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Cancer therapies targeting genetic alterations are a topic of great interest in the field of thyroid cancer, which frequently harbors mutations in the RAS, RAF, and RET genes. Unfortunately, U.S. Food and Drug Administration-approved BRAF inhibitors have relatively low therapeutic efficacy against BRAF-mutant thyroid cancer; in addition, the cancer often acquires drug resistance, which prevents effective treatment. Recent advances in genomics and transcriptomics are leading to a more complete picture of the range of mutations, both driver and messenger, present in thyroid cancer. Furthermore, our understanding of cancer suggests that oncogenic mutations drive tumorigenesis and induce rewiring of cancer cell metabolism, which promotes survival of mutated cells. Synthetic lethality (SL) is a method of neutralizing mutated genes that were previously considered untargetable by traditional genotype-targeted treatments. Because these metabolic events are specific to cancer cells, we have the opportunity to develop new therapies that target tumor cells specifically without affecting healthy tissue. Here, we describe developments in metabolism-based cancer therapy, focusing on the concept of metabolic SL in thyroid cancer. Finally, we discuss the essential implications of metabolic reprogramming and its role in the future direction of SL for thyroid cancer.

Background Thyroid hormone excess induces protein energy wasting, which in turn promotes muscle weakness and bone loss in patients with Graves' disease. Although most studies have confirmed a relationship between thyrotoxicosis and muscle dysfunction, few have measured changes in plasma metabolites and immune cells during the development and recovery from thyrotoxic myopathy. The aim of this study was to identify specific plasma metabolites and T‐cell subsets that predict thyrotoxic myopathy recovery in patients with Graves' disease. Methods One hundred patients (mean age, 40.0 ± 14.2 years; 67.0% female), with newly diagnosed or relapsed Graves' disease were enrolled at the start of methimazole treatment. Handgrip strength and Five Times Sit to Stand Test performance time were measured at Weeks 0, 12, and 24. In an additional 35 patients (mean age, 38.9 ± 13.5 years; 65.7% female), plasma metabolites and immunophenotypes of peripheral blood were evaluated at Weeks 0 and 12, and the results of a short physical performance battery assessment were recorded at the same time. Results In both patient groups, methimazole‐induced euthyroidism was associated with improved handgrip strength and lower limb muscle function at 12 weeks. Elevated plasma metabolites including acylcarnitines were restored to normal levels at Week 12 regardless of gender, body mass index, or age (P trend

Objective CD14 is a lipopolysaccharide-binding protein that serves as a marker of monocytes. The role of circulating CD14 in patients with obesity without diabetes remains unknown. Here, we characterized the relationships between serum CD14 concentration and metabolic parameters related to diabetes and obesity. Methods We performed an observational, prospective case–control study. Eighty participants were evaluated: 26 drug-naïve patients with type 2 diabetes mellitus and 54 healthy individuals. We compared the circulating CD14 concentration and metabolic parameters of the participants with and without diabetes. Results The circulating CD14 concentration did not significantly differ between the two groups, but was lower in participants with obesity than in lean controls. No significant associations existed between CD14 concentration and metabolic parameters in the participants with diabetes, but in those without diabetes, the circulating CD14 concentration significantly negatively correlated with body mass index; waist circumference; the concentrations of fasting insulin, 2-hour post-load glucose, 2-h post-load insulin, and low-density lipoprotein-cholesterol; homeostasis model of assessment (HOMA) of insulin resistance; and HOMA beta-cell function. Conclusions This is the first study to show associations of serum CD14 concentration with metabolic parameters in non-diabetic individuals. Circulating CD14 may represent a useful biomarker of metabolic dysfunction in non-diabetic individuals.

Mitochondrial targeted therapy is a next-generation therapeutic approach for cancer that is refractory to conventional treatments. Mitochondrial damage caused by the excessive accumulation of reactive oxygen species (ROS) is a principle of mitochondrial targeted therapy. ROS in nonthermal plasma-activated media (NTPAM) are known to mediate anticancer effects in various cancers including head and neck cancer (HNC). However, the signaling mechanism of HNC cell death via NTPAM-induced ROS has not been fully elucidated. This study evaluated the anticancer effects of NTPAM in HNC and investigated the mechanism using transcriptomic analysis. The viability of HNC cells decreased after NTPAM treatment due to enhanced apoptosis. A human fibroblast cell line and three HNC cell lines were profiled by RNA sequencing. In total, 1 610 differentially expressed genes were identified. Pathway analysis showed that activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) were upstream regulators. Mitochondrial damage was induced by NTPAM, which was associated with enhancements of mitochondrial ROS (mtROS) and ATF4/CHOP regulation. These results suggest that NTPAM induces HNC cell death through the upregulation of ATF4/CHOP activity by damaging mitochondria via excessive mtROS accumulation, similar to mitochondrial targeted therapy.

Various enzymes in the one-carbon metabolic pathway are closely related to the development of tumors, and they can all be potential targets for cancer therapy. Serine hydroxymethyltransferase2 (SHMT2), a key metabolic enzyme, is very important for the proliferation and growth of cancer cells. However, the function and mechanism of SHMT2 in head and neck cancer (HNC) are not clear. An analysis of The Cancer Genome Atlas (TCGA) data showed that the expression of SHMT2 was higher in tumor tissue than in normal tissue, and its expression was significantly associated with male sex, aggressive histological grade, lymph node metastasis, distant metastasis, advanced TNM stage, and lymphovascular invasion in HNC. SHMT2 knockdown in FADU and SNU1041 cell lines significantly inhibited cell proliferation, colony formation, migration, and invasion. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses using TCGA data revealed that SHMT2 was closely related to cancer stem cell regulation and maintenance. Furthermore, we found that silencing SHMT2 inhibited the expression of stemness markers and tumor spheroid formation compared with a control group. On the contrary, stemness markers were significantly increased after SHMT2 overexpression in HEP-2 cells. Interestingly, we found that knocking down SHMT2 reduced the expression of genes related to the Notch and Wnt pathways. Finally, silencing SHMT2 significantly reduced tumor growth and decreased stemness markers in a xenograft model. Taken together, our study suggests that targeting SHMT2 may play an important role in inhibiting HNC progression.

Thyroid cancer is associated with genetic alterations, e.g. BRAF

Background: Mitochondrial stress is known to activate the mitochondrial unfolded protein response (UPRmt). The UPRmt results in the secretion of mitochondrial cytokines (mitokines), which can promote a hormetic response cell nonautonomously, and has been reported to be protumorigenic. Growth differentiation factor 15 (GDF15) is a well-characterized mitokine, which is reported to have a mitohormetic effect. Thus, we investigated whether GDF15 induction could prime a subpopulation of thyroid cancer cells to provide invasive advantages. Methods: The UPRmt, including mitokine expression, was assessed in the context of thyroid cancer in vitro and in vivo. GDF15 expression in 266 patients with papillary thyroid carcinoma (PTC) was determined by immunohistochemistry. The serum levels of GDF15 were measured in healthy subjects and PTC patients. In addition, our own and The Cancer Genome Atlas data were analyzed to determine the expression level of GDF15 in thyroid cancers. The role of GDF15 in tumor aggressiveness was investigated by observing the effects of GDF15 knockdown in BCPAP, TPC-1, 8505C, and FRO cells. Results: Pharmacological inhibition of mitochondrial oxidative phosphorylation function in thyroid cancer cells robustly increased GDF15 expression. The expression of GDF15 was associated with activation of the mitochondrial integrated stress response pathway in PTC patients. Circulating GDF15 levels were significantly higher in PTC patients than in the controls, and tumor expression of GDF15 was related to tumor aggressiveness. In vitro and in vivo knockdown of GDF15 in a thyroid cancer model showed decreased viability, migration, and invasion compared with the control cells via regulation of STAT3. Conclusions: In this study, we demonstrated that GDF15 is a mitokine induced in thyroid cancer cells upon mitochondrial stress. GDF15-induced STAT3 activation determined tumor progression in thyroid cancer. The GDF15-STAT3 signaling axis may be a target in aggressiveness of thyroid cancer.

Background: A Korean Multicenter Prospective cohort study of Active Surveillance or Surgery (KoMPASS) for papillary thyroid microcarcinomas (PTMCs) has been initiated. The aim is to compare clinical outcomes between active surveillance (AS) and an immediate lobectomy for low-risk PTMCs. We here outline the detailed protocol for this study.Methods: Adult patients with a cytopathologically confirmed PTMC sized 6.0 to 10.0 mm by ultrasound (US) will be included. Patients will be excluded if they have a suspicious extra-thyroidal extension or metastasis of a PTMC or multiple thyroid nodules or other thyroid diseases which require a total thyroidectomy. Printed material describing the prognosis of PTMCs, and the pros and cons of each management option, will be provided to eligible patients to select their preferred intervention. For the AS group, thyroid US, thyroid function, and quality of life (QoL) parameters will be monitored every 6 months during the first year, and then annually thereafter. Disease progression will be defined as a ≥3 mm increase in maximal diameter of a PTMC, or the development of new thyroid cancers or metastases. If progression is detected, patients should undergo appropriate surgery. For the lobectomy group, a lobectomy with prophylactic central neck dissection will be done within 6 months. After initial surgery, thyroid US, thyroid function, serum thyroglobulin (Tg), anti-Tg antibody, and QoL parameters will be monitored every 6 months during the first year and annually thereafter. Disease progression will be defined in these cases as the development of new thyroid cancers or metastases.Conclusion: KoMPASS findings will help to confirm the role of AS, and develop individualized management strategies, for low-risk PTMCs.

Background Brn3a/Pou4f1 is a class IV POU domain-containing transcription factor and has been found to be expressed in a variety of cancers. However, the mechanism and action of Brn3a in thyroid cancer has not been investigated. Purpose To investigate the role of Brn3a in thyroid cancer progression and its clinical implication. Methods We examined Brn3a expression status in patients with thyroid cancer and analyzed relationships between Brn3a expression and clinicopathological findings using The Cancer Genome Atlas (TCGA) database. For functional in vitro analysis, proliferation, migration, invasion assay, and Western blotting were performed after overexpression or suppression of Brn3a. Results The promoter hypermethylation of Brn3a was found in patients with aggressive thyroid cancer and Brn3a was downregulated in tissues of patients with thyroid cancer. In TCGA database, the low-Brn3a-expression group revealed a more aggressive phenotype, including T stage and extrathyroid extension when compared with the high-Brn3a-expression group. Overexpression of Brn3a suppressed cell migration and invasion via regulation of epithelial-mesenchymal transition (EMT)-associated proteins in thyroid cancer cell lines. Brn3a overexpression also downregulated signal transducer and activator of transcription 3 (STAT3) signaling through suppression of tyrosine-protein kinase Met (c-MET). In contrast, knockdown of Brn3a by small interfering ribonucleic acid (siRNA) significantly increased cell migration and invasion through upregulation of c-MET/STAT3. These results imply that Brn3a suppresses tumor metastasis via c-MET/STAT3 inhibition and EMT suppression in thyroid cancer. Conclusions Our findings show that Brn3a is a potential tumor suppressor that leads to reduced cancer cell migration and invasion in thyroid cancer. Elucidation of the Brn3a-regulated cancer pathways may therefore provide novel therapeutic strategies to control thyroid cancer metastasis.

Genetic variations in mitoribosomal subunits and mitochondrial transcription factors are related to type 2 diabetes. However, the role of islet mitoribosomes in the development of type 2 diabetes has not been determined. We investigated the effects of the mitoribosomal gene on β-cell function and glucose homeostasis. Mitoribosomal gene expression was analyzed in datasets from the NCBI GEO website (GSE25724, GSE76894, and GSE76895) and the European Nucleotide Archive (ERP017126), which contain the transcriptomes of type 2 diabetic and nondiabetic organ donors. We found deregulation of most mitoribosomal genes in islets from individuals with type 2 diabetes, including partial downregulation of CRIF1. The phenotypes of haploinsufficiency in a single mitoribosomal gene were examined using β-cell-specific Crif1 (Mrpl59) heterozygous-deficient mice. Crif1beta+/− mice had normal glucose tolerance, but their islets showed a loss of first-phase glucose-stimulated insulin secretion. They also showed increased β-cell mass associated with higher expression of Reg family genes. However, Crif1beta+/− mice showed earlier islet failure in response to high-fat feeding, which was exacerbated by aging. Haploinsufficiency of a single mitoribosomal gene predisposes rodents to glucose intolerance, which resembles the early stages of type 2 diabetes in humans.

ContextThyroid-stimulating hormone (TSH) suppression is recommended to reduce tumor recurrence following surgery for differentiated thyroid cancer (DTC). However, prolonged subclinical hyperthyroidism caused by levothyroxine treatment has deleterious effects on various organs.ObjectiveTo evaluate the relationships of TSH concentration with muscle mass, muscle strength, and physical performance related to sarcopenia in patients with DTC undergoing TSH suppression following surgery.MethodsWe studied 134 patients of >60 years who were undergoing TSH suppression therapy following surgery for DTC. We evaluated muscle mass and muscle function-related parameters and diagnosed sarcopenia using the threshold for Asian people.ResultsThe participants were 68.3 ± 7.2 years old and 36/134 (26.9%) were diagnosed with sarcopenia. They were allocated to high-TSH and low-TSH groups using a threshold concentration of 0.40 μU/mL, and grip strength was significantly lower in the low-TSH group. The data were further analyzed according to age and sex, and in the low-TSH group, male participants and those of ConclusionsLow-TSH concentrations is associated with low grip strength, and this is most pronounced in individuals of

Keloids are a common form of pathologic wound healing and are characterized by an excessive production of extracellular matrix. This study examined the major contributing mechanism of human keloid pathogenesis using transcriptomic analysis. We identified the upregulation of mitochondrial oxidative stress response, protein processing in the endoplasmic reticulum, and TGF-β signaling in human keloid tissue samples compared to controls, based on ingenuity pathway and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Electron microscopic examinations revealed an increased number of dysmorphic mitochondria and expanded endoplasmic reticulum (ER) in human keloid tissue samples than that in controls. Western blot analysis performed using human tissues suggested noticeably higher ER stress signaling in keloids than in normal tissues. Treatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, significantly decreased scar formation in rabbit models, compared to normal saline and steroid injections. In summary, our findings demonstrate the contributions of mitochondrial dysfunction and dysregulated ER stress signaling in human keloid formation and the potential of TUDCA in the treatment of keloids.

This study aimed to determine whether completion thyroidectomy is necessary based on long-term follow-up oncological results according to various clinical and pathological characteristics of patients with papillary thyroid carcinoma (PTC) who underwent lobectomy.We enrolled 1815 patients with PTC who underwent thyroid lobectomy from January 2003 to December 2014. Various clinical and pathological characteristics were reviewed retrospectively, and clinicopathologic characteristics and recurrence rates were analyzed.Eighty-two (4.5%) patients showed locoregional recurrence during the average 10.2-year follow-up period. There was no significant difference in tumor size, multifocality, lymphovascular invasion (LVI), microscopic or strap muscle-extrathyroidal extension, and central neck lymph node (LN) micrometastasis between the recurrence and non-recurrence groups. The gross strap muscle-extrathyroidal extension group was associated with older age (p lt; 0.001), larger tumor size (p lt; 0.001), more capsular invasion (p lt; 0.001), and more LVI (p lt; 0.001) than the negative extrathyroidal extension group; there was no significant difference in recurrence between the groups (p = 0.096). Patients with five or more central LN micrometastases were associated with younger age (p = 0.006), larger tumor size (p = 0.04), and presence of LVI (p = 0.033) than patients with less than five central LN metastases; there was no significant difference in recurrence between the groups (p = 0.867). All patients with recurrence were cured through reoperation after recurrence was confirmed.After thyroid lobectomy, PTC patients with multifocality, LVI, extrathyroidal extension to the strap muscles, or five or more central LN micrometastases may not require immediate completion thyroidectomy.

Background: Recent in vivo studies indicated that R-spondin 1 (RSPO1) regulates food intake and increases insulin secretion, but its role in humans remains unknown. This study investigated the association between serum levels of RSPO1 and diverse meta bolic parameters in humans. Methods: The study population consisted of 43 subjects with newly diagnosed diabetes mellitus, and 79 non-diabetic partici pants. Serum levels of RSPO1 were measured using the enzyme-linked immunosorbent assay. The relationships between circulat ing RSPO1 and diverse metabolic parameters were analyzed. Results: Circulating RSPO1 levels increased to a greater extent in the obese group than in the lean group. Moreover, serum levels of RSPO1 were higher in the insulin-resistant group than in the insulin-sensitive group. Serum levels of RSPO1 were significantly correlated with a range of metabolic parameters including body mass index, fasting C-peptide, homeostasis model assessment of insulin resistance index, and lipid profile. Moreover, levels were significantly associated with insulin resistance and obesity in non-diabetic subjects. Conclusion: This study demonstrated the association between serum levels of RSPO1 and a range of metabolic parameters in hu mans. Serum levels of RSPO1 are significantly related to obesity and insulin resistance, although the precise mechanisms remain unknown.

Background Postoperative thyroid stimulating hormone (TSH) suppression therapy is recommended for patients with intermediate- and high-risk differentiated thyroid cancer to prevent the recurrence of thyroid cancer. With the recent increase in small thyroid cancer cases, the extent of resection during surgery has generally decreased. Therefore, questions have been raised about the efficacy and long-term side effects of TSH suppression therapy in patients who have undergone a lobectomy. Methods This is a multicenter, prospective, randomized, controlled clinical trial in which 2,986 patients with papillary thyroid cancer are randomized into a high-TSH group (intervention) and a low-TSH group (control) after having undergone a lobectomy. The principle of treatment includes a TSH-lowering regimen aimed at TSH levels between 0.3 and 1.99 μIU/mL in the low-TSH group. The high-TSH group targets TSH levels between 2.0 and 7.99 μIU/mL. The dose of levothyroxine will be adjusted at each visit to maintain the target TSH level. The primary outcome is recurrence-free survival, as assessed by neck ultrasound every 6 to 12 months. Secondary endpoints include disease-free survival, overall survival, success rate in reaching the TSH target range, the proportion of patients with major cardiovascular diseases or bone metabolic disease, the quality of life, and medical costs. The follow-up period is 5 years. Conclusion The results of this trial will contribute to establishing the optimal indication for TSH suppression therapy in low-risk papillary thyroid cancer patients by evaluating the benefit and harm of lowering TSH levels in terms of recurrence, metabolic complications, costs, and quality of life.

Particulate matter (PM) is an environmental exposure factor that adversely affects human health. PM is a risk factor for various diseases. However, the mechanism by which PM affects the vocal folds (VF) has not yet been evaluated. Thus, we investigated the cytotoxic effects of PM on human vocal fold fibroblasts (hVFF) and the underlying signaling pathways. hVFF were isolated from human VF. The effect of PM on hVFF, and the underlying mechanism, were analyzed using Western blot, quantitative real-time polymerase chain reaction, and flow cytometry. In addition, a histological evaluation was performed in animal experiments. Cell proliferation decreased after the PM treatment. PM increased the expression of interleukin (IL)-6 and IL-1&beta, The generation of reactive oxygen species (ROS) in PM-treated hVFF and subsequent activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-&kappa, B (NF-&kappa, B) pathways were confirmed. Furthermore, PM increased the expression of fibrosis-related markers and induced the accumulation of collagen in the extracellular matrix. As a result, PM exposure significantly enhances the inflammatory response on VF through the ROS-mediated activation of the MAPK and NF-&kappa, B signaling pathways. In addition, PM promotes differentiation into myofibroblasts and induces fibrosis. These results suggest that PM triggers an inflammatory reaction through ROS production and causes VF fibrosis.

Anaplastic thyroid cancer (ATC) is a rapidly growing, highly metastatic cancer with limited therapeutic alternatives, thus targeted therapies need to be developed. This study aimed to examine desmoglein 2 (Dsg2) expression in ATC and its biological role and potential as a therapeutic target in ATC. Consequently, Dsg2 was downregulated or aberrantly expressed in ATC tissues. ATC patients with low Dsg2 expression levels also presented with distant metastasis. Dsg2 depletion significantly increased cell migration and invasion, with a relatively limited effect on ATC cell proliferation in vitro and increased distant metastasis in vivo. Dsg2 knockdown induced cell motility through the hepatocyte growth factor receptor (HGFR, c-Met)/Src/Rac1 signaling axis, with no alterations in the expression of EMT-related molecules. Further, specific targeting of c-Met significantly inhibited the motility of shDsg2-depleted ATC cells. Decreased membrane Dsg2 expression increased the metastatic potential of ATC cells. These results indicate that Dsg2 plays an important role in ATC cell migration and invasiveness. Therapies targeting c-Met might be effective among ATC patients with low membrane Dsg2 expression levels, indicating that the analysis of Dsg2 expression potentially provides novel insights into treatment strategies for ATC.

Background: Type 2 deiodinase (DIO2)-mediated thyroid hormone synthesis stimulates osteoblast activity and increases the expression of osteoblast differentiation markers. Moreover, recent clinical studies identified a significant relationship between bone mineral density and thyroid hormone level in humans, but these studies had limitations that may have influenced their results, including small sample size, gender bias and enrollment of participants with specific diseases. Therefore, large cohort studies to identify the role of the DIO2 polymorphism in bone mineral density in humans are needed to provide additional information. Methods: To investigate the hypothesis that individuals with the DIO2 gene polymorphism are susceptible to osteoporosis, we assessed the polymorphism of the DIO2 gene in 7,524 Koreans drawn from the large-scale Ansan-Anseong cohort of the Korean Genome and Epidemiology Study (KoGES). Participants who were prescribed drugs that influence bone mineral density, those who provided insufficient information, and those with other diseases associated with osteoporosis were excluded from the study. All of the participants underwent genotyping of the DIO2 Thr92Ala polymorphism. We estimated the association of the DIO2 gene polymorphism with bone mineral density and other diverse clinical parameters using the chi-square test and ANOVA, and the risk of osteoporosis was determined using Cox regression analysis. Findings: A total of 6,022 participants were recruited; 1,991 (33.0%) were homozygous for the Thr allele, 2,967 (49.3%) were heterozygous (Thr/Ala), and 1,064 (17.7%) were homozygous for the Ala allele. The effects of the DIO2 Thr92Ala polymorphism on axial speed of sound (SOS) and the T-score in the tibia and radius were assessed, with age, gender, estrogen status, body mass index (BMI), serum calcium, 25-hydroxyvitamin D, and parathyroid hormone (PTH) included as covariables. Subjects carrying the DIO2 Thr92Ala polymorphism had consistently lower SOS and T-scores than heterozygous subjects. Additionally, female patients carrying the DIO2 Thr92Ala polymorphism had significantly lower SOS and T-scores than heterozygous participants. Cox regression analysis revealed a significant relationship between the DIO2 polymorphism and diagnosis of osteoporosis in female participants. Interpretation: We conclude that the DIO2 Thr92Ala polymorphism is associated with decreased SOS and T-scores in the tibia independent of other clinical parameters, where this indicates a potential functional role of DIO2 in the maintenance of bone mineral density. Funding Statement: This study was conducted with bioresources from the National Biobank of Korea, the Centers for Disease Control and Prevention, Republic of Korea (2018-022). This work was supported by the Korean Endocrine Society of New Faculty Research Award, 2018. Hyon-Seung Yi was also supported by the Basic Science Research Program, National Research Foundation, Ministry of Science and ICT, Future Planning, Korea (NRF-2018R1C1B6004439). Young Mi Kang and Yea Eun Kang were supported by the Basic Science Research Program, National Research Foundation, Ministry of Science and ICT, Future Planning, Korea (NRF2017R1D1A1B03027820). Declaration of Interests: All other authors declare no competing interests. Ethics Approval Statement: All subjects participated voluntarily and the study procedures were in accordance with our institutional guidelines and were approved by the Institutional Review Committee of the Korean National Institute of Health (CNUH-2018-03-028)

Objective Neuropilin-2 (NRP2) is a coreceptor of vascular endothelial growth factor-C/D (VEGF-C/D) and plays the important role in the development of lymphatic endothelial cells, as well as neuronal development. NRP2 is known to affect aggressiveness by increasing expression in various human cancers, but the role of NRP2 in thyroid cancer is not fully understood. The purpose of this study was to investigate the NRP2 expression and its role in regulating the tumor aggressiveness in the papillary thyroid carcinoma (PTC). Methods The NRP2 expression and its clinicopathologic correlation to PTC was determined using the data from the 262 PTC patients at a tertiary referral medical center and The Cancer Genome Atlas (TCGA) database. The potential role of NRP2 in modulating tumor growth, invasion, and metastasis in PTC was examined by using small interfering RNA (siRNA)-mediated knockdown of NRP2. Results High expression of NRP2 was significantly associated with capsular invasion, lymphovascular invasion, lymph node metastasis, 5 or more metastatic lymph nodes, and recurrence in PTC patients. In TCGA data, the higher NRP2 expression group was significantly associated with extrathyroid extension, lymph node metastasis, and BRAFV600E mutation. The siRNA mediated knockdown of NRP2 in the PTC cells reduced the cell proliferation, migration and invasion. We also have confirmed that NRP2 knockdown suppressed epithelial-mesenchymal transition (EMT) by regulating AKT and ERK phosphorylation signaling pathways. Conclusion Our results suggest that NRP2 regulates tumor progression in PTC and may act as a predictive factor for aggressiveness of PTC.

Chronic inflammation is a driving force for the development of metabolic disease including diabetes and obesity. However, the functional characteristics of T-cell senescence in the abnormal glucose homeostasis are not fully understood. We studied the patients visiting a hospital for routine health check-ups, who were divided into two groups: normal controls and people with prediabetes. Gene expression profiling of peripheral blood mononuclear cells from normal controls and patients with type 2 diabetes was undertaken using microarray analysis. We also investigated the immunometabolic characteristics of peripheral and hepatic senescent T cells in the normal subjects and patients with prediabetes. Moreover, murine senescent T cells were tested functionally in the liver of normal or mice with metabolic deterioration caused by diet-induced obesity. Human senescent (CD28−CD57+) CD8+ T cells are increased in the development of diabetes and proinflammatory cytokines and cytotoxic molecules are highly expressed in senescent T cells from patients with prediabetes. Moreover, we demonstrate that patients with prediabetes have higher concentrations of reactive oxygen species (ROS) in their senescent CD8+ T cells via enhancing capacity to use glycolysis. These functional properties of senescent CD8+ T cells contribute to the impairment of hepatic insulin sensitivity in humans. Furthermore, we found an increase of hepatic senescent T cells in mouse models of aging and diet-induced obesity. Adoptive transfer of senescent CD8+ T cells also led to a significant deterioration in systemic abnormal glucose homeostasis, which is improved by ROS scavengers in mice. This study defines a new clinically relevant concept of T-cell senescence-mediated inflammatory responses in the pathophysiology of abnormal glucose homeostasis. We also found that T-cell senescence is associated with systemic inflammation and alters hepatic glucose homeostasis. The rational modulation of T-cell senescence would be a promising avenue for the treatment or prevention of diabetes.

We investigated an association between serum Growth Differentiation Factor 15 (GDF15) level and cardiovascular risk in patients with newly diagnosed type 2 diabetes mellitus (T2D). A total of 107 participants were screened for T2D and divided into a T2D group and a control group (without diabetes). We used the Framingham risk score (FRS) and the New Pooled Cohort Equation score to estimate the 10-year risk of atherosclerotic cardiovascular disease. Serum GDF15 levels were measured using an enzyme-linked immunosorbent assay. Correlation analyses were performed to evaluate the associations between GDF15 level and cardiovascular risk scores. The mean serum GDF15 level was elevated in the T2D group compared to the control group (P < 0.001). A positive correlation was evident between serum GDF15 level and age (r = 0.418, P = 0.001), the FRS (r = 0.457, P < 0.001), and the Pooled Cohort Equation score (r = 0.539, P < 0.001). After adjusting for age, LDL-C level, and body mass index (BMI), the serum GDF15 level was positively correlated with the FRS and the New Pooled Cohort Equation score. The serum GDF15 level is independently associated with cardiovascular risk scores of newly diagnosed T2D patients. This suggests that the level of GDF15 may be a useful predictive biomarker of cardiovascular risk in newly diagnosed T2D patients., Graphical Abstract

The purpose of this systematic review and meta-analysis was to determine the optimal extent of lateral neck dissection in patients with well-differentiated thyroid carcinoma with clinically confirmed lateral neck lymph node metastases. All studies reporting the distribution of metastatic lymph nodes in level IIb or level V, complication rate, recurrence rate, or clinical outcomes according to the extent of lateral neck dissection were collected from MEDLINE and Embase databases. Two reviewers independently retrieved articles, extracted data, and assessed the quality of the studies. A total of 40 criteria-meeting studies were included in the systematic review and meta-analysis, representing a total of 6 027 patients. The distribution of metastatic lymph nodes was 13.7% (95% confidence interval [CI]: 8.2-21.9%) in level IIb and 22.1% (95% CI: 18.6-26.1%) in level V. Shoulder syndrome complication showed a tendency to increase when comprehensive neck dissection was performed. The recurrence rate was 11.2% (95% CI: 8.4-14.9%) in the comprehensive neck dissection group and 11.0% (95% CI: 4.2-26.1%) in the selective neck dissection group. Clinical outcomes showed no difference between groups. In conclusion, selective neck dissection may be considered in patients with well-differentiated thyroid carcinoma with lateral neck lymph node metastases without any other risk factors.

The clinical implications of human brown adipose tissue (BAT) were investigated based on the analysis of cervical adipose tissue gene expression under normal physiological conditions.Matched-pair specimens of adipose tissue (AT) were collected from beneath the incision plane (subcutaneous AT) and from the area surrounding the carotid sheath (carotid AT) from 60 patients undergoing thyroidectomy. The mRNA expression of BAT-associated genes in these tissues was examined, and this expression was correlated with the clinical characteristics of the subjects.The UCP1 mRNA level was significantly higher in the carotid AT than in the subcutaneous AT. There was an inverse correlation between subject age and the ratio of UCP1 mRNA expression in the carotid AT relative to the subcutaneous AT, which is a measure of BAT activity (r = -0.459; P = 0.004), and there was a negative correlation between BMI and the ratio of UCP1 mRNA expression in subjects with higher BAT activity (r = -0.532; P = 0.016).UCP1 was identified as the only marker of cervical BAT in humans. There was a negative correlation between obesity and BAT activity in subjects with higher BAT activity, although BAT activity decreased with age.

We investigated the expression of angiopoietins in patients with papillary thyroid carcinoma (PTC) and the role of angiopoietins as biomarkers predicting the aggressiveness of PTC. Expression of angiopoietins was evaluated by immunohistochemistry of tumor specimens from patients with PTC. We demonstrated potential correlations between expression of angiopoietins and clinicopathologic features. High expression of Ang-1 was positively correlated with a tumor size >1 cm, capsular invasion, extrathyroid extension, lymphovascular invasion, lymph node metastasis, and recurrence (P

We analyzed circulating Meteorin-like (METRNL) levels in human. Serum METRNL levels were significantly lower in subjects with diabetes mellitus compared with those without diabetes. Serum METRNL was negatively correlated with the serum glucose level and insulin resistance. Metformin treatment did not increase the serum METRL levels after 12 weeks.

The functional unit of the thyroid gland, the thyroid follicle, dynamically responds to various stimuli to maintain thyroid hormone homeostasis. However, thyroid follicles in the adult human thyroid gland have a very limited regenerative capacity following partial resection of the thyroid gland. To gain insight into follicle regeneration in the adult thyroid gland, we observed the regeneration processes of murine thyroid follicles after partial resection of the lower third of the thyroid gland in 10-week-old male C57BL/6 mice. Based on sequential observation of the partially resected thyroid lobe, we found primitive follicles forming in the area corresponding to the central zone of the intact lateral thyroid lobe. The primitive thyroid follicles were multiciliated and had coarsely vacuolated cytoplasm and large vesicular nuclei. Consistently, these primitive follicular cells did not express the differentiation markers paired box gene-8 and thyroid transcription factor-1 (clone SPT24), but were positive for forkhead box protein A2 and leucine-rich repeat-containing G-protein-coupled receptor 4/GPR48. Follicles newly generated from the primitive follicles had clear or vacuolar cytoplasm with dense, darkly stained nuclei. At day 21 after partial thyroidectomy, the tall cuboidal follicular epithelial cells had clear or vacuolar cytoplasm, and the intraluminal colloid displayed pale staining. Smaller activated follicles were found in the central zone of the lateral lobe, whereas larger mature follicles were located in the peripheral zone. Based on these observations, we propose that the follicle regeneration process in the partially resected adult murine thyroid gland associated with the appearance of primitive follicular cells may be a platform for the budding of differentiated follicles in mice.

Primary cilia are found in the apical membrane of thyrocytes, where they may play a role in the maintenance of follicular homeostasis. In this study, we examined the distribution of primary cilia in the human thyroid cancer to address the involvement of abnormal ciliogenesis in different thyroid cancers. We examined 92 human thyroid tissues, including nodular hyperplasia, Hashimoto's thyroiditis, follicular tumor, Hürthle cell tumor, and papillary carcinoma to observe the distribution of primary cilia. The distribution and length of primary cilia facing the follicular lumen were uniform across variable-sized follicles in the normal thyroid gland. However, most Hürthle cells found in benign and malignant thyroid diseases were devoid of primary cilia. Conventional variant of papillary carcinoma (PTC) displayed longer primary cilia than those of healthy tissue, whereas both the frequency and length of primary cilia were decreased in oncocytic variant of PTC. In addition, ciliogenesis was markedly defective in primary Hürthle cell tumors, including Hürthle cell adenomas and carcinomas, which showed higher level of autophagosome biogenesis. Remarkably, inhibition of autophagosome formation by Atg5 silencing or treatment with pharmacological inhibitors of autophagosome formation restored ciliogenesis in the Hürthle cell carcinoma cell line XTC.UC1 which exhibits a high basal autophagic flux. Moreover, the inhibition of autophagy promoted the accumulation of two factors critical for ciliogenesis, IFT88 and ARL13B. These results suggest that abnormal ciliogenesis, a common feature of Hürthle cells in diseased thyroid glands, is associated with increased basal autophagy.

The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance have been explored in both animal and human studies. However, our current understanding of obesity-associated insulin resistance relies on studies of artificial metabolic extremes. The purpose of this study was to explore the roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in human patients with modest obesity and early metabolic dysfunction. We obtained omental adipose tissue and fasting blood samples from 51 females undergoing gynecologic surgery. We investigated serum concentrations of proinflammatory cytokines and adipokines as well as the mRNA expression of proinflammatory and macrophage phenotype markers in visceral adipose tissue using ELISA and quantitative RT-PCR. We measured adipose tissue inflammation and macrophage infiltration using immunohistochemical analysis. Serum levels of adiponectin and leptin were significantly correlated with HOMA-IR and body mass index. The levels of expression of MCP-1 and TNF-α in visceral adipose tissue were also higher in the obese group (body mass index ≥ 25). The expression of mRNA MCP-1 in visceral adipose tissue was positively correlated with body mass index (r = 0.428, p = 0.037) but not with HOMA-IR, whereas TNF-α in visceral adipose tissue was correlated with HOMA-IR (r = 0.462, p = 0.035) but not with body mass index. There was no obvious change in macrophage phenotype or macrophage infiltration in patients with modest obesity or early metabolic dysfunction. Expression of mRNA CD163/CD68 was significantly related to mitochondrial-associated genes and serum inflammatory cytokine levels of resistin and leptin. These results suggest that changes in the production of inflammatory biomolecules precede increased immune cell infiltration and induction of a macrophage phenotype switch in visceral adipose tissue. Furthermore, serum resistin and leptin have specific roles in the regulation of adipose tissue macrophages in patients with modest obesity or early metabolic dysfunction.

Background: The aim of this study was to investigate the role of the urinary chiro- and myo-inositol levels in predicting type 2 diabetes mellitus (T2DM).Subjects and methods: A total of 212 normal controls and 101 type 2 diabetic patients were enrolled this study. The concentrations of urinary chiro- and myo-inositol were measured by high performance liquid chromatography/mass spectrometry.Results: The concentration of urinary chiro-inositol was significantly higher in the diabetic subjects (2.24 ± 5.18 ng/L) than those in the control group (0.38 ± 0.62 ng/L;p< 0.001). The urinary myo-inositol level of the diabetic subjects (36.95 ± 37.77 ng/L) was also significantly higher than that of the controls (8.17 ± 13.29 ng/L;p< 0.001). The urinary chiro-inositol multiplied by myo-inositol level of the diabetic subjects (148.10 ± 544.91) was significantly higher than in the controls (5.12 ± 24.15;p< 0.001). The area under the receiver operating characteristic curve for the urinary chiro-inositol multiplied by myo-inositol level to predict T2DM was 0.840 (confidence interval 0.789–0.891,p< 0.001). The cut-off value for the urinary chiro-inositol multiplied by myo-inositol level to predict T2DM was 2.20 (sensitivity 81.3%, specificity 70.3%).Conclusions: The urinary chiro- and myo-inositol concentrations were increased in the type 2 diabetic patients and the urinary chiro- times the myo-inositol was considered to be a sufficient marker in predicting T2DM.

We explored the role of Neuregulin 4 (Nrg4), a newly described factor secreted by adipose tissue, by measuring serum Nrg4 levels in humans. Circulating Nrg4 levels were significantly higher in patients with diabetes mellitus compared with controls without diabetes and were correlated with the serum glucose level and insulin resistance.