BACKGROUND: Exosomes from mesenchymal stem cells (MSCs) show anti-inflammatory effect on osteoarthritis (OA); however, their biological effect and mechanism are not yet clearly understood. This study investigated the anti-inflammatory effect and mechanism of MSC-derived exosomes (MSC-Exo) primed with IL-1β in osteoarthritic SW982 cells. METHODS: SW982 cells were treated with interleukin (IL)-1β and tumor necrosis factor (TNF)-α to induce the OA phenotype. The effect of exosomes without priming (MSC-Exo) or with IL-1β priming (MSC-IL-Exo) was examined on the expression of pro- or anti-inflammatory factors, and the amount of IκBα was examined in SW982 cells. Exosomes were treated with RNase to remove RNA. The role of miR-147b was examined using a mimic and an inhibitor. RESULTS: MSC-IL-Exo showed stronger inhibitory effects on the expression of pro-inflammatory cytokines (IL-1β, IL-6, and monocyte chemoattractant protein-1) than MSC-Exo. The expression of anti-inflammatory factors (SOCS3 and SOCS6) was enhanced by MSCs-IL-Exo. Priming with IL-1β increased RNA content in MSC-IL-Exo, and pretreatment with RNase abolished anti-inflammatory effect in SW982 cells. miR-147b was found in much larger amounts in MSC-IL-Exo than in MSC-Exo. The miR-147b mimic significantly inhibited the expression of inflammatory cytokines, while the miR-147b inhibitor only partially blocked the anti-inflammatory effect of MSC-IL-Exo. MSC-IL-Exo and miR-147b mimic inhibited the reduction of IκBα, an nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor, by IL-1β and TNF-α. CONCLUSION This study showed that MSC exosomes with IL-1β priming exhibit significantly enhanced anti-inflammatory activity in osteoarthritic SW982 cells. The effect of IL-1β-primed MSC exosomes is mediated by miRNAs such as miR-147b and involves inhibition of the NF-κB pathway.

BACKGROUND: Exosomes from mesenchymal stem cells (MSCs) show anti-inflammatory effect on osteoarthritis (OA); however, their biological effect and mechanism are not yet clearly understood. This study investigated the anti-inflammatory effect and mechanism of MSC-derived exosomes (MSC-Exo) primed with IL-1β in osteoarthritic SW982 cells. METHODS: SW982 cells were treated with interleukin (IL)-1β and tumor necrosis factor (TNF)-α to induce the OA phenotype. The effect of exosomes without priming (MSC-Exo) or with IL-1β priming (MSC-IL-Exo) was examined on the expression of pro- or anti-inflammatory factors, and the amount of IκBα was examined in SW982 cells. Exosomes were treated with RNase to remove RNA. The role of miR-147b was examined using a mimic and an inhibitor. RESULTS: MSC-IL-Exo showed stronger inhibitory effects on the expression of pro-inflammatory cytokines (IL-1β, IL-6, and monocyte chemoattractant protein-1) than MSC-Exo. The expression of anti-inflammatory factors (SOCS3 and SOCS6) was enhanced by MSCs-IL-Exo. Priming with IL-1β increased RNA content in MSC-IL-Exo, and pretreatment with RNase abolished anti-inflammatory effect in SW982 cells. miR-147b was found in much larger amounts in MSC-IL-Exo than in MSC-Exo. The miR-147b mimic significantly inhibited the expression of inflammatory cytokines, while the miR-147b inhibitor only partially blocked the anti-inflammatory effect of MSC-IL-Exo. MSC-IL-Exo and miR-147b mimic inhibited the reduction of IκBα, an nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor, by IL-1β and TNF-α. CONCLUSION This study showed that MSC exosomes with IL-1β priming exhibit significantly enhanced anti-inflammatory activity in osteoarthritic SW982 cells. The effect of IL-1β-primed MSC exosomes is mediated by miRNAs such as miR-147b and involves inhibition of the NF-κB pathway.

BACKGROUND: Thyrotoxic periodic paralysis (TPP) is a rare complication of thyrotoxicosis characterized by acute attacks of muscle weakness and hypokalemia. Recently, variation in several genes was suggested to be associated with TPP. This study evaluated the genetic predisposition to TPP in terms of the β2-adrenergic receptor (ADRB2), androgen receptor (AR), and γ-aminobutyric acid receptor α3 subunit (GABRA3) genes. METHODS: This study enrolled 48 men with Graves disease (GD) and TPP, and 48 GD patients without TPP. We compared the frequencies of candidate polymorphisms between the two groups. RESULTS: The frequency of the Gly16/Gly16 genotype in ADRB2 was not significantly associated with TPP (P=0.32). More CAG repeats (≥26) in the AR gene were not correlated with TPP (odds ratio [OR], 2.46; 95% confidence interval [CI], 0.81 to 8.09; P=0.08). The allele frequency of the TT genotype in the GABRA3 gene was not associated with TPP (OR, 1.83; 95% CI, 0.54 to 6.74; P=0.41). CONCLUSION: The polymorphisms in the ADRB2, AR, and GABRA3 genes could not explain the genetic susceptibility to TPP in Korean men with GD.
Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Graves Disease* ; Humans ; Hypokalemia ; Male ; Muscle Weakness ; Paralysis* ; Receptors, Androgen ; Thyrotoxicosis

BACKGROUND AND OBJECTIVES: The relationship between Hashimoto thyroiditis (HT) and papillary thyroid cancer (PTC) is still controversial. Some studies suggested that molecular basis of the association between HT and PTC. BRAF(V600E) mutation is the most common genetic alteration founded in PTC. This study was to determine a role of BRAF(V600E) mutation in PTC with concurrent HT and their association with other clinicopathological factors. MATERIALS AND METHODS: We enrolled 452 patients who underwent thyroid surgery between 2009 and 2012 for classical PTC. The status of BRAF(V600E) mutation was evaluated by direct sequencing. HT was defined as presence of lymphocytic thyroiditis in pathology or positive serum anti-thyroid peroxidase antibody. RESULTS: Total 139 patients (30%) with PTC had coexistence HT. HT was significantly associated female (p=0.006), and younger age (p=0.045). BRAF(V600E) mutation was confirmed in 264 patients (58%). The frequency of BRAF(V600E) mutation was significantly lower in PTC with coexistence HT (48.2%) compared by PTC without HT (62.9%, p=0.004). However, there was no significant difference in clinicopathological feature of PTC according to the presence of HT in patients with BRAF(V600E) mutated PTC. BRAF(V600E) mutation was less frequent in PTC with coexistence HT. CONCLUSION: These findings suggested that HT and BRAF(V600E) mutation might be independent factors in development and progression of PTC.
Female ; Hashimoto Disease* ; Humans ; Pathology ; Peroxidase ; Thyroid Gland ; Thyroid Neoplasms ; Thyroiditis, Autoimmune

BACKGROUND: Mass production of exosomes is a prerequisite for their commercial utilization. This study investigated whether three-dimensional (3D) spheroid culture of mesenchymal stem cells (MSCs) could improve the production efficiency of exosomes and if so, what was the mechanism involved. METHODS: We adopted two models of 3D spheroid culture using the hanging-drop (3D-HD) and poly(2-hydroxyethyl methacrylate) (poly-HEMA) coating methods (3D-PH). The efficiency of exosome production from MSCs in the 3D spheroids was compared with that of monolayer culture in various conditions. We then investigated the mechanism of the 3D spheroid culture-induced increase in exosome production. RESULTS: The 3D-HD formed a single larger spheroid, while the 3D-PH formed multiple smaller ones. However, MSCs cultured on both types of spheroids produced significantly more exosomes than those cultured in conventional monolayer culture (2D). We then investigated the cause of the increased exosome production in terms of hypoxia within the 3D spheroids, high cell density, and non-adherent cell morphology. With increasing spheroid size, the efficiency of exosome production was the largest with the least amount of cells in both 3D-HD and 3D-PH. An increase in cell density in 2D culture (2D-H) was less efficient in exosome production than the conventional, lower cell density, 2D culture. Finally, when cells were plated at normal density on the poly-HEMA coated spheroids (3D-N-PH); they formed small aggregates of less than 10 cells and still produced more exosomes than those in the 2D culture when plated at the same density. We also found that the expression of F-actin was markedly reduced in the 3D-N-PH culture. CONCLUSION: These results suggested that 3D spheroid culture produces more exosomes than 2D culture and the non-adherent round cell morphology itself might be a causative factor. The result of the present study could provide useful information to develop an optimal process for the mass production of exosomes.
Actins ; Anoxia ; Cell Count ; Exosomes ; Mesenchymal Stromal Cells* ; Polyhydroxyethyl Methacrylate

PURPOSE: Parathyroid adenoma detection with dual-phase (99m)Tc-sestamibi (MIBI) scintigraphy depends on differential MIBI washout from thyroid. However, autoimmune thyroid disease (AITD) may cause MIBI to be retained in the thyroid gland and reduce parathyroid detection.We evaluated the impact of AITD on MIBI thyroid retention and additional benefit of SPECT/CT in these patients.METHODS: Dual phase planar MIBI and SPECT/CT was performed on 82 patients. SPECT/CTwas performed immediatelyafter delayed planar scan. Thyroid density (Hounsfield unit, CT-HU) and size were measured on CT component of SPECT/CT. MIBI uptake in early scans and retention in delayed scans were visually graded and correlated with clinical factors and CT findings. Finally, planar and SPECT/CT findings were compared for parathyroid lesion visualization according to thyroid MIBI retention.RESULTS: In early scan, multivariate analysis showed only thyroid size predicted early uptake. In delayed scan, multivariate analysis showed higher visual grade in early scan, lower CTHU or AITD were significant predictors for delayed thyroid parenchymal retention. Overall, ten more parathyroid lesions were visualized on SPECT/CT compared to planar scans (57 vs. 47, p = 0.002). SPECT/CT was especially more useful in patients with thyroidal MIBI retention, as eight out of the ten additional lesions detected were found in patients with thyroid MIBI retention.CONCLUSION: AITD is an important factor for MIBI thyroid parenchymal retention on delayed scans, and may impede parathyroid lesion detection. Patients with MIBI retention in the thyroid parenchyma on delayed scans are likely to benefit from an additional SPECT/CT.
Humans ; Multivariate Analysis ; Parathyroid Neoplasms ; Radionuclide Imaging ; Thyroid Diseases ; Thyroid Gland

Purpose: We aimed to compare different reference regions and select one with the most clinical relevance on C11-acetate (ACE) positron emission tomography/computed tomography (PET/CT) in patients with cerebral glioma. Methods: We retrospectively reviewed 51 patients with cerebral glioma who underwent baseline ACE PET/CT at diagnosis.Other than the standardized uptake value (SUV) of the primary tumor, SUVs of the reference regions including the normal gray matter, white matter, choroid plexus, and cerebellum were measured. Then, the SUV ratio (SUVR = tumor SUV max /reference region SUV mean ) was calculated. The effect of patient age on the SUV mean of each reference was examined and the SUVRs of each reference region were compared between grades. age, sex, tumor size, histological grades, SUVR , and the presence of isocitrate dehydrogenase (IDH) mutation were included for survival analyses. Results: Except for the cerebellum showing a mild negative correlation, we found no correlations between age and SUV mean using the gray matter, white matter, and choroid plexus (r = − 0.280, P < = 0.047). Only the SUVR -choroid plexus was able to differentiate between the WHO grades (Grade II vs. III, P < = 0.035; grade III vs. IV, P < < 0.001; grade II vs. IV, P < 0.001). Multivariate Cox proportional hazards models found that the SUVR-choroid plexus and IDH mutation were statistically significant for predicting OS. Conclusion Of the different reference regions used for grading cerebral gliomas, the choroid plexus was found to be the most optimal.In addition, the SUV ratio is useful to predict the overall survival in the model with the choroid plexus as a reference region.

BACKGROUND: Hyperthyroidism relapse in Graves disease after antithyroid drug (ATD) withdrawal is common; however, measuring the thyrotropin receptor antibody (TRAb) at ATD withdrawal in order to predict outcomes is controversial. This study compared measurement of thyroid stimulatory antibody (TSAb) and thyrotropin-binding inhibitory immunoglobulin (TBII) at ATD withdrawal to predict relapse. METHODS: This retrospective study enrolled patients with Graves disease who were treated with ATDs and whose serum thyroid-stimulating hormone levels were normal after receiving low-dose ATDs. ATD therapy was stopped irrespective of TRAb positivity after an additional 6 months of receiving the minimum dose of ATD therapy. Patients were followed using thyroid function tests and TSAb (TSAb group; n=35) or TBII (TBII group; n=39) every 3 to 6 months for 2 years after ATD withdrawal. RESULTS: Twenty-eight patients (38%) relapsed for a median follow-up of 21 months, and there were no differences in baseline clinical characteristics between groups. In the TSAb group, relapse was more common in patients with positive TSAb at ATD withdrawal (67%) than patients with negative TSAb (17%; P=0.007). Relapse-free survival was shorter in TSAb-positive patients. In the TBII group, there were no differences in the relapse rate and relapse-free survivals according to TBII positivity. For predicting Graves disease relapse, the sensitivity and specificity of TSAb were 63% and 83%, respectively, whereas those of TBII were 28% and 65%. CONCLUSION: TSAb at ATD withdrawal can predict the relapse of Graves hyperthyroidism, but TBII cannot. Measuring TSAb at ATD withdrawal can assist with clinical decisions making for patients with Graves disease.
Follow-Up Studies ; Graves Disease* ; Humans ; Hyperthyroidism ; Immunoglobulins ; Immunoglobulins, Thyroid-Stimulating* ; Prognosis ; Receptors, Thyrotropin ; Recurrence* ; Retrospective Studies ; Sensitivity and Specificity ; Thyroid Function Tests ; Thyroid Gland* ; Thyrotropin

BACKGROUND/AIMS: The diagnostic accuracy of thyroid dysfunctions is primarily affected by the validity of the reference interval for serum thyroid-stimulating hormone (TSH). Thus, the present study aimed to establish a reference interval for TSH using a normal Korean population. METHODS: This study included 19,465 subjects who were recruited after undergoing routine health check-ups. Subjects with overt thyroid disease, a prior history of thyroid disease, or a family history of thyroid cancer were excluded from the present analyses. The reference range for serum TSH was evaluated in a normal Korean reference population which was defined according to criteria based on the guidelines of the National Academy of Clinical Biochemistry, ultrasound (US) findings, and smoking status. Sex and age were also taken into consideration when evaluating the distribution of serum TSH levels in different groups. RESULTS: In the presence of positive anti-thyroid peroxidase antibodies or abnormal US findings, the central 95 percentile interval of the serum TSH levels was widened. Additionally, the distribution of serum TSH levels shifted toward lower values in the current smokers group. The reference interval for TSH obtained using a normal Korean reference population was 0.73 to 7.06 mIU/L. The serum TSH levels were higher in females than in males in all groups, and there were no age-dependent shifts. CONCLUSIONS: The present findings demonstrate that the serum TSH reference interval in a normal Korean reference population was higher than that in other countries. This result suggests that the upper and lower limits of the TSH reference interval, which was previously defined by studies from Western countries, should be raised for Korean populations.
Adult ; Age Factors ; Aged ; Biomarkers/blood ; Case-Control Studies ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Predictive Value of Tests ; Reference Values ; Republic of Korea ; Sex Factors ; Smoking/blood ; Thyroid Diseases/blood/*diagnosis/ultrasonography ; Thyroid Function Tests/*standards ; Thyroid Gland/*metabolism/*ultrasonography ; Thyrotropin/*blood ; Time Factors ; Young Adult

BACKGROUND: Obesity is associated with aggressive pathological features and poor clinical outcomes in breast and prostate cancers. In papillary thyroid carcinoma (PTC), these relationships remain still controversial. This study aimed to evaluate the associations between body mass index (BMI) and the clinical outcomes of patients with PTC. METHODS: This retrospective study included 1,189 patients who underwent total thyroidectomy for PTCs equal to or larger than 1 cm in size. Clinical outcomes were evaluated and compared based on the BMI quartiles. RESULTS: There were no significant associations between BMI quartiles and primary tumor size, extrathyroidal invasion, cervical lymph node metastasis, or distant metastasis. However, an increase in mean age was associated with an increased BMI (P for trend <0.001). Multifocality and advanced tumor-node-metastasis (TNM) stage (stage III or IV) were significantly associated with increases of BMI (P for trend 0.02 and <0.001, respectively). However, these associations of multifocality and advanced TNM stage with BMI were not significant in multivariate analyses adjusted for age and gender. Moreover, there were no differences in recurrence-free survivals according to BMI quartiles (P=0.26). CONCLUSION: In the present study, BMI was not associated with the aggressive clinicopathological features or recurrence-free survivals in patients with PTC.
Body Mass Index* ; Breast ; Humans ; Lymph Nodes ; Multivariate Analysis ; Neoplasm Metastasis ; Obesity ; Prognosis ; Prostatic Neoplasms ; Retrospective Studies ; Thyroid Gland* ; Thyroid Neoplasms* ; Thyroidectomy