Zhaowei Meng

Nuclear Factor-Kappa B Inhibition Can Enhance Apoptosis of Differentiated Thyroid Cancer Cells Induced by 131I

Objective To evaluate changes of nuclear factor-kappa B (NF-κB) during radioiodine 131 (131I) therapy and whether NF-κB inhibition could enhance 131I-induced apoptosis in differentiated thyroid cancer (DTC) cells in a synergistic manner. Methods Three human DTC cell lines were used. NF-κB inhibition was achieved by using a NF-κB inhibitor (Bay 11-7082) or by p65 siRNA transfection. Methyl-thiazolyl-tetrazolium assay was performed for cell viability assessment. DNA-binding assay, luciferase reporter assay, and Western blot were adopted to determine function and expression changes of NF-κB. Then NF-κB regulated anti-apoptotic factors XIAP, cIAP1, and Bcl-xL were measured. Apoptosis was analyzed by Western blot for caspase 3 and PARP, and by flow cytometry as well. An iodide uptake assay was performed to determine whether NF-κB inhibition could influence radioactive iodide uptake. Results The methyl-thiazolyl-tetrazolium assay showed significant decrease of viable cells by combination therapy than by mono-therapies. The DNA-binding assay and luciferase reporter assay showed enhanced NF-κB function and reporter gene activities due to 131I, yet significant suppression was achieved by NF-κB inhibition. Western blot proved 131I could increase nuclear NF-κB concentration, while NF-κB inhibition reduced NF-κB concentration. Western blot also demonstrated significant up-regulation of XIAP, cIAP1, and Bcl-xL after 131I therapy. And inhibition of NF-κB could significantly down-regulate these factors. Finally, synergism induced by combined therapy was displayed by significant enhancements of cleaved caspase 3 and PARP from Western blot, and of Annexin V positively staining from flow cytometry. The iodine uptake assay did not show significant changes when NF-κB was inhibited. Conclusion We demonstrated that 131I could induce NF-κB activation, which would attenuate 131I efficacy in DTC cells. NF-κB inhibition by Bay 11-7082 or by p65 siRNA transfection was effective in suppressing NF-κB regulated anti-apoptotic changes and in combined regimen apoptosis was achieved synergistically.

Gender and Age Impacts on the Association Between Thyroid Function and Metabolic Syndrome in Chinese.

AbstractThe relationship between thyroid dysfunction and metabolic syndrome (MS) is complex. We aimed to explore the impact of gender and age on their association in a large Chinese cohort.This cross-sectional study enrolled 13,855 participants (8532 male, 5323 female), who self-reported as healthy without any known previous diseases. Clinical data including anthropometric measurements, thyroid function, and serum metabolic parameters were collected. The associations between thyroid function and MS of both genders were analyzed separately after dividing thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and age into subgroups. MS risks were calculated by binary logistic regression models.Young males had significantly higher MS prevalence than females, yet after menopause, females had higher prevalence than males. Females had higher incidence of thyroid dysfunction than males. By using TSH quartiles as the categorical variables and the lowest quartile as reference, significantly increased MS risk was demonstrated in quartile 4 for males, yet quartiles 3 and 4 for females. By using FT3 quartiles as the categorical variables, significantly increased MS risk was demonstrated in quartile 2 to 4 for females only. By using age subgroups as the categorical variables, significantly increased MS risk was shown in both genders, with females (4.408–58.455) higher than males (2.588–4.943).Gender and age had substantial influence on thyroid function and MS. Females with high TSH and high FT3 had higher MS risks than males. Aging was a risk for MS, especially for females. Urgent need is necessary to initiate interventional programs.

MiR-26a enhances invasive capacity by suppressing GSK3β in human lung cancer cells

ABSTRACT Lung cancer is the common cause of death from cancer, and most lung cancer patients die of metastasis. MicroRNAs (miRNAs) function as either oncogenes or tumor suppressors, playing crucial role not only in tumorigenesis, but also in tumor invasion and metastasis. There are several studies showed that miR‐26a is involved in carcinogenesis, however, its role in tumor metastasis need to be elucidated. In this study, we showed that ectopic expression of miR‐26a enhanced migration and invasion of lung cancer cells. Glycogen synthase kinase‐3&bgr; (GSK3&bgr;) was identified as a direct target of miR‐26a. GSK3&bgr; expression negatively correlated with miR‐26a expression in lung cancer tissues. Silencing of GSK3&bgr; achieved similar effect as miR‐26a over‐expression; over‐expression of GSK3&bgr; reversed the enhanced effect of miR‐26a on lung cancer cell migration and invasion. Further study indicated that miR‐26a increased &bgr;‐catenin expression and nuclear translocation. C‐myc and cyclin D1, the downstream genes of &bgr;‐catenin, were also up‐regulated by miR‐26a. Furthermore, xenograft study showed that miR‐26a promoted lung cancer cell growth in vivo, and suppressed GSK3&bgr; expression. Collectively, our results demonstrated that miR‐26a enhanced metastatic potential of lung cancer cells via activation of &bgr;‐catenin pathway by targeting GSK3&bgr;, suggesting the potential applicability of miR‐26a as a target for cancer treatment. HighlightsmiR‐26a enhances migration and invasion of lung cancer cells.GSK3&bgr; is identified as a direct target of miR‐26a.miR‐26a activates &bgr;‐catenin pathway by targeting GSK3&bgr;.miR‐26a promotes lung cancer cell growth in vivo.

Visualization of thyroglossal duct cyst in differentiated thyroid cancer patient.

Iodine-131 (I-131) treatment and subsequent whole body iodine-131 scans (WBSs) are important in the management of differentiated thyroid carcinoma (DTC). Nevertheless, false positive benign lesions in WBS should be interpreted with reliable anatomic imaging methodologies to differentiate from true metastases. We report a DTC case with a concurrent thyroglossal duct cyst (TDC), which is relatively uncommon compared with an accompanying lingual thyroid. After thyroid remnant ablation, subsequent posttherapeutic WBS showed a stable I-131 avid lesion in the neck despite cumulative dosage of 346 mCi I-131. Low level of thyroglobulin indicated that the lesion should be from thyroid origin, yet only a small amount of thyroid remnant should be contained. Magnetic resonance imaging and computed tomography were performed and revealed a dumbbell-shaped TDC. Part of the lesion was behind the hyoid bone, part of it protruded to the anterior surface of the thyroid cartilage, and the isthmus penetrated through the thyrohyoid membrane. Although the shape of this TDC reflects the route of the thyroglossal duct in embryological perspective, its coincidence with DTC is rarely documented. Our case also proved that the possibility of concurrent TDC should be considered as the cause of residual thyroglobulin for an I-131 avid lesion in the midline anterior cervical area, which could show great resistance to I-131 therapy.

Different Radioiodine Dose for Remnant Thyroid Ablation in Patients With Differentiated Thyroid Cancer: A Meta-analysis.

Objective Remnant thyroid ablation is crucial in the management of patients with differentiated thyroid cancer. However, the optimal dose of radioactive 131I for ablation is still controversial. This study aimed to compare the success rate of different activities of 131I for postoperative remnant ablation in randomized controlled trials (RCTs) and to determine the optimal dose. Patients and Methods Sources were retrieved from the Cochrane Library, Medline, Embase, Scopus, and Google Scholar until March 2014. All RCTs that assessed the efficacy of different doses of 131I for ablation were selected. After data extraction, statistics were performed by Review Manager 5.2 software. Results Seventeen RCTs were considered eligible, involving 3737 patients. The overall methodological quality of the studies was good. The rate of successful remnant ablation of low versus moderate 131I activities (risk ratio [RR], 0.89; 95% confidence interval [CI], 0.80–1.00; P = 0.06) and moderate versus high 131I activities (RR, 0.94; 95% CI, 0.89–1.00; P = 0.05) showed no significant differences. However, high 131I activities had 11% higher successful ablation rate than low activities with an RR of 0.89 (95% CI, 0.81–0.97; P = 0.008), which was significant. Conclusions We summarized all available randomized evidence to demonstrate that high dose of 131I was significantly better than low dose to achieve successful remnant thyroid ablation.

Immunohistochemical evaluation of midkine and nuclear factor-kappa B as diagnostic biomarkers for papillary thyroid cancer and synchronous metastasis.

AIMS Midkine (MK) is a multifunctional cytokine identified to be a promising cancer biomarker. Nuclear factor-kappa B (NF-κB) is an important transcription factor that plays a pivotal role in tumorigenesis. We aimed to investigate values of MK and NF-κB as markers for diagnosis and synchronous metastasis prediction in papillary thyroid cancer (PTC). MAIN METHODS 76 cases of PTC and 70 cases of multi-nodular goiter (MNG) were retrieved. The PTC group was further divided into subgroup 1 (16 cases with synchronous metastases) and subgroup 2 (60 cases without metastases). A retrospective review of demographic and clinical information was performed. Immunohistochemistry of MK, NF-κB p65 and Ki-67 was performed on paraffin-embedded specimens and results were quantified. Diagnostic values of the parameters were conducted by receiver operating characteristic (ROC) curves. Protein levels of MK and NF-κB p65 were then confirmed by Western blot. KEY FINDINGS Immunoreactivities of MK, NF-κB p65 and Ki-67 were significantly higher in the PTC group than in the MNG group with good differential diagnostic capabilities. Moreover, immunoreactivities of all three parameters were significantly higher in subgroup 1 than in subgroup 2 with good synchronous metastasis predictive efficacies. Western blot showed that MK and NF-κB p65 protein levels in lesions from subgroup 1 were significantly higher than those from subgroup 2, both of which were significantly higher than in MNG lesions. SIGNIFICANCE We discovered that MK and NF-κB immunohistochemistries can potentially be used for differential diagnosis between PTC and MNG, and for prediction of synchronous metastases.

Nuclear factor-kappa B inhibition can enhance therapeutic efficacy of 131I on the in vivo management of differentiated thyroid cancer

AIM Nuclear factor-kappa B (NF-κB) plays a key role in cancer development and therapy resistance. We aimed to determine whether NF-κB inhibition can enhance (131)I efficacy in differentiated thyroid cancer (DTC) in vivo. MAIN METHODS Every nude mouse was ip injected with 1mCi of (131)I for thyroid ablation. Four weeks later, DTC cells were implanted. Another six weeks later, mice received four types of therapies, namely control vehicle, 1mCi of (131)I once, 10mg/kg of Bay 11-7082 (a NF-κB inhibitor) trice and combination treatment. Pre-ablation (99m)Tc-pertechnetate imaging, post ablative and post therapeutic imaging were performed. Target-to-background ratios (T/Bs) on xenograft tumors were calculated and compared. Nuclear extract from tumor samples were assessed by DNA-binding assay and Western blot. Apoptotic indices by TUNEL assay were determined and tumor volume curve was drawn to compare therapeutic effects in different groups. KEY FINDINGS Post therapeutic imaging displayed (131)I-avidity of xenograft tumors and completeness of thyroid ablation. T/Bs comparison showed no significant differences in mice received either (131)I mono-therapy or combined therapy. DNA-binding assay and Western blot showed enhanced function and expression of NF-κB by (131)I, which were inhibited substantially by Bay 11-7082 combination. Apoptotic indices were significantly increased by combined treatment than by any mono-therapy. And DTC lesional volumes were significantly regressed by combined treatment than by any mono-therapy. SIGNIFICANCE We demonstrated that NF-κB inhibition can be a good interventional avenue to enhance therapeutic potentiation of (131)I on the in vivo management of DTC.

Gender and Age Impact on the Association Between Thyroid-Stimulating Hormone and Serum Lipids

AbstractThe relationship between thyroid-stimulating hormone (TSH) and hyperlipidemia is still a topic of debate. We aimed to explore the impact of gender and age on the association between serum TSH and lipid profile in a large cohort of Chinese.This cross-sectional study enrolled 13,915 participants (8565 male, 5350 female), who self-reported as healthy without any known previous diseases. Clinical data including anthropometric measurements, thyroid function, and other serum parameters were collected. The associations between TSH and hyperlipidemia of males and females were analyzed separately after dividing TSH and age into subgroups. Odds ratio for hyperlipidemia was calculated by binary logistic regression models.Young males had significantly higher prevalence of hypercholesterolemia, hypertriglyceridemia, and high serum low-density lipoprotein-cholesterol than females, yet after menopause, females had higher prevalence than males. TSH was positively associated with hyperlipidemia independent of thyroid hormones. Males showed more reduced risks of hyperlipidemia in low TSH concentrations, while females demonstrated more enhanced risks of hyperlipidemia in high TSH concentrations. For instance, if TSH was lower than 0.3 &mgr;IU/mL, the risks of developing hypercholesterolemia and hypertriglyceridemia in males were only 0.198 (P < 0.01) and 0.425 (P < 0.05) of the reference TSH risks (between 2.0 and 3.0 &mgr;IU/mL), while in females the risks were 0.553 (P < 0.05) and 0.642 (P > 0.05), respectively. If TSH was higher than 4.0 &mgr;IU/mL, women displayed significantly higher risks of developing hypertriglyceridemia than the reference TSH risks (P < 0.05), yet, men did not demonstrate such significances.Our results showed thyroid hormone independent positive associations between serum TSH and lipids, which were substantially influenced by gender and age. Males demonstrated more protective effects of low TSH against hyperlipidemia, while females showed more detrimental effects of high TSH on hyperlipidemia.

Scintigraphic Detection of Dual Ectopic Thyroid Tissue: Experience of a Chinese Tertiary Hospital

Purpose To assess scintigraphic pattern, clinical indication and relevance of dual ectopic thyroid tissue (ETT). Literature is reviewed for such cases. Methods In this 5-year retrospective study, we reviewed all thyroid scintigraphies in our data base. Patients diagnosed with suspected ETT were identified. Literature is reviewed. Statistics were done by one-way analysis of variance and least significant difference test. Results From 11905 thyroid scintigraphies during the 5-year period, we retrieved 121 patients eligible for analysis. The top two indications were assessing a palpable front neck mass to determine whether it was an ETT, and primary hypothyroidism. Patients were divided into 3 groups. Group 1 with single ETT (83 cases); group 2 with dual ETT (6 cases) and group 3 with athyroid (32 cases). Age and thyroid hormones were highest in group 2, and lowest in group 3. Thyrotropin was highest in group 3, and lowest in group 2. Thyroxine was given to hypothyroid patients, while no surgery was performed. There were 42 published cases with dual ETT, most of whom were under 30 years old. 38.10% of them were euthyroid, 33.33% hypothyroid, and 21.43% subclinical hypothyroid. Most frequent ectopic positions included lingual (33.73%), sublingual (27.71%) and subhyoid (22.89%). Conclusions In our cohort, incidence of dual ETT was 0.05% if the denominator was total number of thyroid scintigraphies. The incidence was 4.96% if the denominator was the number of patients with suspected ETT. Important clinical indication is a front neck palpable mass suggestive of an ETT. Important clinical relevance of recognizing the dual ETT pattern is to avoid inappropriate surgery. After reviewing all published cases, we find dual ETT is often seen in young patients. Most of such patients are euthyroid or mildly hypothyroid. Thyroid ectopia often resides in lingual, sublingual and subhyoid areas.

Thyrotoxicosis due to functioning metastatic follicular thyroid carcinoma after twelve I-131 therapies.

We present a case of functioning metastatic follicular thyroid carcinoma (FTC) causing severe thyrotoxicosis despite four years 12 iodine-131 therapies (1.461 Ci cumulatively). Initially, the patient had ostalgia and fracture in the right femur. Surgery-confirmed metastatic bone FTC and thyroidectomy-confirmed FTC. One month later, iodine-131 treatment commenced. During the follow-up, different metastatic sites showed different outcomes. Lung metastases disappeared, a thigh metastasis persisted, a new metastasis in the head occurred and pelvic metastases deteriorated into a huge mass elevating thyroglobulin and causing thyrotoxicosis within 3 months. Presurgical PET/CT also demonstrated the massiveness of the pelvic metastases. Thyrotoxicosis disappeared after surgical removal of the pelvic lesion.