The clinical management of advanced thyroid carcinoma presents substantial therapeutic challenges due to non-curative surgical outcomes and resistance to both radioiodine therapy and conventional chemotherapeutic agents. Emerging evidence implicates copper dysregulation in thyroid cancer pathogenesis, yet monotherapy with copper ionophores demonstrates constrained efficacy due to tumor-intrinsic adaptive resistance mechanisms. In this study, we investigated the therapeutic potential of combining Sunitinib with copper ionophore Elesclomol as a novel strategy against thyroid carcinoma. Mechanically, we identified that Sunitinib treatment induces ROS accumulation, activating the stress-responsive transcription factor ATF3, which directly binds and transactivates the copper transporter gene SLC31A1. Clinically, TCGA analysis reveals SLC31A1 as a vulnerability in advanced thyroid cancer, with expression significantly downregulated in metastatic lesions, a deficit rescued by Sunitinib. Overall, these results demonstrate that Sunitinib and copper ionophores can induce synergistic cytotoxic effect, shedding light on therapeutic strategy for advanced thyroid carcinomas.

Lenvatinib resistance is a major clinical obstacle in the treatment of radioiodine-refractory papillary thyroid cancer (PTC). Clarification of the molecular mechanisms of this resistance is of utmost importance to devise effective therapeutic strategies. We investigated the role of Keratin 15 (KRT15) in lenvatinib resistance through comprehensive in vitro and in vivo studies. Tumor and normal thyroid tissues were analyzed for KRT15 expression and correlation with patient survival. Metabolic profiling was performed to investigate KRT15-dependent alterations in lipid metabolism, namely fatty acid oxidation (FAO). Mechanistic investigations explored the interaction between KRT15, Keratin 81 (KRT81), and Diacylglycerol Kinase B (DGKB). The therapeutic potential of targeting this pathway was evaluated using shRNA-mediated knockdown and pharmacological inhibition. KRT15 overexpression was associated with unfavorable clinical prognosis in thyroid cancer patients. We identified that KRT15 interacts with KRT81 to constitute a regulatory complex, which induces DGKB upregulation. The KRT15-KRT81-DGKB axis controls metabolic reprogramming by upregulating key FAO enzymes (CPT1A and ACOX1), resulting in increased cellular energetics and survival against therapeutic stress. Inhibition of this pathway successfully restored lenvatinib sensitivity in resistant cells. This study illustrates a novel mechanism of cytoskeletal proteins involvement in metabolic adaptation of drug-resistant thyroid cancer cells. The KRT15-KRT81-DGKB pathway is a promising therapeutic target, particularly in combination with lenvatinib, for refractory thyroid cancer patients.

Background:Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are both rare and aggressive thyroid cancers. Advances in targeted therapy and immunotherapy have changed treatment strategies and improved prognosis in these patients. Methods:This single-center cohort study included patients diagnosed with locally advanced or metastatic PDTC/ATC at Fudan University Shanghai Cancer Center (FUSCC) between 2019 and 2023. Patients were either enrolled in clinical trials or received treatment based on clinical guidelines and expert consensus. Gene testing was conducted using next-generation sequencing of clinical samples. Results:95 patients were analyzed (PDTC = 34, ATC = 61). Median overall survival (OS) was 19.7 months for PDTC and 9.5 months for ATC (P = 0.478). Among 82 patients who underwent gene testing, the most frequent gene alterations in PDTC were BRAF (50.0%), TERT promoter (39.3%), and TP53 (25.0%) mutations; in ATC, they were TERT promoter (55.6%), BRAF (42.6%), and TP53 (25.9%) mutations. Compared with ATC patients, PDTC patients were more likely to receive best supportive care and less likely to be enrolled in clinical trials or treated with PD-1 inhibitors. The 1-year OS rates for PDTC/ATC patients receiving neoadjuvant therapy + surgery, systemic treatment, and supportive care only were 83.3, 51.2, and 5.7%, respectively (P < 0.001). After adjusting for covariates, neoadjuvant therapy + surgery (hazard ratio = 0.216, 95% confidence interval: 0.647-0.718, P = 0.012) was an independent predictor of superior OS. Conclusion:Despite the generally poor prognosis, aggressive treatment, particularly neoadjuvant therapy, has been shown to improve survival. Personalized treatment is crucial for optimizing treatment strategies for PDTC/ATC.

Cuproptosis represents a new type of cell death that intricately associated with copper homeostasis and protein lipoylation. The cuproptosis suppression has been characterized in the hypoxic tumor microenvironment (TME). Here we reveal that hypoxia inducible factor-1α (HIF-1α) is a driver of cuproptosis resistance in solid tumor. We found that HIF-1α activates pyruvate dehydrogenase kinase 1 and 3 (PDK1/3), resulting in decreased expression of dihydrolipoamide S-acetyltransferase (DLAT) (target of copper), and promotes the accumulation of metallothionein, which sequesters mitochondrial copper, leading to resistance to cuproptosis under hypoxic conditions. Furthermore, we discovered that high levels of copper reduce ubiquitination and increase the stability of HIF-1α protein without affecting its mRNA levels. Inhibition of HIF-1α increases the susceptibility of cancer to cuproptosis in vivo. This study unveils the multifaceted role of HIF-1α in cuproptosis and demonstrates the molecular mechanism of hypoxia-promoted carcinogenesis.

The management of benign thyroid nodules has evolved significantly with the advent of minimally invasive techniques, offering patients effective alternatives to traditional surgery. Among these, radiofrequency ablation (RFA) and microwave ablation (MWA) have emerged as the leading modalities. RFA, the most widely adopted method, uses high frequency alternating current to induce thermal coagulation. MWA, though less established in thyroid applications, employs electromagnetic waves to generate rapid and intense heat, making it particularly effective for larger or hypervascular nodules. These approaches are particularly advantageous for patients with symptomatic nodules or cosmetic concerns, as they preserve thyroid function while minimizing complications and recovery time. This protocol establishes a standardized approach for RFA and MWA of benign thyroid nodules. The procedure begins with cytological confirmation (Bethesda II) and ultrasound evaluation, followed by local anesthesia and protective hydrodissection with 40-80 mL of 5% dextrose or distilled water to safeguard critical structures. Under real-time ultrasound guidance, the trans-isthmic approach is employed for needle placement. Ablation is performed at 30-40 W (RFA) or 35-50 W (MWA) using the moving-shot technique. Complete nodule devascularization is confirmed by contrast-enhanced ultrasound (CEUS) during post-ablation assessment, with immediate supplementary ablation being performed if residual enhancement is identified. Clinical and sonographic follow-up is conducted at 1, 3, 6, and 12 months to assess volume reduction ratio, symptom relief, and cosmetic outcomes. The protocol also details the patient selection criteria, technical nuances for cystic/solid nodules, and management of intraoperative complications. This comprehensive guide aims to optimize the reproducibility, safety, and efficacy of thermal ablation for benign thyroid nodules, serving as a practical reference for clinicians adopting these minimally invasive techniques.

Background:A deep convolutional neural network (DCNN) model was employed for the differentiation of thyroid nodules diagnosed as atypia of undetermined significance (AUS) according to the 2023 Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). The aim of this study was to investigate the efficiency of ResNeSt in improving the diagnostic accuracy of fine-needle aspiration (FNA) biopsy.Methods:Fragmented images were used to train and test DCNN models. A training dataset was built from 1,330 samples diagnosed as papillary thyroid carcinoma (PTC) or benign nodules, and a test dataset was built from 173 samples diagnosed as AUS. ResNeSt was trained and tested to provide a differentiation. With regard to AUS samples, the characteristics of the cell nuclei were compared using the Wilcoxon test.Results:The ResNeSt model achieved an accuracy of 92.49% (160/173) on fragmented images and 84.78% (39/46) from a patient wise viewpoint in discrimination of PTC and benign nodules in AUS nodules. The sensitivity and specificity of ResNeSt model were 95.79% and 88.46%. The κ value between ResNeSt and the pathological results was 0.847 (P<0.001). With regard to the cell nuclei of AUS nodules, both area and perimeter of malignant nodules were larger than those of benign ones, which were 2,340.00 (1,769.00, 2,807.00) vs. 1,941.00 (1,567.50, 2,455.75), P<0.001 and 190.46 (167.64, 208.46) vs. 171.71 (154.95, 193.65), P<0.001, respectively. The grayscale (0 for black, 255 for white) of malignant lesions was lower than that of benign ones, which was 37.52 (31.41, 46.67) vs. 45.84 (31.88, 57.36), P <0.001, indicating nuclear staining of malignant lesions were deeper than benign ones.Conclusions:In summary, the DCNN model ResNeSt showed great potential in discriminating thyroid nodules diagnosed as AUS. Among those nodules, malignant nodules showed larger and more deeply stained nuclei than benign nodules.

Background:Over 500,000 new cases are diagnosed with papillary thyroid cancer (PTC) globally per year, of whom the vast majority are in the low-risk stratification. Although thyroid-stimulating hormone (TSH) suppression is traditionally recommended for all postoperative PTCs in current guidelines, its necessity remains highly controversial in low-risk patients. Since relevant recommendations in current guidelines are still empirical, we aim to provide a direct, large-scale, real-world evidence. Methods:This large-scale real-world retrospective study included 11,140 low-risk PTC patients from two Chinese large-volume centers (Fudan University Shanghai Cancer Center [FUSCC] and Cancer Hospital of Chinese Academy of Medical Sciences [CH-CAMS]) treated from January 1, 2000 to June 30, 2022. The mean TSH level was calculated based on postoperative serum TSH values during follow-up. The primary outcome was the association between postoperative TSH level and structural recurrence assessed by Kaplan-Meier, log-rank, multivariate Cox regression analyses and equivalence testing by Two One-Sided Tests (TOST) procedure. Propensity score matching (PSM) was used to adjust for confounders among groups. Findings:A total of 11,140 patients with low-risk PTC were included with a median follow-up of 70 months. Based on the mean TSH level, we classified these patients into ≤0.5 (n = 1,504, 13.5%), (0.5-1] (n = 4,336, 38.9%), (1-2] (n = 4,285, 38.5%), (2-3] (n = 704, 6.3%) and >3 (n = 311, 2.8%) mU/L groups. After PSM adjusting for age, sex, T and N stage, 8991 patients were included in further analysis, for whom the log-rank analyses showed no significant differences between any two groups (all P > 0.05) in recurrence-free survival (RFS), locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS), and suppressed TSH was not associated with tumor recurrence in the multivariate Cox analysis (TSH > 2 group vs TSH ≤ 2 group: HR = 1.30, 95% CI = 0.85-2.01, P = 0.23). Furthermore, the TOST equivalence tests showed that tumor recurrence status of any two TSH groups were statistically comparable (all Bonferroni-corrected P values < 0.005). Subgroup multivariate analyses showed that TSH level did not impact tumor recurrence regardless of age, tumor size, lymph node metastasis, multifocality, surgical extent, biochemical evidence. Interpretation:Our results suggested that postoperative TSH level was not associated with tumor recurrence in patients with low-risk PTC, for whom deliberate TSH suppression may be exempted to avoid potential secondary complications. Maintaining a TSH level within the normal range may be safe for these patients. Funding:The study was supported by the National Natural Science Foundation of China (82072951 to Y.W.; 82373008 to X.S.), Shanghai Hospital Development Center (SHDC2020CR6003-001 to Y.W., SHDC2024CRI087 to Y.-J.W.), the Science and Technology Commission of Shanghai Municipality (22Y21900100/23DZ2305600 to Y.W.; 23ZR1412000 to X.S.), the Shanghai Anticancer Association Foundation (SACA-AX202213 to Yu Wang), Shanghai Municipal Health Commission and Shanghai Medicine and Health Development Foundation (WJWRC202302 to X.S.).

BACKGROUND:Abnormal arachidonic acid metabolism in the tumor microenvironment is closely related to cancer progression; however, thyroid cancer was rarely researched. METHODS:Through lipidomic analysis, we disclosed that dysregulated arachidonic acid metabolism plays dual effects on thyroid cancer. The promoting role of arachidonic acid in the progression of thyroid cancer cells was evaluated utilizing cell viability (CCK-8 assay) and transwell invasion assays, confirmed by corresponding inhibitors. Lipid peroxidation and the use of various cell death inhibitors confirmed that arachidonic acid confers vulnerability to ferroptosis in thyroid cancer. The roles of arachidonic acid and ferroptosis inducer in thyroid cancer were assessed in a xenograft mouse model. RESULTS:On one hand, arachidonic acid promotes the progression of thyroid cancer through the cyclooxygenase/prostaglandin pathway; on another hand, arachidonic acid confers vulnerability to ferroptosis through lipoxygenases. Moreover, iPLA2β drives converse roles of arachidonic acid between cancer-progression and ferroptosis vulnerability through releasing free arachidonic acid from the cell membrane. Finally, we confirmed high arachidonic acid diet promotes the development of thyroid cancer in vivo, whereas ferroptosis inducer sulfasalazine dramatically reduced tumor growth of mice with feeding arachidonic acid. CONCLUSIONS:Our research demonstrated the roles of iPLA2β in conversing dual effects of arachidonic acid in thyroid cancer and provides ferroptosis inducer as a potential therapeutic strategy.

Anaplastic thyroid cancer (ATC) is the most lethal tumor arising from thyroid follicular epithelium. Lenvatinib is an off-label use option for ATC patients in many countries but an approved prescription in Japan. However, lenvatinib resistance is a substantial clinical challenge. Clinical ATC samples including lenvatinib-resistant tumors are used to build patient-derived cells and patient-derived xenografts. High-throughput drug screening and synergy analyses are performed to identify an effective combination partner for lenvatinib. Cellular functions are detected by cell senescence, apoptosis, cell cycle, cell viability and colony formation assays. CDK2 inhibition showed the significant synthetic lethality with lenvatinib via inhibiting G1/S transition and inducing cell senescence in ATC. High expression of CDK2 is associated with lenvatinib resistance and poor clinical outcomes of ATC patients. Lenvatinib increased protein expression of CDK2 in lenvatinib-resistant ATC cells. Mechanistically, lenvatinib inhibited protein degradation of CDK2 via reducing CDK2's interaction with the RACK1-FBW7 complex, which is involved in ubiquitination and subsequent proteasomal degradation of CDK2. Combination of CDK2 inhibitors in clinical trials (Dinaciclib or PF-07104091) and lenvatinib markedly suppressed growth of xenograft tumors from the lenvatinib-resistant patient. The findings support the combination therapy strategy of lenvatinib and CDK2 inhibitor for lenvatinib-resistant ATC patients with high CDK2 expression.

Context:Presently, there is a paucity of prospective clinical trials investigating neoadjuvant therapy for locally advanced thyroid cancer. Objective:This study was a multicenter, open-label, single-arm, phase II trial evaluating the efficacy and safety of apatinib as neoadjuvant therapy in patients with local advanced differentiated thyroid cancer (DTC). Methods:Patients were treated with preoperative apatinib over a course of 2 to 4 cycles, culminating in surgical resection. The primary endpoints were objective response rate (ORR) and disease control rate (DCR); the secondary endpoints were the rate of R0 surgery, alterations in serum thyroglobulin levels, disease-free survival, and adverse events (AEs). Results:A total of 14 patients who met the inclusion criteria were administered neoadjuvant apatinib. Among these, 13 patients underwent surgical procedures following apatinib treatment and were enrolled in the ITT population. The ORR was 53.8% and the DCR was 100%. Of the patients, 84.6% received R0 surgery, while the remaining 15.4% underwent R1 resection. Predominant among the observed AEs were hypertension, hand-foot syndrome, hepatic dysfunction, proteinuria, and hypothyroidism, with no instances of grade 4 or 5 AEs reported. Subsequent to surgery, patients were followed up for a median period of 34 months, during which disease progression occurred in 5 individuals (35.7%), encompassing 3 cases of locoregional recurrences and 2 cases of distant metastases. Conclusion:Apatinib may be an effective agent in the use of neoadjuvant therapy for locally advanced DTC. Patients may therefore benefit from surgical outcomes and their long-term prognosis.

The sirtuin family has been reported to participate in the regulation of oxidative stress, cancer metabolism, aging, and so on. However, few studies have demonstrated its role in ferroptosis. Our previous studies confirmed that SIRT6 is upregulated in thyroid cancer and associated with cancer development by regulating glycolysis and autophagy. In this research, we aimed to elucidate the association between SIRT6 and ferroptosis. RSL3, erastin, ML210, and ML162 were applied to induce ferroptosis. Cell death and lipid peroxidation were measured by flow cytometry. We found that overexpression of SIRT6 significantly increased the sensitivity of cells to ferroptosis, whereas knockout of SIRT6 promoted resistance to ferroptosis. Furthermore, we demonstrated that SIRT6 induced NCOA4-dependent autophagic degradation of ferritin, thus driving sensitivity to ferroptosis. The clinically used ferroptosis inducer sulfasalazine showed promising therapeutic effects on SIRT6-upregulated thyroid cancer cells in vivo. In conclusion, our research demonstrated SIRT6-driven sensitivity to ferroptosis via NCOA4-dependent autophagy and proposed ferroptosis inducers as promising therapeutic agents for anaplastic thyroid cancer patients.

Solid tumors have developed robust ferroptosis resistance. The mechanism underlying ferroptosis resistance regulation in solid tumors, however, remains elusive. Here, we report that the hypoxic tumor microenvironment potently promotes ferroptosis resistance in solid tumors in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner. In combination with HIF-2α, which promotes tumor ferroptosis under hypoxia, HIF-1α is the main driver of hypoxia-induced ferroptosis resistance. Mechanistically, HIF-1α-induced lactate contributes to ferroptosis resistance in a pH-dependent manner that is parallel to the classical SLC7A11 and FSP1 systems. In addition, HIF-1α also enhances transcription of SLC1A1, an important glutamate transporter, and promotes cystine uptake to promote ferroptosis resistance. In support of the role of hypoxia in ferroptosis resistance, silencing HIF-1α sensitizes mouse solid tumors to ferroptosis inducers. In conclusion, our results reveal a mechanism by which hypoxia drives ferroptosis resistance and identify the combination of hypoxia alleviation and ferroptosis induction as a promising therapeutic strategy for solid tumors.

Since it was proposed by western scholars in the late 1970s and early 1980s, heritage politics has evolved into an important exchange platform for political science to communicate with cultural studies, sociology, archaeology and other adjacent disciplines. It is through this research paradigm that relevant research can reveal the impact of “Western-centrism” in the current western-dominated concept of cultural heritage protection. Although western scholars and the international community have tried to resolve this problem from both theoretical and practical aspects, and have put forward critical heritage theories and promoted the reform of the world heritage protection system, relevant efforts have not been able to fundamentally eliminate this problem. In response to the tasks of the times entrusted to the cause of cultural heritage protection by the development of human society, this paper proposes to build a concept of protection and utilization of cultural heritage with Chinese characteristics based on the values of a community with a shared future for mankind, and promote the development of world cultural heritage protection system towards a more inclusive, open and equal destination.

Background:Despite the high incidence of lateral neck lymph node (LN) metastasis in papillary thyroid cancer (PTC), the management of the lateral neck remains controversial. We aimed to map the draining LNs in the lateral neck using carbon nanoparticles and explore its potential in neck evaluation.Methods:We conducted a multicenter, prospective study in PTC patients who had non-palpable yet suspicious metastatic lateral LNs on ultrasound and/or computed tomography (CT) but could not be confirmed by fine needle aspiration. Carbon nanoparticle suspension was injected peritumorally into the thyroid and modified lateral neck dissection was subsequently performed.Results:A total of 154 patients were enrolled for analysis. And 5,070 lateral LNs were removed, of which 1,079 (21.3%) were dyed. The median of dyed LNs was 6 per case (range, 1-33). The distribution of dyed LNs in neck compartments was IV > III > IIA > IIB/V, independent of tumor size, location, multifocality or microscopic extra-thyroidal extension (ETE). Compared with undyed LNs, the probabilities of metastasis in dyed LNs were significantly increased in compartment III, IV, V, and II-V (III: 29.3% vs. 15.4%, P<0.001; IV: 26.3% vs. 14.5%, P<0.001; V: 16.7% vs. 3.3%, P=0.005; II-V: 26.3% vs. 10.0%, P<0.001). The relative risks of metastasis in dyed LNs compared with undyed LNs were 1.90, 1.82, 5.04 and 2.62 in compartment III, IV, V, and II-V, respectively.Conclusions:It was the first prospective multicenter study to map the lateral neck LNs with carbon nanoparticles, which could help surgeons visualize the suspicious LNs during surgery. Instead of unguided LN biopsy, this method has a potential role in lateral neck assessment for indeterminate lateral LNs in PTC.

Accurate quantification of disease-related unsaturated fatty acids (UFAs) in biomedical samples plays an important role in clinical diagnosis. Here, we reported a quaterization derivatization-stable isotope labeling strategy for accurate quantitative analysis of UFAs by high-performance liquid chromatography-mass spectrometry. [d0]/[d10]-Bis(pyridine) iodine tetrafluoroboride ([d0]/[d10]-IPy2BF4) was employed as the carbon-carbon double bond derivatization reagent with high efficiency and high specificity, to introduce a charge tag on UFAs and avoid the interference of saturated fatty acids. After labeling, the detection sensitivity was significantly enhanced by up to three orders of magnitude compared to intact UFAs. The standard curves showed good linearity (R2 > 0.999) over a wide concentration range. This strategy was successfully applied to determine the content of 12 UFAs in human thyroid carcinoma and para-carcinoma tissues. A significant difference was found in the content of several UFAs between these two kinds of tissues (p < 0.05). These results indicated that the proposed strategy may be valuable for the discovery of abnormal UFA content in early clinical diagnosis.

Introduction Locally advanced thyroid cancer refers to thyroid cancer that invades important structures of the neck, with poor prognosis. Neoadjuvant targeted therapy has the potential to increase the R0/1 resection rate in locally advanced thyroid cancer and improve the outcome in these patients. Methods We conducted a systematic review of studies that reported neoadjuvant targeted therapy in locally advanced thyroid cancer. Individual patient data was extracted from eligible studies. Objective response rate (ORR) and R0/1 resection rate were calculated. Results Sixteen studies and 32 patients were included into analysis, including 18 differentiated thyroid cancer (DTC), 3 medullary thyroid cancer (MTC), 8 anaplastic thyroid cancer (ATC) and 3 poor-differentiated thyroid cancer (PDTC). Most patients were stage T4a (53.1%) and T4b (28.1%). 81.3% patients had regional lymph node metastasis and 37.5% had distant metastasis. RET mutated MTC and BRAF mutated ATC were treated with selective RET inhibitor and selective BRAF/MEK inhibitors. Other treatment regimens were multitarget tyrosine kinase inhibitors (mTKIs). The average duration of treatment was 4.3 months (SD = 4.1). The overall ORR was 78.1% (95%CI: 60.0%–90.7%), and the R0/1 resection rate for the intention to treat population was 78.1% (95%CI: 60.0%–90.7%). With a median follow-up time of 12.1 months, 1 DTC patient and 3 ATC patients died of the disease. Conclusions Neoadjuvant targeted therapy was a new treatment option for locally advanced thyroid cancer and might improve the R0/1 resection rate in selective cases. However, more clinical trials with longer follow-up time are awaited to confirm the clinical benefit of neoadjuvant targeted treatment.

Specific locations of carbon-carbon double bonds (C═C) in lipids often play an essential role in biological processes, and there has been a booming development in C═C composition analysis by mass spectrometry. However, a universal derivatization and fragmentation pattern for the annotation of C═C positions in lipids is still challenging and attractive. To expand this field in lipidomics, a flexible and convenient N-tosylaziridination method was developed, with high derivatization efficiency, sensitivity, and specificity. The derivatization was very fast (15 s), and C═C numbers as well as locations could be pinpointed specifically in tandem mass spectra. By qualitative and quantitative studies of paratumor and tumor thyroid tissues of human beings, the total content of unsaturated fatty acids was suggested to be increased in tumor tissues, and good correlations in and between lysophosphatidylcholines and phosphatidylcholines were revealed by Spearman analysis. Further studies of C═C isomers showed that n-6/n-3 ratios were closely associated with human thyroid tumorigenesis, and high ratios of n-6/n-3 isomers seemed to suffer a high risk of carcinogenesis. Other isomers were not very representative; however, C═C in n-9/n-7 could also be significant for oncology research. Generally, it is supposed that both total amounts and C═C isomer ratios were related to cancer, and N-tosylaziridine derivatization could provide an alternative strategy for the C═C isomer study of disease models.

Background: The techniques of DNA microarray and bioinformatic analysis have exhibited efficiency in identifying dysregulated gene expression in human cancers. In this study, we used integrated bioinformatics analysis to improve our understanding of the pathogenesis of papillary thyroid cancer (PTC). Methods: In this study, we integrated four Gene Expression Omnibus (GEO) datasets, GSE33630, GSE35570, GSE60542 and GSE29265, including 136 normal samples and 157 PTC specimens. The contents of the four datasets are based on GPL570, an Affymetrix Human Genome U133 Plus 2.0 array. Gene ontology (GO) analysis was used to identify characteristic the biological attributes of differentially expressed genes (DEGs) between PTC and normal samples. GO annotation was performed on the DEGs obtained, and the process relied on the DAVID online tool. Kyoto Encyclopedia of Genes and Genomes (KEGG) approach enrichment analyses were adopted to obtain the basic functions of the DEGs. The KOBAS online analysis database was used to complete DEG KEGG pathway comparison and analysis. The search tool (STRING) database was mainly used to search for interacting genes and complete the construction of protein-protein interaction (PPI) networks. Results: Five hundred-ninety DEGs were consistently expressed in the four datasets; 327 of them were upregulated, while 263 were downregulated. Ten DEGs, including five upregulated (ENTPD1, THRSP, KLK10, ADAMTS9, MIR31HG) and five downregulated (SCARA5, EPHB1, CHRDL1, LOC440934, FOXP2) genes, were randomly selected for q-PCR in our own tissue samples to validate the integrated data. The most highly enriched GO terms were extracellular exosome (GO:0070062), cell adhesion (GO:0070062), positive regulation of gene expression (GO:0010628), and extracellular matrix ( ECM) organization (GO:0030198). KEGG pathway analysis was performed, and it was found that abnormally expressed genes effectively participated in pathways such as tyrosine metabolism, complement and coagulation cascades, cell adhesion molecules (CAMs), transcriptional misregulation and ECM-receptor interaction pathways. Conclusions: Five hundred-ninety DEGs were identified in PTC by integrated microarray analysis. The GO and KEGG analyses presented here suggest that the DEGs were enriched in extracellular exosome, tyrosine metabolism, CAMs, complement and coagulation cascades, transcriptional misregulation and ECMreceptor interaction pathways. Functional studies of PTC should focus on these pathways.

In this work, we developed a rapid and high-sensitivity method for simultaneous analyses of fatty alcohols, fatty aldehydes, and sterols by combining the optimized derivatization reaction with electrospray ionization-ion mobility-mass spectrometry (ESI-IM-MS). Pyridine and thionyl chloride were used as derivatization reagents as they were easily removed after the derivatization reaction and could generate permanently charged tags on different functional groups including hydroxyls and aldehydes. Through this one-step derivatization reaction, the sensitivity of detection for fatty alcohols, fatty aldehydes, and sterols was significantly increased. Moreover, the introduction of ion mobility spectrometry (IMS), offering an additional resolution power, ensured more sensitive and accurate detection of derivative products without increasing analytical time. Being connected with high-performance liquid chromatography, more than 15 kinds of compounds were analyzed within 4 min. Relative quantification using peak intensity ratios between d0-/d5-labeled ions were subsequently applied for analyzing these 15 kinds of compounds in human thyroid carcinoma and para-carcinoma tissues. The results showed significant differences in content of some analytes between these two kinds of tissues (p < 0.05). The correlations between most of the analytes in thyroid carcinoma tissues are better than the correlations in para-carcinoma tissues.

Tripartite motif (TRIM)-containing protein 14 (TRIM14) is implicated in many malignancies. Presently, we studied whether TRIM14 played a role in human papillary thyroid carcinoma (PTC). Herein, TRIM14 was up-regulated in tumor tissues when compared with normal thyroid samples. Among PTC patients, enhanced TRIM14 predicted short recurrence free survival (RFS) time. Then, we found that knockdown of TRIM14 in human PTC K1 cells inhibited cell proliferation, induced cell apoptosis and prevented the tumorigenicity in nude mice. On the contrary, TRIM14 overexpression in human PTC TPC1 cells promoted cell proliferation while inhibited cell apoptosis. TRIM14 exerted its oncogenic activities via promoting the activation of signal transducer and activator of transcription 3 (STAT3). Further, TRIM14 interacted with the suppressor of cytokine-signaling-1 (SOCS1), a negative regulator of STAT3 activation, and knockdown of TRIM14 inhibited SOCS1 ubiquitination. In conclusion, TRIM14 may be a prognostic factor and oncogene in PTC, and may be a potential target for PTC intervention.