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

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

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

Positron emission tomography/computed tomography (PET/CT) has dramatically altered the landscape of noninvasive glioma evaluation, offering complementary insights to those gained through magnetic resonance imaging (MRI). PET/CT scans enable a multifaceted analysis of glioma biology, supporting clinical applications from grading and differential diagnosis to mapping the full extent of tumors and planning subsequent treatments and evaluations. With a broad array of specialized radiotracers, researchers and clinicians can now probe various biological characteristics of gliomas, such as glucose utilization, cellular proliferation, oxygen deficiency, amino acid trafficking, and reactive astrogliosis. This review aims to provide a recent update on the application of versatile PET/CT radiotracers in glioma research and clinical practice.

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: Second-generation thyroglobulin immunometric assays (Tg-IMAs) have been developed with improved sensitivity. Our aim was to compare the diagnostic value of Tg-IMA measurements using a Kryptor (BRAHMS AG) kit (Tg-K) and an ACCESS (Beckman Coulter) kit (Tg-A) with that of the first-generation Tg measurement using a Tg-plus (BRAHMS AG) kit (Tg+). METHODS: We enrolled 82 differentiated thyroid cancer patients who underwent total thyroidectomy with radioactive iodine remnant ablation and who underwent diagnostic whole body scan using recombinant human thyroid stimulating hormone (rhTSH). The Tg+, Tg-K, and Tg-A were measured before rhTSH administration during levothyroxine treatment (suppressed Tg) from the same sample. Serum Tg+ was measured after rhTSH stimulation (stimulated Tg). RESULTS: Suppressed Tg+ was more significantly correlated with suppressed Tg-K (R²=0.919, P<0.001) than with suppressed Tg-A (R²=0.536, P<0.001). The optimal cut-off values of suppressed Tg+, Tg-K, and Tg-A for predicting stimulated Tg+ of 1 ng/mL were 0.3, 0.2, and 0.2 ng/mL, respectively. The sensitivity, specificity, and accuracy of suppressed Tg+ were 67%, 100%, and 90%, respectively; those of suppressed Tg-K were 83%, 90%, and 88%; those of suppressed Tg-A were 96%, 82%, and 87%, respectively. The positive predictive and negative predictive values of Tg+ were 100% and 87%, respectively; those of Tg-K were 79% and 92%; and those of Tg-A were 73% and 98%. CONCLUSION: We could not clearly demonstrate which kit had better diagnostic performance after comparison of first-generation Tg measurements with Tg-IMA measurements. Also, there were kit-to-kit variations between Tg-IMA kits. Suppressed Tg measured by Tg-IMA was insufficient to completely substitute for a stimulated Tg measurement.
Humans ; Immunoassay* ; Iodine ; Sensitivity and Specificity ; Thyroglobulin* ; Thyroid Neoplasms ; Thyroidectomy ; Thyrotropin ; Thyrotropin Alfa ; Thyroxine ; Whole Body Imaging

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