Charged multivesicular body protein 5 (CHMP5) has a key role in multivesicular body biogenesis and a critical role in the downregulation of signaling pathways through receptor degradation. However, the role of CHMP5 in T-cell receptor (TCR)-mediated signaling has not been previously investigated. In this study, we utilized a short hairpin RNA-based RNA interference approach to investigate the functional role of CHMP5. Upon TCR stimulation, CHMP5-knockdown (CHMP5(KD)) Jurkat T cells exhibited activation of TCR downstream signaling molecules, such as PKCθ and IKKαβ, and resulted in the activation of nuclear factor-κB and the marked upregulation of TCR-induced gene expression. Moreover, we found that activator protein-1 and nuclear factor of activated T-cells transcriptional factors were markedly activated in CHMP5(KD) Jurkat cells in response to TCR stimulation, which led to a significant increase in interleukin-2 secretion. Biochemical studies revealed that CHMP5 endogenously forms high-molecular-weight complexes, including TCR molecules, and specifically interacts with TCRβ. Interestingly, flow cytometry analysis also revealed that CHMP5(KD) Jurkat T cells exhibit upregulation of TCR expression on the cell surface compared with control Jurkat T cells. Taken together, these findings demonstrated that CHMP5 might be involved in the homeostatic regulation of TCR on the cell surface, presumably through TCR recycling or degradation. Thus CHMP5 is implicated in TCR-mediated signaling.
Down-Regulation ; Flow Cytometry ; Gene Expression ; Humans ; Interleukin-2 ; Jurkat Cells ; Multivesicular Bodies ; Receptors, Antigen, T-Cell* ; Recycling ; RNA Interference ; T-Lymphocytes* ; Transcription Factor AP-1 ; Up-Regulation

Neutrophils and eosinophils, 2 prominent granulocytes, are commonly derived from myelocytic progenitors through successive stages in the bone marrow. Our previous genome-wide transcriptomic data unexpectedly showed that genes encoding a multitude of neutrophil primary granule proteins (NPGPs) were markedly downregulated during the end period of eosinophilic terminal differentiation when cord blood (CB) cluster of differentiation (CD) 34+ cells were induced to differentiate toward the eosinophil lineage during a 24-day culture period. Accordingly, this study aimed to examine whether NPGP genes were expressed on the way to eosinophil terminal differentiation stage and to compare their expression kinetics with that of genes encoding eosinophil-specific granule proteins (ESGPs). Transcripts of all NPGP genes examined, including proteinase 3, myeloperoxidase, cathepsin G (CTSG), and neutrophil elastase, reached a peak at day 12 and sharply declined thereafter, while transcript of ESGP genes including major basic protein 1 (MBP1) attained maximum expression at days 18 or 24. Growth factor independent 1 (GFI1) and CCAAT/enhancer-binding protein α (C/EBPA), transactivators for the NPGP genes, were expressed immediately before the NPGP genes, whereas expression of C/EBPA, GATA1, and GATA2 kinetically paralleled that of eosinophil granule protein genes. The expression kinetics of NPGPs and ESGPs were duplicated upon differentiation of the eosinophilic leukemia cell line (EoL-1) immature eosinophilic cells. Importantly, confocal image analysis showed that CTSG was strongly coexpressed with MBP1 in differentiating CB eosinophils at days 12 and 18 and became barely detectable at day 24 and beyond. Our results suggest for the first time the presence of an immature stage where eosinophils coexpress NPGPs and ESGPs before final maturation.
Bone Marrow ; Cathepsin G ; Cell Line ; Eosinophils* ; Fetal Blood ; Granulocytes ; Hypereosinophilic Syndrome ; Kinetics ; Leukocyte Elastase ; Myeloblastin ; Neutrophils* ; Peroxidase ; Trans-Activators

BACKGROUND AND OBJECTIVES: The recurrence rate of patients with Graves' disease (GD) is estimated to be 50-55% after withdrawal of antithyroid drug therapy, and relapse is frequent in the first year after discontinuing the medication. Follow-up examination of these patients frequently reveals laboratory findings consistent with subclinical thyrotoxicosis in the first year after stopping the antithyroid agents. We investigated the risk of recurrence of GD among patients with resurfacing subclinical thyrotoxicosis state after remission of initial GD with antithyroid treatments. MATERIALS AND METHODS: We reviewed the patients diagnosed with GD who visited the Department of Endocrinology at two tertiary medical centers: Wonju Severance Christian Hospital and Gangneung Asan Hospital. We enrolled patients whose GD was completely treated after initial treatment with antithyroid agents who then developed subclinical thyrotoxicosis after discontinuation of antithyroid agents. RESULTS: We reviewed a total of 44 patients (29 females, 15 males; age, 48.93±18.04; range, 17-85 years). The recurrence rate was 27.3% (12/44 patients), and recurrence occurred 3 months to 12 months later resurfacing of subclinical thyrotoxicosis. Patients with recurred GD was significantly older than non-recurred patients (44.63±17.75 years vs. 58.58±15.48 years, p=0.02). Other clinical parameters measured at the time of initial diagnosis were not different between the two groups. CONCLUSION: The recurrence rate of GD in patients with resurfacing subclinical thyrotoxicosis after initial remission of the disease was less than 30%. A close monitoring is recommended in these subgroup patients, especially in older patients.
Antithyroid Agents* ; Chungcheongnam-do ; Diagnosis ; Drug Therapy ; Endocrinology ; Female ; Follow-Up Studies ; Gangwon-do ; Graves Disease* ; Humans ; Male ; Recurrence* ; Thyrotoxicosis*

Peroxiredoxin-3 (Prdx3) is a mitochondrial protein of the thioredoxin family of antioxidant peroxidases and is the principal peroxidase responsible for metabolizing mitochondrial hydrogen peroxide. Recent reports have shown that mitochondrial reactive oxygen species (mROS) contribute to macrophage-mediated bactericidal activity in response to Toll-like receptors. Herein, we investigated the functional effect of Prdx3 in bactericidal activity. The mitochondrial localization of Prdx3 in HEK293T cells was confirmed by cell fractionation and confocal microscopy analyses. To investigate the functional role of Prdx3 in bactericidal activity, Prdx3-knockdown (Prdx3(KD)) THP-1 cells were generated. The mROS levels in Prdx3(KD) THP-1 cells were significantly higher than those in control THP-1 cells. Moreover, the mROS levels were markedly increased in response to lipopolysaccharide. Notably, the Salmonella enterica serovar Typhimurium infection assay revealed that the Prdx3(KD) THP-1 cells were significantly resistant to S. Typhimurium infection, as compared with control THP-1 cells. Taken together, these results indicate that Prdx3 is functionally important in bactericidal activity through the regulation of mROS.
Cell Fractionation ; Humans ; Hydrogen Peroxide ; Lipopolysaccharides ; Microscopy, Confocal ; Mitochondrial Proteins ; Peroxidase ; Peroxidases ; Reactive Oxygen Species* ; Salmonella enterica ; Serogroup ; Thioredoxins ; Toll-Like Receptors

Purpose: : This study aimed to identify intensive care units (ICU) nurses’ experience of traumatic events, deliberate rumination, self-disclosure, social support, and post-traumatic growth (PTG), and to explore relationships among the variables. Methods: : Participants were 157 nurses who have provided direct patient care for six months or more in ICUs at a university hospital. Collected data were analyzed using descriptive statistics, independent t-tests, one-way ANOVAs, Pearson correlations, and multiple linear regressions using the SPSS/WIN version 23.0. Results: : The PTG was found to be significantly associated with deliberate rumination (r=0.36, p<.001), self-disclosure (r=0.39, p<.001), and social support (r=0.54, p<.001). Factors that affect PTG significantly were found in the order of social support (β=0.40, p<.001), self-disclosure (β=0.25, p<.001), and deliberate rumination (β=0.24, p<.001). The final regression model explained 40.1% of the variance of PTG (F=26.33, p<.001). Conclusion : The influencing factors identified in this study on PTG, including social support, self-disclosure, and deliberate rumination should be included in programs to promote PTG for ICU nurses who may experience traumatic events repeatedly.

Diabetic ketoacidosis (DKA) is a medically fatal condition in poorly controlled hyperglycemia or newly diagnosed diabetes mellitus. Severe hypertriglyceridemia (HTG) is an uncommon complication of DKA and can be associated with acute pancreatitis (AP). We present the clinical manifestations, laboratory findings, and management of AP associated with HTG in a 14-year-old girl with DKA. The patient, with a 7-year history of type 2 diabetes presented with epigastric pain, 1 month after stopping insulin injection. DKA, severe HTG, and AP were diagnosed based on the laboratory and imaging tests. She recovered from DKA after conventional treatment for DKA, and her triglyceride (TG) level was reduced from 10,867 mg/dL to the normal range after 7 days of admission without antilipid medication. Given that her C-peptide level was not too low and considering her negative diabetes-related antibodies and high TG level, targeted gene panel sequencing was performed on the genes associated with diabetes and HTG. We identified a heterozygous mutation, c.4607C>T (p. Ala1537Val), in ABCC8 related to maturityonset diabetes of the young (MODY) 12. To our knowledge, this is the first reported case of HTG-induced AP with DKA in a patient with MODY. In addition, we reviewed the literature for pediatric cases of HTG with DKA. In patients with DKA, timely awareness of severe HTG related to insulin deficiency is crucial for improving the consequences of AP. We recommend considering AP in all DKA patients presenting with severe HTG to ensure early and proper management.

Ovarian leiomyoma is a rare mesenchymal tumor, accounting for only 1% of all benign ovarian neoplasm. Most patients are asymptomatic and the tumors are usually found incidentally during operation or at autopsies. Ovarian adenofibroma is a rare benign tumor which originates from the germinal lining and the stroma of the ovary. This tumor may be solid, semisolid or cystic, depending on the relative amount of the epithelial and stromal component. We have experienced a case of ovarian leiomyoma accompanied with ovarian serous adenofibroma in a 42-year-old woman and report this case with a brief review of literature.
Adenofibroma* ; Adult ; Autopsy ; Female ; Humans ; Leiomyoma* ; Ovarian Neoplasms ; Ovary

Wilson disease (WD) is a relatively common genetic hepatic disease in children and is characterized by excessive copper accumulation, predominantly in the liver and brain. It is an autosomal recessive disease caused by an ATP7B mutation that causes brain degeneration and is potentially fatal if diagnosed late or untreated. In the early phase of WD, its initial presentation may include mild hepatic involvement. WD may be overlooked as a cause of liver disease due to severe obesity but should not be excluded from differential diagnosis. We report a case of WD with severe obesity and fatty liver diagnosed in the early phase by targeted gene panel sequencing and review the endocrine problems associated with WD. Early suspicion of WD is important for good prognosis.

PURPOSE: OPB-31121 is an oral STAT3 inhibitor with a good preclinical antitumor activity. This phase I dose-escalation study of OPB-31121 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors. MATERIALS AND METHODS: Patients received OPB-31121 once daily for 28 days of each cycle followed by 2 weeks rest. A standard 3+3 design was used for dose-escalation. Safety and response were evaluated by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) ver. 3.0 and Response Evaluation Criteria in Solid Tumor (RECIST) ver. 1.0, respectively. RESULTS: Twenty-five patients were treated with OPB-31121 at five dose levels: 100 mg (n=4), 200 mg (n=3), 400 mg (n=3), 600 mg (n=7), and 800 mg (n=8). Seven patients discontinued treatment during cycle 1 for various reasons other than study drug-related adverse events. Among 18 patients who were evaluable for dose-limiting toxicity (DLT), three DLTs were observed: one DLT (grade 3 vomiting) at 600 mg and two DLTs (grade 3 vomiting, grade 3 diarrhea) at 800 mg. The MTD was determined as 800 mg/day. Common adverse events were gastrointestinal adverse event including nausea (84%), vomiting (80%), and diarrhea (72%). Pharmacokinetics did not demonstrate dose-proportionality of OPB-31121. Eight patients had stable disease and 10 patients had disease progression. Two patients (1 colon cancer, 1 rectal cancer) showed tumor shrinkage. One gastric cancer patient continued treatment up to cycle 13 before disease progression. CONCLUSION: This study demonstrates feasibility of STAT3 inhibition in patients with advanced solid tumor. OPB-31121, at the MTD of 800 mg/day, was safe and relatively well tolerated, and has a preliminary antitumor activity.
Colonic Neoplasms ; Diarrhea ; Disease Progression ; Humans ; Nausea ; Pharmacokinetics ; Stomach Neoplasms ; Vomiting