Publications by authors named "Sunghoon Kim"

429 Publications

Structure-based modification of pyrazolone derivatives to inhibit mTORC1 by targeting the leucyl-tRNA synthetase-RagD interaction.

Bioorg Chem 2021 Apr 20;112:104907. Epub 2021 Apr 20.

Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seoul 03722, Republic of Korea; Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; Department of pharmacy, College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea. Electronic address:

The enzyme leucyl-tRNA synthetase (LRS) and the amino acid leucine regulate the mechanistic target of rapamycin (mTOR) signaling pathway. Leucine-dependent mTORC1 activation depends on GTPase activating protein events mediated by LRS. In a prior study, compound BC-LI-0186 was discovered and shown to interfere with the mTORC1 signaling pathway by inhibiting the LRS-RagD interaction. However, BC-LI-0186 exhibited poor solubility and was metabolized by human liver microsomes. In this study, in silico physicochemical properties and metabolite analysis of BC-LI-0186 are used to investigate the addition of functional groups to improve solubility and microsomal stability. In vitro experiments demonstrated that 7b and 8a had improved chemical properties while still maintaining inhibitory activity against mTORC1. The results suggest a new strategy for the discovery of novel drug candidates and the treatment of diverse mTORC1-related diseases.
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http://dx.doi.org/10.1016/j.bioorg.2021.104907DOI Listing
April 2021

Bayesian neural network with pretrained protein embedding enhances prediction accuracy of drug-protein interaction.

Bioinformatics 2021 May 12. Epub 2021 May 12.

Department of Physics and Astronomy, Institute of Applied Physics, Seoul National University, Gwanak-gu, Seoul 08826, Republic of Korea.

Motivation: Characterizing drug-protein interactions is crucial to the high-throughput screening for drug discovery. The deep learning-based approaches have attracted attention because they can predict drug-protein interactions without human trial and error. However, because data labeling requires significant resources, the available protein data size is relatively small, which consequently decreases model performance. Here we propose two methods to construct a deep learning framework that exhibits superior performance with a small labeled dataset.

Results: At first, we use transfer learning in encoding protein sequences with a pretrained model, which trains general sequence representations in an unsupervised manner. Second, we use a Bayesian neural network to make a robust model by estimating the data uncertainty. Our resulting model performs better than the previous baselines at predicting interactions between molecules and proteins. We also show that the quantified uncertainty from the Bayesian inference is related to confidence and can be used for screening DPI data points.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab346DOI Listing
May 2021

Clinical utility of methionyl-tRNA synthetase 1 immunostaining in cytologic brushings of indeterminate biliary strictures: a multicenter prospective study.

Gastrointest Endosc 2021 May 6. Epub 2021 May 6.

Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine. Electronic address:

Background And Aims: Endobiliary brushings are routinely used in the diagnosis, treatment, and prognostication of biliary strictures. However, standard Papanicolaou (Pap) staining has a low sensitivity in this setting, and the accuracy of brush cytology has not been established for indeterminate strictures. We therefore evaluated the diagnostic merit of methionyl-tRNA synthetase 1 (MARS1) immunofluorescence (IF) staining in such cytologic specimens.

Methods: During endoscopic retrograde cholangiopancreatography, endobiliary brushings were obtained from patients with extrahepatic biliary strictures prospectively enrolled at 6 tertiary hospitals. Using liquid-based cytologic preparations of these samples, we performed Pap and MARS1 IF staining.

Results: In total, 240 patients were eligible; of these, we compared the Pap and MARS1 IF staining results of 218 (malignant, 157; benign, 61). By conventional Pap staining, the diagnoses were distributed as follows: malignant, 55 suspicious of malignancy, 60 atypical, 45; and negative for malignancy, 58. MARS1 IF staining was strongly positive in malignant biliary stricture, but not so in specimens negative for malignancy. The diagnostic parameters (sensitivity, specificity, positive predictive value, negative predictive value, and accuracy) of the MARS1 IF (93.6%, 96.7%, 98.7%, 85.5%, and 94.5%, respectively) and conventional Pap (73.2%, 100%, 100%, 59.2%, and 80.7%, respectively) staining methods differed significantly (p < 0.0001).

Conclusions: The high sensitivity and accuracy of MARS1 IF staining enabled detection of malignancy in patients with biliary strictures. Further prospective studies are needed to validate our findings (NCT03708445 at ClinicalTrials.gov).
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http://dx.doi.org/10.1016/j.gie.2021.04.026DOI Listing
May 2021

Leucine-sensing mechanism of leucyl-tRNA synthetase 1 for mTORC1 activation.

Cell Rep 2021 Apr;35(4):109031

Medicinal Bioconvergence Research Center, Institute for Artificial Intelligence and Biomedical Research, College of Pharmacy & College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon 21983, Republic of Korea. Electronic address:

Leucyl-tRNA synthetase 1 (LARS1) mediates activation of leucine-dependent mechanistic target of rapamycin complex 1 (mTORC1) as well as ligation of leucine to its cognate tRNAs, yet its mechanism of leucine sensing is poorly understood. Here we describe leucine binding-induced conformational changes of LARS1. We determine different crystal structures of LARS1 complexed with leucine, ATP, and a reaction intermediate analog, leucyl-sulfamoyl-adenylate (Leu-AMS), and find two distinct functional states of LARS1 for mTORC1 activation. Upon leucine binding to the synthetic site, H251 and R517 in the connective polypeptide and FPYPY in the catalytic domain change the hydrogen bond network, leading to conformational change in the C-terminal domain, correlating with RagD association. Leucine binding to LARS1 is increased in the presence of ATP, further augmenting leucine-dependent interaction of LARS1 and RagD. Thus, this work unveils the structural basis for leucine-dependent long-range communication between the catalytic and RagD-binding domains of LARS1 for mTORC1 activation.
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http://dx.doi.org/10.1016/j.celrep.2021.109031DOI Listing
April 2021

High mobility group box-1 promotes inflammation in endometriotic stromal cells through Toll-like receptor 4/nuclear factor-kappa B.

Am J Transl Res 2021 15;13(3):1400-1410. Epub 2021 Mar 15.

Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine Seoul, Republic of Korea.

Objective: To investigate whether high-mobility group box-1 induces cell proliferation, invasion and mediates inflammation in ectopic human endometrial stromal cells through Toll-like receptor 4.

Methods: Ectopic endometrial specimens were retrieved from patients with ovarian endometrioma having laparoscopy. Ectopic HESCs were treated with HO and recombinant HMGB-1 to induce oxidative stress. The effect of oxidative stress on cell proliferation and invasion was demonstrated. Receptors for HMGB-1 in NF-κB pathway (TLR4, RAGE), angiogenic molecule (VEGF), adhesion molecules (ICAM-1, E-cadherin), and inflammatory cytokines were measured simultaneously to the oxidative stress.

Results: Ectopic HESCs showed markedly decreased cell viability with the increased release of HMGB-1 following treatment with HO. When ectopic HESCs were stressed by rHMGB-1, cell proliferation and cell migration numbers increased significantly in a dose-dependent manner. Increased TLR4 and RAGE mRNA and protein expression levels were noted to rHMGB-1 treatment in a dose-dependent manner. VEGF synthesis was also increased by rHMGB-1 treatment. The gene expression of ICAM-1 was upregulated, whereas that of E-cadherin was downregulated with rHMGB-1 treatment. Interleukin-6, IL-1β, tumor necrosis factor-alpha, and IL-10 were increased significantly by rHMGB-1 treatment. Inversely, after transfection of small interfering RNA against TLR4, rHMGB treatment resulted in decreased cell proliferation and invasion.

Conclusion: HMGB-1 activates the NF-κB pathway via TLR4 to increase cell proliferation, invasion, and the production of various inflammatory markers in HESCs. Thus, HMGB-1, TLR4, and NF-κB may represent potential therapeutic targets for the treatment of endometriosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014341PMC
March 2021

Discovery of novel potent migrastatic Thiazolo[5,4-b]pyridines targeting Lysyl-tRNA synthetase (KRS) for treatment of Cancer metastasis.

Eur J Med Chem 2021 Jun 30;218:113405. Epub 2021 Mar 30.

College of Pharmacy, CHA University, Gyeonggi-do, 11160, Republic of Korea; College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. Electronic address:

Recently, non-canonical roles of Lysyl-tRNA Synthetase (KRS), which is associated with cell migration and cancer metastasis, have been reported. Therefore, KRS has emerged as a promising target for the treatment of cell migration-related diseases, especially cancer metastasis, although the satisfying chemical inhibitors targeting KRS have not yet been identified. Here, we report the discovery of novel, mechanistically unique, and potent cell migration inhibitors targeting KRS, including the chemical and biological studies on the most effective N,N-dialkylthiazolo [5,4-b]pyridin-2-amine (SL-1910). SL-1910 exhibited highly potent migration inhibition (EC = 81 nM against the mutant KRS-overexpressed MDA-MB-231 cells) and was superior to the previously reported KRS inhibitor (migration inhibitory EC = 8.5 μM against H226 cells). The KRS protein binding study via fluorescence-based binding titration and KRS protein 2D-NMR mapping study, in vitro concentration-dependent cell migration inhibition, and in vivo anti-metastatic activity of SL-1910, which consists of a new scaffold, have been reported in this study. In addition, in vitro absorption, distribution, metabolism, and excretion studies and mouse pharmacokinetics experiments for SL-1910 were conducted.
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http://dx.doi.org/10.1016/j.ejmech.2021.113405DOI Listing
June 2021

Diagnostic evolution of vestibular neuritis after long-term monitoring.

Braz J Otorhinolaryngol 2021 Mar 5. Epub 2021 Mar 5.

Inha University College of Medicine, Department of Otorhinolaryngology-Head and Neck Surgery, Incheon, South Korea. Electronic address:

Introduction: The diagnosis of vestibular neuritis is based on clinical and laboratory findings after exclusion of other disease. There are occasional discrepancies between clinical impressions and laboratory results. It could be the first vertigo episode caused by other recurrent vestibular disease, other than vestibular neuritis.

Objective: This study aimed to analyze the clinical features and identify the diagnostic evolution of patients with clinically suspected vestibular neuritis.

Methods: A total of 201 patients clinically diagnosed with vestibular neuritis were included in this study. Clinical data on the symptoms and signs of vertigo along with the results of vestibular function test were analyzed retrospectively. Patients were categorized in terms of the results of caloric testing (CP - canal paresis) group; canal paresis ≥25%; (MCP -minimal canal paresis) group; canal paresis <25%). Clinical features were compared between the two groups and the final diagnosis was reviewed after long-term follow up of both groups.

Results: Out of 201 patients, 57 showed minimal canal paresis (CP<25%) and 144 showed definite canal paresis (CP≥25%). A total of 48 patients (23.8%) experienced another vertigo episode and were re-diagnosed. Recurring vestibular symptoms were seen more frequently in patients with minimal canal paresis (p=0.027). Repeated symptoms were observed on the same affected side more frequently in the CP group. The proportion of final diagnosis were not different between two groups.

Conclusions: Patients with minimal CP are more likely to have recurrent vertigo than patients with definite CP. There was no significant difference in the distribution of the final diagnoses between two groups when the vertigo recurs.
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http://dx.doi.org/10.1016/j.bjorl.2021.02.004DOI Listing
March 2021

Extracellular vesicles derived from macrophages display glycyl-tRNA synthetase 1 and exhibit anti-cancer activity.

J Extracell Vesicles 2020 Nov 1;10(1):e12029. Epub 2020 Dec 1.

Institute for Artificial Intelligence and Biomedical Research Medicinal Bioconvergence Research Center College of Pharmacy & College of Medicine Gangnam Severance Hospital Yonsei University Incheon Korea.

Glycyl-tRNA synthetase 1 (GARS1), a cytosolic enzyme secreted from macrophages, promotes apoptosis in cancer cells. However, the mechanism underlying GARS1 secretion has not been elucidated. Here, we report that GARS1 is secreted through unique extracellular vesicles (EVs) with a hydrodynamic diameter of 20-58 nm (mean diameter: 36.9 nm) and a buoyant density of 1.13-1.17 g/ml. GARS1 was anchored to the surface of these EVs through palmitoylated C390 residue. Proteomic analysis identified 164 proteins that were uniquely enriched in the GARS1-containing EVs (GARS1-EVs). Among the identified factors, insulin-like growth factor II receptor, and vimentin also contributed to the anti-cancer activity of GARS1-EVs. This study identified the unique secretory vesicles containing GARS1 and various intracellular factors that are involved in the immunological defence response against tumorigenesis.
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http://dx.doi.org/10.1002/jev2.12029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890555PMC
November 2020

Universal Theory of Dynamic Force Microscopy for Exact and Robust Force Reconstruction Using Multiharmonic Signal Analysis.

Phys Rev Lett 2021 Feb;126(7):076804

Center for 0D Nanofluidics, Institute of Applied Physics, Department of Physics and Astronomy, Seoul National University, Seoul 08826, Republic of Korea.

Force reconstruction in dynamic force microscopy (DFM) is a nontrivial problem that requires the deconvolution of integrals. However, conventional reconstruction methods, which recover forces from single-frequency motion of the cantilever at its resonance, exhibit non-negligible error and reconstruction instability in the highly nonlinear force regime when the tip oscillates with its amplitude comparable to the decay length of the interaction. Here, we develop a theoretical platform of DFM based on multiharmonic signal analysis for exact and robust reconstruction of conservative and dissipative forces, valid for all oscillation amplitudes and entire tip-sample distances in both amplitude- and frequency-modulation atomic force microscopy. We achieve accuracy improvement by an order of magnitude for oscillation amplitudes comparable to or larger than the decay length, and by 2 orders of magnitude for smaller amplitudes at the force minimum, even in cases where conventional methods show poor accuracy (≳5%). Moreover, we obtain greater robustness with respect to the oscillation amplitude error, resulting in a fivefold increase in reconstruction precision. Our results demonstrate a fast and versatile reconstruction scheme for nanomechanical force characterization, with higher harmonics measured with sufficient signal-to-noise ratio, which provides unprecedented accuracy and stability beyond conventional methods.
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http://dx.doi.org/10.1103/PhysRevLett.126.076804DOI Listing
February 2021

Association between PD-L1 expression and F-FDG uptake in ovarian cancer.

Ann Nucl Med 2021 Apr 3;35(4):415-420. Epub 2021 Mar 3.

Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemungu, Seoul, 03722, South Korea.

Objective: Immunotherapy for programmed cell death 1 (PD-1) and its ligand, PD-L1, has been considered an effective treatment for ovarian cancer. F-labeled fluoro-2-deoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) is a widely used noninvasive imaging tool for diagnosing several cancers. In this study, we investigated the association between PD-L1 expression and the maximum standardized uptake value (SUVmax) using F-FDG PET/CT.

Methods: We retrospectively analyzed clinical data of patients with ovarian cancer who underwent F-FDG PET/CT. Patients were categorized into two groups according to PD-L1 expression results. The relationship between clinicopathological characteristics of patients with ovarian cancer and PD-L1 expression was examined.

Results: SUVmax was significantly higher in PD-L1-positive tumors than in PD-L1-negative tumors (16.1 ± 5.2 and 12.7 ± 7.0, respectively; p = 0.026). There were no significant differences in age, histologic type, and tumor grade between the PD-L1-negative and PD-L1-positive groups. The receiver operating characteristic curve analysis demonstrated that the highest accuracy (61.8%) for predicting PD-L1 expression was obtained with an SUVmax cutoff value of 10.5.

Conclusion: There was a significant correlation between F-FDG uptake and PD-L1 expression, suggesting a role of F-FDG PET/CT in selecting ovarian cancer candidates for anti-PD-L1 antibody therapy.
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http://dx.doi.org/10.1007/s12149-020-01571-7DOI Listing
April 2021

Unique Noncontact Monitoring of Human Respiration and Sweat Evaporation Using a CsPbBr-Based Sensor.

ACS Appl Mater Interfaces 2021 Feb 26;13(4):5602-5613. Epub 2021 Jan 26.

Department of Electronic Materials Engineering, Kwangwoon University, Seoul 01897, Republic of Korea.

Respiration monitoring and human sweat sensing have promising application prospects in personal healthcare data collection, disease diagnostics, and the effective prevention of human-to-human transmission of fatal viruses. Here, we have introduced a unique respiration monitoring and touchless sensing system based on a CsPbBr/BaTiO humidity-sensing layer operated by water-induced interfacial polarization and prepared using a facile aerosol deposition process. Based on the relationship between sensing ability and layer thickness, the sensing device with a 1.0 μm thick layer was found to exhibit optimal sensing performance, a result of its ideal microstructure. This sensor also exhibits the highest electrical signal variation at 0.5 kHz due to a substantial polarizability difference between high and low humidity. As a result, the CsPbBr/BaTiO sensing device shows the best signal variation of all types of breath-monitoring devices reported to date when used to monitor sudden changes in respiratory rates in diverse situations. Furthermore, the sensor can effectively detect sweat evaporation when placed 1 cm from the skin, including subtle changes in capacitance caused by finger area and motion, skin moisture, and contact time. This ultrasensitive sensor, with its fast response, provides a potential new sensing platform for the long-term daily monitoring of respiration and sweat evaporation.
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http://dx.doi.org/10.1021/acsami.0c21097DOI Listing
February 2021

4-1BB co-stimulation further enhances anti-PD-1-mediated reinvigoration of exhausted CD39 CD8 T cells from primary and metastatic sites of epithelial ovarian cancers.

J Immunother Cancer 2020 12;8(2)

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

Background: Responses to immunotherapy vary between different cancer types and sites. Here, we aimed to investigate features of exhaustion and activation in tumor-infiltrating CD8 T cells at both the primary and metastatic sites in epithelial ovarian cancer.

Methods: Tumor tissues and peripheral blood were obtained from 65 patients with ovarian cancer. From these samples, we isolated tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells. These cells were used for immunophenotype using multicolor flow cytometry, gene expression profile using RNA sequencing and ex vivo functional restoration assays.

Results: We found that CD39 CD8 TILs were enriched with tumor-specific CD8 TILs, and that the activation status of these cells was determined by the differential programmed cell death protein 1 (PD-1) expression level. CD39 CD8 TILs with high PD-1 expression (PD-1) exhibited features of highly tumor-reactive and terminally exhausted phenotypes. Notably, PD-1 CD39 CD8 TILs showed similar characteristics in terms of T-cell exhaustion and activation between the primary and metastatic sites. Among co-stimulatory receptors, 4-1BB was exclusively overexpressed in CD39 CD8 TILs, especially on PD-1 cells, and 4-1BB-expressing cells displayed immunophenotypes indicating higher degrees of T-cell activation and proliferation, and less exhaustion, compared with cells not expressing 4-1BB. Importantly, 4-1BB agonistic antibodies further enhanced the anti-PD-1-mediated reinvigoration of exhausted CD8 TILs from both primary and metastatic sites.

Conclusion: Severely exhausted PD-1 CD39 CD8 TILs displayed a distinctly heterogeneous exhaustion and activation status determined by differential 4-1BB expression levels, providing rationale and evidence for immunotherapies targeting co-stimulatory receptor 4-1BB in ovarian cancers.
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http://dx.doi.org/10.1136/jitc-2020-001650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745695PMC
December 2020

Comparison of single-port laparoscopy and laparotomy in early ovarian cancer surgical staging.

Obstet Gynecol Sci 2021 Jan 7;64(1):90-98. Epub 2020 Dec 7.

Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei Cancer Center and Institute of Women's Life Medical Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

Objective: s The aims of this study were to assess the feasibility of single-port laparoscopic surgical staging (SPLS) in early ovarian cancer and to compare the surgical outcomes of SPLS with those of staging laparotomy.

Methods: Between January 2014 and December 2018, 40 patients underwent SPLS and 41 patients underwent staging laparotomy at Yonsei Cancer Center. The patients were diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I ovarian cancer. Variables such as patient age, body mass index (BMI), tumor size, FIGO stage, and perioperative surgical outcomes and survival outcomes of SPLS and laparotomy were compared.

Results: The total operation time was similar between the 2 groups (SPLS: 201.4 vs. laparotomy: 203.0 minutes, P=0.806). The median tumor diameters in the SPLS and laparotomy groups were 11.0 (2.5-28 cm) and 15.4 (6-40 cm), respectively (P=0.001). The SPLS group had lower tumor spillage rate (5.0% vs. 19.5%, P=0.047), less intraoperative blood loss (102.0 vs. 371.5 mL, P<0.001), less postoperative pain, and shorter postoperative hospital stay (5 vs. 9.5 days, P<0.001). The intraoperative major complication rate was similar between groups (2.5% vs. 4.9%, P=0.571). There was no significant difference in progression-free survival between the 2 groups (P=0.945). There were no deaths in either group.

Conclusion: SPLS is feasible in early ovarian cancer and has better perioperative surgical outcomes, in some aspects, than staging laparotomy without compromising survival outcomes. SPLS could be performed in patients suspected to have early ovarian cancer.
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http://dx.doi.org/10.5468/ogs.20216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834751PMC
January 2021

Effects of Korean Red Ginseng ( C.A. Meyer) on Menopausal Symptoms in Premenopausal Women After Gynecologic Cancer Surgery: A Double-Blind, Randomized Controlled Trial.

J Altern Complement Med 2021 Jan 20;27(1):66-72. Epub 2020 Nov 20.

Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea.

Korean red ginseng (KRG) has been widely used as an alternative medicine to relieve menopausal symptoms. However, there is still a lack of clinical studies showing the effects of KRG on menopausal symptoms after gynecologic cancer surgery. Therefore, the authors investigated the effects of KRG on surgical menopause symptoms in premenopausal women with gynecologic cancer. A double-blind, randomized, placebo-controlled clinical trial was conducted. The study was performed at Severance Hospital at the Yonsei University College of Medicine in Seoul, Korea. Fifty-five premenopausal women diagnosed with gynecologic cancer were enrolled in the study. Patients were randomly assigned to a KRG ( = 29) or a placebo control group ( = 26). Subjects were administered either KRG (a total of 3 g per day) or placebo supplements for 12 weeks. Patients' physical measurements (height, weight, and blood pressure) and blood samples (lipid profiles, hormone profiles, biochemical profiles, and neutrophil-to-lymphocyte ratio) at baseline and at 12 weeks were compared. Changes in menopausal symptoms based on the Menopause Rating Scale (MRS) were also compared between these two time points and two groups. After 12 weeks, the MRS score was significantly reduced in each group ( = 0.001 and  = 0.001, respectively), but there were no significant differences between the two groups ( = 0.661). No adverse events were observed in either group. After comparing 11 MRS symptoms between the two groups, the KRG group seemed to be superior to the placebo group on the subscale of sexual complaints ( < 0.05). Through the study, KRG did not show absolute relief of surgical menopause symptoms in premenopausal women after gynecologic cancer surgery. However, the study did demonstrate that KRG may be effective in reducing sexual complaints. Further studies are required to evaluate the long-term effects of KRG in a larger patient population.
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http://dx.doi.org/10.1089/acm.2019.0429DOI Listing
January 2021

GCIceNet: a graph convolutional network for accurate classification of water phases.

Phys Chem Chem Phys 2020 Nov;22(45):26340-26350

Center for 0D Nanofluidics, Department of Physics and Astronomy, Institute of Applied Physics, Seoul National University, Gwanak-gu, Seoul 08826, Republic of Korea.

Understanding the phases of water molecules based on local structure is essential for understanding their anomalous properties. However, due to complicated structural motifs formed via hydrogen bonds, conventional order parameters represent water molecules incompletely. In this paper, we develop GCIceNet, which automatically generates machine-based order parameters for classifying the phases of water molecules via supervised and unsupervised learning. The multiple graph convolutional layers in GCIceNet can learn topological information on the complex hydrogen bond networks. It shows a substantial improvement in accuracy for predicting the phase of water molecules in a bulk system and an ice/vapor interface system. A relative importance analysis shows that GCIceNet can capture the structural features of the given system hidden in the input data. Augmented with the vast amount of data provided by molecular dynamics simulations, GCIceNet is expected to serve as a powerful tool for the fields of glassy liquids and hydration layers around biomolecules.
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http://dx.doi.org/10.1039/d0cp03456hDOI Listing
November 2020

Amyloid-like oligomerization of AIMP2 contributes to α-synuclein interaction and Lewy-like inclusion.

Sci Transl Med 2020 11;12(569)

Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute (SBRI), Suwon 16419, Republic of Korea.

Lewy bodies are pathological protein inclusions present in the brain of patients with Parkinson's disease (PD). These inclusions consist mainly of α-synuclein with associated proteins, such as parkin and its substrate aminoacyl transfer RNA synthetase complex-interacting multifunctional protein-2 (AIMP2). Although AIMP2 has been suggested to be toxic to dopamine neurons, its roles in α-synuclein aggregation and PD pathogenesis are largely unknown. Here, we found that AIMP2 exhibits a self-aggregating property. The AIMP2 aggregate serves as a seed to increase α-synuclein aggregation via specific and direct binding to the α-synuclein monomer. The coexpression of AIMP2 and α-synuclein in cell cultures and in vivo resulted in the rapid formation of α-synuclein aggregates with a corresponding increase in toxicity. Moreover, accumulated AIMP2 in mouse brain was largely redistributed to insoluble fractions, correlating with the α-synuclein pathology. Last, we found that α-synuclein preformed fibril (PFF) seeding, adult deletion, or oxidative stress triggered a redistribution of both AIMP2 and α-synuclein into insoluble fraction in cells and in vivo. Supporting the pathogenic role of AIMP2, AIMP2 knockdown ameliorated the α-synuclein aggregation and dopaminergic cell death in response to PFF or 6-hydroxydopamine treatment. Together, our results suggest that AIMP2 plays a pathological role in the aggregation of α-synuclein in mice. Because AIMP2 insolubility and coaggregation with α-synuclein have been seen in the PD Lewy body, targeting pathologic AIMP2 aggregation might be useful as a therapeutic strategy for neurodegenerative α-synucleinopathies.
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http://dx.doi.org/10.1126/scitranslmed.aax0091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082540PMC
November 2020

Single-cell analysis of AIMP2 splice variants informs on drug sensitivity and prognosis in hematologic cancer.

Commun Biol 2020 Oct 30;3(1):630. Epub 2020 Oct 30.

Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

Aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is a non-enzymatic component required for the multi-tRNA synthetase complex. While exon 2 skipping alternatively spliced variant of AIMP2 (AIMP2-DX2) compromises AIMP2 activity and is associated with carcinogenesis, its clinical potential awaits further validation. Here, we found that AIMP2-DX2/AIMP2 expression ratio is strongly correlated with major cancer signaling pathways and poor prognosis, particularly in acute myeloid leukemia (AML). Analysis of a clinical patient cohort revealed that AIMP2-DX2 positive AML patients show decreased overall survival and progression-free survival. We also developed targeted RNA-sequencing and single-molecule RNA-FISH tools to quantitatively analyze AIMP2-DX2/AIMP2 ratios at the single-cell level. By subclassifying hematologic cancer cells based on their AIMP2-DX2/AIMP2 ratios, we found that downregulating AIMP2-DX2 sensitizes cells to anticancer drugs only for a subgroup of cells while it has adverse effects on others. Collectively, our study establishes AIMP2-DX2 as a potential biomarker and a therapeutic target for hematologic cancer.
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http://dx.doi.org/10.1038/s42003-020-01353-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599330PMC
October 2020

Use of cryoanalgesia as a postoperative pain management for open pectus carinatum repair.

Pediatr Surg Int 2021 Jan 28;37(1):179-181. Epub 2020 Oct 28.

Division of Pediatric Surgery, University of California San Francisco, San Francisco, USA.

Purpose: Cryoanalgesia has shown to have safety and efficacy as an adjunct post-operative pain management for Nuss procedure. One retrospective study reported its efficacy for analgesia with the Ravitch procedure, with improved pain scores and decreased length of stay versus thoracic epidural. We describe our initial experience with the use of cryoanalgesia for an open repair of pectus carinatum.

Methods: We retrospectively reviewed the medical records of all patients who received cryoanalgesia during an open repair of pectus carinatum from 2016 to 2019 at our institution. We recorded pain scores at immediate post-operative and at 1-week follow up after hospital discharge. Length of stay and mean follow up time were also recorded.

Results: Five pediatric patients underwent open repair of pectus carinatum with cryoanalgesia. The median postoperative length of stay (LOS) was 1 (range 1-2) day. Only one patient reported a non-zero pain score during their hospitalization, and this was a 3 out of 10 in the post-analgesia care unit. At 1-week postoperative visit, all patients had a pain score of 0. Median follow up was 1 (0.5-2) year. No patients developed neuralgia.

Conclusion: Cryoanalgesia is a safe and effective pain management strategy for pediatric patients undergoing open pectus carinatum repair.
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http://dx.doi.org/10.1007/s00383-020-04768-zDOI Listing
January 2021

Aminoacyl-tRNA synthetases and amino acid signaling.

Biochim Biophys Acta Mol Cell Res 2021 01 20;1868(1):118889. Epub 2020 Oct 20.

Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon 21983, South Korea; Medicinal Bioconvergence Research Center, College of Pharmacy and College of Medicine, Gangnam Severance Hospital, Yonsei University, South Korea. Electronic address:

Aminoacyl-tRNA synthetases (ARSs) are a family of evolutionarily conserved housekeeping enzymes used for protein synthesis that have pivotal roles in the ligation of tRNA with their cognate amino acids. Recent advances in the structural and functional studies of ARSs have revealed many previously unknown biological functions beyond the classical catalytic roles. Sensing the sufficiency of intracellular nutrients such as amino acids, ATP, and fatty acids is a crucial aspect for every living organism, and it is closely connected to the regulation of diverse cellular physiologies. Notably, among ARSs, leucyl-tRNA synthetase 1 (LARS1) has been identified to perform specifically as a leucine sensor upstream of the amino acid-sensing pathway and thus participates in the coordinated control of protein synthesis and autophagy for cell growth. In addition to LARS1, other types of ARSs are also likely involved in the sensing and signaling of their cognate amino acids inside cells. Collectively, this review focuses on the mechanisms of ARSs interacting within amino acid signaling and proposes the possible role of ARSs as general intracellular amino acid sensors.
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http://dx.doi.org/10.1016/j.bbamcr.2020.118889DOI Listing
January 2021

Impact of the Learning Curve on the Survival of Abdominal or Minimally Invasive Radical Hysterectomy for Early-Stage Cervical Cancer.

Cancer Res Treat 2021 Jan 12;53(1):243-251. Epub 2020 Oct 12.

Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea.

Purpose: The objective of this study was to define the learning curve required to attain satisfactory oncologic outcomes of cervical cancer patients who were undergoing open or minimally invasive surgery for radical hysterectomy, and to analyze the correlation between the learning curve and tumor size.

Materials And Methods: Cervical cancer patients (stage IA-IIA) who underwent open radical hysterectomy (n=280) or minimal invasive radical hysterectomy (n=282) were retrospectively reviewed. The learning curve was evaluated using cumulative sum of 5-year recurrence rates. Survival outcomes were analyzed based on the operation period ("learning period," P1 vs. "skilled period," P2), operation mode, and tumor size.

Results: The 5-year disease-free and overall survival rates between open and minimally invasive groups were 91.8% and 89.0% (p=0.098) and 96.1% and 97.2% (p=0.944), respectively. The number of surgeries for learning period was 30 and 60 in open and minimally invasive group, respectively. P2 had better 5-year disease-free survival than P1 after adjusting for risk factors (hazard ratio, 0.392; 95% confidence interval, 0.210 to 0.734; p=0.003). All patients with tumors < 2 cm had similar 5-year disease-free survival regardless of operation mode or learning curve. Minimally invasive group presented lower survival rates than open group when tumors ≥ 2 cm in P2. Preoperative conization improved disease-free survival in patients with tumors ≥ 2 cm, especially in minimally invasive group.

Conclusion: Minimally invasive radical hysterectomy required more cases than open group to achieve acceptable 5-year disease-free survival. When tumors ≥ 2 cm, the surgeon's proficiency affected survival outcomes in both groups.
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http://dx.doi.org/10.4143/crt.2020.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811999PMC
January 2021

Mismatch repair status influences response to fertility-sparing treatment of endometrial cancer.

Am J Obstet Gynecol 2021 04 9;224(4):370.e1-370.e13. Epub 2020 Oct 9.

Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.

Background: Patients younger than 40 years usually present with early-stage endometrial cancer with favorable prognosis. However, such patients are usually in their childbearing age and may desire fertility-sparing options. The identification of biomarkers may improve the clinical outcomes in these patients and aid in fertility-sparing management; however, there has been no reports on biomarker analysis so far.

Objective: This study aimed to evaluate the prognostic significance of Proactive Molecular Risk Classifier for Endometrial Cancer in the fertility-sparing management of endometrial cancer.

Study Design: A total of 57 endometrial biopsy specimens obtained before hormone therapy were evaluated, and patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer molecular subtypes (mismatch repair deficiency, DNA polymerase epsilon mutation, wild-type p53, and abnormal p53). The primary endpoint was the response rate after hormone therapy. The secondary endpoint was the recurrence rate after the complete response, hysterectomy rate owing to treatment failure, and upstaged diagnosis rate after hysterectomy.

Results: Of 57 patients, 9 (15.8%) had mismatch repair deficiency, 2 (3.5%) had DNA polymerase epsilon mutation, 45 (78.9%) had wild-type p53, and 1 (1.8%) had abnormal p53. Overall, the complete response rate was 75.4% after hormone therapy. Patients with mismatch repair deficiency had a significantly lower complete response or partial response rate than those with wild-type p53 in terms of the best overall response (44.4% [95% confidence interval, 4.0-85.0] vs 82.2% [95% confidence interval, 71.0-94.0]; P=.018) and complete response rate at 6 months (11.1% [95% confidence interval, 0.2-37.0] vs 53.3% [95% confidence interval, 38.0-68.0]; P=.010). Among patients with mismatch repair deficiency, 4 underwent immediate hysterectomy because of treatment failure and 3 presented upstaged diagnosis after hysterectomy.

Conclusion: The Proactive Molecular Risk Classifier for Endometrial Cancer molecular classification has prognostic significance in the fertility-sparing management of endometrial cancer, thereby enabling early stratification and risk assignment to direct care. Mismatch repair status could be used as a predictive biomarker for selecting patients who could benefit from hormone therapy. These findings need to be validated in larger studies.
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http://dx.doi.org/10.1016/j.ajog.2020.10.003DOI Listing
April 2021

Association between relative hand-grip strength and chronic cardiometabolic and musculoskeletal diseases in Koreans: A cross-sectional study.

Arch Gerontol Geriatr 2021 Jan - Feb;92:104181. Epub 2020 Jul 9.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon, South Korea. Electronic address:

Objectives: This study evaluated clinical and cardiometabolic markers associated with relative hand-grip strength (HGS), and investigated odds ratios (ORs) for chronic cardiometabolic and musculoskeletal diseases according to relative HGS.

Methods: This cross-sectional observational study enrolled subjects from the Korea National Health and Nutrition Examination Survey who were 50 years and older (N = 2451). Information on chronic diseases was taken by individual surveys and other proper criteria were applied for undiagnosed subjects. Absolute HGS was calculated from the maximal bilateral HGS (kg) as measured by a dynamometer and relative HGS was calculated by dividing absolute HGS by body mass index (BMI). Associated clinical and cardiometabolic markers to relative HGS were investigated and ORs for chronic diseases according to relative HGS tertiles were estimated from multivariate linear or logistic regression analyses.

Results: The mean relative HGS (kg/BMI) was 3.1 ± 0.6 for men and 1.9 ± 0.5 for women. Insulin-resistance parameters and high-sensitivity C-reactive protein were negatively and high-density lipoprotein cholesterol was positively related with relative HGS in both sexes adjusting for age and lifestyle factors, while systolic blood pressure showed negative relationship in women. High ORs for various chronic diseases were observed in the lowest relative HGS tertile of both sexes, but high OR for hyperlipidemia was observed only in women.

Conclusions: Relative HGS is a convenient measure for overall muscle strength according to body size and may have an influence on chronic disease development or aggravation. Thus, relative HGS might be a cost-effective and useful tool to screen for prevalent chronic diseases in elderly population.
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http://dx.doi.org/10.1016/j.archger.2020.104181DOI Listing
February 2021

Laparoscopic Treatment of Slipping Rib Syndrome in Pediatric Patients.

J Laparoendosc Adv Surg Tech A 2020 Nov 21;30(11):1253-1256. Epub 2020 Sep 21.

Department of Surgery, University of California San Francisco, San Francisco, California, USA.

Slipping rib syndrome (SRS) is an often unrecognized cause of lower chest and upper abdominal pain in children and adolescents. Surgical resection of the cartilaginous portions of the slipping rib often provides permanent pain relief, with the standard surgical approach being an open resection. A minimally invasive approach has not been reported previously; we report a novel laparoscopic technique for the treatment of SRS with satisfactory results. A retrospective review of all consecutive pediatric patients who underwent laparoscopic cartilage resection during the year 2019 and open cartilage resection during the year 2018 was included. Following data were recorded: age of patients, length of symptoms, length of procedure, length of cartilage resection, length of stay, resolution of pain, cosmetic acceptability, and postoperative complications. Four patients underwent laparoscopic slipping rib resection without complication during the year 2019. The mean age of symptom onset was 15 (range 14-16) years old, mean length of symptoms was 1.4 (0.5-2.0) years, and mean age at operation was 16.5 (16-18) years old. The average length of the procedure was 72.8 (55-102) minutes, and mean length of cartilage removed was 2.3 (1.9-3.0) cm. Three patients underwent standard open operation during the year 2018. All patients reported complete resolution of their chronic pain at their 6-month follow-up visit. Laparoscopic technique can be used to treat SRS. All patients reported high satisfaction from resolution of chronic pain and the cosmetic appearance of their surgical scars.
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http://dx.doi.org/10.1089/lap.2020.0314DOI Listing
November 2020

Comprehensive Immuno-Molecular Profiles for Liposarcoma: Roles of Programmed Death Ligand 1, Microsatellite Instability, and PIK3CA.

Oncology 2020 4;98(11):817-826. Epub 2020 Sep 4.

Yonsei Song-Dang Institute for Cancer Research, Yonsei University Health System, Seoul, Republic of Korea,

Background: Developing personalized strategies for cancer has shown good efficacies.

Methods: We assessed the molecular targets programmed death ligand 1 (PD-L1), microsatellite instability (MSI), and PIK3CA. Seventy-four patients with liposarcomas who underwent curative resection were assessed for PD-L1 expression in the tumor and tumor-infiltrating lymphocytes (TILs), mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry, MSI using polymerase chain reaction, and PIK3CA mutation/amplification using pyrosequencing and fluorescence in situ hybridization.

Results: Seventeen (23%) cases were TIL+ (≥1 + expression) and associated with longer 5-year overall survival than those with TIL- tumors (84.4 vs. 60.8%, p = 0.007). Six (35.3%) PD-L1+ tumors were detected only in TIL+ cases, with none detected in tumor cells. Two well-differentiated liposarcomas showed MSI, one low and one high with concurrent loss of MLH1, MSH6, and PMS2. PIK3CA mutation was detected in 7 (9.5%) [exon 9 (n = 4) and exon 20 (n = 3)] and only 1 Q546K mutation was a PD-L1+ tumor. PIK3CA copy number gain was detected in 18 (24.4%) and was associated with TIL+ tumors (p = 0.045).

Conclusions: Our comprehensive immuno-molecular panel suggests that liposarcoma should be categorized based on the molecular genomic subtype for precision medicine.
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http://dx.doi.org/10.1159/000509004DOI Listing
November 2020

Survival outcomes of single-port access laparoscopic radical hysterectomy for early-stage cervical cancer.

Surg Oncol 2020 Sep 17;34:140-145. Epub 2020 Apr 17.

Institute of Women's Life Medical Science, Women's Cancer Center, Department of Obstetrics and Gynecology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Background: Emerging data from the Laparoscopic Approach to Cervical Cancer trial (NCT00614211) suggested that minimally invasive surgery (MIS) for cervical cancer is correlated with worse survival outcomes than open surgery. This finding could be attributed to the different learning curves for laparoscopic surgery among surgeons. This study aimed to assess the feasibility, safety, and survival outcomes of single-port access (SPA) laparoscopic radical hysterectomy (LRH) for treating early cervical cancer.

Methods: This was a retrospective cohort study of consecutive patients with early-stage cervical cancer who underwent SPA LRH between 2009 and 2018 performed by a single surgeon with expertise in SPA laparoscopy using conventional instrumentation and a homemade glove port system.

Results: Type C (93.2%) and B (6.8%) radical hysterectomy were performed in 59 women with cervical cancer classified as IA (3.4%), IB (94.9%), and IIA (1.7%). Forty-one patients (69.5%) had squamous cell carcinoma and 32 patients (52.5%) had tumors < 2 cm. The median operative time was 235 (125-382) minutes. There were no perioperative complications or cases of conversion to open surgery. Postoperative complications, including chylous ascites, low hemoglobin, lymphedema, and vault dehiscence, were observed in 5 patients (8.5%). Median follow-up time was 3.1 (0.6-8.6) years and 3 patients experienced recurrence (1 local and 2 distant failures). Five-year disease-free survival was 94.9% (56/59) and the 5-year overall survival rate was 98.3% (58/59).

Conclusions: SPA LRH is feasible and safe for patients with early-stage cervical cancer when performed by experienced surgeons without compromising the radicality and oncologic outcomes.
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http://dx.doi.org/10.1016/j.suronc.2020.04.005DOI Listing
September 2020

O-GlcNAcylation of Mef2c regulates myoblast differentiation.

Biochem Biophys Res Commun 2020 08 18;529(3):692-698. Epub 2020 Jul 18.

Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Glycosylation Network Research Center, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Interdisciplinary Program of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. Electronic address:

Unlike other types of glycosylation, O-GlcNAcylation is a single glycosylation which occurs exclusively in the nucleus and cytosol. O-GlcNAcylation underlie metabolic diseases, including diabetes and obesity. Furthermore, O-GlcNAcylation affects different oncogenic processes such as osteoblast differentiation, adipogenesis and hematopoiesis. Emerging evidence suggests that skeletal muscle differentiation is also regulated by O-GlcNAcylation, but the detailed molecular mechanism has not been fully elucidated. In this study, we showed that hyper-O-GlcNAcylation reduced the expression of myogenin, a transcription factor critical for terminal muscle development, in C2C12 myoblasts differentiation by O-GlcNAcylation on Thr9 of myocyte-specific enhancer factor 2c. Furthermore, we showed that O-GlcNAcylation on Mef2c inhibited its DNA binding affinity to myogenin promoter. Taken together, we demonstrated that hyper-O-GlcNAcylation attenuates skeletal muscle differentiation by increased O-GlcNAcylation on Mef2c, which downregulates its DNA binding affinity.
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http://dx.doi.org/10.1016/j.bbrc.2020.06.031DOI Listing
August 2020

Design of reinforcement learning for perimeter control using network transmission model based macroscopic traffic simulation.

PLoS One 2020 30;15(7):e0236655. Epub 2020 Jul 30.

Department of Civil and Environmental Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.

Perimeter control is an emerging alternative for traffic signal control, which regulates the traffic flows on the periphery of a road network. Some model-based approaches have been suggested earlier for the optimization of perimeter control based on macroscopic fundamental diagrams (MFDs). However, there are several limitations when considering their application to a large-scale urban area because the model-based approaches may not be scalable to multiple regions and inappropriate for handling various effects caused by the shape change of MFDs. Therefore, we propose a model-free and data-driven approach that combines reinforcement learning (RL) with the macroscopic traffic simulation based on the recently developed network transmission model. First, we design four perimeter control models with different macroscopic traffic variables and parametrizations. Then, we validate the proposed models by evaluating their performances with the test demand scenarios at different levels. The validation results show that the model containing travel demand information adapts to a new demand scenario better than the model containing only density-related factors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236655PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392337PMC
September 2020

Pelvic malakoplakia presenting as endometrial cancer: a case report.

Obstet Gynecol Sci 2020 Jul 30;63(4):538-542. Epub 2020 Jun 30.

Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea.

Malakoplakia is a rare granulomatous, inflammatory disease generally manifesting as ulcers of the urogenital tract, especially in the bladder, but it can occur in any part of the body. Because of its varied clinical presentations, malakoplakia is considered for differential diagnosis upon suspicion. The final diagnosis is confirmed by the presence of Michaelis-Gutmann bodies. We report a case of pelvic malakoplakia accompanied by left lower quadrant pain that was misdiagnosed as endometrial cancer with pelvic mass based on imaging studies. The patient underwent dilatation and curettage, and the pathology report revealed no malignancy. Because of persistent pain and septic shock, she underwent a debulking operation to remove the mass. Histopathologic examination revealed malakoplakia. For postoperative management, she received broad-spectrum antibiotics, but abdominal pelvic computerized tomography performed on postoperative day 9 revealed pelvic mass recurrence. To the best of our knowledge, this is the only rare case report of pelvic malakoplakia mimicking endometrial cancer.
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http://dx.doi.org/10.5468/ogs.19245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393746PMC
July 2020

Impact of subcutaneous negative pressure drains on surgical wound healing in ovarian cancer.

Int J Gynecol Cancer 2021 Feb 15;31(2):245-250. Epub 2020 Jul 15.

Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea.

Introduction: Subcutaneous negative pressure wound drains have been used to reduce wound complication rates in various surgical procedures. However, research on the benefits of subcutaneous drains on wound healing after ovarian cancer surgery is limited. The aim of this study was to assess the effects of subcutaneous negative pressure drains on wound healing after abdominal surgery for ovarian cancer.

Methods: Patients who underwent surgery with a midline incision for ovarian cancer between February 2015 and May 2019 were retrospectively examined. Patients were divided into two groups according to the presence (group 1; n=99) or absence (group 2; n=213) of subcutaneous wound drains. The primary endpoint was the incidence of wound complications within 8 weeks after abdominal surgery. The secondary endpoints were time interval from surgery to adjuvant chemotherapy and survival.

Results: Patients in group 1 were older (mean 58.5 vs 55.4 years; p=0.02), and had higher rates of previous abdominal surgery (66.7% vs 47.9%; p=0.002), bowel surgery (47.5% vs 34.3%; p=0.026), and had a high surgical complexity score (53.5% vs 33.8%; p<0.001) compared with patients in group 2. Median body mass index was not different between the two groups: group 1, 22.9 kg/m (range 16.0 to 33.3) and group 2, 22.8 kg/m (range 16.4 to 37.5) (p=0.858). A higher rate of clear wound healing (82.8% vs 71.8%; p=0.036) and a lower rate of seroma formation (6.1% vs 16.0%; p=0.015) were observed in group 1 compared with group 2. After multivariate analysis, subcutaneous wound drain placement was identified as an independent predictive factor for preventing wound complications (adjusted odds ratio 0.43; 95% confidence interval 0.21 to 0.87). Time interval from surgery to adjuvant treatment was significantly longer in patients with wound complications than in those with clear wound healing (mean 23.6 vs 19.2 days; p=0.003). Kaplan-Meier analysis, however, showed no significant differences in progression free or overall survival between the two groups (p=0.35 and p=0.96, respectively).

Conclusion: The prophylactic use of subcutaneous negative pressure drains after abdominal surgery for ovarian cancer significantly reduced the incidence of wound complications in this study.
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http://dx.doi.org/10.1136/ijgc-2020-001299DOI Listing
February 2021

Genetic characteristics of gastric-type mucinous carcinoma of the uterine cervix.

Mod Pathol 2021 03 8;34(3):637-646. Epub 2020 Jul 8.

Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.

Gastric-type mucinous carcinoma (GAS) is a recently established variant of endocervical mucinous adenocarcinoma that is characterized as being unrelated to HPV and having aggressive behavior and chemoresistance. GAS has a distinct morphology resembling nonneoplastic gastric glands or pancreaticobiliary adenocarcinoma, and their possible genetic similarity has been posed. In this study, next-generation sequencing was performed in 21 GAS cases using a customized panel including 94 cancer-associated genes. A total of 54 nonsynonymous somatic mutations were detected with an average mutation rate of 2.6 per lesion (range: 0-9). The most frequently mutated gene was TP53 (11/21, 52.4%), followed by STK11, HLA-B, PTPRS (4/21, 19.0%), FGFR4 (3/21, 14.3%), GNAS, BRCA2, ELF3, ERBB3, KMT2D, SLX4 (2/21, 9.5%), CDH1, EPCAM, KRAS, MLH1, RNF43, SNAI1, TWIST1, ZEB1, ZEB2, and so on (1/21, 4.8%). The mutated genes were mostly involved in signal transduction, DNA damage repair, and epithelial-mesenchymal transition (EMT). Correlation of TP53 mutation and p53 protein expression demonstrated that 31.3% with abnormal p53 expression harbored wild-type TP53. Compared to genetic features of gastric and pancreaticobiliary adenocarcinoma, TP53 mutations were frequent in both GAS and gastrointestinal adenocarcinoma. While KMT2D, ERBB3, and RNF43 mutations were shared between GAS and gastric adenocarcinoma, highly mutated genes in pancreatic ductal adenocarcinoma such as KRAS, SMAD4, and CDKN2A were rarely mutated in GAS. Of frequently mutated genes in cholangiocarcinoma, BAP1 and HLA-B were identified in GAS. Frequent EMT-related gene mutations suggested a possible role of EMT-related pathways in tumor dissemination and chemoresistance of GAS. In addition, GAS shared some genetic features with gastrointestinal adenocarcinoma. These findings provide a clue in understanding the biological basis of GAS.
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http://dx.doi.org/10.1038/s41379-020-0614-0DOI Listing
March 2021