Association of Subclinical Thyroid Dysfunction with Cognitive Impairment in Rats: The Role of Autophagy.

BACKGROUND: We investigated the effect of subclinical hyperthyroidism and subclinical hypothyroidism on cognitive function in rats and the role of autophagy in this process. METHODS: Forty Wistar rats were randomized into normal control (NC), hyperthyroidism (Hyper), hypothyroidism (Hypo), subclinical hyperthyroidism (sHyper), and subclinical hypothyroidism (sHypo) groups. Cognitive function (spatial learning and memory) was tested by the Morris water maze test. Hippocampal histopathology was analyzed by H&E staining, and expression levels of caspase-3 in hippocampal CA1 neurons were measured. In addition, immunoblot analysis was performed to detect hippocampal autophagy-related proteins. RESULTS: Escape latency from day 1 to day 4 was significantly longer in the Hypo, Hyper, and sHyper groups than in the NC group (P < 0.01). In addition, the number of rats crossing the virtual platform was significantly lower in the Hypo, Hyper, and sHyper groups than in the NC group (P < 0.01). Compared with the NC group, all four groups had significantly lower residence time in the target quadrant (P < 0.05). Beclin-1 and LC3-II protein expression in hippocampal tissues was significantly higher in the Hyper and sHyper groups than in the NC group (P < 0.01). Beclin-1 and LC3-II protein expression in hippocampal tissues did not significantly differ between the sHypo group and NC group (P > 0.05). CONCLUSIONS: Subclinical thyroid dysfunction in rats might lead to cognitive impairment. Subclinical hyperthyroidism might be associated with excessive activation of autophagy and hippocampal neuron damage and necrosis.

Cognitive dysfunction associated with activation of the mTOR signaling pathway after TSH suppression therapy in rats.

Thyroid stimulating hormone (TSH) suppression therapy after thyroid carcinoma surgery could lead to cognitive impairment. But, the possible mechanism of TSH suppression therapy impairs cognitive function is yet unknown. In this study, forty Wistar rats were randomized into the sham operation control (OC), total thyroidectomy (TD), thyroxine replacement therapy (TR), and TSH suppression therapy (TS) groups. We observed that compared to the OC group, escape latency on 1-4 days was significantly prolonged in the TD and TS groups, and the number of rats crossing the virtual platform was significantly reduced in the TD and TS groups. In the TD, TR, and TS groups, the residence time in the target quadrant was significantly decreased, while the activity distance in the target quadrant in the TD group was significantly decreased compared with OC group. In the TD and TS groups, the pyramidal cells in the hippocampal CA1 region showed a disordered arrangement. The cytoplasm was lightly stained, the cells were swollen and round, and spotty liquefaction necrosis could be observed. Compared to the OC group, hippocampal p-mTOR and p-p70s6k levels were significantly decreased in the TD group, while no significant changes were detected in the TR group. Hippocampal p-mTOR and p-p70s6k amounts in the TS group were significantly increased compared with OC group. These results indicated that TSH suppression therapy after total thyroidectomy in rats could impair cognitive function, which might be related to the activation of the mTOR signaling pathway and the damage and necrosis of hippocampal neurons.

Proteomic analysis of the papillary thyroid microcarcinoma.

OBJECTIVE: The present study applied iTRAQ and LC-MS/MS techniques for proteome analysis and compared data between specimens of papillary thyroid microcarcinoma (PTMC) vs appropriate controls, in order to investigate the mechanisms underlying the invasion and metastasis process in PTMC development. MATERIALS AND METHODS: Fresh-tissue specimens were collected from 40 patients with thyroid disease who underwent surgical treatment. Specimens were divided into four groups: normal histology (NH; n=8), benign thyroid tumor (BTT; n=10), classic PTMC with lymph node metastasis (PTC-LNM(+); n=11), and classic PTMC without lymph node metastasis (PTC-LNM(-); n=11). Proteomic studies were conducted on PTMC tissue samples without capsule invasion and with tumor diameter ranging from 0.5cm to 1cm, so as to focus the study on PTMC development excluding metastasis. RESULTS: A total of 8036 proteins were identified in the four groups. Based on protein function analysis, proteins that might be associated with PTMC invasion and metastasis were screened: alpha-actinin-1, alpha-1-antitrypsin, hepatoma-derived growth factor (HDGF), high-mobility group protein HMGI-C, and carbonic anhydrase 4. In addition, proteins involved in the focal adhesion pathway were examined. Immunohistochemistry confirmed the reliability of the iTRAQ results and the universality of differentially expressed proteins. The data showed that HDGF and high-mobility group protein HMGI-C are up-regulated in PTMC and that the focal adhesion pathway that promotes PTMC LNM is activated. CONCLUSIONS: These findings provide insight into the mechanisms underlying PTMC invasion and metastasis.

Naming difficulties after thyroid stimulating hormone suppression therapy in patients with differentiated thyroid carcinoma: a prospective cohort study.

BACKGROUND: Thyroid stimulating hormone (TSH) suppression therapy after differentiated thyroid carcinoma surgery causes cognitive impairment. However, data on naming difficulties (anomia)-related specific cognitive impairment are lacking. METHODS: A prospective cohort study was conducted, in which, patients with differentiated thyroid carcinoma and benign thyroid nodules were given oral L-T4 therapy after surgery, after meeting the criteria of TSH suppression therapy and thyroxine replacement therapy, respectively, the patients were continually given L-T4 therapy for 6 and 12 months, and then, the neuropsychological test was performed. RESULTS: Of the 255 subjects, 212 cases (83.13%) completed all the tests, including 33 cases in the normal control group (NC group), 110 cases in the TSH suppression therapy group (TS group), and 69 cases in the thyroxine replacement therapy group (TR group). There was no significant difference in background data among the three groups (P > 0.05). The scores of mini-mental state examination, clock drawing test, digit symbol substitution test, personal history, temporal and spatial orientation, digit order relation, visual object recognition, associative learning, and color naming in the TS and TR groups were not significantly different from those in the NC group after 6 and 12 months of L-T4 therapy (P > 0.05); the scores of picture recall, visual recall, comprehension memory, and digit span forward in the TS and TR groups were notably lower than those in the NC group (P < 0.01); the scores of confrontation naming and listing the names in the TS group were significantly lower than those in the NC and TR groups, and the scores decreased with the prolongation of TSH suppression therapy (P < 0.01). CONCLUSION: TSH suppression therapy after differentiated thyroid carcinoma surgery could lead to short-term memory impairment, attention impairment, word selection anomia, and depression, of which, word selection anomia was aggravated with the prolongation of TSH suppression therapy. Therefore, we suggested that optimal TSH goals for individual patients must balance the potential benefit of TSH suppression therapy with the possible harm from subclinical hyperthyroidism especially in low risk differentiated thyroid carcinoma patients (ClinicalTrials.gov Protocol Registration System: ClinicalTrials.gov ID NCT0266532, Registered on 21 June 2016).

Establishing a prediction model for lateral neck lymph node metastasis in patients with papillary thyroid carcinoma.

This study aimed to establish a model for predicting lateral neck lymph node metastasis in patients with papillary thyroid carcinoma. A total of 106 patients with papillary thyroid carcinoma undergoing initial treatment of neck lymph node dissection (including central and lateral neck lymph nodes) at the thyroid surgery department were enrolled from January 2009 to April 2017. Logistic regression analysis was used to screen the factors influencing lateral neck lymph node metastasis and develop a prediction model. The receiver operating characteristic curve was used to evaluate the predictive power and boundary value of the model for lateral neck lymph node metastasis. Prediction model: Logistic(P) = -5.699 + 0.681 × (TSH) + 0.342 × (Metastatic rate of central lymph nodes) + 1.463 × (Combined with Hashimoto's disease) + 1.525 × (Number of tumors). When logistic (P) was ≥ 0.821, it was predicted that lateral neck lymph node metastasis occurred in patients with papillary thyroid carcinoma. When logistic (P) was <0.821, it was predicted that no metastasis was found in the lateral neck lymph node. The prediction accuracy was 78.3%. The model helped in evaluating lateral neck lymph node metastasis in patients with papillary thyroid carcinoma. Also, it had significance in determining reasonable surgical range, reducing unnecessary lateral neck lymph node dissection, and further improving the quality of life of patients.

Effect of PrP105-132 on the secretion of interleukin-6 and interleukin-8 from microglial cells in vitro.

In the present study, the effect of prion protein (PrP) on the secretion of interleukin-6 (IL-6) and IL-8 from microglial cells in vitro and its possible underlying pathway were investigating by establishing a cell model for prion disease. Rat neuroglial cells were cultured in vitro, and were treated with 80 µM PrP peptides 105-132 (PrP105-132) only, PrP+MG132 or PrP+cyclosporin A (CsA). After 48 h, the IL-6 and IL-8 levels in the supernatant fluid of the treated cells were detected using enzyme-linked immunosorbent assay. In addition, the expression levels of nuclear factor-κB (NF-κB) and nuclear factor of activated T cells (NFAT) were evaluated using reverse transcription-polymerase chain reaction. The results indicated that the microglial cells were activated by treatment with PrP peptides. Cell bodies were augmented and appeared to have round, rod and amoeba-like shapes. In addition, the protuberances were shortened and eventually disappeared. Furthermore, the mRNA expression levels of NF-κB and NFAT in microglial cells increased, as well as the IL-6 and IL-8 levels in the supernatant fluid after treatment with PrP. However, the mRNA expression levels of NF-κB, and the IL-6 and IL-8 levels decreased after these cells were treated with MG132, a specific inhibitor of NF-κB. The mRNA expression of NFAT decreased after these cells were treated with CsA, a specific inhibitor of NFAT; however, the IL-6 level decreased, while no significant difference was observed in the IL-8 level. In conclusion, PrP-treated microglial cells secreted IL-6 and IL-8, and the secretion of IL-6 was associated with the activation of NF-κB and NFAT pathways. In addition, the secretion of IL-8 was mainly dependent on the NF-κB pathway.

Signaling Pathways in Thyroid Cancer.

The morbidity of thyroid cancer is increasing gradually year by year, showing an increasing tendency in nationality, sex, age, tumor size, and tumor staging. The changes of thyroid cell genes, signaling pathways, and related molecular dysfunction promote the occurrence, development, invasion, and metastasis of thyroid cancer. Surgical operation, radioiodine, and endocrinotherapy models can achieve a better prognosis for most patients with thyroid cancer. Although targeted therapeutic drugs bring possible therapeutic opportunities for refractory thyroid cancer, there is a great gap between their predictive value and their actual efficacy. Currently, there is still no completely effective drug for the treatment. Based on the signaling pathways, the "reclaim therapy" for residual tumor and systemic intervention aims to increase anticancer ability and to encourage new directions and thoughts in the treatment of refractory thyroid cancer.

Clinical Study on the Etiology of Postthyroidectomy Skin Sinus Formation.

Background. Thyroidectomy is one of the most frequently performed surgical procedures worldwide. Despite technical advances and high experience of thyroidectomy of specialized centers, it is still burdened by a significant rate of postoperative complications. Among them, the skin sinus formation is an extremely rare postthyroidectomy complication. Here, we first report the incidence of the skin sinus formation after thyroidectomy to identify the causes for skin sinus formation after thyroidectomy and to discuss its prevention and treatment options. Methods. A retrospective analysis was carried out of patients who underwent excision operation of fistula for postthyroidectomy skin sinus formation. Data were retrieved from medical records department of the Affiliated Hospital of Inner Mongolia Medical University. Results. Of the 5,686 patients who underwent thyroid surgery, only 5 patients (0.088%) had developed skin sinus formation. All 5 patients successfully underwent complete excision of fistula. Conclusion. Infection, foreign body, thyroid surgery procedure, combined disease, and iatrogenic factors may be related with skin sinus formation after thyroidectomy. To reduce the recurrence of postoperative infections and sinus formation, intra- and postoperative compliance with aseptic processing, intraoperative use absorbable surgical suture/ligature, repeated irrigation and drainage, and postoperative administration of anti-inflammatory treatment are to be followed.

Signaling Pathways in Thyroid Cancer and Their Therapeutic Implications.

Thyroid cancer is a common malignancy of endocrine system, and has now become the fastest increasing cancer among all the malignancies. The development, progression, invasion, and metastasis are closely associated with multiple signaling pathways and the functions of related molecules, such as Src, Janus kinase (JAK)-signal transducers and activators of transcription (STAT), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt, NF-κB, thyroid stimulating hormone receptor (TSHR), Wnt-ß-catenin and Notch signaling pathways. Each of the signaling pathways could exert its function singly or through network with other pathways. These pathways could cooperate, promote, antagonize, or interact with each other to form a complex network for the regulation. Dysfunction of this network could increase the development, progression, invasion, and metastasis of thyroid cancer. Inoperable thyroid cancer still has a poor prognosis. However, signaling pathway-related targeted therapies offer the hope of longer quality of meaningful life for this small group of patients. Signaling pathway-related targets provide unprecedented opportunities for further research and clinical development of novel treatment strategies for this cancer. In the present work, the advances in these signaling pathways and targeted treatments of thyroid cancer were reviewed.