 May-Jun;35(3):1549-1553

Department of Pathology, Gyeongsang National University School of Medicine, Jinju, Republic of Korea;

Background/aim: Programmed death ligand-1 (PD-L1) and programmed death protein 1 (PD-1) expression levels in many tumors and their correlation with prognosis have been actively studied. However, studies on PD-1 expression and its prognostic value in clear cell renal cell carcinoma (ccRCC) are limited and controversial. In this study, we describe the expression of PD-1 and its prognostic significance and association with clinical features in patients with ccRCC.

Materials And Methods: We obtained clinicopathological data from 166 patients with ccRCC who were treated at Gyeongsang National University Hospital, Jinju, Korea between January 2000 and December 2009. Tissue microarray blocks were made using representative paraffin blocks of ccRCC specimens. Two pathologists analyzed PD-L1 and PD-1 expression in both tumor and inflammatory cells.

Results: PD-1 expression in tumor-infiltrating inflammatory cells was significantly correlated with unfavorable disease-free survival (DFS) (p<0.001) and disease-specific survival (DSS) (p=0.002) in the univariate analysis. A statistically significant correlation between PD-1 expression and unfavorable DFS (p=0.025) was observed in the multivariate analysis.

Conclusion: PD-1 expression in tumor-infiltrating inflammatory cells serves as an independent prognostic factor for unfavorable DSS in patients with ccRCC.
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http://dx.doi.org/10.21873/invivo.12409DOI Listing
March 2021

Expression Patterns of ERα, ERβ, AR, SIRT1, SIRT2, and SIRT3 in Prostate Cancer Tissue and Normal Prostate Tissue.

Anticancer Res 2021 Mar;41(3):1377-1386

Department of Urology, Gyeongsang National University Hospital, Jinju, Republic of Korea;

Background/aim: The purpose of this study was to examine the expression of estrogen receptor α (ERα) and β (ERβ), androgen receptor (AR), SIRT1, SIRT2 and SIRT3 in prostate cancer (PCa).

Materials And Methods: From October 2010 to January 2015, 70 patients who had undergone radical prostatectomy following a PCa diagnosis were enrolled in our study. Normal prostate tissue (NPT) and prostate cancer tissues (PCAT) were separated, and the expression of each receptor in each tissue was analyzed with immunochemical staining. Univariate and multivariate analyses were performed to identify factors affecting the development of PCa.

Results: ERβ and AR were highly expressed in PCAT compared with NPT (p<0.05). SIRT2 was highly expressed in NPT and PCAT (p<0.05). Univariate and multivariate analyses showed that AR and SIRT2 affect PCa development.

Conclusion: AR is a risk factor for PC, and SIRT2 is associated with a lower incidence of PCa.
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http://dx.doi.org/10.21873/anticanres.14895DOI Listing
March 2021

Usefulness of CD109 expression as a prognostic biomarker in patients with cancer: A systematic review and meta-analysis.

Medicine (Baltimore) 2021 Mar;100(11):e25006

Department of Pathology, Gyeongsang National University School of Medicine.

Background: It has been revealed that CD109 expression is associated with prognosis in cancer patients, but it remains unclear thus far. Therefore, we performed a meta-analysis in the present study for a better assessment of the prognostic role of CD109 expression in cancer patients.

Methods: Eligible studies were collected through a search of the PubMed, Embase, Cochrane Library, and Scopus databases. The pooled hazard ratio (HR) with 95% confidence interval (CI) was evaluated to reveal the association between CD109 expression and overall survival (OS) in cancer patients.

Results: Seven studies with 1583 patients were enrolled. The pooled HR with 95% CI was calculated as 2.31 (95% CI 1.93-2.76, P < .001), suggesting an association between high expression of CD109 and unfavorable OS in cancer patients.

Conclusion: This analysis indicated that CD109 expression could be used as a prognostic biomarker in cancer patients. This is the first meta-analysis to report the relationship between CD109 expression and prognosis in cancer patients.
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http://dx.doi.org/10.1097/MD.0000000000025006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982172PMC
March 2021

Prescription patterns of herbal medicine for menopausal disorders in major Korean medicine hospitals: a multicenter retrospective study.

Integr Med Res 2021 Sep 4;10(3):100706. Epub 2020 Dec 4.

You & Green Korean Medical Clinic, Daejeon, Korea.

Background: This study aimed to obtain the symptom, prescription and therapeutic patterns for the treatment of patients with menopausal syndrome in major Korean medicine (KM) hospitals.

Methods: We used a retrospective chart review of climacteric disorder and postmenopausal syndrome patients by examining medical records (ICD-10, menopausal and female climacteric states: N95.1, Menopausal and perimenopausal disorder, unspecified: N95.9) from eight university KM hospitals in South Korea.

Results: The main symptoms of 1,682 patients with menopausal disorders visiting eight college-affiliated oriental medicine hospitals were hot flush, hyperhidrosis, fatigue, insomnia, and chest tightness. Guipi decoction, Si-wu guipi decoction, Qing-xin lianzi-yin, Jiawei xiao-yao-san and Guipi wen-dan decoction were the most commonly prescribed treatments for menopausal disorders. Patients were most often treated with a combination of herbal medicine and acupuncture.

Conclusion: Our study shows that the current prescribed herbal medicines were used for treating menopausal disorders in Korean medicine hospitals. However, the objectivity of the efficacy assessment should be studied further.
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http://dx.doi.org/10.1016/j.imr.2020.100706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903342PMC
September 2021

Analysis of Risk Factors for Hepatotoxicity Induced by Immune Checkpoint Inhibitors.

J Immunother 2021 Jan;44(1):16-21

College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Graduate School of Clinical Biohealth, Ewha Womans University.

Although hepatotoxicity induced by immune checkpoint inhibitors (ICPIs) can cause severe clinical complications, the risk factors associated with hepatotoxicity have rarely been investigated. The purpose of this study was to determine the potential risk factors for the incidence of hepatotoxicity and for time to ICPI-induced hepatotoxicity. Patients who received ICPIs (atezolizumab, nivolumab, pembrolizumab, and ipilimumab) were included in this retrospective 2-center study. Collected data included sex, age, body weight, body surface area, Eastern Cooperative Oncology Group performance status, underlying disease, liver metastasis, programmed cell death ligand-1 expression, interval from previous chemotherapy, and concomitant drug use. Among the 194 patients, patients who experienced hepatotoxicity after ICPI administration was 64.4% (n=125) in all grade and 10.8% (n=21) in grade III or higher. Multivariate analysis showed that patients aged 30-50 and 50-70 years had increased risks of hepatotoxicity by 4.9-fold (95% confidence interval, 1.3-18.0) and 2.7-fold (95% confidence interval, 1.3-5.5), respectively, compared with those older than 70 years. The use of acetaminophen increased the occurrence of hepatotoxicity by 2.1 times; the attributable risk was 53.2%. Male patients and patients younger than 65 years had around 1.5-fold increased hazard of time to reach hepatotoxicity. Patients treated with 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors had a 4.7-fold higher risk of grade III-IV hepatotoxicity compared with those without HMG-CoA reductase inhibitors; the attributable risk was 78.8%. In conclusion, close monitoring of liver function is recommended, especially in male patients, patients younger than 65 years old, and when there is concomitant use of hepatotoxic drugs including acetaminophen and HMG-CoA reductase inhibitors.
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http://dx.doi.org/10.1097/CJI.0000000000000347DOI Listing
January 2021

Anthocyanins Derived from Contributes Anti-Cancer Effects by Suppressing NF-κB Pathways in Hep3B Human Hepatocellular Carcinoma Cells and In Vivo.

Molecules 2020 Nov 20;25(22). Epub 2020 Nov 20.

Department of Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, 90 Chilam-dong, Jinju 660-702, Korea .

We previously demonstrated that anthocyanins from the fruits of (AIMs) induced the apoptosis of hepatocellular carcinoma cells. However, many researchers argued that the concentrations of AIMs were too high for in vivo experiments. Therefore, we performed in vitro at lower concentrations and in vivo experiments for the anti-cancer effects of AIMs. AIMs inhibited the cell proliferation of Hep3B cells in a dose-dependent manner with a maximum concentration of 100 µg/mL. AIMs also inhibited the invasion and migration at 100 µg/mL concentration with or without the presence of TNF-α. To establish the relevance between the in vitro and in vivo results, we validated their effects in a Xenograft model of Hep3B human hepatocellular carcinoma cells. In the in vivo test, AIMs inhibited the tumorigenicity of Hep3B cells in the xenograft mouse model without showing any clinical signs of toxicity or any changes in the body weight of mice. AIMs inhibited the activation NF-κB and suppressed the NF-κB-regulated proteins, intra-tumoral microvessel density (IMVD) and the Ki67 activity of Hep3B xenograft tumors in athymic nude mice. In conclusion, this study indicates that AIMs have anti-cancer effects (inhibition of proliferation, invasion, and angiogenesis) on human hepatocellular carcinoma xenograft through the inhibition of NF-κB and its target protein.
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http://dx.doi.org/10.3390/molecules25225445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699833PMC
November 2020

Solitary sclerotic fibroma on the thigh.

Arch Craniofac Surg 2020 Oct 20;21(5):323-325. Epub 2020 Oct 20.

Department of Plastic and Reconstructive Surgery, Bundang Jesaeng Hospital, Seongnam, Korea.

Sclerotic fibroma is a rare fibrous tumor of the skin associated with Cowden's disease. In 1989, Rapini described sclerotic fibroma without Cowden's disease as solitary sclerotic fibroma of the skin. It is a solid, well-circumscribed, slow-growing nodular tumor and it looks similar to a keloid scar. Consequently, it is extremely difficult to make a differential diagnosis of solitary sclerotic fibroma with keloid scar based on clinical findings only. The authors report a case of solitary sclerotic fibroma arising at the left lateral thigh of a 25-year-old man.
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http://dx.doi.org/10.7181/acfs.2020.00360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644342PMC
October 2020

A Review of Skin Banking Guidelines and Standards Worldwide: Towards the Harmonization of Guidelines for Skin Banking in Therapeutic Applications for the Regions under the Asia Pacific Burn Association (APBA).

Burns Trauma 2020 20;8:tkaa019. Epub 2020 Oct 20.

Transplant Tissue Centre, Singhealth Duke-NUS Transplant Centre, Singapore.

Currently, there are no harmonized guidelines which govern skin banking in the Asia Pacific region. Therefore, skin banks are either unregulated or rely on their nation's legislation or international accreditation to uphold their quality standards. A new set of skin banking guidelines was developed through a comprehensive review and collation of best international practices for the Asia Pacific Burn Association (APBA) members, from donor screening and testing, to skin recovery, processing, storage and distribution, and quality assurance. National regulatory requirements reviewed include the European directives, Australia's Therapeutic Goods Administration and Singapore's tissue banking standards. Further technical and quality management recommendations are referenced from the American Association of Tissue Banks (AATB), the United States Food and Drug Administration standards and guidance documents, various relevant European guides, Japanese Society of Tissue Transplantation guidelines and the Asia Pacific Association of Surgical Tissue Banking. Adapted mainly from the AATB standards, the new Asia Pacific Burn Association Guidelines for Skin Banking in Therapeutic Applications offer a comprehensive manual, addressing: governance and contracts; staff responsibilities; quality management; facilities, equipment and supplies management; donor consent and testing; and recommendations of good practices pertaining to skin recovery, processing, storage and distribution. Besides complementing current generic regulations, they provide technical specifications of major aspects unaddressed in most legislations. This inaugural set of new regional skin banking guidelines would be a start for regional members of the APBA to adopt, and will hopefully culminate in a set of standards so that, in the long run, skin allografts from this region can be of similar quality, which can simplify import process and facilitate the exchange of allografts between members.
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http://dx.doi.org/10.1093/burnst/tkaa019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573737PMC
October 2020

Recommendations for pathologic practice using digital pathology: consensus report of the Korean Society of Pathologists.

J Pathol Transl Med 2020 Nov 8;54(6):437-452. Epub 2020 Oct 8.

Department of Pathology, Catholic Kwandong University College of Medicine, Gangneung, Korea.

Digital pathology (DP) using whole slide imaging (WSI) is becoming a fundamental issue in pathology with recent advances and the rapid development of associated technologies. However, the available evidence on its diagnostic uses and practical advice for pathologists on implementing DP remains insufficient, particularly in light of the exponential growth of this industry. To inform DP implementation in Korea, we developed relevant and timely recommendations. We first performed a literature review of DP guidelines, recommendations, and position papers from major countries, as well as a review of relevant studies validating WSI. Based on that information, we prepared a draft. After several revisions, we released this draft to the public and the members of the Korean Society of Pathologists through our homepage and held an open forum for interested parties. Through that process, this final manuscript has been prepared. This recommendation contains an overview describing the background, objectives, scope of application, and basic terminology; guidelines and considerations for the hardware and software used in DP systems and the validation required for DP implementation; conclusions; and references and appendices, including literature on DP from major countries and WSI validation studies.
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http://dx.doi.org/10.4132/jptm.2020.08.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674756PMC
November 2020

Prognostic Value of CD63 Expression in Solid Tumors: A Meta-analysis of the Literature.

In Vivo 2020 Sep-Oct;34(5):2209-2215

Department of Pathology, Gyeongsang National University School of Medicine, Jinju, Republic of Korea

Background: CD63 has been described as a key factor in extracellular vesicle production and endosomal cargo sorting, and there have been certain reports suggesting an association between CD63 expression and survival in patients with tumors including gastric, colon and lung cancer. However, the prognostic value of CD63 expression remains contradictory. Hence, we performed this meta-analysis to assess the prognostic value of CD63 expression in solid tumors.

Materials And Methods: Eligible studies were collected by searching the PubMed, Embase and Cochrane libraries. The hazard ratio (HR) with 95% confidence interval (CI) were evaluated to reveal the association between CD63 expression and survival in solid tumors.

Results: Five studies with a total of 1,454 patients were included. The HR evaluating CD63 expression on survival was 1.34 (95%CI=0.92-1.97, p=0.129). In subgroup analysis, the HRs of lung cancer and other tumors were 0.50 (95% CI=0.32-0.77, p=0.002) and 2.16 (95% CI=1.93-2.42, p<0.001) respectively. CD63 expression was significantly associated with poor disease-specific survival (HR=1.69, 95% CI=1.15-2.49, p=0.008), but not with disease-free survival and overall survival. Also, there was a significant association between CD63 expression with poor survival in the group of sample size more than 150 patients (HR=2.15, 95% CI=2.92-2.41, p<0.001), but not in the group of sample size with fewer than 150 patients.

Conclusion: This meta-analysis suggested that CD63 expression may be a potential prognostic marker in solid tumors.
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http://dx.doi.org/10.21873/invivo.12031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652479PMC
May 2020

Prognostic significance of Rab27 expression in solid cancer: a systematic review and meta-analysis.

Sci Rep 2020 08 24;10(1):14136. Epub 2020 Aug 24.

Department of Pathology, Gyeongsang National University School of Medicine, 79 Gangnam-ro, Jinju, 52727, South Korea.

Rab27 is an essential molecule of vesicle fusion and trafficking in exosome secretion process, which plays important roles in cancer progression and metastasis. Recent studies reported that Rab27 expression is also associated with cancer prognosis. Therefore, we performed a meta-analysis to reveal the prognostic significance of Rab27 expression in solid cancer. Data were extracted by searching on PubMed, Embase and Cochrane library until February 15 2020. Pooled hazard ratio (HR) with confidence interval (CI) was calculated to evaluate the association between Rab27 expression and survival in solid cancer. Ten studies with 1434 cancer patients were including for this meta-analysis. High expression of Rab27 was associated with poor survival (HR 2.67, 95% CI 1.52-4.69, p = 0.001). High expression of Rab27A was significantly associated with lymph node metastasis (HR 1.53, 95% CI 1.00-2.34, p = 0.048). High expression of Rab27B was significantly correlated with lymph node and distant metastasis (HR 2.15, 95% CI 1.56-2.95, p < 0.001; HR 6.80, 95% CI 3.12-14.85, p < 0.001), and higher TNM stage (HR 2.55, 95% CI 1.78-3.65, p < 0.001). This meta-analysis revealed that Rab27 expression could be a potential prognostic marker in solid cancer.
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http://dx.doi.org/10.1038/s41598-020-71104-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445175PMC
August 2020

Prognostic significance of macrophage migration inhibitory factor expression in cancer patients: A systematic review and meta-analysis.

Medicine (Baltimore) 2020 Aug;99(32):e21575

Department of Pathology, Gyeongsang National University School of Medicine.

Background: Recent studies showed that Macrophage migration inhibitory factor (MIF) is overexpressed and closely associated with prognosis in cancer patients. The present study was systematically evaluated the prognostic significance of MIF expression in cancer patients.

Methods: PubMed, Cochrane library and Scopus were searched for eligible studies up to January 2020. Pooled hazard ratio with confidence interval (CI) was determined to assess the relationship between MIF expression and survival in cancer patients.

Results: A total of 8 studies comprising 847 cancer patients were included in this meta-analysis. For overall survival, the pooled hazard ratio was 2.23 (95% CI 1.67-2.99, P < .001). For disease-free survival, the pooled hazard ratio was 2.24 (95% CI 1.69-2.96, P < .001). The results suggested that high expression of MIF was significantly related to poor overall survival and disease-free survival in cancer patients.

Conclusion: MIF expression could be a valuable prognostic factor in cancer patients.
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http://dx.doi.org/10.1097/MD.0000000000021575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592988PMC
August 2020

P2YR has a significant correlation with Notch-4 in patients with breast cancer.

Oncol Lett 2020 Jul 14;20(1):647-654. Epub 2020 May 14.

Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, South Gyeongsang 52727, Republic of Korea.

Our previous study found that highly metastatic breast cancer cells, such as MDA-MB-231 cells, release higher levels of ATP and exhibit greater P2Y receptor (P2YR) activity than lowly metastatic breast cancer cells, and that P2YR activation mediated by ATP plays a significant role in tumor progression and metastasis. In addition, we reported that radiotherapy-resistant (RT-R) breast cancer cells promote invasion and tumor growth through the activation of P2YR by ATP released from RT-R-breast cancer cells than breast cancer cells. Moreover, increased numbers of cancer stem cells (CSCs) were observed among the RT-R-breast cancer cell population. Therefore, in this study, we investigated the expression level of five CSC markers (CD24, CD44, Oct3/4, Notch-4 and ALDH1A1) as well as P2YR in the tumor tissues of patients with breast cancer and determined which CSC marker correlates with P2YR in breast cancer. According to the immunohistochemical analysis, CD44, Oct3/4 and Notch-4 but not ALDH1A1 were significantly expressed in the tumor tissues (n=180) compared with the normal epithelial tissues (n=20) of patients with breast cancer. It was demonstrated that P2YR expression was increased in tumor tissues of patients with breast cancer compared with normal epithelial tissue. Notably, it was identified that P2YR expression has a significant correlation with only the CSC marker Notch-4 in patients with breast cancer. The results of this study suggested for the first time to the best of our knowledge that Notch-4 has a notable correlation with P2YR, which has important roles in tumor progression and metastasis.
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http://dx.doi.org/10.3892/ol.2020.11630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286009PMC
July 2020

Characteristics of Gastric Carcinomas With High ERCC1 Expression and the Prognostic Value of ERCC1 Expression.

Anticancer Res 2020 Jun;40(6):3203-3208

Department of Pathology, Gyeongsang National University School of Medicine, Jinju, Republic of Korea

Background/aim: We aimed to evaluate the characteristics of gastric carcinoma with high excision repair cross complementing 1 (ERCC1) expression and the prognostic value of ERCC1 expression.

Materials And Methods: ERCC1 expression was evaluated by immunohistochemistry in 309 surgically resected gastric carcinoma specimens using a tissue microarray. Cancer-related survival was analysed using competing risk analysis.

Results: Compared to ERCC1-low gastric carcinomas, ERCC1-high gastric carcinomas showed less local invasion (p=0.0013), lower N stage (p=0.0302), earlier pTNM stage (p=0.0003), and less frequent recurrence (p=0002). Patients with ERCC1-high gastric carcinoma showed lower cumulative incidence function estimate of cancer-related death [3.37; 95% confidence intervaI (CI)=0.89-8.75] than did those with ERCC1-low gastric carcinoma (17.12; 95% CI=12.24-22.69; p-value by Gray's test=0.0012). Adjusted proportional sub-distribution hazard ratio for cancer-related death in the patients with ERCC1-high tumour was 0.272 (95% CI=0.084-0.878; p=0.0295).

Conclusion: High ERCC1 expression may be an independent positive prognostic marker for gastric carcinoma.
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http://dx.doi.org/10.21873/anticanres.14301DOI Listing
June 2020

Prognostic role of macrophage migration inhibitory factor expression in patients with squamous cell carcinoma of the lung.

Thorac Cancer 2019 12 10;10(12):2209-2217. Epub 2019 Oct 10.

Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon, South Korea.

Background: Macrophage migration inhibitory factor (MIF) has been shown to play an important role in the inflammatory and immune response in squamous cell carcinoma (SCC). Recent studies have reported that MIF is involved in the tumorigenesis and overexpressed in various cancers. In this study, we assessed the prognostic role of MIF expression in SCC of the lung, and demonstrated the effect of knockdown of MIF on the migration in lung SCC cell lines.

Methods: The relationship between MIF expression and clinicopathological parameters and the prognostic role of MIF expression were evaluated with immunohistochemical staining in 96 patients with SCC of the lung. The expression of MIF mRNA and protein was analyzed by semi-quantitative polymerase chain reaction and Western blot in lung SCC cell. The effect of knockdown of MIF was assessed by wound healing assay.

Results: The high percentage of MIF-positive cells was significantly associated with lymph node metastasis (P = 0.004), and was a poor prognostic factor of disease-free survival (DFS) (hazard ratio [HR]: 3.125; 95% confidence interval [CI], 1.628-5.998; P = 0.001) and disease-specific survival (DSS) (HR: 2.303; 95% CI, 1.172-4.525; P = 0.016). Moreover, Kaplan-Meier analysis showed that SCC patients with a high percentage of MIF-positive cells had a significantly lower DFS (P = 0.001) and DSS (P = 0.014) than those with a low percentage. Furthermore, wound healing assay revealed that knockdown of MIF resulted in decreased cellular migration.

Conclusion: MIF is closely associated with tumor progression and could be a prognostic factor in SCC of the lung.
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http://dx.doi.org/10.1111/1759-7714.13198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885432PMC
December 2019

Prognostic role of S100A9 expression in patients with clear cell renal cell carcinoma.

Medicine (Baltimore) 2019 Oct;98(40):e17188

Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon.

S100A9 was originally regarded as a regulator of immune response and a mediator of the inflammatory process. Recent studies have suggested that S100A9 expression plays an important role during tumor development, progression and metastasis in various cancers. The present study aimed to investigate the expression and prognostic role of S100A9 in clear cell renal cell carcinoma (ccRCC).S100A9 expression was examined by immunohistochemical staining in 152 patients who underwent surgical resection due to ccRCC. The correlation between S100A9 expression and clinicopathological data and its prognostic role were evaluated in patients with ccRCC.S100A9 revealed high expression in 37 cores (12.6%) of ccRCC. S100A9 expression was significantly associated with T stage (P < .001) and Fuhrman nuclear grade (P < .001), but not with patient age (P = .821) and sex (P = .317). Survival analysis revealed that high S100A9 expression is an independent factor for unfavorable disease-free survival (hazard ratio, 2.423; 95% confidence interval, 1.044-5.621; P = .039) and disease-specific survival (hazard ratio, 2.428; 95% confidence interval, 1.130-5.214; P = .023) in patients with ccRCC.S100A9 expression can be a useful prognostic factor in patients with ccRCC.
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http://dx.doi.org/10.1097/MD.0000000000017188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783177PMC
October 2019

Myoferlin silencing inhibits VEGFR2-mediated proliferation of metastatic clear cell renal cell carcinoma.

Sci Rep 2019 09 2;9(1):12656. Epub 2019 Sep 2.

Gyeongsang National University School of Medicine, Jinju, South Korea.

Recently, ramucirumab, a drug that targets vascular endothelial growth factor receptor (VEGFR), was clinically approved; therefore, we evaluated VEGFR2 expression and its predictive roles in tumor progression in clear cell renal cell carcinoma (CCRCC). Since we do not have many options for treating aggressive renal cell carcinoma patients, the application of anti-VEGFR2 therapy might be useful. Myoferlin (MYOF) is a 230 kDa transmembrane multi-C2-domain protein that contributes to plasma membrane repair, fusion, and endocytosis and is overexpressed in several invasive cancer cell lines, including breast, pancreas, and malignant melanoma. It forms a complex with VEGFR2 to inhibit VEGFR2 degradation. In this study, a total of 152 patients who had undergone nephrectomy for CCRCC were enrolled. Based on tissue microarray (TMA) blocks, the positive intensity and high proportion of MYOF showed a statistically significant correlation with the negative intensity (p < 0.001) and low proportion (p < 0.001) of VEGFR2, respectively. In addition, Fuhrman's nuclear grade ≥3 showed a significant correlation with VEGFR2 expression. In multivariate analysis, CCRCC patients with positive MYOF and negative VEGFR2 expression demonstrated poor clinical outcomes. We confirmed that positive MYOF expression and negative VEGFR2 expression were positively correlated in this CCRCC population. Knocking down MYOF in Caki-1 cells resulted in the downregulation of VEGFR2 at both mRNA and protein levels. Wound healing assays revealed that the loss of MYOF in Caki-1 cells decreased cell confluence compared to that in control cells. We demonstrated that MYOF influences cellular proliferation of the metastatic CCRCC cell line by regulating VEGFR2 degradation. Combined therapies targeting the MYOF and VEGFR2 pathways might be effective against metastatic CCRCC to increase patient survival.
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http://dx.doi.org/10.1038/s41598-019-48968-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718427PMC
September 2019

Identification of Myoferlin Expression for Prediction of Subsequent Primary Malignancy in Patients With Clear Cell Renal Cell Carcinoma.

In Vivo 2019 Jul-Aug;33(4):1103-1108

Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea

Background/aim: Multiple primary malignant tumors are common in patients with renal cell carcinoma. However, reports on the factors that can identify patients with a risk for subsequent primary malignancies have been lacking. This study aimed to investigate whether myoferlin expression can be used as a potential marker to predict subsequent primary malignancies in patients with clear cell renal cell carcinoma (ccRCC).

Materials And Methods: We evaluated the relationship of subsequent primary malignancies with clinicopathological factors and myoferlin expression in 152 patients with ccRCC, and we analyzed the strength of the association with myoferlin expression.

Results: The development of subsequent primary malignancies exhibited significant correlation with patient age (p=0.029), sex (p=0.015), T stage (p<0.001), and myoferlin expression (p=0.017). Furthermore, myoferlin hyperexpression was determined as an independent risk factor for developing a subsequent primary malignant tumor in patients with ccRCC (odds ratio(OR), 2.485, 95% Confidence Interval(CI)=1.052-5.870, p=0.038).

Conclusion: Myoferlin hyperexpression can be a useful marker for predicting the development of subsequent primary malignancies in patients with ccRCC.
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http://dx.doi.org/10.21873/invivo.11579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689344PMC
December 2019

Single GaAs Nanowire/Graphene Hybrid Devices Fabricated by a Position-Controlled Microtransfer and an Imprinting Technique for an Embedded Structure.

ACS Appl Mater Interfaces 2019 Apr 29;11(14):13514-13522. Epub 2019 Mar 29.

Department of Electronic Systems , Norwegian University of Science and Technology (NTNU) , NO-7491 Trondheim , Norway.

We developed a new technique to fabricate single nanowire devices with reliable graphene/nanowire contacts using a position-controlled microtransfer and an embedded nanowire structure in a planar junction configuration. A thorough study of electrical properties and fabrication challenges of single p-GaAs nanowire/graphene devices was carried out in two different device configurations: (1) a graphene bottom-contact device where the nanowire-graphene contact junction is formed by transferring a nanowire on top of graphene and (2) a graphene top-contact device where the nanowire-graphene contact junction is formed by transferring graphene on top of an embedded nanowire. For the graphene top-contact devices, graphene-nanowire-metal devices, where graphene is used as one electrode and metal is the other electrode to a nanowire, and graphene-nanowire-graphene devices, where both electrodes to a nanowire are graphene, were investigated and compared with conventional metal/p-GaAs nanowire devices. Conventional metal/p-GaAs nanowire contact devices were further investigated in embedded and nonembedded nanowire device configurations. A significantly improved current in the embedded device configuration is explained with a "parallel resistors model" where the high-resistance parts with the metal-semiconductor Schottky contact and the low-resistance parts with noncontacted facets of the hexagonal nanowires are taken into consideration. Consistently, the nonembedded nanowire structure is found to be depleted much easier than the embedded nanowires from which an estimation for a fully depleted condition has also been established.
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http://dx.doi.org/10.1021/acsami.8b20581DOI Listing
April 2019

GaN/AlGaN Nanocolumn Ultraviolet Light-Emitting Diode Using Double-Layer Graphene as Substrate and Transparent Electrode.

Nano Lett 2019 03 6;19(3):1649-1658. Epub 2019 Feb 6.

Department of Electronic Systems , Norwegian University of Science and Technology (NTNU) , NO-7491 Trondheim , Norway.

The many outstanding properties of graphene have impressed and intrigued scientists for the last few decades. Its transparency to light of all wavelengths combined with a low sheet resistance makes it a promising electrode material for novel optoelectronics. So far, no one has utilized graphene as both the substrate and transparent electrode of a functional optoelectronic device. Here, we demonstrate the use of double-layer graphene as a growth substrate and transparent conductive electrode for an ultraviolet light-emitting diode in a flip-chip configuration, where GaN/AlGaN nanocolumns are grown as the light-emitting structure using plasma-assisted molecular beam epitaxy. Although the sheet resistance is increased after nanocolumn growth compared with pristine double-layer graphene, our experiments show that the double-layer graphene functions adequately as an electrode. The GaN/AlGaN nanocolumns are found to exhibit a high crystal quality with no observable defects or stacking faults. Room-temperature electroluminescence measurements show a GaN related near bandgap emission peak at 365 nm and no defect-related yellow emission.
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http://dx.doi.org/10.1021/acs.nanolett.8b04607DOI Listing
March 2019

RAB27A is an independent prognostic factor in clear cell renal cell carcinoma.

Biomark Med 2019 03 21;13(4):239-247. Epub 2019 Jan 21.

Gyeongsang National University School of Medicine, Jinju, Korea.

Aim: To examine the expression of RAB27A and RAB27B in clear cell renal cell carcinoma (CCRCC).

Materials & Methods: The intensity and proportion of tumor cells staining positive for RAB27A and RAB27B in a total of 304 cores were evaluated.

Results: The T stage showed a significant correlation with RAB27A intensity (p < 0.001). In multivariate analysis, CCRCC with negative intensity of RAB27A expression demonstrated poor disease-specific survival (hazard ratio: 6.821, 95% CI: 1.128-41.241; p-value = 0.036).

Conclusion: RAB27A is an independent prognostic factor in CCRCC.
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http://dx.doi.org/10.2217/bmm-2018-0336DOI Listing
March 2019

Prognostic Role of S100A8 and S100A9 Protein Expressions in Non-small Cell Carcinoma of the Lung.

J Pathol Transl Med 2019 Jan 26;53(1):13-22. Epub 2018 Nov 26.

Department of pathology, Gyeongsang National University Changwon Hospital, Changwon, Korea.

Background: S100A8 and S100A9 have been gaining recognition for modulating tumor growthand metastasis. This study aimed at evaluating the clinical significance of S100A8 and S100A9 innon-small cell lung cancer (NSCLC).

Methods: We analyzed the relationship between S100A8and S100A9 expressions, clinicopathological characteristics, and prognostic significance in tumorcells and peritumoral inflammatory cells.

Results: The positive staining of S100A8 in tumorcells was significantly increased in male (p < .001), smoker (p = .034), surgical method other thanlobectomy (p = .024), squamous cell carcinoma (SQCC) (p < .001) and higher TNM stage (p = .022)compared with female, non-smoker, lobectomy, adenocarcinoma (ADC), and lower stage. Theproportion of tumor cells stained for S100A8 was related to histologic type (p < .001) and patientsex (p = .027). The proportion of inflammatory cells stained for S100A8 was correlated with patientage (p = .022), whereas the proportion of inflammatory cells stained for S100A9 was correlatedwith patient sex (p < .001) and smoking history (p = .031). Moreover, positive staining in tumorcells, more than 50% of the tumor cells stained and less than 30% of the inflammatory cellsstained for S100A8 and S100A9 suggested a tendency towards increased survivability in SQCCbut towards decreased survivability in ADC.

Conclusions: S100A8 and S100A9 expressions might be potential prognostic markers in patients with NSCLC.
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http://dx.doi.org/10.4132/jptm.2018.11.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344806PMC
January 2019

Robust Inductive Matrix Completion Strategy to Explore Associations Between LincRNAs and Human Disease Phenotypes.

IEEE/ACM Trans Comput Biol Bioinform 2019 Nov-Dec;16(6):2066-2077. Epub 2018 Jun 7.

Over the past few years, it has been established that a number of long intergenic non-coding RNAs (lincRNAs) are linked to a wide variety of human diseases. The relationship among many other lincRNAs still remains as puzzle. Validation of such link between the two entities through biological experiments is expensive. However, piles of information about the two are becoming available, thanks to the High Throughput Sequencing (HTS) platforms, Genome Wide Association Studies (GWAS), etc., thereby opening opportunity for cutting-edge machine learning and data mining approaches. However, there are only a few in silico lincRNA-disease association inference tools available to date, and none of these utilizes side information of both the entities. The recently developed Inductive Matrix Completion (IMC) technique provides a recommendation platform among two entities considering respective side information. But, the formulation of IMC is incapable of handling noise and outliers that may present in the dataset, while data sparsity consideration is another issue with the standard IMC method. Thus, a robust version of IMC is needed that can solve these two issues. As a remedy, in this paper, we propose Robust Inductive Matrix Completion (RIMC) using l norm loss function as well as l norm based regularization. We applied RIMC to the available association data between human lincRNAs and OMIM disease phenotypes as well as a diverse set of side information about the lincRNAs and the diseases. Our method performs better than the state-of-the-art methods in terms of precision@k and recall@k at the top- k disease prioritization to the subject lincRNAs. We also demonstrate that RIMC is equally effective for querying about novel lincRNAs, as well as predicting rank of a newly known disease for a set of well-characterized lincRNAs. Availability: All the supporting datasets are available at the publicly accessible URL located at http://biomecis.uta.edu/~ashis/res/RIMC/.
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http://dx.doi.org/10.1109/TCBB.2018.2844816DOI Listing
July 2020

Myoferlin Expression and Its Correlation with FIGO Histologic Grading in Early-Stage Endometrioid Carcinoma.

J Pathol Transl Med 2018 Mar 14;52(2):93-97. Epub 2018 Mar 14.

Department of Pathology, Gyeongsang National University Hospital, Jinju, Korea.

Background: For endometrioid carcinoma patients, International Federation of Gynecologists and Obstetricians (FIGO) histologic grading is very important for identifying the appropriate treatment method. However, the interobserver discrepancy with this three-tiered grading system is a serious potential problem. In this study, we used immunohistochemistry to analyze the relationship between FIGO histologic grading score and myoferlin expression.

Methods: We studied the endometrioid carcinoma tissues of 60 patients from Gyeongsang National University Hospital between January 2002 and December 2009. Immunohistochemical analysis of myoferlin was performed on tissue microarray blocks from surgical specimens.

Results: Myoferlin expression was observed in 58 of 60 patients. Moderate and strong myoferlin expression was observed in low-grade endometrioid carcinoma, while there was a tendency toward loss of myoferlin expression in high-grade endometrioid carcinoma (p<.001).

Conclusions: Our study revealed that myoferlin loss is significantly correlated with high FIGO grade of endometrioid carcinoma.
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http://dx.doi.org/10.4132/jptm.2017.11.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859243PMC
March 2018

Myxoid Solitary Fibrous Tumor on the Scalp.

Arch Craniofac Surg 2017 Dec 23;18(4):269-272. Epub 2017 Dec 23.

Department of Pathology, Bundang Jesaeng Hospital, Seongnam, Korea.

Myxoid solitary fibrous tumor (SFT) is very rare soft tissue neoplasm. It is microscopically composed of spindle cells which is individually separated by delicate band of collagen fibers. And this tumor cells are immunohisto-chemistrically highlighted by CD34. Myxoid SFT has indolent clinical course and a good prognosis, so it is important to make a diagnosis because of its morphological similarities to myxoid spindle cell neoplasms that have different prognoses and treatment. We report the case of a 20-year-old female with a myxoid SFT found in the left temporo-parietal scalp. This case report appears to be the first reported scalp occurrence of this rare tumor.
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http://dx.doi.org/10.7181/acfs.2017.18.4.269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759655PMC
December 2017

Prognostic role of myoferlin expression in patients with clear cell renal cell carcinoma.

Oncotarget 2017 Oct 6;8(51):89033-89039. Epub 2017 Oct 6.

Gyeongsang National University School of Medicine, Jinju, South Korea.

Objectives: In patients with cancer, myoferlin protein hyperexpression has been correlated with poor patient prognosis. Here, we evaluated myoferlin expression in patients with clear cell renal cell carcinoma (ccRCC) and investigated the prognostic significance of myoferlin expression in these patients.

Materials And Methods: One hundred and fifty-two patients with ccRCC who underwent treatment at Gyeongsang National University Hospital, Korea, between January 2000 and December 2009 were enrolled. Immunohistochemical analysis was performed on tissue microarray blocks produced from surgical specimens. Surgical specimen cancerous cells were graded as showing myoferlin hyperexpression or hypoexpression by comparison with intratumoral endothelial cells. Disease-free survival was evaluated using Kaplan-Meier analysis. Cox regression analysis was used to determine the relationships between myoferlin expression levels, risk factors, and prognosis.

Results: Seventy-one of 304 cores exhibited myoferlin hyperexpression. T stage was not associated with myoferlin hyperexpression, whereas a high Fuhrman nuclear grade was significantly associated with myoferlin hyperexpression. Kaplan-Meier analysis revealed that patients with T stage >2, Fuhrman nuclear grade >2, and those with myoferlin hyperexpression had poorer disease-free survival compared to those with lower T stage, lower Fuhrman nuclear grade, and myoferlin hypoexpression (all p <0.001). Furthermore, myoferlin hyperexpression was significantly associated with disease-free survival on Cox regression analysis (hazard ratio, 4.604; 95% confidence interval, 1.893-11.199; p = 0.001).

Conclusion: Myoferlin expression could be a potential prognosticator in patients with ccRCC, and might be a useful marker for oncologic surveillance in such patients.
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http://dx.doi.org/10.18632/oncotarget.21645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687666PMC
October 2017

Programmed Death-Ligand 1 Expression and Its Correlation with Lymph Node Metastasis in Papillary Thyroid Carcinoma.

J Pathol Transl Med 2018 Jan 3;52(1):9-13. Epub 2017 Oct 3.

Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon, Korea.

Background: The immunotherapeutic role of programmed death-ligand 1 (PD-L1) in life expectancy in many cancers has been highlighted. However, data regarding PD-L1 expression in papillary thyroid carcinoma (PTC) are limited. In this study, we describe the PD-L1 and programmed cell death protein 1 (PD-1) expressions in PTC and analyze their correlation with lymph node (LN) metastasis.

Methods: Clinicopathological data were obtained from 116 patients with PTC who were treated in Gyeongsang National University Hospital, Jinju, Korea in 2009. Tissue microarray blocks were made using representative paraffin blocks of classical PTCs excluding follicular variants. Two pathologists graded the proportion and intensity of PD-L1 and PD-1 expression in both tumor and inflammatory cells. According to their proportions, positive PTC cells were scored as negative (0%), grade 1 (1%-50%), and grade 2 (51%-100%). Similarly, positive inflammatory cells were graded as negative (0%), grade 1 (1%-10%), and grade 2 (11%-20%). The intensity of each protein expression was simplified as positive or negative.

Results: A statistically significant correlation exists between the proportions of PD-1 and PD-L1 expression both in papillary carcinoma (p=.001) and peritumoral lymphoid cells in the thyroid (p<.001). In addition, the proportion of PD-L1 expression in PTC cells was closely related to metastatic LNs (p=.036).

Conclusions: PD-L1 is a valuable predictive marker for LN metastasis in PTC. Immunomodulating therapies that inhibit PD-L1 might be an option for patients with LN metastasis.
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http://dx.doi.org/10.4132/jptm.2017.07.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784225PMC
January 2018

Acute Osteomyelitis in the Hand Due to Dog Bite Injury: A Report of 3 Cases.

Arch Plast Surg 2017 Sep 15;44(5):444-448. Epub 2017 Sep 15.

Department of Plastic and Reconstructive Surgery, Bundang Jesaeng General Hospital, Seongnam, Korea.

As many people keep small dogs as pets, dog bites are common injuries, accounting for approximately 80%-90% of all animal bite injuries. These injuries usually occur on the upper extremities, most commonly on the fingers. Most of these injuries appear as simple lacerations or abrasions of the skin. Common symptoms include inflammatory reactions of the soft tissue, such as pain, swelling, erythema, and cellulitis. However, the complications of small dog bites may include joint or cartilage injuries, including acute osteomyelitis. Once osteomyelitis develops, it is difficult to diagnose since it has a latency period of approximately 2 weeks. Plain radiography, magnetic resonance imaging, and 3-phase bone scans should be performed when acute osteomyelitis is suspected, and broad-spectrum empiric antibiotic treatment should be administered for approximately 8-12 weeks. We report 3 very rare cases of acute osteomyelitis that occurred after a dog bite injury.
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http://dx.doi.org/10.5999/aps.2017.44.5.444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621810PMC
September 2017