The insular cortex is not insular in thyroid eye disease: neuroimaging revelations of central-peripheral system interaction.

BACKGROUND: Thyroid eye disease (TED) is highly correlated with dysregulated immunoendocrine status. The insular cortex was found to regulate peripheral inflammation and immunomodulation in mice. This study aimed to explore whether the insular cortex in patients with TED played a modulatory role including the aberrant brain functional alteration and its association with immunoendocrine status. METHODS: This study included 34 active patients (AP), 30 inactive patients (IP) with TED, and 45 healthy controls (HC) matched for age, sex, and educational level. Comprehensive clinical details (especially immunoendocrine markers) and resting-state functional magnetic resonance imaging data were collected from each participant. The amplitude of low-frequency fluctuation (ALFF) was used to probe the aberrant alterations of local neural activity. The seed-based functional connectivity (FC) analysis was used to explore the relationship between the insular cortex and each voxel throughout the whole brain. The correlation analysis was conducted to assess the association between insular neurobiomarkers and immunoendocrine parameters. RESULTS: When compared with the IP and HC groups, the AP group displayed significantly higher ALFF values in the right insular cortex (INS.R) and lower FC values between the INS.R and the bilateral cerebellum. None of the neurobiomarkers differed between the IP and HC groups. Besides, correlations between insular neurobiomarkers and immunoendocrine markers (free thyroxine, the proportion of T cells, and natural killer cells) were identified in both AP and IP groups. CONCLUSIONS: This study was novel in reporting that the dysregulation of the insular cortex activity in TED was associated with abnormal peripheral immunoendocrine status. The insular cortex might play a key role in central-peripheral system interaction in TED. Further research is crucial to enhance our understanding of the central-peripheral system interaction mechanisms involved in autoimmune diseases.

Correlation between serum sex hormone-binding globulin levels and nutrition indicators and malnutrition exposure risk in men and postmenopausal women with type 2 diabetes.

BACKGROUND: This study sought to investigate the correlation between serum sex hormone-binding globulin (SHBG) levels and nutrition indicators and the malnutrition exposure risk in men and postmenopausal women with type 2 diabetes mellitus (T2DM). METHODS: A cross-sectional analysis was conducted, involving patients diagnosed with T2DM at the Guangdong Provincial People's Hospital between May 2018 and December 2019. RESULTS: The study comprised 551 participants (363 men, mean age of 55.55 ± 11.57 years), among whom 167 (30.31%) were classified as with malnutrition exposure risk (GNRI ≤ 98). Multivariable logistic regression analysis revealed that SHBG (OR = 1.04, 95% CI: 1.02-1.05, P < 0.001), glycated hemoglobin (OR = 1.36, 95% CI: 1.22-1.51, P < 0.001), hemoglobin (OR = 0.96, 95% CI: 0.94-0.97, P < 0.001), and non-alcoholic fatty liver disease (OR = 0.41, 95% CI: 0.23-0.73, P < 0.003) were independently associated with the malnutrition exposure risk. SHBG was inversely correlated with body mass index (males: r = -0.34; postmenopausal females: r = -0.22), albumin (males: r = -0.30; postmenopausal females: r = -0.20), transferrin (males: r = -0.28; postmenopausal females: r = -0.19), and prealbumin (males: r = -0.35; postmenopausal females: r = -0.30) (all P < 0.05). CONCLUSIONS: Serum SHBG levels are correlated with nutritional indicators and the risk of malnutrition in men and postmenopausal women with T2DM. A multicenter prospective study is imperative to verify this result in the future.

A new discriminant strategy combined with four TIRADS screening procedures increases ultrasound diagnostic accuracy-focusing on "wrong diagnostic" thyroid nodules.

OBJECTIVE: To utilize the discrepancies of different TIRADS, including ACR-TIRADS, Kwak-TIRADS, C-TIRADS, and EU-TIRADS, to explore methods for improving ultrasound diagnostic accuracy. METHODS: In total, 795 nodules with cytological or surgical pathology were included. All nodules were screened by the four TIRADS according to their diagnostic concordance (Screening procedures, SP). Discriminant strategy (DS) derived from predictor variables was combined with SP to construct the evaluation method (SP+DS). The diagnostic performance of the SP+DS method alone and its derivational methods and two-TIRADS combined tests was evaluated. RESULTS: A total of 86.8% (269/310) malignant nodules and 93.6% (365/390) benign cases diagnosed by the four TIRADS simultaneously were pathologically confirmed, while 12.0% (95/795) nodules could not be consistently diagnosed by them. The criteria of DS were that iso- or hyper-echogenicity nodules should be considered benign, while hypo- or marked hypo-echogenicity nodules malignant. For 95 inconsistently diagnosed nodules screened by at least two TIRADS, DS performed best with an accuracy of 79.0%, followed by Kwak-TIRADS (72.6%). In the overall sample, the sensitivity and AUC were highest for the SP+DS method compared to the four TIRADS (91.3%, 0.895). Combining ACR-TIRADS and Kwak-TIRADS via parallel test resulted in significant improvements in the sensitivity and AUC compared to ACR-TIRADS (89.2% vs. 81.4%, 0.889 vs. 0.863). Combining C-TIRADS and DS in serial resulted in the highest AUC (0.887), followed by Kwak-TIRADS (0.884), while EU-TIRADS was the lowest (0.879). CONCLUSIONS: For undetermined or suspected thyroid nodules, two-TIRADS combined tests can be used to improve diagnostic accuracy. Otherwise, considering the inconsistent diagnosis of two TIRADS may require attention to the echo characteristics to differentiate between benign and malignant nodules. KEY POINTS: • The discrepancies in the diagnostic performance of different TIRADS arise from their performance on inconsistently diagnosed nodules. • ACR-TIRADS improves sensitivity via combining with Kwak-TIRADS in parallel (from 81.4 to 89.2%), while C-TIRADS increases specificity via combining with EU-TIRADS in serial (from 80.9 to 85.7%). • If the diagnostic findings of two TIRADS are inconsistent, echo characteristics will be helpful for the differentiation of benign and malignant nodules with an accuracy of 79.0%.

Performance of current ultrasound-based malignancy risk stratification systems for thyroid nodules in patients with follicular neoplasms.

OBJECTIVES: To investigate the ability of the currently used ultrasound-based malignancy risk stratification systems for thyroid neoplasms (ATA, AACE/ACE/AME, K-TIRADS, EU-TIRADS, ACR-TIRADS and C-TIRADS) in distinguishing follicular thyroid carcinoma (FTC) from follicular thyroid adenoma (FTA). Additionally, we evaluated the ability of these systems in correctly determining the indication for biopsy. METHODS: Three hundred twenty-nine follicular neoplasms with definitive postoperative histopathology were included. The nodules were categorized according to each of six stratification systems, based on ultrasound findings. We dichotomized nodules into the positive predictive group of FTC (high and intermediate risk) and negative group of FTC based on the classification results. Missed biopsy was defined as neoplasms that were diagnosed as FTCs but for which biopsy was not indicated based on lesion classification. Unnecessary biopsy was defined as neoplasms that were diagnosed as FTAs but for whom biopsy was considered indicated based on classification. The diagnostic performance and missed and unnecessary biopsy rates were evaluated for each stratification system. RESULTS: The area under the curve of each system for distinguishing follicular neoplasms was < 0.700 (range, 0.511-0.611). The missed biopsy rates were 9.0-22.4%. The missed biopsy rates for lesions ≤ 4 cm and lesions sized 2-4 cm were 16.2-35.1% and 0-20.0%, respectively. Unnecessary biopsy rates were 65.3-93.1%. In ≤ 4 cm group, the unnecessary biopsy rates were 62.2-89.7%. CONCLUSION: The malignancy risk stratification systems can select appropriate nodules for biopsy in follicular neoplasms, while they have limitations in distinguishing follicular neoplasms and reducing unnecessary biopsy. Specific stratification systems and recommendations should be established for follicular neoplasms. KEY POINTS: • Current ultrasound-based malignancy risk stratification systems of thyroid nodules had low efficiency in the characterization of follicular neoplasms. • The adopted stratification systems showed acceptable performance for selecting FTC for biopsy but unsatisfactory performance for reducing unnecessary biopsy.

Thyroid Feedback Quantile-Based Index Is Associated With Blood Pressure and Other Hemodynamic Measures: A Cross-sectional Study.

OBJECTIVE: Previous studies have reported inconsistent relationships between thyroid function and blood pressure (BP) levels. We aimed to explore the associations between thyroid hormone sensitivity and BP parameters. METHODS: This retrospective study included 6272 participants who underwent a health examination at the First Hospital of China Medical University between January 2017 and December 2018. The Thyroid Feedback Quantile-based Index (TFQI), Parametric TFQI, thyroid-stimulating hormone index, and thyrotroph thyroxine resistance index were calculated to reflect thyroid hormone sensitivity. Mean arterial pressure, pulse pressure, and rate-pressure product were used to indirectly represent arterial stiffness. RESULTS: The TFQI was positively associated with systolic BP (ß = 3.22), diastolic BP (ß =2.32), and mean arterial pressure (ß = 2.62) (P < .001, for all). Analyses of the Parametric TFQI, thyroid-stimulating hormone index, and thyrotroph thyroxine resistance index yielded similar results. The TFQI was positively related to pulse pressure and rate-pressure product. With a 1 SD increase in the TFQI, the adjusted odds ratio for hypertension was 1.11 (95% CI 1.04-1.18). When comparing the fourth quartile of the TFQI with the first, the odds ratio for hypertension was 1.27 (95% CI 1.07-1.51, Pfor trend = .006). These relationships remained significant when stratified by age, sex, and body mass index. Similar results were observed in a euthyroid or normotensive population. CONCLUSION: The TFQI was positively associated with BP and markers of arterial stiffness. Impaired thyroid hormone sensitivity was related to increased risk for hypertension.

MKL1 overexpression predicts poor prognosis in patients with papillary thyroid cancer and promotes nodal metastasis.

Papillary thyroid cancer (PTC), the most common thyroid malignancy, has a strong propensity for cervical lymph node metastasis (LNM), which increases the risk of locoregional recurrence and decreases survival probability in some high-risk groups. Hence, there is a pressing requirement for a reliable biomarker to predict LNM in thyroid cancer. In the present study, MKL1 (also known as MRTFA) expression was significantly increased in PTC patients with LNM compared with those without. Further receiver operating characteristic (ROC) analysis showed that MKL1 expression had a diagnostic value in the differentiation of LNM in PTC. Furthermore, Kaplan-Meier analysis revealed that high MKL1 expression was associated with significantly decreased survival in PTC. Additionally, our study indicated that MKL1 promoted the migration and invasion of PTC cells. MKL1 interacted with and recruited Smad3 to the promoter of MMP2 to activate MMP2 transcription upon treatment with TGF-ß. Moreover, there was significant correlation between expression of TGF-ß, MKL1 and MMP2 in our clinical cohort of specimens from individuals with PTC. Our results suggest that the detection of MKL1 expression could be used to predict cervical LNM and inform post-operative follow-up in individuals with PTC.

Choosing Optimal Microcarcinoma Patients for Active Surveillance Study (Compass): Effectiveness Evaluation of a Preoperative Clinical Framework.

OBJECTIVE: Active surveillance (AS) is a management alternative for patients with low-risk papillary thyroid microcarcinoma (PTMC). To decide the best candidates for AS, clinicians can use a framework to classify PTMC patients as ideal, appropriate, or inappropriate. This study aimed to explore the correlation between the framework categories and surgical pathology. METHODS: This multicenter retrospective study was conducted between 2014 and 2016. We included 1997 patients who underwent thyroid surgery for the first time due to suspected PTMC and were confirmed as PTMC by postoperative pathology. The consistency of modified preoperative risk stratification and the pathologic condition were evaluated using a consistency ratio and the Kappa coefficient. Stratified analysis was also performed to test consistency in different age groups. RESULTS: Based on the decision-making framework, 558 (27.9%) patients could receive AS while 810 (40.6%) patients did not require immediate surgery according to the actual postoperative pathology. The sensitivity, false-positive rate, specificity, false-negative rate, and consistency rate were 82.39%, 56.91%, 43.09%, 17.61%, and 66.45%, respectively. The Kappa value was 0.268. Stratified analysis showed that the sensitivity was 87.7% among patients aged 18 to 59 years. In the group aged ≥60 years, the specificity was up to 87.5%, but the sensitivity was low. CONCLUSION: The results of the modified risk-stratified clinical decision-making framework did not have a high consistency with the postoperative results. However, the framework showed a good effect in selecting patients for immediate surgery in the younger group and patients for AS in the older group.

Diallyl trisulfide, a H2 S donor, inhibits cell growth of human papillary thyroid carcinoma KTC-1 cells through a positive feedback loop between H2 S and cystathionine-gamma-lyase.

Diallyl trisulfide (DATS), derived from garlic, is a well-known hydrogen sulfide (H2 S) donor. H2 S has recently emerged as a novel gasotransmitter involved in the regulation of cancer progression. The present study demonstrated that DATS along with other two H2 S donors, NaHS and GYY4137, significantly inhibited papillary thyroid carcinoma KTC-1 cells growth. DATS treatment triggered a rapid H2 S generation within 5 min in KTC-1 cells. Iodoacetamide, a potent thiol blocker reagent, partially rescued the cell membrane damage and ultimate cell death induced by DATS, indicating H2 S contributed to the apoptosis-inducing efficacy of DATS on thyroid cancer cells. Specifically, DATS treatment significantly upregulated the expression and enzymatic activity of cystathionine gamma-lyase (CTH), one of H2 S-producing enzymes, which was responsible for endogenous H2 S generation. After DATS treatment, H2 S quickly permeated cell membranes and activated NF-κΒ/p65 signaling pathway in KTC-1 cells. Nuclear translocated NF-κB bound to the promoter of CTH to enhance its transcription. These evidences proved that exogenous H2 S elevated CTH expression. CTH, in turn, catalytically generated a much higher level of endogenous H2 S. This positive feedback sustained excess H2 S production, which resulted in PTC cells growth inhibition. These findings may shed light on the development of novel H2 S-based antitumor agents.

Association of abnormal serum electrolyte levels with hypertension in a population with high salt intake.

OBJECTIVE: The present epidemiological study aimed to evaluate the association of serum electrolyte levels with hypertension in a population with a high-salt diet. DESIGN: Secondary analysis of epidemiology data from the Northeast China Rural Cardiovascular Health Study conducted in 2012-2013. Blood pressure and hypertension status were analysed for association with serum sodium, potassium, chloride, total calcium, phosphate and magnesium levels using regression models. SETTING: High-salt diet, rural China.ParticipantsAdult residents in Liaoning, China. RESULTS: In total 10 555 participants were included, of whom 3287 had incident hypertension (IH) and 1655 had previously diagnosed hypertension (PDH). Fifty-six per cent of participants had electrolyte disturbance. Sixty-two per cent of hypercalcaemic participants had hypertension, followed by hypokalaemia (56 %) and hypernatraemia (54 %). Only hypercalcaemia showed significant associations with both IH (OR=1·70) and PDH (OR=2·25). Highest serum calcium quartile had higher odds of IH (OR=1·58) and PDH (OR=1·64) than the lowest quartile. Serum sodium had no significant correlation with hypertension. Serum potassium had a U-shaped trend with PDH. Highest chloride quartile had lower odds of PDH than the lowest chloride quartile (OR=0·65). Highest phosphate quartile was only associated with lower odds of IH (OR=0·75), and the higher magnesium group had significantly lower odds of IH (OR=0·86) and PDH (OR=0·77). CONCLUSIONS: We have shown the association of serum calcium, magnesium and chloride levels with IH and/or PDH. In the clinical setting, patients with IH may have concurrent electrolyte disturbances, such as hypercalcaemia, that may indicate other underlying aetiologies.

Resistance to thyroid hormone ß in autoimmune thyroid disease: a case report and review of literature.

BACKGROUND: Resistance to thyroid hormone beta (RTHß) results in symptoms of both increased and decreased thyroid hormone action. The effect of thyroid hormone changes in different types of autoimmune thyroid disease (AITD) in RTHß is dynamic. CASE PRESENTATION: A 25-year-old Asian female had a RTHß Y321C mutation with Hashimoto's thyroiditis and type 2 diabetes mellitus. She was followed-up through gestation and two years postpartum, revealing development of postpartum thyroiditis (PPT) with characteristic wide fluctuations in serum thyrotropin levels, and of spontaneous recovery from an episode of transient hypothyroidism. The presence of RTHß did not prolong thyroiditis duration nor progressed toward permanent hypothyroidism. Prenatal genetic analysis was not performed on the unaffected fetus, and did not result in congenital hypothyroidism, possibly because maternal free thyroxine (FT4) levels were mildly elevated at less than 50% above the reference range in early gestation and gradually decreased to less than 20% after the 28th gestational week. CONCLUSION: In RTHß patients with autoimmune thyroid disease, episodes of thyroid dysfunction can significantly alter thyrotropin levels. During pregnancy, mildly elevated maternal free thyroxine levels less than 20% above the upper limit may not be harmful to unaffected fetuses. Unnecessary thyroid hormone control and fetal genetic testing was avoided during the gestational period with monthly follow-up.

Curcumin inhibits metastasis in human papillary thyroid carcinoma BCPAP cells via down-regulation of the TGF-ß/Smad2/3 signaling pathway.

Thyroid cancers usually possess a good prognosis while the risks of recurrence and metastasis turn out to be a disturbing issue. Curcumin [bis(4-hydroxy-3-methoxy-phenyl)-1,6-heptadiene-3,5-dione] is a natural polyphenolic compound mainly found in turmeric (Curcuma longa). Our previous studies have demonstrated that curcumin showed proliferation-inhibitory and apoptosis-inducing effects on K1 papillary thyroid cancer cells. However, the mechanism underlying the inhibition effects of curcumin on thyroid cancer cells remains unclear. Herein, we demonstrated that curcumin remarkably increased the expression of the epithelial marker E-cadherin and repressed the expression of the mesenchymal marker vimentin in human papillary thyroid carcinoma BCPAP cells. Curcumin also suppressed multiple metastatic steps of BCPAP cells, including cell attachment, spreading as well as migration. In addition, the transcription, secretion and activation of matrix metalloproteinases (MMPs) induced by transforming growth factor-ß1 (TGF-ß1) in BCPAP cells were mitigated upon curcumin treatment. Further evidence showed that curcumin decreased TGF-ß1-mediated phosphorylation of Smad2 and Smad3. These results revealed that curcumin inhibited the TGF-ß1-induced epithelial-mesenchymal transition (EMT) via down-regulation of Smad2/3 signaling pathways. Our findings provide new evidence that the anti-metastatic and anti-EMT activities of curcumin may contribute to the development of chemo-preventive agents for thyroid cancer treatment.

Pycnogenol Reduces Toll-Like Receptor 4 Signaling Pathway-Mediated Atherosclerosis Formation in Apolipoprotein E-Deficient Mice.

Pycnogenol (PYC) is an extract from French maritime pine bark. Its antioxidative and anti-inflammatory effects have been shown to be beneficial for atherosclerosis. Here, we tested whether PYC could suppress high cholesterol and fat diet (HCD)-induced atherosclerosis formation in apolipoprotein E (apoE)-deficient mice. In our study, PYC suppressed oxidized low-density lipoprotein (ox-LDL)-induced lipid accumulation in peritoneal macrophages. Apolipoprotein E-deficient mice were orally administered PYC or a control solvent for ten weeks, and these mice were fed a standard diet or high cholesterol and fat diet during the latter eight weeks. Pycnogenol markedly decreased the size of atherosclerotic lesions induced by high cholesterol and fat diet compared with the nontreated controls. In addition, TLR4 expression in aortic sinus was stimulated by high cholesterol and fat diet feeding and was significantly reduced by PYC. A mechanistic analysis indicated that lipopolysaccharide (LPS) significantly increased expression of fatty acid binding protein (aP2) and macrophage scavenger receptor class A (SR-A), which were blocked by a JNK inhibitor. Furthermore, PYC inhibited the lipopolysaccharide-induced upregulation of aP2 and scavenger receptor class A via the JNK pathway. In conclusion, PYC administration effectively attenuates atherosclerosis through the TLR4-JNK pathway. Our results suggest that PYC could be a potential prophylaxis or treatment for atherosclerosis in humans.

Continuous effect with long-term safety in zoledronic acid therapy for polyostotic fibrous dysplasia with severe bone destruction.

Polyostotic fibrous dysplasia (PFD) is a rare non-inherited genetic disorder characterized by osteolytic lesions in multiple bones causing bone pain, deformity, and pathological fracture. As an anti-osteolytic agent, the new generation bisphosphonate zoledronic acid (ZOL) restricts lesion progression by inhibiting osteoclastic activity. Although ZOL is more effective than pamidronate, its efficacy and safety in long-term therapy in PFD is unknown. We report a case of PFD advanced to extensive bone destruction in the skull and ribs and evaluate the efficacy and long-term safety of early first-line ZOL in PFD with severe bone disease, recommending possible future treatments. The annual infusion of 5 mg ZOL was intravenously administered, cumulatively 20 mg over four courses, with oral supplementation of calcium, vitamin D, and potassium. No long-term use side effect was observed, and mild transient symptoms were easily resolved. Significant radiological improvement was seen in filling of destroyed bone and cortical thickening. ZOL decreased both serum collagen type 1 cross-linked C-telopeptide and type 1 procollagen N-terminal (P1NP) from extremely high baseline levels. An unexpected direct increase in P1NP after long-term therapy could indicate discontinuation of ZOL to observe its prolonged effect. Early first-line ZOL therapy is effective in PFD with severe bone destruction and is safe for long-term therapy. The use of bisphosphonates in FD remains off-label, and regular monitoring is highly advised.

Tumor-associated macrophages promote the metastatic potential of thyroid papillary cancer by releasing CXCL8.

Tumor-associated macrophages (TAMs) can promote cancer initiation and progression by releasing cytokines. Previously, we have found the density of TAMs correlated with lymph node metastasis in papillary thyroid carcinoma (PTC). However, the mechanisms of how TAMs promote PTC progression remain unclear. In this study, we first showed that the TAMs density in the tumor core was associated with progressive PTC features and TAMs conditioned medium enhanced PTC cells invasion. Cytokine profiling identified a mixed M1/M2 phenotype and CXCL8 was the most consistently abundant cytokine in PTC-derived TAMs. CXCL8 receptors, CXCR1 and CXCR2, were positively stained in PTC cell lines and tissues, though no association with lymph node metastasis or extrathyroid extension. PTC cell invasion was abrogated by anti-CXCL8-neutralizing antibody, whereas addition of exogenous recombinant human CXCL8 enhanced the invasiveness. More importantly, CXCL8 promoted PTC metastasis in vivo. No difference was found for TAMs-derived CXCL8 expression in patients with and without lymph node metastasis or extrathyroid extension. These findings indicated that TAMs may facilitate PTC cell metastasis through CXCL8 and its paracrine interaction with CXCR1/2.

The involvement of CXCR7 in modulating the progression of papillary thyroid carcinoma.

BACKGROUND: Although papillary thyroid carcinoma (PTC) has favorable prognosis, it is prone to cervical lymph node metastasis. Chemokine receptors play a role in metastasis of tumor cells, and accumulating evidence suggests an important role for the chemokine receptor CXCR7 in cancer development. We previously demonstrated high expression of CXCR7 protein in PTC tissue. In this study, we further evaluated the role of CXCR7 in PTC. METHODS: The expression of CXCR7 messenger RNA and protein in 79 cases of PTC and peritumoral tissues was detected by real-time quantitative polymerase chain reaction and Western blot. The association between CXCR7 expression and clinicopathologic characteristics in PTC was analyzed. Stable CXCR7 overexpression and knockdown PTC cells were constructed and used to examine proliferation, cell cycle, apoptosis and invasion of PTC cells by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, propidium iodide staining, 7-amino-actinomycin D staining, and invasion assay. We examined cell cycle regulatory protein levels by Western blot. RESULTS: CXCR7 messenger RNA and protein levels were markedly increased in PTC and correlated with tumor progression. CXCR7 could regulate proliferation, cell cycle, apoptosis, invasion, and the expression of cell cycle regulatory proteins involved in the S-G2 phase transition. Knockdown of CXCR7 in PTC cells suppressed cell proliferation and invasion, decreased expression of cyclin A, CDK2 and PCNA, increased expression of p21 and p57, induced S phase arrest, and promoted apoptosis. CONCLUSIONS: CXCR7 plays an important role in regulating growth and metastasis ability of PTC cell and provides a potential target for therapeutic interventions in PTC.

Adiponectin Inhibits the Progression of Obesity-Associated Papillary Thyroid Carcinoma Through Autophagy.

CONTEXT: Obesity is a risk factor for the development of papillary thyroid cancer (PTC). However, the molecular mechanisms by which obesity promotes PTC are unclear. OBJECTIVE: This study aims to identify adipokines that are linked to PTC progression. METHODS: An adipokine antibody array was used to determine the serum levels of 40 adipokines in normal-weight and obese PTC patients. Enzyme-linked immunosorbent assay was used to determine the serum levels of adiponectin. Recombinant human adiponectin was produced by human adipose-derived stem cells and used to treat PTC cells. Cell proliferation and migration were evaluated using the CCK8 and Transwell assays. Bioinformatics analysis was used to predict mechanisms by which adiponectin affects PTC. RESULTS: Adipokines differentially expressed between normal-weight and obese patients showed a gender-dependent pattern. Obese PTC patients had a significantly lower serum adiponectin level than normal-weight patients, especially in female individuals. Adiponectin levels were negatively correlated with aggressive features of PTC, including tumor diameter > 1 cm, extrathyroidal extension, and lymph node metastasis. Recombinant human adiponectin inhibited the proliferation and migration of human PTC cells in vitro. Bioinformatics analysis identified adiponectin receptor 2 (ADIPOR2) and the autophagy pathway as possible mediators of adiponectin function in TC. In vitro experiments confirmed that adiponectin activated autophagy in PTC cells. These findings shed new lights into the role and mechanisms of adiponectin in TC pathogenesis. CONCLUSION: Adiponectin is involved in development of obesity-related PTC. Adiponectin can directly inhibit thyroid cancer growth and metastasis through the autophagy pathway.

Uncovering the connection between obesity and thyroid cancer: the therapeutic potential of adiponectin receptor agonist in the AdipoR2-ULK axis.

Adiponectin, a unique adipose-derived factor, is significantly downregulated in obesity, making it a crucial target for tumor-related metabolic research. AdipoRon is a novel adiponectin receptor agonist with the advantages of a small molecular weight, high stability and a long half-life. By screening the cervical adipose tissue of papillary thyroid carcinoma (PTC) patients with adipokine antibody array, we found that adiponectin was a potential correlation factor between obesity and PTC progression. AdipoRon has oral activity and is easily absorbed and delivered to target tissues. The effects of AdipoRon on thyroid cancer have not been reported. In this study, we identified adiponectin receptor 1 (AdipoR1) and AdipoR2 on the surface of thyroid cancer cell lines. AdipoRon inhibited the proliferation and migration of thyroid cancer cells, limited energy metabolism in thyroid cancer cells, promoted differentiation of thyroid cancer cells, and induced autophagy and apoptosis. Mechanistic studies revealed that AdipoRon inhibited p-mTOR Ser2448 and p-p70S6K Thr389, and activated ULK1 and p-ULK1. ULK1 knockdown suppressed the effect of AdipoRon on LC3BII/I protein and lysosomes. AdipoR2 knockdown reduced AdipoRon-induced autophagy in thyroid cancer cells. This study is the first to demonstrate the role of AdipoRon in PTC. Our findings illustrate a previously unknown function and mechanism of the AdipoRon-AdipoR2-ULK/p-ULK1 axis in PTC and lay the foundation for clinical translation of AdipoRon to PTC. Targeting the AdipoRon-AdipoR2-ULK/p-ULK1 axis may represent a new therapeutic strategy for PTC.

Diabetes exerts a causal impact on the nervous system within the right hippocampus: substantiated by genetic data.

INTRODUCTION: Diabetes and neuronal loss in the hippocampus have been observed to be correlated in several studies; however, the exact causality of this association remains uncertain. This study aims to explore the potential causal relationship between diabetes and the hippocampal nervous system. METHODS: We utilized the two-sample Mendelian randomization (MR) analysis to investigate the potential causal connection between diabetes and the hippocampal nervous system. The summary statistics of Genome-wide association study (GWAS) for diabetes and hippocampus neuroimaging measurement were acquired from published GWASs, all of which were based on European ancestry. Several two-sample MR analyses were conducted in this study, utilizing inverse-variance weighted (IVW), MR Egger, and Weight-median methods. To ensure the reliability of the results and identify any horizontal pleiotropy, sensitivity analyses were undertaken using Cochran's Q test and the MR-PRESSO global test. RESULTS: Causal associations were found between diabetes and the nervous system in the hippocampus. Type 1 and type 2 diabetes were both identified as having adverse causal connections with the right hippocampal nervous system. This was supported by specific ranges of IVW-OR values (P < 0.05). The consistency of the sensitivity analyses further reinforced the main findings, revealing no significant heterogeneity or presence of horizontal pleiotropy. CONCLUSIONS: This study delved into the causal associations between diabetes and the hippocampal nervous system, revealing that both type 1 and type 2 diabetes have detrimental effects on the right hippocampal nervous system. Our findings have significant clinical implications as they indicate that diabetes may play a role in the decline of neurons in the right hippocampus among European populations, often resulting in cognitive decline.

Soluble immune checkpoints associated with disease activity and treatment response in GD and TED.

CONTEXT: Soluble immune checkpoints play an important role in peripheral tolerance that has seldom been investigated in Graves' disease (GD) and thyroid eye disease (TED). OBJECTIVE: The objective of this work is to examine the alteration of soluble immune checkpoints in GD and TED. METHODS: We performed a quantitative multiplex analysis of 17 immune checkpoint proteins in serum from 50 GD patients without TED, 28 GD patients with TED and 40 healthy controls. The association with demographical, serological, clinical features and 27 cytokines was analyzed. A follow-up was conducted in GD patients without TED. Functional outcomes of sLAG-3 and sGITR were assessed in cell cultures using rh-LAG3, rh-GITR, an antagonistic LAG-3 antibody and an antagonistic GITR antibody. RESULTS: GD patients with TED had distinct sICP and cytokine profiles compared with GD patients without TED. Active TED patients exhibited elevation in the levels of sBTLA, sLAG-3, sGITR, sCD80, sCD86 and sPD-L1. Further, GD patients without TED with high sBTLA, sCD27 and sCD40 levels at baseline showed a better improvement in thyrotropin receptor antibody (TRAb) titers after antithyroid drug (ATD) treatment. Adding recombinant human GITR and LAG-3 to PBMC cultures resulted in increased inflammatory cytokine secretion and decreased anti-inflammatory cytokine secretion. CONCLUSIONS: The present study uncovers disturbed soluble immune checkpoints and cytokines in GD patients with and without TED, and may pave the way for novel immunological screening, allowing for identification of TED patients at higher risk of developing active disease and GD patients with better treatment response after ATD treatment.

Immune checkpoint inhibitors-related endocrinopathies exhibit increased severity in breast cancer patients: a real-world study.

PURPOSE: This study aims to systematically evaluate the incidence of immune checkpoint inhibitors (ICIs)-related endocrinopathies and their onset time in patients with breast cancer (BC) in a real-world setting. METHODS: An analysis was conducted on the medical records of 122 BC patients who underwent ICIs therapy at the Department of Breast Surgery, Guangdong Provincial People's Hospital, from April 2019 to September 2021. Follow-up data continued until October 2022. RESULTS: The research indicated that 60.66% of BC patients experienced ICI-related endocrinopathies. The endocrinopathies included pituitary injury (7.38%), primary thyroid dysfunction (34.43%), supranormal fasting blood glucose or glycohemoglobin levels (16.39%), and adrenal injury (2.46%). Subgroup analyses were further performed based on clinical characteristics, demonstrated variability in the incidence of ICI-related endocrinopathies. Notably, subpopulations harboring genetic mutations exhibited a markedly higher prevalence of hypophysitis, as evidenced by a statistically significant association (P = 0.022). Similarly, individuals with HER2 positivity were found to have a significantly increased incidence of pancreatic islet injury (P = 0.023). Moreover, the study documented that the median onset times of ICIs-related endocrinopathies in pituitary, thyroid, pancreatic, and adrenal damage were 264, 184, 99 and 141 days, respectively, which were substantially longer compared to previous reports involving other tumors. Remarkably, even after 500 days of initiating ICI therapy, new cases of ICI-related endocrine disorders continue to emerge, suggesting a situation of delayed onset of ICI-related endocrinopathies in BC patients. CONCLUSION: The retrospective analysis confirmed a higher incidence and longer median onset time of ICI-related endocrinopathies in BC patients compared to other cancers. These outcomes underscore the critical need for regular and extended monitoring of endocrine functions in BC patients receiving ICI therapy, advocating for personalized monitoring approaches based on individual clinical profiles.