Publications by authors named "Bo-Kyung Kim"

144 Publications

Hemophagocytic lymphohistiocytosis associated with parvovirus B19-induced aplastic crisis in a hereditary spherocytosis patient: A case report and literature review.

Pediatr Hematol Oncol 2021 Aug 9:1-8. Epub 2021 Aug 9.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation. It occurs because of severe inflammation due to uncontrolled proliferation of activated lymphocytes and histiocytes, characterized by the production of excessive levels of cytokines. Virus-associated HLH is a well-known entity, and parvovirus B19 is one of the common causes. Parvovirus B19 can also affect blood cell lineages. Therefore, HLH may be accompanied by several diseases such as cytopenia, aplastic anemia, and myelodysplastic syndrome. Herein, we report the case of a patient with hereditary spherocytosis who was diagnosed with parvovirus B19-induced HLH and aplastic crisis. A 7-year-old girl presented to our hospital with fever, pleural effusion, pancytopenia, hepatosplenomegaly, and hypotension. A bone marrow biopsy was performed under the suspicion of HLH, which revealed hemophagocytes. The diagnostic criteria for HLH were met, and prompt chemoimmunotherapy was initiated considering the clinically unstable situation. Her health improved rapidly after initiating treatment. Further study revealed that she had hereditary spherocytosis, and parvovirus B19 had caused aplastic crisis and HLH. The patient's clinical progress was excellent, and chemoimmunotherapy was reduced and discontinued at an early stage. This case shows that aplastic crisis and HLH can coexist with parvovirus B19 infection in patients with hereditary spherocytosis. Although the prognosis was good in this case of HLH caused by parvovirus B19, early detection and active treatment are essential.
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http://dx.doi.org/10.1080/08880018.2021.1949082DOI Listing
August 2021

Open-Label, Multicenter Phase II Study of Combination Therapy of Imatinib Mesylate and Mycophenolate Mofetil in Pediatric Patients with Steroid-Refractory Sclerotic/Fibrotic Type Chronic Graft-versus-Host Disease.

Transplant Cell Ther 2021 Jul 24. Epub 2021 Jul 24.

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea; Wide River Institute of Immunology, Seoul National University, Gangwon, Republic of Korea. Electronic address:

Steroid-refractory chronic graft-versus-host disease (cGVHD) is associated with high morbidity. To date, there is no standard therapy for patients who fail to respond to steroids. In this nonrandomized, open-label, single-arm, multicenter prospective phase II study, we evaluated the efficacy and safety of imatinib mesylate and mycophenolate mofetil (MMF) to treat sclerotic/fibrotic type cGVHD. The primary endpoint was the overall response rate (ORR) to imatinib mesylate plus MMF in 1 year, and the secondary endpoints included safety, quality of life, discontinuation of steroids, and overall survival (OS) rate. A total of 13 patients were enrolled, with a median age of 10.4 years (range, 5.0 to 20.1 years). All patients received a myeloablative conditioning regimen. Specifically, 6 of these patients had previously experienced acute GVHD. The most frequently affected organs were the eyes, lungs, skin, and liver. There were 2 premature deaths. One patient died of pulmonary infection and progression of cGVHD, and the other patient died from neuroblastoma progression and septic shock. The ORR was 76.9% (10 of 13 patients), and the median steroid dose was decreased from 1.0 mg/kg/day to 0.21 mg/kg/day. One-year OS was 84.6% (n = 13), and common adverse events included elevated liver enzyme and serum creatinine levels and fever. Although our sample size was limited, treatment of cGVHD with imatinib mesylate plus MMF shows promising results with acceptable toxicity.
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http://dx.doi.org/10.1016/j.jtct.2021.07.019DOI Listing
July 2021

Decrease of ceramides with long-chain fatty acids in psoriasis: Possible inhibitory effect of interferon gamma on chain elongation.

Exp Dermatol 2021 Jul 16. Epub 2021 Jul 16.

Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.

Reportedly, decreases in fatty acid (FA) chain length of ceramide (CER) are associated with interferon-γ (IFN-γ), which shows increased expression in psoriasis. However, the underlying mechanism of this association remains unclear. Therefore, in this study, we aimed to clarify this association between FA chain length of CER, IFN-γ, and the major transcriptional factors involving psoriasis. CER profiling according to FA chain length and class was performed in murine epidermis (n = 10 BALB/c mice topically treated with imiquimod, n = 10 controls) and human stratum corneum (SC) (n = 12 psoriasis, n = 11 controls). The expression of lipid synthetic enzymes, including elongases (ELOVLs), in murine epidermis was also measured using RT-PCR. Furthermore, the association of IFN-γ with various enzymes and transcription factors involved in the generation of long-chain CERs was also investigated using in vitro keratinocyte. A significant decrease in the percentage of long-chain CERs was observed in psoriasis-like murine epidermis and human psoriatic SC. Additionally, the expression levels of ELOVL1, ELOVL4, and ceramide synthase3 (CerS3) were significantly decreased in psoriasis-like murine epidermis and IFN-γ-treated keratinocyte. There was also a significant decrease in the expression of transcriptional factors, including peroxisome proliferator-activated receptor (PPAR), in IFN-γ treated keratinocyte. Thus, it could be suggested that IFN-γ may regulate ELOVL and CerS levels by down-regulating the transcriptional factors. Additionally, given the possible involvement of PPARs or liver X receptor agonist in the CER elongation process, they may serve as potential therapeutic agents for lengthening the CER FAs in psoriasis.
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http://dx.doi.org/10.1111/exd.14431DOI Listing
July 2021

Targeting HSF1 as a Therapeutic Strategy for Multiple Mechanisms of EGFR Inhibitor Resistance in EGFR Mutant Non-Small-Cell Lung Cancer.

Cancers (Basel) 2021 Jun 15;13(12). Epub 2021 Jun 15.

Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 111 Gwahangno, Yuseong-gu, Daejeon 34141, Korea.

Although EGFR-TKI treatment of NSCLC (non-small-cell lung cancer) patients often achieves profound initial responses, the efficacy is transient due to acquired resistance. Multiple receptor tyrosine kinase (RTK) pathways contribute to the resistance of NSCLC to first- and third-generation EGFR-TKIs, such as erlotinib and osimertinib. To identify potential targets for overcoming EGFR-TKI resistance, we performed a gene expression signature-based strategy using connectivity map (CMap) analysis. We generated erlotinib-resistant HCC827-ErlR cells, which showed resistance to erlotinib, gefitinib, osimertinib, and doxorubicin. A list of differentially expressed genes (DEGs) in HCC827-ErlR cells was generated and queried using CMap analysis. Analysis of the top 4 compounds from the CMap list suggested HSF1 as a potential target to overcome EGFR-TKI resistance. HSF1 inhibition by using HSF1 shRNAs or KRIBB11 decreased the expression of HSF1 downstream proteins, such as HSP70 and HSP27, and also decreased the expression of HSP90/HSP70/BAG3 client proteins, such as BCL2, MCL1, EGFR, MET, and AXL, causing apoptosis of EGFR-TKI-resistant cancer cells. Finally, we demonstrated the efficacy of the HSF1 inhibitor on PC9-ErlR cells expressing mutant EGFR (T790M) in vivo. Collectively, these findings support a targetable HSF1-(HSP90/HSP70/BAG3)-(BCL2/MCL1/EGFR/MET/AXL) pathway to overcome multiple mechanisms of EGFR-TKI resistance.
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http://dx.doi.org/10.3390/cancers13122987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232331PMC
June 2021

Development of a multiplex real-time PCR assay for the simultaneous detection of four bacterial pathogens causing pneumonia.

PLoS One 2021 17;16(6):e0253402. Epub 2021 Jun 17.

Department of Molecular Diagnostics, Seegene Medical Foundation, Seoul, Republic of Korea.

Classification of clinical symptoms and diagnostic microbiology are essential to effectively employ antimicrobial therapy for lower respiratory tract infections (LRTIs) in a timely manner. Empirical antibiotic treatment without microbial identification hinders the selective use of narrow-spectrum antibiotics and effective patient treatment. Thus, the development of rapid and accurate diagnostic procedures that can be readily adopted by the clinic is necessary to minimize non-essential or excessive use of antibiotics and accelerate patient recovery from LRTI-induced damage. We developed and validated a multiplex real-time polymerase chain reaction (mRT-PCR) assay with good analytical performance and high specificity to simultaneously detect four bacterial pathogens causing pneumonia: Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and Moraxella catarrhalis. The analytical performance of mRT-PCR against target pathogens was evaluated by the limit of detection (LOD), specificity, and repeatability. Two hundred and ten clinical specimens from pneumonia patients were processed using an automatic nucleic acid extraction system for the "respiratory bacteria four" (RB4) mRT-PCR assay, and the results were directly compared to references from bacterial culture and/or Sanger sequencing. The RB4 mRT-PCR assay detected all target pathogens from sputum specimens with a coefficient of variation ranging from 0.29 to 1.71 and conservative LOD of DNA corresponding to 5 × 102 copies/reaction. The concordance of the assay with reference-positive specimens was 100%, and additional bacterial infections were detected from reference-negative specimens. Overall, the RB4 mRT-PCR assay showed a more rapid turnaround time and higher performance that those of reference assays. The RB4 mRT-PCR assay is a high-throughput and reliable tool that assists decision-making assessment and outperforms other standard methods. This tool supports patient management by considerably reducing the inappropriate use of antibiotics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253402PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211157PMC
June 2021

The school-to-prison pipeline for probation youth with special education needs.

Am J Orthopsychiatry 2021 ;91(3):375-385

School of Social Work.

Juvenile justice-involved youth with special education eligibility may have distinct needs from other justice-involved youth that place them at higher risk of re-offending. This study examines the extent to which the comorbidity of risk factors, such as school challenges and mental and emotional health problems, is related to recidivism among probation youth with a diagnosis eligible for special education. Data came from the Washington State Juvenile Court Assessment provided to 4,317 youth adjudicated to probation for at least 3 months. We used independent sample t-tests and chi-square tests to assess the difference in mental health and school problems (e.g., suspension/expulsion history) between those with and without special education needs. Multiple regression models estimated the unique and cumulative role of special education status, mental health, and school problems in future recidivism. In the study sample, 39.6% (n = 1,708) of the youth had diagnoses eligible for special education; over 42% of these youth had two or more qualifying diagnoses. Controlling for demographics, mental health, and self-regulation skills, our findings suggest that probation youth with special education needs, compared to the rest of the probation youth, were more likely to recidivate. School exclusion increased the number of recidivisms significantly more for justice-involved youth with special education needs than those without special education needs. The findings of the study illuminate important factors for continued justice-involvement as well as insights into service and treatment planning for youth serving probation in the community, especially for those who are eligible for special education. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/ort0000538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432608PMC
January 2021

DGG-100629 inhibits lung cancer growth by suppressing the NFATc1/DDIAS/STAT3 pathway.

Exp Mol Med 2021 Apr 15;53(4):643-653. Epub 2021 Apr 15.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Korea.

DNA damage-induced apoptosis suppressor (DDIAS) promotes the progression of lung cancer and hepatocellular carcinoma through the regulation of multiple pathways. We screened a chemical library for anticancer agent(s) capable of inhibiting DDIAS transcription. DGG-100629 was found to suppress lung cancer cell growth through the inhibition of DDIAS expression. DGG-100629 induced c-Jun NH(2)-terminal kinase (JNK) activation and inhibited NFATc1 nuclear translocation. Treatment with SP600125 (a JNK inhibitor) or knockdown of JNK1 restored DDIAS expression and reversed DGG-100629-induced cell death. In addition, DGG-100629 suppressed the signal transducer and activator of transcription (STAT3) signaling pathway. DDIAS or STAT3 overexpression restored lung cancer cell growth in the presence of DGG-100629. In a xenograft assay, DGG-100629 inhibited tumor growth by reducing the level of phosphorylated STAT3 and the expression of STAT3 target genes. Moreover, DGG-100629 inhibited the growth of lung cancer patient-derived gefitinib-resistant cells expressing NFATc1 and DDIAS. Our findings emphasize the potential of DDIAS blockade as a therapeutic approach and suggest a novel strategy for the treatment of gefitinib-resistant lung cancer.
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http://dx.doi.org/10.1038/s12276-021-00601-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102629PMC
April 2021

Development of Mesopore Structure of Mixed Metal Oxide through Albumin-Templated Coprecipitation and Reconstruction of Layered Double Hydroxide.

Nanomaterials (Basel) 2021 Mar 2;11(3). Epub 2021 Mar 2.

Department of Energy and Materials Engineering, Dongguk University-Seoul, Seoul 04620, Korea.

Mixed metal oxide (MMO) with relatively homogeneous mesopores was successfully obtained by calcination and reconstruction of albumin-templated layered double hydroxide (LDH). The aggregation degree of albumin-template was controlled by adjusting two different synthesis routes, coprecipitation and reconstruction. X-ray diffraction patterns and scanning electron microscopic images indicated that crystal growth of LDH was fairly limited during albumin-templated coprecipitation due to the aggregation. On the hand, crystal growth along the lateral direction was facilitated in albumin-templated reconstruction due to the homogeneous distribution of proteins moiety. Different state of albumin during LDH synthesis influenced the local disorder and porous structure of calcination product, MMO. The N adsorption-desorption isotherms demonstrated that calcination on reconstructed LDH produced MMO with large specific surface area and narrow distribution of mesopores compared with calcination of coprecipitated LDH.
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http://dx.doi.org/10.3390/nano11030620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999424PMC
March 2021

Intracerebral hemorrhage as a rare complication of imatinib in a Philadelphia chromosome positive acute lymphoblastic leukemia pediatric patient.

Pediatr Hematol Oncol 2021 May 3;38(4):378-384. Epub 2021 Mar 3.

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Republic of Korea.

Imatinib is a BCR-ABL tyrosine kinase inhibitor used for the treatment of a variety of diseases including Philadelphia chromosome positive (Ph+) leukemia. We report a 15 year old male patient presenting with symptomatic acute intracerebral hemorrhage (ICH) in midbrain while on imatinib more than three years after completion of therapy for Ph + B-ALL. The patient denied recent trauma history and consumption of other medication. Laboratory findings did not show any signs of relapse, coagulopathy nor thrombocytopenia. Under the impression of imatinib related ICH, imatinib was discontinued and with conservative management the patient recovered without neurologic sequalae. This case demonstrates the first pediatric case of spontaneous ICH as a rare complication of imatinib.
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http://dx.doi.org/10.1080/08880018.2020.1843577DOI Listing
May 2021

School Engagement Among Youth Entering Probation.

J Youth Adolesc 2021 Jun 19;50(6):1098-1113. Epub 2021 Feb 19.

School of Social Work, University of Buffalo, Buffalo, NY, USA.

Strong school engagement is crucial for school success among adolescents and particularly important for reducing recidivism. Yet, little is known about school engagement among youth serving probation while attending community schools. This study tested the multivariate associations between risk and promotive factors with three components of school engagement (behavioral, cognitive, and emotional). The study's sample was derived from 5,378 intake assessments (23.6% female) of youth entering juvenile probation in a Pacific Northwest county who were assessed as either moderate or high risk for recidivism. The racial composition of the sample was predominantly White or European American (56.0%) and Black or African American (24.2%) and ranged in age from 10 to 19 years old (M = 15.5, SD = 1.46). The results suggest that dimensions of school engagement can be strengthened by increased relational and skill-building supports throughout youth's social ecologies. The promotive factors of prosocial attitudes and prosocial community connections were significantly associated with increased school engagement. The implications of these findings are discussed regarding opportunities and strategies that promote school engagement for youth on probation.
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http://dx.doi.org/10.1007/s10964-021-01405-3DOI Listing
June 2021

Different Biochemical Compositions of Particulate Organic Matter Driven by Major Phytoplankton Communities in the Northwestern Ross Sea.

Front Microbiol 2021 21;12:623600. Epub 2021 Jan 21.

Department of Oceanography, Pusan National University, Busan, South Korea.

Marine particulate organic matter (POM) largely derived from phytoplankton is a primary food source for upper trophic consumers. Their biochemical compositions are important for heterotrophs. Especially, essential amino acids (EAAs) in phytoplankton are well known to have impacts on the survival and egg productions of herbivorous zooplankton. To estimate the nutritional quality of POM, the biochemical compositions [biomolecular and amino acid (AA) compositions] of POM were investigated in the northwestern Ross Sea during the late austral summer in 2018. Carbohydrates (CHO) accounted for the highest portion among different biomolecules [CHO, proteins (PRT), and lipids (LIP)] of POM. However, the higher contribution of PRT and lower contribution of CHO were observed in the southern section of our study area compared to those in the northern section. The spatial distribution of total hydrolyzable AAs in POM was considerably influenced by phytoplankton biomass, which indicates that the main source of particulate AA was generated by phytoplankton. Our results showed that the relative contribution of EAA to the total AAs was strongly associated with EAA index (EAAI) for determining protein quality. This result indicates that higher EAA contribution in POM suggests a better protein quality in consistency with high EAAI values. In this study, variations in the biochemical compositions in POM were principally determined by two different bloom-forming taxa (diatoms and ). The southern region dominated majorly by diatoms was positively correlated with PRT, EAA, and EAAI indicating a good protein quality, while abundant northern region with higher CHO contribution was negatively correlated with good protein quality factors. Climate-driven environmental changes could alter not only the phytoplankton community but also the physiological conditions of phytoplankton. Our findings could provide a better understanding for future climate-induced changes in the biochemical compositions of phytoplankton and consequently their potential impacts on higher trophic levels.
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http://dx.doi.org/10.3389/fmicb.2021.623600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858670PMC
January 2021

Rapid Interference-free Analysis of β-Lapachone in Clinical Samples Using Liquid Chromatography-Mass Spectrometry for a Pharmacokinetic Study in Humans.

Anal Sci 2021 Aug 25;37(8):1105-1110. Epub 2020 Dec 25.

Department of Molecular Medicine, School of Medicine, Kyungpook National University and Department of Clinical Pharmacology, Kyungpook National University Hospital.

A rapid analytical method developed for the analysis of β-lapachone in in vitro samples could not be directly applied to the analysis of clinical samples because of interference from unknown substances. Here, we developed and validated a rapid interference-free analytical method to accurately determine β-lapachone levels in human plasma using liquid chromatography-tandem mass spectrometry. First, we achieved the baseline-separation of β-lapachone from any interfering substances within a total run time of 4 min by adjusting the eluent strength of the mobile phase. Second, precursor-ion scanning revealed the identity of the interfering substances. Sulfonate- or glucuronide-conjugated metabolites were converted to β-lapachone in an electrospray ion source, causing interference. In a method validation study, calibration curves for β-lapachone in human plasma were linear over a concentration range from 0.5 to 200 ng/mL (r > 0.999), and the lower limit of quantification was 0.5 ng/mL. The other validation parameters, including intra- and interday accuracy and precision, were acceptable with a coefficient of variation less than 10% (n = 5). The validated analytical method was successfully applied to a pharmacokinetic study of a single, oral dose of 100 mg MB12066 (a clinical form of β-lapachone) in healthy volunteers.
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http://dx.doi.org/10.2116/analsci.20P385DOI Listing
August 2021

Efficacy and Safety of Electroacupuncture for Insomnia Disorder: A Multicenter, Randomized, Assessor-Blinded, Controlled Trial.

Nat Sci Sleep 2020 10;12:1145-1159. Epub 2020 Dec 10.

Department of Acupuncture and Moxibustion Medicine, College of Korean Medicine, Sangji University, Wonju-si, Gangwon-do, Republic of Korea.

Purpose: To evaluate the efficacy and safety of electroacupuncture in treating insomnia.

Patients And Methods: In a multicenter, randomized, assessor-blinded, controlled trial, 150 patients with DSM-5-diagnosed insomnia with Insomnia Severity Index (ISI) scores ≥ 15 were randomly assigned to three different groups that underwent 10 sessions of electroacupuncture, sham-electroacupuncture, or usual care for 4 weeks from October 2015 to June 2016 at four Korean medicine hospitals, Republic of Korea. The primary outcome included the ISI score at Week 4; the secondary outcomes included evaluations of Pittsburgh Sleep Quality Index (PSQI), sleep diary, Hospital Anxiety and Depression Scale (HADS), EuroQoL five dimension (EQ-5D), Patient Global Impression of Change (PGIC), and salivary melatonin and cortisol levels. Assessments were performed at baseline (Week 0) and at Weeks 2, 4, 8, and 12.

Results: Compared with the usual care group, electroacupuncture group showed a greater improvement in ISI, PSQI, sleep diary-derived variables and HADS and EQ-5D scores at Week 4. The effects mostly persisted until Week 12. There were no significant differences between electroacupuncture and sham-electroacupuncture groups at Week 4 in all outcome measures, except sleep diary-derived sleep efficiency. However, the ISI score showed a significant difference between these groups at Weeks 8 and 12. Treatment success as per PGIC was significantly and borderline higher for electroacupuncture compared with usual care and sham-electroacupuncture, respectively. No significant changes in salivary melatonin and cortisol levels before and after treatment were observed in all groups. No serious adverse events were reported. Blinding was maintained in the sham-electroacupuncture group.

Conclusion: Ten sessions of electroacupuncture can improve the sleep quality of patients with insomnia without serious adverse effects. Thus, it can be recommended as an effective, safe, and well-tolerated intervention.
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http://dx.doi.org/10.2147/NSS.S281231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735782PMC
December 2020

The disubstituted adamantyl derivative LW1564 inhibits the growth of cancer cells by targeting mitochondrial respiration and reducing hypoxia-inducible factor (HIF)-1α accumulation.

Exp Mol Med 2020 11 25;52(11):1845-1856. Epub 2020 Nov 25.

College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Korea.

Targeting cancer metabolism has emerged as an important cancer therapeutic strategy. Here, we describe the synthesis and biological evaluation of a novel class of hypoxia-inducible factor (HIF)-1α inhibitors, disubstituted adamantyl derivatives. One such compound, LW1564, significantly suppressed HIF-1α accumulation and inhibited the growth of various cancer cell lines, including HepG2, A549, and HCT116. Measurements of the oxygen consumption rate (OCR) and ATP production rate revealed that LW1564 suppressed mitochondrial respiration, thereby increasing the intracellular oxygen concentration to stimulate HIF-1α degradation. LW1564 also significantly decreased overall ATP levels by inhibiting mitochondrial electron transport chain (ETC) complex I and downregulated mammalian target of rapamycin (mTOR) signaling by increasing the AMP/ATP ratio, which increased AMP-activated protein kinase (AMPK) phosphorylation. Consequently, LW1564 promoted the phosphorylation of acetyl-CoA carboxylase, which inhibited lipid synthesis. In addition, LW1564 significantly inhibited tumor growth in a HepG2 mouse xenograft model. Taken together, the results indicate that LW1564 inhibits the growth of cancer cells by targeting mitochondrial ETC complex I and impairing cancer cell metabolism. We, therefore, suggest that LW1564 may be a potent therapeutic agent for a subset of cancers that rely on oxidative phosphorylation for ATP generation.
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http://dx.doi.org/10.1038/s12276-020-00523-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080809PMC
November 2020

Outcomes of pediatric acute myeloid leukemia patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era.

Blood Res 2020 Dec;55(4):217-224

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea.

Background: Acute myeloid leukemia (AML) with internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with poor outcomes. This study aimed to analyze the outcomes of pediatric AML patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era.

Methods: We retrospectively reviewed and identified 18 patients diagnosed with non-M3 AML with FLT3-ITD mutations at Seoul National University Children's Hospital between May 2008 and August 2019.

Results: The median age was 13 years (range, 6?19 yr). The median follow-up time was 43 months (range, 6?157 mo). Fourteen patients received BH-AC-based (N4-Behenoy1-1-b-D-arabinofuranosy1cytosine) and 4 received cytarabine-based induction chemotherapy. Complete remission (CR) was achieved in 72.2% of the patients after the first induction chemotherapy and 80% of the patients achieved CR after salvage therapy. The overall CR rate was 94% (17/18 patients). These 17 patients underwent hematopoietic stem cell transplantation (9 matched unrelated donors, 5 matched related donors, and 3 haploidentical donors). Relapse occurred in 22% of the patients. Event free survival and overall survival rates were 53.8±12.1% and 53.6±12.1%, respectively, and they were not significantly different according to the type of induction chemotherapy (P=0.690) or the type of donor (P=0.102).

Conclusion: This study outlines the outcomes of pediatric AML patients with FLT3-ITD-mutations in one institution over a decade. Outcomes were significantly improved in this study compared to our previous report in 2004, where RFS and EFS were 0%. This study can provide baseline data for pediatric patients in the pre-FLT3 inhibitor era.
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http://dx.doi.org/10.5045/br.2020.2020127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784129PMC
December 2020

VGLL1 phosphorylation and activation promotes gastric cancer malignancy via TGF-β/ERK/RSK2 signaling.

Biochim Biophys Acta Mol Cell Res 2021 01 16;1868(1):118892. Epub 2020 Oct 16.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Republic of Korea; KRIBB School of Bioscience, University of Science and Technology, Daejeon, 34113, Republic of Korea; R&D Center, OneCureGEN Co., Ltd, Daejeon, 34141, Republic of Korea,. Electronic address:

We previously reported that vestigial-like 1 (VGLL1), a cofactor of transcriptional enhanced associate domain 4 (TEAD4), is transcriptionally regulated by PI3K and β-catenin signaling and is involved in gastric cancer malignancy. However, the precise mechanism underlying the regulation of VGLL1 activation remains unknown. Therefore, we aimed to investigate the molecular mechanism underlying the transforming growth factor-β (TGF-β)-mediated activation of VGLL1 and the VGLL1-TEAD4 interaction in gastric cancer cells. We showed that TGF-β enhanced VGLL1 phosphorylation and that this phosphorylated VGLL1 functioned as a transcription cofactor of TEAD4 in NUGC3 cells. TGF-β also increased the phosphorylation of ERK and ribosomal S6 kinase 2 (RSK2) in NUGC3 cells, thereby triggering the translocation of phosphorylated RSK2 to the nucleus. Site-directed mutagenesis and immunoprecipitation experiments revealed that RSK2 phosphorylated VGLL1 at S84 in the presence of TGF-β. Mutation of VGLL1 at S84 suppressed VGLL1-TEAD4 binding and the subsequent transcriptional activation of matrix metalloprotease 9 (MMP9). Moreover, VGLL1 peptide containing S84 suppressed the TGF-β-induced MMP9 expression and reduced the invasion and proliferation of gastric cancer cells, whereas VGLL1 peptide containing S84A did not. Furthermore, suppression of expression or activation of VGLL1 enhances the therapeutic effects of lapatinib. Collectively, these results indicate that VGLL1 phosphorylation via TGF-β/ERK/RSK2 signaling plays a crucial role in MMP9-mediated malignancy of gastric cancer. In addition, our study highlights the therapeutic potential of the peptide containing VGLL1 S84 for the treatment of gastric cancer.
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http://dx.doi.org/10.1016/j.bbamcr.2020.118892DOI Listing
January 2021

Treatment outcome and long-term follow-up of central nervous system germ cell tumor using upfront chemotherapy with subsequent photon or proton radiation therapy: a single tertiary center experience of 127 patients.

BMC Cancer 2020 Oct 9;20(1):979. Epub 2020 Oct 9.

Departments of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.

Background: Central nervous system germ cell tumors (CNS GCTs) are a heterogeneous group of brain tumors, which are more common in Asian countries. There have been different therapeutic strategies in treating germinoma and non-germinomatous germ cell tumors (NGGCT), depending on prognosis. Moreover, long-term follow up should be emphasized due to higher late complication rates. Here, we investigated long-term outcomes and complication profiles of 127 CNS GCT patients who received uniform upfront chemotherapy.

Methods: We retrospectively evaluated outcomes of CNS GCT patients treated in Seoul National University Children's Hospital from August 2004 to April 2019. Patients were classified as low risk (LR) or high risk (HR) based on pathologic diagnosis and tumor markers. Most patients received upfront systemic chemotherapy with carboplatin, cyclophosphamide, etoposide, and/or bleomycin, followed by either proton or photon radiation therapy according to patients' choice.

Results: The median age at diagnosis was 11.9 (range, 3.8-25.1) years, and 54.3% of patients were LR. Photon and proton radiation therapy were administered to 73.2 and 25.2% of patients, respectively. In both LR and HR groups, there were no significant differences in survival between photon and proton radiation therapy. The 10-year relapse incidences were 9.3 and 5.6% in the LR and HR groups, respectively. All recurrences, except one, were local relapse. Six secondary malignancies occurred; the 10-year incidences of secondary malignancy were 2.2 and 7.6% in the LR and HR groups, respectively. The 10-year overall survival rates were 98.3 ± 1.7 and 91.8 ± 3.9% in the LR and HR groups, respectively. In a subgroup analysis of HR group, pathologically diagnosed NGGCT patients (n = 20) showed worse 10-year EFS (65.9 ± 11.9%, p < 0.001) and OS (77.9 ± 9.8%, p = 0.024) rates compared to other HR patients who were not pathologically diagnosed or were confirmed as germinoma with elevated tumor markers. All mortalities were related to disease progression or secondary malignancy.

Conclusion: The strategy of treating CNS GCTs with upfront chemotherapy according to risk groups resulted in good clinical outcomes and acceptable relapse incidence. However, further modification in the definition of the HR group is needed to reduce long-term complications.
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http://dx.doi.org/10.1186/s12885-020-07484-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547441PMC
October 2020

Reconnecting Homeless Adolescents and Their Families: Correlates of Participation in a Family Intervention.

Prev Sci 2020 11;21(8):1048-1058

University of Southern California Suzanne Dworak-Peck School of Social Work, Los Angeles, CA, USA.

Behavioral family interventions are an effective way to intervene to prevent negative developmental outcomes for adolescents. Participation in family interventions encompasses behavioral and cognitive/attitudinal dimensions, among others, indicated by retention and engagement, respectively. Two dimensions of participation, retention and engagement, in a family intervention were examined in a sample of newly homeless adolescents and their parents or guardians. Correlates of participation included parents with more income and less perceived family conflict and adolescents with higher endorsement of depression, anxiety, somatization, obsessive-compulsive, phobic, and psychotic symptoms on the Brief Symptom Inventory (BSI). Stronger therapeutic alliance was correlated with being more distressed (i.e., lower income, more hostility), being a female adolescent participant, and having greater comfort discussing sex with parents. Furthermore, parents and adolescents with greater distress and thus greater need were more apt to finish the intervention. The finding that families who were experiencing more distress had higher alliance scores suggests that there is an additional need for development of interventions for families in crisis. Both participant and provider perceptions are also important in development of a strong therapeutic alliance. This study's findings have implications for further exploration of the development of cultural humility and improving mental health literacy among facilitators of behavioral interventions.
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http://dx.doi.org/10.1007/s11121-020-01157-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577401PMC
November 2020

Four-week repeated dose oral toxicity study of KDS2010, a novel selective monoamine oxidase B inhibitor, in Sprague Dawley rats.

Regul Toxicol Pharmacol 2020 Nov 3;117:104733. Epub 2020 Aug 3.

Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeonbuk, 56212, Republic of Korea. Electronic address:

Repeated dose oral toxicity and toxicokinetic of KDS2010, a new drug for Parkinson's disease, was investigated after 4-week repeated oral administration at 30, 50, 75, or 100 mg/kg/day in rats. Body weight and body weight gain decreased in rats of both sexes in the 75 and 100 mg/kg groups, and food consumption was reduced in male rats of the 75 and 100 mg/kg male groups. Histological alterations were observed in the kidney (urothelial hyperplasia, inflammatory cell infiltration in the renal pelvis, tubular vacuolation/degeneration, basophilic tubules, and hyaline droplets in the proximal tubules) of the 75 and 100 mg/kg male groups and the 50 and 100 mg/kg female groups. The 75 and 100 mg/kg male groups showed adverse effect in the testes (degeneration/exfoliation of germ cells, seminiferous tubules atrophy) and epididymis (cellular debris, oligospermia). These changes were partially recovered after a 2-week recovery period. However, basophilic tubules and hyaline droplets in the proximal tubules in the kidney and germ cell degeneration/exfoliation in the testis were not recovered. In toxicokinetics study, systemic exposure to KDS2010 increased proportionally in both sexes by in a dose -dependent manner. In addition, repeated administration for 4 weeks led to increased tendency of systemic exposure in both sexes compared with that in Day 1. In conclusion, KDS2010 was shown to target the kidney and testis with a no-observed-adverse-effect level of 50 and 30 mg/kg/day for males and females, respectively.
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http://dx.doi.org/10.1016/j.yrtph.2020.104733DOI Listing
November 2020

Four-week repeated dose oral toxicity study of KDS2010, a novel selective monoamine oxidase B inhibitor, in Sprague Dawley rats.

Regul Toxicol Pharmacol 2020 Nov 3;117:104733. Epub 2020 Aug 3.

Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeonbuk, 56212, Republic of Korea. Electronic address:

Repeated dose oral toxicity and toxicokinetic of KDS2010, a new drug for Parkinson's disease, was investigated after 4-week repeated oral administration at 30, 50, 75, or 100 mg/kg/day in rats. Body weight and body weight gain decreased in rats of both sexes in the 75 and 100 mg/kg groups, and food consumption was reduced in male rats of the 75 and 100 mg/kg male groups. Histological alterations were observed in the kidney (urothelial hyperplasia, inflammatory cell infiltration in the renal pelvis, tubular vacuolation/degeneration, basophilic tubules, and hyaline droplets in the proximal tubules) of the 75 and 100 mg/kg male groups and the 50 and 100 mg/kg female groups. The 75 and 100 mg/kg male groups showed adverse effect in the testes (degeneration/exfoliation of germ cells, seminiferous tubules atrophy) and epididymis (cellular debris, oligospermia). These changes were partially recovered after a 2-week recovery period. However, basophilic tubules and hyaline droplets in the proximal tubules in the kidney and germ cell degeneration/exfoliation in the testis were not recovered. In toxicokinetics study, systemic exposure to KDS2010 increased proportionally in both sexes by in a dose -dependent manner. In addition, repeated administration for 4 weeks led to increased tendency of systemic exposure in both sexes compared with that in Day 1. In conclusion, KDS2010 was shown to target the kidney and testis with a no-observed-adverse-effect level of 50 and 30 mg/kg/day for males and females, respectively.
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http://dx.doi.org/10.1016/j.yrtph.2020.104733DOI Listing
November 2020

Corrigendum to "Acupuncture using pattern-identification for the treatment of insomnia disorder: a systematic review and meta-analysis of randomized controlled trials" [Integr Med Res 8 (2019) 216-226].

Integr Med Res 2020 Jun 1;9(2):100420. Epub 2020 May 1.

Department of Neuropsychiatry of Korean Medicine, Collerge of Korean Medicine in Dong-Eui University, Busan, Republic of Korea.

[This corrects the article DOI: 10.1016/j.imr.2019.08.002.].
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http://dx.doi.org/10.1016/j.imr.2020.100420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327767PMC
June 2020

A longitudinal examination of African American adolescent females detained for status offense.

Child Youth Serv Rev 2020 Jan 28;108. Epub 2019 Nov 28.

School of Social Work, University of Toronto, 246 Bloor Street West, Toronto, ON M5S 1V4, Canada.

Introduction: Behaviors like truancy, running away, curfew violation, and alcohol possession fall under the status offense category and can have serious consequences for adolescents. The Juvenile Justice and Delinquency and Prevention Act prohibited detaining status offenders. We explored the degree to which African American adolescent girls were being detained for status offenses and the connections to their behavioral health risks and re-confinement.

Methods: 188 African American girls (aged 13-17), recruited from detention facilities, were surveyed at baseline and 3-month follow-ups. Logistic regression models estimated the likelihood of longitudinal re-confinement, controlling for sexual and behavioral health risk factors.

Results: One third of the overall sample was detained for a status offense. Status offenders were exposed to higher peer risk profiles. At follow-up, nearly 39% of status offenders reported re-confinement. Compared to youth with other offenses, those who violated a court order (type of status offense) were 3 times more likely to be re-confined. Controlling for sexual and behavioral health risk factors, the odds of re-confinement was not statistically significant.

Conclusion: Overall findings suggest that courts and detention facilities must devote specialized resources to addressing the socio-behavioral needs of African American girls with status offenses so as not to use detention as an intervention.
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http://dx.doi.org/10.1016/j.childyouth.2019.104648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304544PMC
January 2020

Identifying and predicting criminal career profiles from adolescence to age 39.

Crim Behav Ment Health 2020 Aug 2;30(4):210-220. Epub 2020 Jun 2.

Social Development Research Group, School of Social Work, University of Washington, Seattle, Washington, USA.

Few longitudinal studies are capable of identifying criminal career profiles using both self-report and official court data beyond the 30s. The current study aims to identify criminal career profiles across three developmental periods using self-report data, validate these profiles with official court records and determine early childhood predictors. Data came from the Seattle Social Development Project (n = 808). Latent Class Analysis was used to examine criminal careers from self-reported data during adolescence (aged 14-18), early adulthood (aged 21-27) and middle adulthood (aged 30-39). Official court records were used to validate the classes. Childhood risk and promotive factors measured at ages 11-12 were used to predict classes. Findings revealed four career classes: non-offending (35.6%), adolescence-limited (33.2%), adult desister (18.3%) and life-course/persistent (12.9%). Official court records are consistent with the description of the classes. Early life school and family environments as well as having antisocial beliefs and friends differentiate membership across the classes. The results of this study, with a gender-balanced and racially diverse sample, bolster the current criminal career knowledge by examining multiple developmental periods into the 30s using both self-report and official court data.
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http://dx.doi.org/10.1002/cbm.2156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704554PMC
August 2020

Miconazole inhibits signal transducer and activator of transcription 3 signaling by preventing its interaction with DNA damage-induced apoptosis suppressor.

Cancer Sci 2020 Jul 31;111(7):2499-2507. Epub 2020 May 31.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon, Korea.

DNA damage-induced apoptosis suppressor (DDIAS) facilitates the survival of lung cancer by suppressing apoptosis. Moreover, DDIAS promotes tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3) via their interaction. Here, we identified miconazole as an inhibitor of DDIAS/STAT3 interaction by screening a chemical library using a yeast two-hybrid assay. Miconazole inhibited growth, migration and invasion of lung cancer cells. Furthermore, miconazole suppressed STAT3 tyrosine Y705 phosphorylation and the expression of its target genes, such as cyclin D1, survivin and snail but had no suppressive effect on the activation of ERK1/2 or AKT, which is involved in the survival of lung cancer. As expected, no interaction between DDIAS and STAT3 occurred in the presence of miconazole, as confirmed by immunoprecipitation assays. Mouse xenograft experiments showed that miconazole significantly suppressed both tumor size and weight in an NCI-H1703 mouse model. Tyrosine phosphorylation of STAT3 at Y705 and expression of its targets, such as cyclin D1, survivin and snail, were decreased in miconazole-treated tumor tissues, as compared with those in vehicle-treated tumor tissues. These data suggest that miconazole exerts an anti-cancer effect by suppressing STAT3 activation through inhibiting DDIAS/STAT3 binding.
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http://dx.doi.org/10.1111/cas.14432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385363PMC
July 2020

Automated Assembly of Wafer-Scale 2D TMD Heterostructures of Arbitrary Layer Orientation and Stacking Sequence Using Water Dissoluble Salt Substrates.

Nano Lett 2020 May 23;20(5):3925-3934. Epub 2020 Apr 23.

NanoScience Technology Center, University of Central Florida, Orlando, Florida 32826, United States.

We report a novel strategy to assemble wafer-scale two-dimensional (2D) transition metal dichalcogenide (TMD) layers of well-defined components and orientations. We directly grew a variety of 2D TMD layers on "water-dissoluble" single-crystalline salt wafers and precisely delaminated them inside water in a chemically benign manner. This manufacturing strategy enables the automated integration of vertically aligned 2D TMD layers as well as 2D/2D heterolayers of arbitrary stacking orders on exotic substrates insensitive to their kind and shape. Furthermore, the original salt wafers can be recycled for additional growths, confirming high process sustainability and scalability. The generality and versatility of this approach have been demonstrated by developing proof-of-concept "all 2D" devices for diverse yet unconventional applications. This study is believed to shed a light on leveraging opportunities of 2D TMD layers toward achieving large-area mechanically reconfigurable devices of various form factors at the industrially demanded scale.
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http://dx.doi.org/10.1021/acs.nanolett.0c01089DOI Listing
May 2020

Combination Therapy With Chemotherapy, Donor Lymphocyte Infusion With Concurrent Blinatumomab in Relapsed/Refractory Acute Precursor B-Lymphoblastic Leukemia.

J Pediatr Hematol Oncol 2021 03;43(2):e280-e283

Department of Pediatrics, Seoul National University College of Medicine.

The therapeutic approach for relapsed/refractory acute lymphoblastic leukemia (ALL) remains to be a challenge. The patient was diagnosed as B-cell ALL at 6 months of age and relapsed for the second time following repeat allogeneic hematopoietic stem cell transplantation (one after first complete remission [CR1] and the other after CR2). During blinatumomab monotherapy, he developed an extramedullary relapse. Finally, the combined therapy with clofarabine, donor lymphocyte infusion, and blinatumomab induced CR of the bone marrow and extramedullary relapse. Unfortunately, the patient developed central nervous system relapse, however, this case showed a promising potential for combination therapy with clofarabine, donor lymphocyte infusion, and blinatumomab in relapsed/refractory B-cell ALL.
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http://dx.doi.org/10.1097/MPH.0000000000001789DOI Listing
March 2021

Fermented ginseng extract, BST204, disturbs adipogenesis of mesenchymal stem cells through inhibition of S6 kinase 1 signaling.

J Ginseng Res 2020 Jan 8;44(1):58-66. Epub 2018 Aug 8.

School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.

Background: The biological and pharmacological effects of BST204, a fermented ginseng extract, have been reported in various disease conditions. However, its molecular action in metabolic disease remains poorly understood. In this study, we identified the antiadipogenic activity of BST204 resulting from its inhibition of the S6 kinase 1 (S6K1) signaling pathway.

Methods: The inhibitory effects of BST204 on S6K1 signaling were investigated by immunoblot, nuclear fractionation, immunoprecipitation analyses. The antiadipogenic effect of BST204 was evaluated by measuring mRNA levels of adipogenic genes and by chromatin immunoprecipitation and quantitative real-time polymerase chain reaction analysis.

Results: Treatment with BST204 inhibited activation and nuclear translocation of S6K1, further decreasing the interaction between S6K1 and histone H2B in 10T1/2 mesenchymal stem cells. Subsequently, phosphorylation of H2B at serine 36 (H2BS36p) by S6K1 was reduced by BST204, inducing an increase in the mRNA expression of , , and , which disturbed adipogenic differentiation and promoted myogenic and early osteogenic gene expression. Consistently, BST204 treatment during adipogenic commitment suppressed the expression of adipogenic marker genes and lipid drop formation.

Conclusion: Our results indicate that BST204 blocks adipogenesis of mesenchymal stem cells through the inhibition of S6K1-mediated histone phosphorylation. This study suggests the potential therapeutic strategy using BST204 to combat obesity and musculoskeletal diseases.
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http://dx.doi.org/10.1016/j.jgr.2018.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033330PMC
January 2020

Electroacupuncture for treatment-resistant insomnia: study protocol for a randomised, controlled, assessor-blinded, pilot clinical trial.

BMJ Open 2020 02 26;10(2):e034239. Epub 2020 Feb 26.

Department of Neuropsychiatry, School of Korean Medicine, Pusan National University, Yangsan-si, Gyeongsanganm-do, Korea (the Republic of)

Introduction: A considerable number of insomnia patients experience sleep disturbance even with long-term use of hypnotic medication. Previous studies have indicated that electroacupuncture (EA) could be an efficacious treatment for managing insomnia. However, few trials have been conducted to evaluate the effectiveness and safety of EA for treatment-resistant insomnia. This pilot study aims to explore the feasibility and preliminary effectiveness and safety of EA as an adjunct treatment for treatment-resistant insomnia.

Methods And Analysis: This is a multicentre, randomised, usual care controlled and assessor-blinded pilot study protocol. Fifty patients presenting with sleep problems who have been taking hypnotic medication for more than 3 months will be randomly allocated to either an EA group or a usual care group at a 1:1 ratio. The EA group will undergo 12 EA treatment sessions twice a week for 6 weeks whereas the usual care group will not receive EA treatment. All the participants will receive a brochure containing educational information on sleep hygiene. The primary outcome will be the measured mean change of the total score of the Insomnia Severity Index from the baseline to week 7. The secondary outcome regarding sleep quality will be measured using the Pittsburgh Sleep Quality Index, a sleep diary and actigraphy. Moreover, we will assess the quality of life, the direct and indirect cost of treating insomnia for economic evaluation. After 4 weeks, the subjects will visit the research sites for a follow-up assessment.

Ethics And Dissemination: Ethical approval of this study protocol was established by the institutional review boards of the each involved study site. All potential subjects will be provided written informed consent. The results of this study will be accessible in peer-reviewed publications and be presented at academic conference.

Trial Registration Number: KCT0003235.
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http://dx.doi.org/10.1136/bmjopen-2019-034239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202710PMC
February 2020

A Remnant Choledochal Cyst after Choledochal Cyst Excision Treated with a Lumen-Apposing Metal Stent: A Case Report.

Clin Endosc 2020 Jan 8. Epub 2020 Jan 8.

Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

A lumen-apposing metal stent (LAMS) is a saddle-shaped stent with large flanges at both ends, thereby preventing stent migration and helping with approximation of the adjacent structures. We report the case of a 25-year-old female with remnant choledochal cyst which was successfully treated with LAMS after initial treatment failure with a plastic stent. Although complete excision of the cyst is the definite treatment of choledochal cysts, endoscopic ultrasonography-guided cystoduodenostomy can be considered in cases wherein surgery is not feasible and dysplasia is not present. LAMS may be preferred to plastic stents for effective resolution of remnant choledochal cyst and prevention of ascending infection.
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http://dx.doi.org/10.5946/ce.2019.176DOI Listing
January 2020

DDIAS promotes STAT3 activation by preventing STAT3 recruitment to PTPRM in lung cancer cells.

Oncogenesis 2020 Jan 2;9(1). Epub 2020 Jan 2.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Korea.

DNA damage-induced apoptosis suppressor (DDIAS) regulates cancer cell survival. Here we investigated the involvement of DDIAS in IL-6-mediated signaling to understand the mechanism underlying the role of DDIAS in lung cancer malignancy. We showed that DDIAS promotes tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is constitutively activated in malignant cancers. Interestingly, siRNA protein tyrosine phosphatase (PTP) library screening revealed protein tyrosine phosphatase receptor mu (PTPRM) as a novel STAT3 PTP. PTPRM knockdown rescued the DDIAS-knockdown-mediated decrease in STAT3 Y705 phosphorylation in the presence of IL-6. However, PTPRM overexpression decreased STAT3 Y705 phosphorylation. Moreover, endogenous PTPRM interacted with endogenous STAT3 for dephosphorylation at Y705 following IL-6 treatment. As expected, PTPRM bound to wild-type STAT3 but not the STAT3 Y705F mutant. PTPRM dephosphorylated STAT3 in the absence of DDIAS, suggesting that DDIAS hampers PTPRM/STAT3 interaction. In fact, DDIAS bound to the STAT3 transactivation domain (TAD), which competes with PTPRM to recruit STAT3 for dephosphorylation. Thus we show that DDIAS prevents PTPRM/STAT3 binding and blocks STAT3 Y705 dephosphorylation, thereby sustaining STAT3 activation in lung cancer. DDIAS expression strongly correlates with STAT3 phosphorylation in human lung cancer cell lines and tissues. Thus DDIAS may be considered as a potential biomarker and therapeutic target in malignant lung cancer cells with aberrant STAT3 activation.
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http://dx.doi.org/10.1038/s41389-019-0187-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949220PMC
January 2020
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