Publications by authors named "Young-Suk Lee"

83 Publications

The SARS-CoV-2 RNA interactome.

Mol Cell 2021 Apr 27. Epub 2021 Apr 27.

Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea; School of Biological Sciences, Seoul National University, Seoul, Republic of Korea. Electronic address:

SARS-CoV-2 is an RNA virus whose success as a pathogen relies on its abilities to repurpose host RNA-binding proteins (RBPs) and to evade antiviral RBPs. To uncover the SARS-CoV-2 RNA interactome, we here develop a robust ribonucleoprotein (RNP) capture protocol and identify 109 host factors that directly bind to SARS-CoV-2 RNAs. Applying RNP capture on another coronavirus, HCoV-OC43, revealed evolutionarily conserved interactions between coronaviral RNAs and host proteins. Transcriptome analyses and knockdown experiments delineated 17 antiviral RBPs, including ZC3HAV1, TRIM25, PARP12, and SHFL, and 8 proviral RBPs, such as EIF3D and CSDE1, which are responsible for co-opting multiple steps of the mRNA life cycle. This also led to the identification of LARP1, a downstream target of the mTOR signaling pathway, as an antiviral host factor that interacts with the SARS-CoV-2 RNAs. Overall, this study provides a comprehensive list of RBPs regulating coronaviral replication and opens new avenues for therapeutic interventions.
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http://dx.doi.org/10.1016/j.molcel.2021.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075806PMC
April 2021

Collagen type VI‑α1 and 2 repress the proliferation, migration and invasion of bladder cancer cells.

Int J Oncol 2021 Jul 13;59(1). Epub 2021 May 13.

Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Chungcheongbuk 28644, Republic of Korea.

The bladder cancer (BCa) microenvironment comprises heterogeneous tumor cell populations, the surrounding stroma and the extracellular matrix (ECM). Collagen, the scaffold of the tumor microenvironment, regulates ECM remodeling to promote tumor infiltration, angiogenesis, invasion and migration. The present study examined how collagen type VI‑α (COL6A) 1 and 2 function during BCa pathogenesis and progression, with the aim of facilitating the development of precision therapeutics, risk stratification and molecular diagnosis. and mRNA expression in non‑muscle invasive BCa (NMIBC) and MIBC tissue samples was measured using reverse transcription‑quantitative PCR. In addition, the tumor‑suppressive effects of and in human BCa EJ cells (MGH‑U1) were assessed. Compared with normal controls, and mRNA expression was downregulated in both NMIBC and MIBC tissue samples (P<0.05, respectively). and effectively inhibited the proliferation of human BCa EJ cells (MGH‑U1) and induced cell cycle arrest at the G phase. Additionally, and served roles in MAPK and AKT signaling by increasing p38 MAPK phosphorylation and decreasing AKT phosphorylation. Finally, and inhibited wound healing and invasion by suppressing the activity of matrix metalloproteinase (MMP)‑2 and MMP‑9. In conclusion, COL6A1 and COL6A2 may act as classical collagens by forming a physical barrier to inhibit BCa tumor growth and invasion.
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http://dx.doi.org/10.3892/ijo.2021.5217DOI Listing
July 2021

Noncanonical immune response to the inhibition of DNA methylation by Staufen1 via stabilization of endogenous retrovirus RNAs.

Proc Natl Acad Sci U S A 2021 Mar;118(13)

Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea;

DNA-methyltransferase inhibitors (DNMTis), such as azacitidine and decitabine, are used clinically to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Decitabine activates the transcription of endogenous retroviruses (ERVs), which can induce immune response by acting as cellular double-stranded RNAs (dsRNAs). Yet, the posttranscriptional regulation of ERV dsRNAs remains uninvestigated. Here, we find that the viral mimicry and subsequent cell death in response to decitabine require the dsRNA-binding protein Staufen1 (Stau1). We show that Stau1 directly binds to ERV RNAs and stabilizes them in a genome-wide manner. Furthermore, Stau1-mediated stabilization requires a long noncoding RNA TINCR, which enhances the interaction between Stau1 and ERV RNAs. Analysis of a clinical patient cohort reveals that MDS and AML patients with lower Stau1 and TINCR expressions exhibit inferior treatment outcomes to DNMTi therapy. Overall, our study reveals the posttranscriptional regulatory mechanism of ERVs and identifies the Stau1-TINCR complex as a potential target for predicting the efficacy of DNMTis and other drugs that rely on dsRNAs.
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http://dx.doi.org/10.1073/pnas.2016289118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020767PMC
March 2021

RNA demethylation by FTO stabilizes the FOXJ1 mRNA for proper motile ciliogenesis.

Dev Cell 2021 Apr 23;56(8):1118-1130.e6. Epub 2021 Mar 23.

Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea; School of the Biological Sciences, Seoul National University, Seoul 08826, Korea. Electronic address:

Adenosine N6-methylation (m6A) is one of the most pervasive mRNA modifications, and yet the physiological significance of m6A removal (demethylation) remains elusive. Here, we report that the m6A demethylase FTO functions as a conserved regulator of motile ciliogenesis. Mechanistically, FTO demethylates and thereby stabilizes the mRNA that encodes the master ciliary transcription factor FOXJ1. Depletion of Fto in Xenopus laevis embryos caused widespread motile cilia defects, and Foxj1 was identified as one of the major phenocritical targets. In primary human airway epithelium, FTO depletion also led to FOXJ1 mRNA destabilization and a severe loss of ciliated cells with an increase of neighboring goblet cells. Consistently, Fto knockout mice showed strong asthma-like phenotypes upon allergen challenge, a result owing to defective ciliated cells in the airway epithelium. Altogether, our study reveals a conserved role of the FTO-FOXJ1 axis in embryonic and homeostatic motile ciliogenesis.
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http://dx.doi.org/10.1016/j.devcel.2021.03.006DOI Listing
April 2021

Preharvest Application of Chitosan Improves the Postharvest Life of 'Garmrok' Kiwifruit through the Modulation of Genes Related to Ethylene Biosynthesis, Cell Wall Modification, and Lignin Metabolism.

Foods 2021 Feb 9;10(2). Epub 2021 Feb 9.

Department of Horticultural Science, Chungnam National University, Daejeon 34134, Korea.

The influence of the preharvest application of chitosan on physicochemical properties and changes in gene expression of 'Garmrok' kiwifruit during postharvest cold storage (0 °C; RH 90-95%; 90 days) was investigated. Preharvest treatment of chitosan increased the fruit weight but had no significant effect on fruit size. The chitosan treatment suppressed the ethylene production and respiration rate of kiwifruit during the cold storage. The reduction of ethylene production of chitosan-treated kiwifruit was accompanied with the suppressed expression of ethylene biosynthesis genes. Moreover, preharvest application of chitosan diminished weight loss and delayed the changes in physicochemical properties that include firmness, soluble solids content, titratable acidity, total sugars, total acids, total phenols, and total lignin. As a result, the preharvest application of chitosan delayed the maturation and ripening of fruit. Expression of genes related to cell wall modification was down-regulated during the early maturation (ripening) period, while those related to gene expression for lignin metabolism were up-regulated at the later stages of ripening. These results demonstrate that the preharvest application of chitosan maintained the fruit quality and extends the postharvest life of 'Garmrok' kiwifruit, possibly through the modulation of genes related to ethylene biosynthesis, cell wall modification, and lignin metabolism.
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http://dx.doi.org/10.3390/foods10020373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915756PMC
February 2021

A severe case of tenofovir-associated acute kidney injury requiring hemodialysis in a patient with chronic hepatitis B.

Kidney Res Clin Pract 2020 Sep;39(3):373-375

Division of Nephrology, Department of Internal Medicine, Presbyterian Medical Center, Jeonju, Republic of Korea.

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http://dx.doi.org/10.23876/j.krcp.20.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530364PMC
September 2020

Viral hijacking of the TENT4-ZCCHC14 complex protects viral RNAs via mixed tailing.

Nat Struct Mol Biol 2020 06 25;27(6):581-588. Epub 2020 May 25.

Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea.

TENT4 enzymes generate 'mixed tails' of diverse nucleotides at 3' ends of RNAs via nontemplated nucleotide addition to protect messenger RNAs from deadenylation. Here we discover extensive mixed tailing in transcripts of hepatitis B virus (HBV) and human cytomegalovirus (HCMV), generated via a similar mechanism exploiting the TENT4-ZCCHC14 complex. TAIL-seq on HBV and HCMV RNAs revealed that TENT4A and TENT4B are responsible for mixed tailing and protection of viral poly(A) tails. We find that the HBV post-transcriptional regulatory element (PRE), specifically the CNGGN-type pentaloop, is critical for TENT4-dependent regulation. HCMV uses a similar pentaloop, an interesting example of convergent evolution. This pentaloop is recognized by the sterile alpha motif domain-containing ZCCHC14 protein, which in turn recruits TENT4. Overall, our study reveals the mechanism of action of PRE, which has been widely used to enhance gene expression, and identifies the TENT4-ZCCHC14 complex as a potential target for antiviral therapeutics.
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http://dx.doi.org/10.1038/s41594-020-0427-3DOI Listing
June 2020

MS1-Level Proteome Quantification Platform Allowing Maximally Increased Multiplexity for SILAC and Chemical Labeling.

Anal Chem 2020 04 24;92(7):4980-4989. Epub 2020 Mar 24.

Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea.

Quantitative proteomic platforms based on precursor intensity in mass spectrometry (MS1-level) uniquely support metabolic labeling with superior quantification accuracy but suffer from limited multiplexity (≤3-plex) and frequent missing quantities. Here we present a new MS1-level quantification platform that allows maximal multiplexing with high quantification accuracy and precision for the given labeling scheme. The platform currently comprises 6-plex SILAC or diethylation labeling with a dedicated algorithm and is also expandable to higher multiplexity (e.g., nine-plex for SILAC). For complex samples with broad dynamic ranges such as total cell lysates, our platform performs highly accurately and free of missing quantities. Furthermore, we successfully applied our method to measure protein synthesis rate under heat shock response in human cells by 6-plex pulsed SILAC experiments, demonstrating the unique biological merits of our platform to disclose translational regulations for cellular response to stress.
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http://dx.doi.org/10.1021/acs.analchem.9b05148DOI Listing
April 2020

Molecular characteristics of meningiomas.

J Pathol Transl Med 2020 Jan 15;54(1):45-63. Epub 2020 Jan 15.

Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Meningioma is the most common primary intracranial tumor in adults. The grading of meningioma is based on World Health Organization criteria, which rely on histopathological features alone. This grading system is unable to conclusively predict the clinical behavior of these tumors (i.e., recurrence or prognosis in benign or atypical grades). Advances in molecular techniques over the last decade that include genomic and epigenomic data associated with meningiomas have been used to identify genetic biomarkers that can predict tumor behavior. This review summarizes the molecular characteristics of meningioma using genetic and epigenetic biomarkers. Molecular alterations that can predict meningioma behavior may be integrated into the upcoming World Health Organization grading system.
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http://dx.doi.org/10.4132/jptm.2019.11.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986967PMC
January 2020

Comparison of the Efficacy Between Transurethral Coagulation and Transurethral Resection of Hunner Lesion in Interstitial Cystitis/Bladder Pain Syndrome Patients: A Prospective Randomized Controlled Trial.

Eur Urol 2020 05 17;77(5):644-651. Epub 2020 Jan 17.

Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Division of Medical Device, Clinical Trial Center, Samsung Medical Center, Seoul, Korea. Electronic address:

Background: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic condition characterized by chronic pelvic pain related to the bladder with no effective treatment options.

Objective: To evaluate the efficacy and safety of transurethral resection (TUR) and transurethral coagulation (TUC) as treatments for Hunner lesion (HL) in IC/BPS.

Design, Setting, And Participants: A single-center, prospective, randomized controlled trial involving 126 patients with HL in IC/BPS.

Intervention: TUR or TUC.

Outcome Measurements And Statistical Analysis: Primary outcome was recurrence-free time after surgery. Secondary outcomes included change of the number of frequency, nocturia, urgency episodes in voiding diaries, O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI) and Interstitial Cystitis Problem Index (ICPI), pelvic pain and urgency/frequency (PUF) symptom scale, and visual analog scale (VAS) for pain and risk factors for recurrence.

Results And Limitations: There were no differences in the recurrence-free time between treatment groups, a difference of 12.2 mo (95% confidence interval [CI], 11.1-17.6) for TUR, and a difference of 11.5 mo (95% CI, 9.03-16.1; p=0.735) for TUC. No difference was found in decreased mean daytime frequency, nocturia, urgency episodes, ICSI, ICPI, PUF symptom scale, and VAS for pain between both groups over 12 mo. Regardless of treatment types, there were significant improvements in all symptom questionnaires and pain compared with baseline (all, p < 0.05). Treatment type (TUR or TUC), age, sex, previous history of hydrodistension, and number of HLs did not affect recurrence. Incidence of bladder injury was higher in the TUR group (7.9%) than in the TUC group (3.4%).

Conclusions: There was no difference in the recurrence-free time and effect on urinary symptoms, including pain between TUC and TUR, for HL. Taking into account procedure-related complications, the surgeon can choose the method with which he/she is most familiar and comfortable.

Patient Summary: In patients with bladder pain syndrome with Hunner lesions, both endoscopic resection and coagulation of the lesions are effective treatments.
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http://dx.doi.org/10.1016/j.eururo.2020.01.002DOI Listing
May 2020

Myeloid-derived suppressor cells are bound and inhibited by anti-thymocyte globulin.

Innate Immun 2019 01;25(1):46-59

1 Department of Surgery, University of Maryland, Baltimore, USA.

Myeloid-derived suppressor cells (MDSCs) inhibit T cell responses and are relevant to cancer, autoimmunity and transplant biology. Anti-thymocyte globulin (ATG) is a commonly used T cell depletion agent, yet the effect of ATG on MDSCs has not been investigated. MDSCs were generated in Lewis Lung Carcinoma 1 tumor-bearing mice. MDSC development and function were assessed in vivo and in vitro with and without ATG administration. T cell suppression assays, RT-PCR, flow cytometry and arginase activity assays were used to assess MDSC phenotype and function. MDSCs increased dramatically in tumor-bearing mice and the majority of splenic MDSCs were of the polymorphonuclear subset. MDSCs potently suppressed T cell proliferation. ATG-treated mice developed 50% fewer MDSCs and these MDSCs were significantly less suppressive of T cell proliferation. In vitro, ATG directly bound 99.6% of MDSCs. CCR7, L-selectin and LFA-1 were expressed by both T cells and MDSCs, and binding of LFA-1 was inhibited by ATG pre-treatment. Arg-1 and PD-L1 transcript expression were reduced 30-40% and arginase activity decreased in ATG-pretreated MDSCs. MDSCs were bound and functionally inhibited by ATG. T cells and MDSCs expressed common Ags which were also targets of ATG. ATG may be helpful in tumor models seeking to suppress MDSCs. Alternatively, ATG may inadvertently inhibit important T cell regulatory events in autoimmunity and transplantation.
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http://dx.doi.org/10.1177/1753425918820427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830891PMC
January 2019

A Computational Framework for Genome-wide Characterization of the Human Disease Landscape.

Cell Syst 2019 02 23;8(2):152-162.e6. Epub 2019 Jan 23.

Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA; Department of Computer Science, Princeton University, Princeton, NJ, USA; Flatiron Institute, Simons Foundation, New York, NY, USA. Electronic address:

A key challenge for the diagnosis and treatment of complex human diseases is identifying their molecular basis. Here, we developed a unified computational framework, URSA (Unveiling RNA Sample Annotation for Human Diseases), that leverages machine learning and the hierarchy of anatomical relationships present among diseases to integrate thousands of clinical gene expression profiles and identify molecular characteristics specific to each of the hundreds of complex diseases. URSA can distinguish between closely related diseases more accurately than literature-validated genes or traditional differential-expression-based computational approaches and is applicable to any disease, including rare and understudied ones. We demonstrate the utility of URSA in classifying related nervous system cancers and experimentally verifying novel neuroblastoma-associated genes identified by URSA. We highlight the applications for potential targeted drug-repurposing and for quantitatively assessing the molecular response to clinical therapies. URSA is freely available for public use, including the use of underlying models, at ursahd.princeton.edu.
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http://dx.doi.org/10.1016/j.cels.2018.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374759PMC
February 2019

Molecular Basis for the Single-Nucleotide Precision of Primary microRNA Processing.

Mol Cell 2019 02 13;73(3):505-518.e5. Epub 2018 Dec 13.

Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea; School of Biological Sciences, Seoul National University, Seoul 08826, Korea. Electronic address:

Microprocessor, composed of DROSHA and its cofactor DGCR8, initiates microRNA (miRNA) biogenesis by processing the primary transcripts of miRNA (pri-miRNAs). Here we investigate the mechanism by which Microprocessor selects the cleavage site with single-nucleotide precision, which is crucial for the specificity and functionality of miRNAs. By testing ∼40,000 pri-miRNA variants, we find that for some pri-miRNAs the cleavage site is dictated mainly by the mGHG motif embedded in the lower stem region of pri-miRNA. Structural modeling and deep-sequencing-based complementation experiments show that the double-stranded RNA-binding domain (dsRBD) of DROSHA recognizes mGHG to place the catalytic center in the appropriate position. The mGHG motif as well as the mGHG-recognizing residues in DROSHA dsRBD are conserved across eumetazoans, suggesting that this mechanism emerged in an early ancestor of the animal lineage. Our findings provide a basis for the understanding of miRNA biogenesis and rational design of accurate small-RNA-based gene silencing.
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http://dx.doi.org/10.1016/j.molcel.2018.11.005DOI Listing
February 2019

Interpretation of an individual functional genomics experiment guided by massive public data.

Nat Methods 2018 12 26;15(12):1049-1052. Epub 2018 Nov 26.

Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.

A key unmet challenge in interpreting omics experiments is inferring biological meaning in the context of public functional genomics data. We developed a computational framework, Your Evidence Tailored Integration (YETI; http://yeti.princeton.edu/ ), which creates specialized functional interaction maps from large public datasets relevant to an individual omics experiment. Using this tailored integration, we predicted and experimentally confirmed an unexpected divergence in viral replication after seasonal or pandemic human influenza virus infection.
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http://dx.doi.org/10.1038/s41592-018-0218-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941785PMC
December 2018

The insight of in vitro and in silico studies on cholinesterase inhibitors from the roots of Cimicifuga dahurica (Turcz.) Maxim.

J Enzyme Inhib Med Chem 2018 Dec;33(1):1174-1180

c College of Pharmacy, Chungnam National University , Daejeon , Republic of Korea.

Cholinesterases (ChEs) are enzymes that break down neurotransmitters associated with cognitive function and memory. We isolated cinnamic acids (1 and 2), indolinones (3 and 4), and cycloartane triterpenoid derivatives (5-19) from the roots of Cimicifuga dahurica (Turcz.) Maxim. by chromatography. These compounds were evaluated for their inhibitory activity toward ChEs. Compound 1 was determined to have an IC value of 16.7 ± 1.9 μM, and to act as a competitive inhibitor of acetylcholinesterase (AChE). Compounds 3, 4 and 14 were found to be noncompetitive with IC values of 13.8 ± 1.5 and 6.5 ± 2.5 μM, and competitive with an IC value of 22.6 ± 0.4 μM, respectively, against butyrylcholinesterase (BuChE). Our molecular simulation suggested each key amino acid, Tyr337 of AChE and Asn228 of BuChE, which were corresponded with potential inhibitors 1, and 3 and 4, respectively. Compounds 1 and 4 were revealed to be promising compounds for inhibition of AChEs and BuChEs, respectively.
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http://dx.doi.org/10.1080/14756366.2018.1491847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179041PMC
December 2018

Mixed tailing by TENT4A and TENT4B shields mRNA from rapid deadenylation.

Science 2018 08 19;361(6403):701-704. Epub 2018 Jul 19.

Center for RNA Research, Institute for Basic Science, Seoul 151-742, Republic of Korea.

RNA tails play integral roles in the regulation of messenger RNA (mRNA) translation and decay. Guanylation of the poly(A) tail was discovered recently, yet the enzymology and function remain obscure. Here we identify TENT4A (PAPD7) and TENT4B (PAPD5) as the enzymes responsible for mRNA guanylation. Purified TENT4 proteins generate a mixed poly(A) tail with intermittent non-adenosine residues, the most common of which is guanosine. A single guanosine residue is sufficient to impede the deadenylase CCR4-NOT complex, which trims the tail and exposes guanosine at the 3' end. Consistently, depletion of TENT4A and TENT4B leads to a decrease in mRNA half-life and abundance in cells. Thus, TENT4A and TENT4B produce a mixed tail that shields mRNA from rapid deadenylation. Our study unveils the role of mixed tailing and expands the complexity of posttranscriptional gene regulation.
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http://dx.doi.org/10.1126/science.aam5794DOI Listing
August 2018

Efficacy of an Alpha-Blocker for the Treatment of Nonneurogenic Voiding Dysfunction in Women: An 8-Week, Randomized, Double-Blind, Placebo-Controlled Trial.

Int Neurourol J 2018 Mar 31;22(1):30-40. Epub 2018 Mar 31.

Department of Urology, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, Korea.

Purpose: To evaluate the efficacy of an alpha-1 adrenergic receptor (α1-AR) blocker for the treatment of female voiding dysfunction (FVD) through a pressure-flow study.

Methods: This was a randomized, double-blind, placebo-controlled trial. Women aged ≥18 years with voiding symptoms, as defined by an American Urological Association symptom score (AUA-SS) ≥15 and a maximum flow rate (Qmax) <15 mL/sec with a voided volume of >100 mL and/or a postvoid residual (PVR) volume >150 mL, were randomly allocated to either the alfuzosin or placebo group. After 8 weeks of treatment, changes in the AUA-SS, Bristol female lower urinary tract symptoms (BFLUTS) questionnaire, Qmax/PVR, and voiding diary were compared between groups. Patients' satisfaction with the treatment was compared. Patients were categorized into 3 groups according to the Blaivas-Groutz bladder outlet obstruction (BOO) nomogram: none, mild, and moderate to severe. Subgroup comparisons were also made.

Results: Of a total of 187 women, 154 (79 alfuzosin, 75 placebo) were included in the analysis. After 8 weeks of treatment, the AUA-SS decreased by 7.0 in the alfuzosin group and by 8.0 in the placebo group. Changes in AUA-SS subscores, BFLUTS (except the I-sum), the voiding diary, and Qmax/PVR were not significantly different between groups. Approximately 54% of the alfuzosin group and 62% of the placebo group were satisfied with the treatment. No significant difference was observed between groups according to the presence or grade of BOO.

Conclusions: Alfuzosin might not be more effective than placebo for treating FVD. The presence or the grade of BOO did not affect the results. A further study with sufficient power is needed to determine the efficacy of α1-AR blockers for the treatment of FVD.
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http://dx.doi.org/10.5213/inj.1834904.452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885130PMC
March 2018

Myeloid-Derived Suppressor Cells and Their Potential Application in Transplantation.

Transplantation 2018 03;102(3):359-367

Division of Transplantation, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells of the myeloid lineage upregulated by mediators of inflammation, such as IL-2, granulocyte colony-stimulating factor, and S100A8/A9. These cells have been studied extensively by tumor biologists. Because of their robust immunosuppressive potential, MDSCs have stirred recent interest among transplant immunologists as well. MDSCs inhibit T-cell responses through, among other mechanisms, the activity of arginase-1 and inducible nitric oxide synthase, and the expansion of T regulatory cells. In the context of transplantation, MDSCs have been studied in several animal models, and to a lesser degree in humans. Here, we will review the immunosuppressive qualities of this important cell type and discuss the relevant studies of MDSCs in transplantation. It may be possible to exploit the immunosuppressive capacity of MDSCs for the benefit of transplant patients.
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http://dx.doi.org/10.1097/TP.0000000000002022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890230PMC
March 2018

IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment.

Cell 2017 Jun;170(1):127-141.e15

Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cancer Immunology and Melanoma, Harvard Cancer Center, Dana Farber Cancer Center, Boston, MA 02215, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA. Electronic address:

Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.
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http://dx.doi.org/10.1016/j.cell.2017.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569303PMC
June 2017

Change of Ultrasound Estimated Bladder Weight and Bladder Wall Thickness After Treatment of Bladder Outlet Obstruction With Dutasteride.

Low Urin Tract Symptoms 2017 May 27;9(2):67-74. Epub 2015 Jul 27.

Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Objectives: To investigate the change of bladder wall hypertrophy to relieve bladder outlet obstruction (BOO) by treatment with 5α-reductase inhibitor.

Methods: Men who have BOO confirmed by urodynamic study (BOO index ≥40) were treated with dutasteride 0.5 mg once a day for 6 months. We measured ultrasound estimated bladder weight (UEBW), UEBW divided by body surface area (UEBW/BSA), and bladder wall thickness (BWT) before and after treatment. Changes in LUTS parameters were assessed by using the International Prostate Symptom Score, uroflowmetry, residual urine volume, prostate volume, serum prostate-specific antigen (PSA), and LUTS outcome scores (LOS). Correlation between the change of LUTS parameters and UEBW, UEBW/BSA, and BWT were evaluated. We assessed the changes of bladder wall hypertrophy according to the results of benefit, satisfaction, and willingness to continue (BSW) questionnaire.

Results: Thirty patients completed the 6-month study. The mean UEBW was 47.10 ± 7.79 g before and 50.07 ± 5.39 g after dutasteride treatment (P = 0.259). The mean UEBW/BSA was 26.47 ± 4.30 g/m before and 28.2 ± 3.53 g/m after treatment (P = 0.253), and there was no definite change in mean BWT after treatment (P = 0.301). Most LUTS parameters including LOS significantly improved. Increased BOO index value was related to decreased BWT (ρ = 0.361, P = 0.049). There was no definite change in mean UEBW, UEBW/BSA, and BWT according to the results of the BSW questionnaire.

Conclusions: There was no change in UEBW, UEBW/BSA and BWT despite improving most clinical parameters suggesting BOO. The changes of bladder wall hypertrophy parameters still have limitations to directly reflect the relief of BOO.
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http://dx.doi.org/10.1111/luts.12110DOI Listing
May 2017

Clinical Experiences of Uncommon Motor Neuron Disease: Hirayama Disease.

Korean J Spine 2016 Sep 30;13(3):170-172. Epub 2016 Sep 30.

Department of Neurosurgery, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Korea.

Hirayama disease, juvenile muscular atrophy of the distal upper limb, is a rare disease predominantly affecting the anterior horn cells of the cervical spinal cord in young men. This cervical myelopathy is associated with neck flexion. It should be suspected in young male patients with a chronic history of weakness and atrophy involving the upper extremities followed by clinical stability in few years. Herein, we report 2 cases of Hirayama disease on emphasis of diagnostic approach and describe the pathognomonic findings at flexion magnetic resonance imaging.
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http://dx.doi.org/10.14245/kjs.2016.13.3.170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086473PMC
September 2016

Anatomical and Functional Outcomes of Prolift Transvaginal Mesh for Treatment of Pelvic Organ Prolapse.

Low Urin Tract Symptoms 2016 Sep 29;8(3):159-64. Epub 2015 Jan 29.

Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Objectives: To evaluate anatomical and functional outcomes of the Prolift Transvaginal Mesh for treatment of pelvic organ prolapse (POP) with regard to safety and satisfaction.

Methods: We reviewed the medical records of 163 patients who underwent POP repair with Prolift Transvaginal Mesh between December 2005 and March 2012. An "optimal" anatomic outcome was defined as Pelvic Organ Prolapse Quantification System (POP-Q) stage 0, and a "satisfactory" anatomic outcome was defined as POP-Q stage 1.

Resuts: A total of 163 patients were included in this study, with a mean age (range) of 61.6 (35-83) years. An anterior mesh was used in 110 patients, and combined anterior and posterior mesh was used in 53 patients. The mean follow-up period after POP repair was 40.4 (12-63) months. Optimal anatomic outcomes for anterior, apical, and posterior prolapse were achieved in 55.9, 69.2, and 65.8% of cases, respectively. Optimal or satisfactory anatomic outcomes for anterior, apical, and posterior prolapse occurred in 76.7, 85.0, and 82.5% of cases, respectively. Mean values for points in the POP-Q, urinary distress inventory (UDI), and pelvic organ prolapsed distress inventory (POPDI) in the Pelvic Floor Distress Inventory (PFDI) were all significantly improved after the operation. The overall satisfaction rate for the operation was 84.7%. Five patients (3.1%) were diagnosed with vaginal erosion and treated with partial excision of the mesh without evidence of infection.

Conclusions: Pelvic organ prolapse repair using Prolift Transvaginal Mesh is an effective and safe procedure without significant complications.
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http://dx.doi.org/10.1111/luts.12090DOI Listing
September 2016

A Study on the Defensive Stance and Position of Handball Goalkeepers: Facing a Forward Jump Shot Made from 9 Meters.

J Appl Biomech 2016 Oct 19;32(5):504-12. Epub 2016 Aug 19.

2 Seoul National University of Education.

The purpose of this study was to find the defensive stance and calculate an optimal defense position for goalkeepers while blocking forward jump shots made from a distance of 9 m. Nine men's handball matches were recorded and 78 video clips were selected for analysis. These are the top class goalkeepers, which included players from the national team and reserve team of Korea. The goalkeeper's actual defensive position was significantly different from instructional suggestions; the width of both feet of the goalkeeper was approximately 2.5 times the width of the shoulders, and the hands were at waist height. The goalkeeper's actual defense position was about 1.10 (± 0.3) m from the goal line and also significantly different than instructional material (0.75 m). The optimal defense position, which was calculated from the goalkeeper's actual movement, was 1.44 m from the goal line, because the ratio of goalkeeper's defensive area in relation to the total area to be defended is highest at this point. In summary, we recommended that handball goalkeepers move forward, about a half step (0.34 m), when defending a forward jump shot made from 9 m, and instructional material should be modified according to the findings from this study.
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http://dx.doi.org/10.1123/jab.2015-0317DOI Listing
October 2016

Tension-Free Vaginal Tape-SECUR Procedure for the Treatment of Female Stress Urinary Incontinence: 3-Year Follow-Up Results.

Low Urin Tract Symptoms 2015 Jan 28;7(1):9-16. Epub 2013 Oct 28.

Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Objectives: To assess the efficacy and complications associated with the use of the tension-free vaginal tape (TVT)-Secur system device for the treatment of female stress urinary incontinence (SUI) based on a 3-year follow-up.

Methods: Women with SUI were randomly allocated to either the U- or H-type groups depending on the TVT-Secur approach used. Patients were questioned about continence and satisfaction 1, 2, and 3 years after surgery. Patients were assessed postoperatively by questionnaires including Sandvik, Incontinence Quality of Life (I-QoL), Bristol Female Lower Urinary Tract Symptoms-Scored Form (BF-LUTS), incontinence visual analogue scale (I-VAS), and benefit, satisfaction, and willingness to continue questionnaire. Cure was regarded as no leakage on the Sandvik questionnaire.

Results: A total of 115 patients with SUI were included in this study (U-type: 53, H-type: 62). A total of 102 patients were followed-up for 3 years (U-type: 47, H-type: 55). The overall cure rate at the 1-, 2-, and 3-year follow-ups was 87.8, 83.0, and 79.4%, respectively, and there was no difference in the cure rate between the U-and H-type approaches. Approximately 83.4 and 83.3% of patients were satisfied with the surgical outcome at the 1- and 3-year follow-ups. I-QoL, BFLUTS-SF, and I-VAS were improved from baseline regardless of the approach used at the 1- and 2-year follow-ups. Complications included intraoperative vaginal wall perforation (three cases), voiding difficulties such as immediate postoperative retention, and urgency episodes.

Conclusions: Both U- and H-type approaches of TVT-Secur for the treatment of female SUI remains efficacious, safe, and satisfactory for up to 3 years after surgery.
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http://dx.doi.org/10.1111/luts.12040DOI Listing
January 2015

Risk factors for contralateral patent processus vaginalis determined by transinguinal laparoscopic examination.

Exp Ther Med 2015 Feb 1;9(2):421-424. Epub 2014 Dec 1.

Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Concurrent contralateral inguinal exploration in children with unilateral hernia or hydrocele is a subject of debate. The aim of the present study was to investigate the incidence of contralateral patent processus vaginalis (CPPV) using transinguinal laparoscopy (inguinoscopy). In addition, the risk factors of CPPV were evaluated in order to facilitate the selection of appropriate candidates for contralateral examination. A total of 119 patients who presented with unilateral hydrocele, inguinal hernia or cryptorchidism between 2001 and 2008 underwent inguinoscopy during the ipsilateral surgery. All data were collected prospectively. The incidence of CPPV was investigated and the risk factors affecting the presence of CPPV were analyzed. Among these patients, 29 individuals (24.4%) had CPPV confirmed by inguinoscopy. No surgical complications were observed during the inguinoscopy. Cases with suspicious ultrasound findings were at a higher risk of CPPV than cases with normal findings (odds ratio, 13.800; P=0.004). A history of contralateral disease was also found to be a significant risk factor (odds ratio, 4.008; P=0.019). The present study identified that the significant risk factors for CPPV were suspicious findings on ultrasound examination and a history of contralateral disease. Therefore, it is concluded that performing inguinoscopy in children with these risk factors is beneficial.
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http://dx.doi.org/10.3892/etm.2014.2098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280956PMC
February 2015

Tissue-aware data integration approach for the inference of pathway interactions in metazoan organisms.

Bioinformatics 2015 Apr 26;31(7):1093-101. Epub 2014 Nov 26.

Department of Computer Science, Princeton University, Princeton, NJ 08544, USA, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08540, USA and Simons Center for Data Analysis, Simons Foundation, New York, NY, 10010, USA Department of Computer Science, Princeton University, Princeton, NJ 08544, USA, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08540, USA and Simons Center for Data Analysis, Simons Foundation, New York, NY, 10010, USA Department of Computer Science, Princeton University, Princeton, NJ 08544, USA, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08540, USA and Simons Center for Data Analysis, Simons Foundation, New York, NY, 10010, USA.

Motivation: Leveraging the large compendium of genomic data to predict biomedical pathways and specific mechanisms of protein interactions genome-wide in metazoan organisms has been challenging. In contrast to unicellular organisms, biological and technical variation originating from diverse tissues and cell-lineages is often the largest source of variation in metazoan data compendia. Therefore, a new computational strategy accounting for the tissue heterogeneity in the functional genomic data is needed to accurately translate the vast amount of human genomic data into specific interaction-level hypotheses.

Results: We developed an integrated, scalable strategy for inferring multiple human gene interaction types that takes advantage of data from diverse tissue and cell-lineage origins. Our approach specifically predicts both the presence of a functional association and also the most likely interaction type among human genes or its protein products on a whole-genome scale. We demonstrate that directly incorporating tissue contextual information improves the accuracy of our predictions, and further, that such genome-wide results can be used to significantly refine regulatory interactions from primary experimental datasets (e.g. ChIP-Seq, mass spectrometry).

Availability And Implementation: An interactive website hosting all of our interaction predictions is publically available at http://pathwaynet.princeton.edu. Software was implemented using the open-source Sleipnir library, which is available for download at https://bitbucket.org/libsleipnir/libsleipnir.bitbucket.org.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btu786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804827PMC
April 2015

Acute generalized exanthematous pustulosis induced by parvovirus b19 infection.

Ann Dermatol 2014 Jun 12;26(3):399-400. Epub 2014 Jun 12.

Department of Dermatology, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.

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http://dx.doi.org/10.5021/ad.2014.26.3.399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069655PMC
June 2014

Treatment outcomes of transurethral macroplastique injection for postprostatectomy incontinence.

Korean J Urol 2014 Mar 13;55(3):182-9. Epub 2014 Mar 13.

Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: We investigated the efficacy of transurethral injection of Macroplastique bulking agent (Uroplasty) for male stress urinary incontinence (SUI) after prostate surgery.

Materials And Methods: This retrospective review included men with SUI treated by transurethral injection for symptoms resulting from prostate surgery. Patients were evaluated at 1 month and 6 months after injection by determining the number of pads used per day and changes in incontinence symptoms. Treatment success was defined as use of 1 pad or fewer per day combined with subjective symptom improvement.

Results: The study population comprised 30 men with a mean age of 66.1±5.3 years. Of the 30 patients, 24 (80.0%) underwent prostate cancer surgery and the remaining 6 (20.0%) underwent surgery for benign prostatic hyperplasia. The preinjection pad number was 2.9±1.9 pads per day. After injection treatment, the mean follow-up period was 9.3±12.7 months and the success rate was 43% (13/30) at 1 month and 32% (6/19) at 6 months. Injection was more likely to result in a successful outcome in patients with no preinjection radiation treatment history and higher abdominal leak point pressure (ALPP) than in those with a previous history of radiation treatment and lower ALPP, although this result was not statistically significant. Acute urinary retention occurred in 5 patients (17%).

Conclusions: Transurethral Macroplastique injection treatment is a relatively non-invasive treatment method for male SUI with a success rate of 43% at 1 month and 32% at 6 months. Patients with a higher ALPP and no previous history of radiation therapy may experience better treatment outcomes.
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http://dx.doi.org/10.4111/kju.2014.55.3.182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956947PMC
March 2014

Diagnostic role of prostate resection in the elderly patients who experience significant co-morbidity with a high clinical suspicion of prostate cancer.

J Korean Med Sci 2013 Dec 26;28(12):1796-800. Epub 2013 Nov 26.

Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Korea.

The necessity of routine prostate biopsy prior to transurethral resection of the prostate (TURP) in elderly comorbid patients with a high prostate specific antigen (PSA) level remains controversial. We assessed the role of TURP in prostate cancer diagnosis in these individuals. A total of 197 patients underwent TURP in conjunction with prostatic needle biopsy. Pathologic reviews of specimens of TUR chips and biopsy cores were analyzed. Overall, prostate cancer (CaP) was detected in 114 patients (57.6%). Ninety-eight cancers (86%) were detected with TURP and biopsy, and seven cancers (6.1%) with only TURP. The Gleason score of a TUR-specimen was identical to that of the biopsy-core in 43.9% of cases. Variables associated with diagnostic accuracy in the TUR-specimens included the prebiopsy PSA level, prostate specific antigen density (PSAD), and the Gleason score in biopsy cores. In patients with a PSA level and a PSAD that was greater than 15.4 ng/mL and 0.69 ng/mL/g, respectively, 100% of the cancers were detected in the TUR-specimens. Our results suggest that a prostatic biopsy might be omitted prior to TURP in elderly patients with significant co-morbidity and levels for PSA of >15.4 ng/mL.
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http://dx.doi.org/10.3346/jkms.2013.28.12.1796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857377PMC
December 2013

Effectiveness of retropubic tension-free vaginal tape and transobturator inside-out tape procedures in women with overactive bladder and stress urinary incontinence.

Int Neurourol J 2013 Sep 30;17(3):145-51. Epub 2013 Sep 30.

Department of Urology, Pusan National University Yangsan Hospital, Yangsan, Korea.

Purpose: We compared the effectiveness of the retropubic tension-free vaginal tape (TVT) and the transobturator inside-out tape (TVT-O) in treating symptoms of overactive bladder (OAB) in women with stress urinary incontinence (SUI).

Methods: Women with urodynamic SUI and OAB (mean urgency episodes ≥1 and frequency ≥8/24 hours on a 3-day voiding diary) were assigned to the TVT or TVT-O group. Preoperative measures were based on a urodynamic study, 3-day voiding diary, the Bristol Female Lower Urinary Tract Symptoms questionnaire (BFLUTSSF), and the urgency perception scale (UPS). At 12 postoperative months, the 3-day voiding diary, symptoms questionnaire, patient satisfaction, and standing stress test were assessed. The primary endpoint was change in the number of urgency episodes/24 hours from baseline to 12 months.

Results: In this group of 132 women, 42 received TVT and 90 received TVT-O. The mean urgency episodes/24 hours decreased from 6.3±5.5 to 1.6±3.2 in the TVT group and from 5.1±4.4 to 1.8±3.0 in the TVT-O group. The mean percent change was significantly greater after TVT than after TVT-O (73% vs. 60%, P=0.049). All subscales of BFLUTSSF and UPS were significantly improved using either method, with significantly greater improvement seen in the quality of life (QoL) domain after TVT (P=0.002). There were no significant differences in the cure and satisfaction rates between the two groups.

Conclusions: Intervention with the TVT or the TVT-O significantly improved symptoms of OAB in women with SUI and OAB. Urgency and QoL significantly improved after TVT compared with that after TVT-O.
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http://dx.doi.org/10.5213/inj.2013.17.3.145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797895PMC
September 2013