Efficacy and safety of mycophenolate mofetil in the treatment of moderate to severe Graves' orbitopathy: a meta-analysis.

The role of mycophenolate mofetil (MMF) in the treatment of Graves' orbitopathy (GO) has attracted much attention. This study is to evaluate the benefit and safety of MMF in moderate-to-severe GO. A meta-analysis of clinical control trials comparing MMF (with or without glucocorticoid (GC)) for the treatment of GO with GC was conducted. We searched the databases, including PubMed, EMBASE, the Cochrane Library, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI), for articles published up to 15 June 2022. The primary outcome is referred to the improvement in overall response, and secondary outcomes included the change in clinical activity score (CAS) and adverse events (AEs). Of the 289 articles initially searched, 6 studies were finally eligible for inclusion. The results showed that MMF (with or without GC) was superior to GC in the treatment of GO (OR 3.34, 95% CI 2.17-5.14; p < 0.00001). Subgroup analyses also showed that MMF monotherapy was more effective than GC (OR 4.46, 95% CI 2.52-7.87; p < 0.00001). Compared to methylprednisolone (MP) monotherapy, a combination of MP and MMF was more effective. CAS decreased even more significantly (WMD 0.29, 95% CI 0.10-0.48; p = 0.002) and fewer AEs occurred (OR 0.2, 95% CI 0.06-0.72; p = 0.01) in patients receiving MMF. The pooled data suggested that MMF treatment in GO might be promising. Compared with GC therapy, MMF is safer and more effective. However, more large-sample and high-quality studies targeting MMF use in GO patients and long-term surveillance of prognosis are urgently needed.

ß-cell function and insulin sensitivity contributions on incident diabetes in patients with endogenous Cushing's syndrome.

OBJECTIVE: To evaluate the relative contributions of ß-cell function and insulin sensitivity on the deterioration of glucose tolerance from OGTT in patients with endogenous CS. METHODS: We retrospectively analyzed the data of 60 patients with CS and determined the glucose metabolism and ß-cell function through OGTT. Their general characteristics were retrieved. A series of parameters for assessing insulin sensitivity and ß-cell function was calculated. The logistic regression model was used to investigate insulin sensitivity and ß-cell function contributions on incident diabetes. RESULTS: Of the 60 patients with CS, 10 (16.7%), 21 (35%), and 29 (48.3%) were classified as CS/ normal glucose tolerance (NGT), CS/prediabetes, and CS/diabetes mellitus (DM). Compared with the HCs, the CS/NGT patients had higher HOMA-IR and lower ISI-Matsuda but with a compensatory increase in HOMA-ß. Significant decreasing trends were observed in HOMA-ß, AUCI/G and ΔI30/ΔG30 among CS/NGT, CS/prediabetes and CD/DM groups. The OR of incident diabetes compared with the high AUCI/G/high ISI group was significant in the low AUCI/G/high ISI group. CONCLUSION: Impairment of the ß-cell function had a more profound effect on incident diabetes than decreased insulin sensitivity. An approach based on an OGTT has utility for diagnosing dysglycaemia and ß-cell dysfunction in patients with CS.

Development and Validation of Prognostic Nomograms Based on Gross Tumor Volume and Cervical Nodal Volume for Nasopharyngeal Carcinoma Patients With Concurrent Chemoradiotherapy.

PURPOSE: Our study aimed to establish and validate prognostic nomograms based on gross tumor volume (GTV) and cervical nodal volume (CNV) for nasopharyngeal carcinoma (NPC) patients treated with two cycles of concurrent chemoradiotherapy (CCRT). METHODS: From 2012 to 2015, 620 eligible patients who received radical treatment at the Cancer Hospital of Shantou University Medical College were recruited for a nomogram study. Variables were determined in a training set of 463 patients from 2012 to 2014 by X-tile analysis, univariate and multivariate Cox proportional hazard analyses, and the least absolute shrinkage and selection operator (LASSO). Another cohort of 157 patients in 2015 was validated with bootstrap resampling. The concordance index (C-index) and calibration curves were applied to assess its predictive discriminative and accuracy ability, while decision curve analysis (DCA), X-tile analysis and Kaplan-Meier curve for clinical application. RESULTS: Independent prognostic variables for overall survival (OS) were age, GTV, CNV, cranial nerve, positive cervical lymph node laterality below the caudal border of cricoid cartilage (LNBC), and were selected for the nomogram. Optimal prognostic factors including Karnofsky performance status (KPS), age, GTV, CNV, LNBC were incorporated in the nomogram for progression-free survival (PFS). In the training set, the C-index of our nomograms for OS and PFS were 0.755 (95% CI, 0.704 to 0.807) and 0.698 (95% CI, 0.652 to 0.744). The calibration curve showed good agreement between nomogram-predicted and actual survival. DCA indicated that our nomograms were of clinical benefit. CONCLUSION: Our nomograms are capable of effective prognostic prediction for patients with NPC.

Effect of selenium on thyroid autoimmunity and regulatory T cells in patients with Hashimoto's thyroiditis: A prospective randomized-controlled trial.

Selenium (Se) is an essential trace element in human. Recent studies of Se supplementation on the effect of Hashimoto's thyroiditis (HT) have been reported, but the exact benefit is unclear as well as the underlying immunologic mechanism. We aimed to evaluate the clinical effect of Se supplement in patients with HT, and explore the potential mechanism against thyroid autoimmunity. A prospective, randomized-controlled study was performed in patients with HT assigned to two groups. Se-treated group (n = 43) received selenious yeast tablet (SYT) for 6 months, whereas no treatment in control group (n = 47). The primary outcome is the change of thyroid peroxidase antibody (TPOAb) or thyroglobulin antibody (TGAb). Second, thyroid function, urinary iodine, Se, Glutathione peroxidase3 (GPx3), and Selenoprotein P1 (SePP1) levels were measured during the SYT treatment. Meanwhile, regulatory T cells (Tregs) and their subsets activated Tregs (aTregs), resting Tregs, and secreting Tregs, as well as Helios and PD-1 expression on these cells were also detected. The results showed that SYT treatment significantly decreased TPOAb, TGAb, and thyroid stimulating hormone (TSH) levels, accompanied with the increased Se, GPx3, and SePP1, compared with the control group. Subgroup analysis revealed that subclinical HT may benefit more from this treatment in the decrease of TSH levels by interaction test. Moreover, the percentage of aTregs, Helios/Tregs, and Helios/aTregs were significantly higher in the Se-treated group than control. In conclusion, Se supplementation may have a beneficial effect on thyroid autoantibodies and thyroid function by increasing the antioxidant activity and upregulating the activated Treg cells.

The analysis of differential diagnosis of benign and malignant thyroid nodules based on ultrasound reports.

BACKGROUND: Thyroid cancer is a common endocrine tumor, the incidence of which is increasing each year. Early diagnosis and treatment can effectively prevent thyroid cancer. This article uses Chinese's ultrasound reports to determine the value of early diagnosis. METHODS: The clinical data center of the First Affiliated Hospital of Nanjing Medical University was screened for patients diagnosed with a thyroid nodule, who had undergone a thyroid function test, ultrasound records and pathological assessment. A total of 811 patients with a total of 1,290 pathologically confirmed nodules (506 benign and 784 malignant) were enrolled. Logistic regression was used to analyze the variables that significantly affected malignant nodules. The sensitivity and specificity of ultrasound thyroid imaging-reporting and data system (TI-RADS) classification results for benign and malignant tumors were calculated. RESULTS: The age of the patients had a very significant difference in the classification of benign and malignant nodules (P<0.001), and the marital status was significantly different (P<0.05). Gender and medical insurance had no significant effect (P>0.05). Thyroglobulin (TG), free thyroxine (FT4), and free triiodothyronine (FT3) had significant effects (P=0.003) on the incidence of malignant nodules in patients, while thyroid-stimulating hormone (TSH) had no significant effect (P>0.05). Ultrasound analysis showed a Youden's index of 78.97%, a positive predictive value of 93.20%, and a negative predicted value of 84.10% at the most excellent classification effect. The sensitivity was 89.0%, the specificity was 89.9%; much greater than the classification model based on the thyroid function test (sensitivity =80.6%, specificity =55.8%). CONCLUSIONS: The present study verifies the effectiveness of using TI-RADS classification for diagnosis of benign and malignant thyroid nodules, and explores the use of new analysis methods for clinical data. To reduce dependence on the doctors, ultrasound image data and clinical phenotypic data can be further used to assist clinical decision making.

In vitro antifungal activity and possible mechanisms of action of chelerythrine.

Chelerythrine (CHE) possesses broad pharmacological activities. In this study, the extract of Chelidonium majus L. were characterized by high performance liquid chromatography (HPLC), infrared radiation (IR) spectroscopy and nuclear magnetic resonance (NMR). It was proved that the extract was CHE. The antifungal activity of CHE against five fungal pathogens of rice was researched in vitro, revealing that CHE inhibited Ustilaginoidea virens (U. virens) and Cochliobolus miyabeanus (C. miyabeanus) with 50% effective concentrations (EC50) of 6.53 × 10-3 mg/mL and 5.62 × 10-3 mg/mL, respectively. When the concentration of CHE was 7.5 × 10-3 mg/mL, the inhibition rate of U. virens reached 56.1%. Moreover, CHE (4 × 10-3 mg/mL) exhibited the greatest efficacy in inhibiting spore of U. virens growth with an inhibition rate as high as 86.7%. CHE displayed the best inhibitory activity against U. virens at the concentration of 7.5 × 10-3 mg/mL, compared with the other two isoquinoline alkaloids and commercial fungicide validamycin. After treating U. virens mycelia with CHE, twisted and atrophied mycelia were observed by optical microscopy. SEM results demonstrated narrow and locally fractured mycelium. TEM observations showed that the cell wall had become thin and broken, and most organelles were difficult to recognize. Furthermore, membrane of mycelia was destroyed and reactive oxygen species (ROS) of spores was accumulated, which induced apoptosis of pathogenic fungi. From these results, our understanding of the mechanisms of antifungal activity of CHE against U. virens was enriched and this research is relevant for developing novel pesticides.

Risk Factors for the Relapse of Graves' Disease Treated With Antithyroid Drugs: A Systematic Review and Meta-analysis.

PURPOSE: Antithyroid drugs (ATDs) are the first-line treatment for Graves' disease (GD). A common problem with ATD treatment is the high relapse rate after drug withdrawal. The goal of this study was to analyze the influencing factors for the relapse of GD patients treated with ATD by using a systematic review and meta-analysis, provide some predictive indexes for the susceptibility of GD recurrence, and then further explore some useful methods to decrease the GD relapse rate after ATD treatment. METHODS: Articles published in PubMed, EMBASE, The Cochrane Library, China National Knowledge Infrastructure, Wan Fang, and Chinese Biomedical Literature databases before January 2019 were collected. Patients newly diagnosed with GD, who were aged >16 years, were treated with ATD. Follow-up was then conducted for at least 12 months after ATD withdrawal. Only prospective or retrospective studies were eligible. The primary end point was the recurrence of GD during follow-up. All the data from the trials were analyzed via meta-analysis and meta-regression. p values < 0.05 were considered statistically significant, and statistical heterogeneity was assessed by using I2 statistics. FINDINGS: A total of 20 studies and 3242 patients were involved in this meta-analysis, with 1681 patients relapsed (incidence rate, 51.9%) during the follow-up time. Analysis of risk factors suggested that younger age (weighted raw mean difference [RMD], -3.51; 95% CI, -5.74 to -1.29), larger thyroid volume (RMD, 4.38; 95% CI, 1.68 to 7.08), bigger goiter size (1.94% risk; 95% CI, 0.43 to 3.46), higher free triiodothyronine level (RMD, 5.09; 95% CI, 4.42 to 5.77), and higher free thyroxine level (RMD, 4.21; 95% CI, 0.54 to 7.89) were associated with the higher relapse rate of GD. The block-replace ATD regimen (a fixed high dose of an ATD with levothyroxine supplementation to maintain euthyroidism) (risk ratio, 0.64; 95% CI, 0.52 to 0.78) exhibits a lower relapse rate than the titration regimen (an ATD used alone and dose adjusted according to thyroid function tests). IMPLICATIONS: This analysis revealed that certain risk factors were associated with GD relapses such as younger age, larger goiter size or thyroid volume, and the higher free triiodothyronine or free thyroxine level in the diagnosing phase of GD. For patients with these clinical characteristics, early definitive treatment with radioactive iodine or surgery should be offered to those who are unlikely to achieve remission with ATDs only. In addition, more prospective cohort studies with different ATD regimens would help to determine the optimum ATD treatment for patients with GD. PROSPERO identifier: CRD 42019146825.

Thyroid-Associated Orbitopathy: Evaluating Microstructural Changes of Extraocular Muscles and Optic Nerves Using Readout-Segmented Echo-Planar Imaging-Based Diffusion Tensor Imaging.

OBJECTIVE: We aimed to investigate the ability of readout-segmented echo-planar imaging (rs-EPI)-based diffusion tensor imaging (DTI) in assessing the microstructural change of extraocular muscles (EOMs) and optic nerves in patients with thyroid-associated orbitopathy (TAO) as well as in evaluating disease activity. MATERIALS AND METHODS: We enrolled 35 TAO patients and 22 healthy controls (HCs) who underwent pre-treatment rs-EPI-based DTI. Mean, axial, and radial diffusivity (MD, AD, and RD) and fractional anisotropy (FA) of the medial and lateral EOMs and optic nerve for each orbit were calculated and compared between TAO and HC groups and between active and inactive TAO groups. Factors such as age, sex, disease duration, mediation, and smoking history between groups were also compared. Logistic regression analysis was used to evaluate the predictive value of significant variables for disease activity. RESULTS: Disease duration was significantly shorter in active TAOs than in inactive ones (p < 0.001). TAO patients showed significantly lower FA and higher MD, AD, and RD than HCs for both medial and lateral EOMs (p < 0.001), but not the AD value of lateral EOMs (p = 0.619). Active patients had significantly higher FA, MD, and AD than inactive patients for medial EOMs (p < 0.005), whereas only FA differed significantly in the lateral EOMs (p = 0.018). The MD, AD, and RD of optic nerves were significantly lower in TAO patients than HCs (p < 0.05), except for FA (p = 0.129). Multivariate analysis showed that the MD of medial EOMs and disease duration were significant predictors for disease activity. The combination of these two parameters showed optimal diagnostic efficiency for disease activity (area under the curve, 0.855; sensitivity, 68.4%; specificity, 96.9%). CONCLUSION: rs-EPI-based DTI is promising in assessing microstructural changes of EOMs and optic nerves and can help to indicate the disease activity of TAO, especially through the MD of medial EOMs.

Analysis of Regulatory T Cell Subsets and Their Expression of Helios and PD-1 in Patients with Hashimoto Thyroiditis.

Hashimoto thyroiditis (HT) is an autoimmune disease that presumably arises consequent to loss of immune tolerance to autoantigen in thyroid. Regulatory T cells (Tregs) are considered to play a vital role in maintaining the immune balance, as they own intensive suppressive function. This study was undertaken to analyze numbers of Tregs and their expressions of Helios and PD-1 in HT patients. It also aimed to explore the relationship of these with thyroid function and specific autoantibodies. Peripheral blood mononuclear cells (PBMCs) were extracted from blood of 20 healthy controls (HC) and 42 HT patients with varying thyroid functions (10 overt hypothyroidism, 12 subclinical hypothyroidism, and 20 euthyroidism). We performed flow cytometry analysis in PBMCs to detect CD4+CD25+Foxp3+Tregs and their subsets, including CD45RO+Foxp3high activated Treg cells (aTregs), CD45RO-Foxp3low resting Tregs cells (rTregs), and CD45RO+Foxp3low secreting Treg cells (sTregs), as well as the expression of Helios and PD-1 on these cells. The results showed that the percentage of Tregs, aTregs was significantly lower in HT patients and it showed inverse correlation to thyroid function states, in comparison with these in healthy controls. In addition, patients with HT showed decreased expression of Helios in aTregs, while having increased expression of PD-1 in Tregs and sTregs. The levels of Tregs, aTregs, and Helios expressing aTregs were all negatively correlated with antithyroid antibodies. In conclusion, the deficiency of Tregs frequency and aberrant expressions of Helios and PD-1 may possibly contribute to thyroid immune damage in HT.

miR-146a rs2910164 Polymorphism and Risk of Papillary Thyroid Carcinoma: A Meta-Analysis.

Aims: The presence of single nucleotide polymorphisms contributes to genetic diversity, and some are associated with cancer progression. Recent studies concerning the relationship between polymorphisms in miR-146a and the risk of papillary thyroid carcinoma (PTC) have produced conflicting results. Here, a meta-analysis of previous studies was performed to evaluate this relationship. Materials and Methods: Electronic databases, including PubMed, China National Knowledge Infrastructure, Cochrane Library, Embase, and Web of Science, were searched for studies concerning miR-146a and PTC published between January 1, 2000 and January 1, 2018. Fixed/random-effects models were used to calculate the pooled odds ratios (ORs) estimated in each study according to the level of heterogeneity. Results: Eight studies involving 3993 cases and 9919 controls were assessed. Pooled results showed no association between the miR-146a rs2910164 polymorphism and PTC (OR = 1.001, 95% confidence interval [CI] 0.893-1.121). Subgroup analysis showed that the GG/GC genotype did not significantly increase PTC risk versus CC among Asians (OR = 0.939; 95% CI 0.828-1.066). Similarly, the combination of the GG and GC genotypes did not increase the risk of PTC for Caucasians (OR = 1.571, 95% CI 0.949-2.601). Conclusions: The results of our meta-analysis indicated that the miR-146a rs2910164 variant genotype has no effect on susceptibility to PTC.

Histopathologic and immunohistochemical findings in congenital anorectal malformations.

It remains controversial whether the distal rectal pouch should be either resected or used for reconstruction in anorectoplasty for the treatment of anorectal malformations (ARMs). Hence the aim of this study was to investigate whether ARMs were associated with a global neuromuscular maldevelopment of the terminal rectum specimens.There were 36 cases of ARMs (25 recto-bulbar fistula and 11 recto-prostatic fistula) and 10 healthy controls. The hematoxylin and eosin and Masson trichrome stain were used to conduct the histologic examination. The immunohistochemistry (IHC) and Western blot were conducted to analyze the neuron-specific enolase (NSE), S-100 protein, interstitial cells of Cajal marker (C-kit) within the rectal specimens in control group and ARM group.The most frequently observed histologic findings in mucosa were inflammation, congestion, eroded, and hemorrhage in the ARM cases. Submucosal inflammation and congestion were the most common submucosal findings in the ARM cases. Disrupted muscularis propria was observed in 60% of ARM cases. Mature ganglionic cells were reduced and muscularis propria showed reduced and patchy positivity for NSE, S-100, and C-kit protein in ARM group compared to that in control group according to IHC. Western blotting showed the expression levels of NSE, S-100, and C-kit were lower in the ARM group than that in the control group (P < .01).Histopathologic and IHC findings suggest that the distal rectal pouch has distinct defects in the neuromusculature. So it suggested that ARMs are abnormally developed tissue and need to be resected for better functional outcomes of the remaining gut.

The diagnostic value of TROP-2, SLP-2 and CD56 expression in papillary thyroid carcinoma.

OBJECTIVE: The study aimed to explore some novel diagnostic biomarkers for papillary thyroid carcinoma (PTC) by identifying the different expression of TROP-2, SLP-2 and CD56 in benign and malignant thyroid lesions. METHODS: We evaluated the mRNA expressions of TROP-2 and SLP-2 in fine needle aspirates (FNAs) which contained 10 PTCs and 10 benign follicular adenomas (FAs) using quantitative real-time PCR (qRT-PCR). Immunohistochemical (IHC) staining of TROP-2, SLP-2 and CD56 was also performed on postoperative samples of 30 PTCs and 29 FAs. Membranous or cytoplasmic staining in > 10% of cells was considered as positive. Diagnostic sensitivity, specificity, positive predictive value, negative predictive value (NPV) and diagnostic accuracy of these three biomarkers were carried out. We further analyzed the associations between the clinical features and the expressions of markers in PTCs. RESULTS: The mRNA expressions of both TROP-2 and SLP-2 were increased substantially in PTCs in comparison with those in FAs (P < 0.05). Similarly, IHC for these two proteins demonstrated higher positive staining in PTCs than in FAs (96.5% vs. 12.5% for TROP-2, 83.3% vs. 20.7% for SLP-2, P < 0.05). Conversely, CD56 expression was lost with 86.7% of PTCs. In identifying malignancy, TROP-2 was the most sensitive marker and CD56 was the most specific one. When the markers were combined, the sensitivity and NPV increased to 100% and had better diagnostic accuracy. However, no association was found between biomarker expressions and clinicopathological factors in PTCs. CONCLUSIONS: We found that TROP-2, SLP-2 and CD56 were effective diagnostic markers for PTC, especially when they were combined to use.

Associations Between Three CTLA-4 Polymorphisms and Hashimoto's Thyroiditis Risk: An Updated Meta-Analysis with Trial Sequential Analysis.

AIMS: In this article, we conducted an updated meta-analysis with trial sequential analysis (TSA) to refine the associations between three common single nucleotide polymorphisms (SNPs) in the CTLA-4 gene (+49A/G, CT60, and -318C/T) and Hashimoto's thyroiditis (HT). METHODS: Statistical association analyses were performed using four genetic models, including the allelic, codominant, dominant, and recessive models with the Revman 5.3, Stata 14.0, and TSA 0.9 software. For quality evaluation, the Newcastle-Ottawa Scale was used. RESULTS: Our meta-analysis included 29 independent studies with low risk of bias that involved 3614 cases and 8839 controls. The pooled results indicated a significant association between the +49A/G polymorphism and an increased risk of HT in all four genetic models. Furthermore, the TSA demonstrated that the evidence of this association was robust and credible. Subgroup analysis revealed a significantly higher risk of HT in Asians compared with Caucasians associated with the +49A/G polymorphism. Surprisingly, in contrast to the results with adults, we did not find any significant association when analyzing the pediatric subgroup. For the CT60 polymorphism, a significant association with risk of HT was detected overall, and subgroup analysis revealed that this association was significant in the Asian subgroup, but not in the Caucasian subgroup. No statistically significant associations were detected in any of the investigated genetic models for the -318C/T polymorphism. However, the results of the TSA suggested that the sample sizes used for the CTLA-4 CT60 and -318C/T SNPs were insufficient. CONCLUSION: Our meta-analysis showed significant associations between the risk of HT and both the +49A/G and CT60 polymorphisms, but not the -318C/T polymorphism. In addition, the TSA results indicated that CTLA-4 +49A/G should be considered as a biomarker for HT, whereas both the CT60 and -318C/T SNPs warrant confirmation by further studies.

ATRA increases iodine uptake and inhibits the proliferation and invasiveness of human anaplastic thyroid carcinoma SW1736 cells: Involvement of ß-catenin phosphorylation inhibition.

All-trans-retinoic acid (ATRA) can enhance iodine uptake capability of thyroid tumors, but the mechanisms remain poorly understood. The aim of the present study was to investigate the effects of ATRA on isotope susceptibility, proliferation and invasion of anaplastic thyroid carcinoma (ATC) and potential mechanisms. SW1736 cells were treated with 1 µmol/l ATRA or 1% ethanol for 5 days. A cell line stably expressing ß-catenin-shRNA was established. An iodine uptake assay was performed using 125I. Proliferation and invasiveness were tested using MTT and Transwell assays, respectively. Western blotting was used to assess the expression of ß-catenin, glycogen synthase kinase-3ß (GSK-3ß), sodium/iodine symporter (NIS) and proteins involved in epithelial-mesenchymal transition. Cells pretreated with ATRA were injected subcutaneously into SCID mice. Mice were intraperitoneally injected with 131I once on the first day of treatment, and tumor growth was then assessed. After 35 days of 131I treatment, ATRA-pretreated tumor volume and weight were decreased compared with the 131I alone group (163.32±19.57 vs. 332.06±21.37 mm3; 0.35±0.14 vs. 0.67±0.23 g, both P<0.05). Similar results were observed in the ß-catenin shRNA-pretreated tumors. ATRA also increased the uptake of iodine by SW1736 cells (P<0.01), and similar results were observed in ß-catenin shRNA cells. ATRA treatment decreased the cell proliferation and invasion compared with control cells (all P<0.05), similar to ß-catenin shRNA. ATRA treatment decreased the expression of phosphorylated (p-)ß-catenin, p-GSK-3ß, vimentin, and fibronectin, and increased the expression of NIS and E-cadherin, compared with the control. ATRA increased the iodine uptake and inhibited the proliferation and invasion of SW1736 cells, involving ß-catenin phosphorylation. In conclusion, ATRA could be used to improve the isotope sensitivity of ATC.

Inhibiting ß-catenin expression promotes efficiency of radioiodine treatment in aggressive follicular thyroid cancer cells probably through mediating NIS localization.

The present study investigated whether the efficacy of radioiodine therapy towards aggressive thyroid cancer cells was affected by ß-catenin activity and associated with sodium/iodine symporter (NIS) localization. Human thyroid cancer cell line follicular thyroid carcinoma (FTC) 133 was endowed with aggressiveness by HIF-1α or ß-catenin overexpression. The protein amount and subcellular localization of NIS, and the radioiodine uptake capacity were detected in the cells, as well as in cells subsequently undergoing ß-catenin knockdown. Xenograft experiments were conducted to compare the tumor growth ability and responsiveness to radioactive treatment among HIF-1α and ß-catenin overexpressing FTC cells, respectively with or without ß-catenin knockdown. ß-catenin increased upon HIF-1α overexpression, but not vice versa. This signal axis would prompt metastatic propensity in FTC cells, and translocate NIS from cytomembrane to cytoplasm. Consistently the radioiodine uptake capacity in the cells decreased obviously. Knockdown of ß-catenin reversed all these changes. Furthermore, the xenograft experiments showed that radioiodine treatment could thoroughly suppress tumor growth ability of aggressive FTC cells only if the HIF-1α-induced ß-catenin activation was disrupted by ß-catenin knockdown. ß-catenin nuclear translocation in tumor cells was accompanied by abnormal subcellular localization of NIS. Moreover, we found that only after inhibiting ß-catenin expression, can the radioiodine treatment promote apoptosis other than repress proliferation and survival in xenograft tumor cells. In conclusion, aggressive FTC cells overexpressing HIF-1α will be fully cracked down by radioiodine therapy once ß-catenin expression is inhibited, and regulated localization of NIS may account for underlying mechanisms.

Evolutionary features of thyroid cancer in patients with thyroidectomies from 2008 to 2013 in China.

To evaluate the characteristics of thyroid carcinoma over time, we carried out a retrospective study to illustrate the evolutionary features of thyroid carcinoma. All records of thyroidectomies from the First Affiliated Hospital of Nanjing Medical University from 2008 to 2013 were obtained focusing on pathological diagnosis, size, local lymph node metastasis (LNM) of the tumors. The thyroid cancer detection rate increased from 24.6% to 41.5% significantly (P < 0.05). Papillary thyroid carcinoma (PTC) remained to be the most common type counting 86.4% of all thyroid carcinomas. In all 1,704 PTCs, microPTC (mPTC) with maximum diameter less than or equal to 10 mm has become the dominant form taking up 56.5% of all PTCs in 2013 while only 43.1% in 2008. The mean maximum tumor size has decreased from 17.8 mm to 12.2 mm significantly (P < 0.05). However, the average age, female dominance, and local LNM remained similarly in the past six years. Logistic regression test showed that the determinants for local LNM were age, gender and tumor size. mPTC has become the most common form of thyroid carcinoma detected during thyroidectomies in China while other features of thyroid carcinoma remained similarly in the recent years.

Association between TSHR gene polymorphism and the risk of Graves' disease: a meta-analysis.

Thyroid stimulating hormone receptor (TSHR) is thought to be a significant candidate for genetic susceptibility to Graves' disease (GD). However, the association between TSHR gene polymorphism and the risk of GD remains controversial. In this study, we investigated the relationship between the two conditions by meta-analysis. We searched all relevant case-control studies in PubMed, Web of Science, CNKI and Wanfang for literature available until May 2015, and chose studies on two single nucleotide polymorphisms (SNPs): rs179247 and rs12101255, within TSHR intron-1. Bias of heterogeneity test among studies was determined by the fixed or random effect pooled measure, and publication bias was examined by modified Begg's and Egger's test. Eight eligible studies with 15 outcomes were involved in this meta-analysis, including 6,976 GD cases and 7,089 controls from China, Japan, Poland, UK and Brazil. Pooled odds ratios (ORs) for allelic comparisons showed that both TSHR rs179247A/G and rs12101255T/C polymorphism had significant association with GD (OR=1.422, 95%CI=1.353-1.495, P<0.001, Pheterogeneity=0.448; OR=1.502, 95%CI: 1.410-1.600, P<0.001, Pheterogeneity=0.642), and the associations were the same under dominant, recessive and co-dominant models. In subgroup analyses, the conclusions are also consistent with all those in Asian, European and South America subgroups (P<0.001). Our meta-analysis revealed a significant association between TSHR rs179247A/G and rs12101255T/C polymorphism with GD in five different populations from Asia, Europe and South America. Further studies are needed in other ethnic backgrounds to independently confirm our findings.

2,3',4,4',5-Pentachlorobiphenyl Induces Inflammatory Responses in the Thyroid Through JNK and Aryl Hydrocarbon Receptor-Mediated Pathway.

Polychlorinated biphenyls (PCBs) are durable and widely distributed environmental contaminants that can compromise the normal functions of multiple organs and systems; one important mechanism is the induction of inflammatory disorders. In this study, we explored the influences of 2,3',4,4',5-pentachlorobiphenyl (PCB118) on inflammatory responses and its underlying mechanisms in the thyroid. Wistar rats were administered PCB118 intraperitoneally at 0, 10, 100, and 1000 µg/kg/d, 5 days a week for 13 weeks; rat thyroid FRTL-5 cells were treated with PCB118 (0, 0.25, 2.5, and 25 nM) for indicated time. Results revealed that PCB118 promoted the generation of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) in a time- and dose-related manner and decreased sodium/iodide symporter (NIS) protein expression. Moreover, stimulation with PCB118 resulted in the upregulation of the aryl hydrocarbon receptor (AhR)-responsive gene cytochrome P450 1A1 in FRTL-5 cells; whereas pretreatment with the AhR inhibitor α-naphthoflavone or AhR small interfering RNA (siRNA) suppressed AhR, CYP1A1, IL-6, and ICAM-1 and restored NIS expression. In vivo and in vitro studies also suggested that the c-Jun N-terminal kinase (JNK) pathway was activated on PCB118 exposure, and the experiments using siRNA for JNK partially blocked PCB118-induced upregulation of IL-6 and ICAM-1 and downregulation of NIS. Altogether, PCB118 stimulates production of IL-6, TNF-α, and ICAM-1 in the thyroid through AhR and JNK activations and subsequently interferes with NIS expression, resulting in the disruption of thyroid structure and function.

Value of TIRADS, BSRTC and FNA-BRAF V600E mutation analysis in differentiating high-risk thyroid nodules.

The thyroid imaging reporting and data system (TIRADS) and Bethesda system for reporting thyroid cytopathology (BSRTC) have been used for interpretation of ultrasound and fine-needle aspiration cytology (FNAC) results of thyroid nodules. BRAF(V600E) mutation analysis is a molecular tool in diagnosing thyroid carcinoma. Our objective was to compare the diagnostic value of these methods in differentiating high-risk thyroid nodules. Total 220 patients with high-risk thyroid nodules were recruited in this prospective study. They all underwent ultrasound, FNAC and BRAF(V600E) mutation analysis. The sensitivity and specificity of TIRADS were 73.1% and 88.4%. BSRTC had higher specificity (97.7%) and similar sensitivity (77.6%) compared with TIRADS. The sensitivity and specificity of BRAF(V600E) mutation (85.1%, 100%) were the highest. The combination of BSRTC and BRAF(V600E) mutation analysis significantly increased the efficiency, with 97.8% sensitivity, 97.7% specificity. In patients with BSRTC I-III, the mutation rate of BRAF(V600E) was 64.5% in nodules with TIRADS 4B compared with 8.4% in nodules with TIRADS 3 or 4A (P < 0.001). Our study indicated that combination of BSRTC and BRAF(V600E) mutation analysis bears a great value in differentiating high-risk thyroid nodules. The TIRADS is useful in selecting high-risk patients for FNAB and patients with BSRTC I-III for BRAF(V600E) mutation analysis.

Association of common polymorphisms in the IL2RA gene with type 1 diabetes: evidence of 32,646 individuals from 10 independent studies.

Single nucleotide polymorphisms (SNPs) in the interleukin 2 receptor alpha (IL2RA) gene have been suggested to be associated with type 1 diabetes (T1D) susceptibility. However, the results from individual studies are inconsistent. To explore the association of IL2RA polymorphisms with T1D, including rs11594656, rs2104286, rs3118470, rs41295061 and rs706778, a meta-analysis involving 10 independent studies with 19 outcomes was conducted: five studies with a total of 10,572 cases and 12,956 controls were analysed for rs11594656 with T1D risk, three studies with 7300 cases and 8331 controls for rs2104286, three studies with 3880 cases and 5409 controls for rs3118470, five studies with 11,253 cases and 13,834 controls for rs41295061 and three studies with 1896 cases and 1709 controls for rs706778 respectively. Using minor allelic comparison, the five investigated SNPs were all observed to have a significant association with T1D: For rs11594656, fixed effect model (FEM) odds ratio (OR) 0.87, 95% confidence interval (CI) 0.83, 0.91; rs2104286, FEM OR 0.81, 95% CI 0.77, 0.85; rs3118470, FEM OR 1.23, 95% CI 1.16, 1.31; rs41295061, random effect model (REM) OR 0.67, 95% CI 0.60, 0.76 and rs706778 FEM OR 1.20, 95% CI 1.08, 1.33. Similar results were obtained when all the included studies were calculated by a REM. Our meta-analysis suggests that all five SNPs in the IL2RA gene are risk factors for T1D risk, and rs11594656, rs2104286 and rs41295061 are the most associated SNPs in the populations investigated. This conclusion warrants confirmation by further studies.