A synapse with low power consumption based on MoTe2/SnS2heterostructure.

The use of two-dimensional materials and van der Waals heterostructures holds great potential for improving the performance of memristors Here, we present SnS2/MoTe2heterostructure synaptic transistors. Benefiting from the ultra-low dark current of the heterojunction, the power consumption of the synapse is only 19pJ per switching under 0.1 V bias, comparable to that of biological synapses. The synaptic device based on the SnS2/MoTe2demonstrates various synaptic functionalities, including short-term plasticity, long-term plasticity, and paired-pulse facilitation. In particular, the synaptic weight of the excitatory postsynaptic current can reach 109.8%. In addition, the controllability of the long-term potentiation and long-term depression are discussed. The dynamic range (Gmax/Gmin) and the symmetricity values of the synaptic devices are approximately 16.22 and 6.37, and the non-linearity is 1.79. Our study provides the possibility for the application of 2D material synaptic devices in the field of low-power information storage.

Highly sensitive droplet digital PCR for detection of RET fusion in papillary thyroid cancer.

BACKGROUND: Thyroid cancer is the most frequent malignancy of the endocrine system, of which papillary thyroid cancer (PTC) is the predominant form with a rapid increasing incidence worldwide. Rearranged during transfection (RET) fusions are common genetic drivers of PTC and the potent RET inhibitor selpercatinib has been recently approved for treating advanced or metastatic RET fusion-positive thyroid cancer. In this study we aimed to develop a droplet digital PCR (ddPCR) system to accurately detect RET fusion in PTC samples. METHODS: The frequency and distribution of RET fusions in PTC were analyzed using genomic data of 402 PTC patients in The Cancer Genome Atlas (TCGA) database. To establish the ddPCR system for detecting CCDC6::RET fusion, a plasmid containing CCDC6::RET infusion fragment was constructed as standard template, the annealing temperature and concentrations of primers and probe were optimized. The analytical performance of ddPCR and quantitative reverse transcription PCR (qRT-PCR) were assessed in standard templates and tissue samples from 112 PTC patients. Sanger sequencing was performed in all the RET fusion-positive samples identified by ddPCR. RESULTS: RET fusions were observed in 25 (6.2%) of the 402 TCGA samples, and 15 (60%) of the RET fusion-positive patients had the CCDC6::RET fusion. Compared with qRT-PCR, the ddPCR method showed a lower limit of detection (128.0 and 430.7 copies/reaction for ddPCR and qRT-PCR, respectively). When applying the two methods to 112 tissue samples of PTC, eleven (9.8%) CCDC6::RET fusion-positive samples were detected by qRT-PCR, while ddPCR identified 4 additional positive samples (15/112, 13.4%). All the CCDC6::RET fusion-positive cases identified by ddPCR were confirmed by Sanger sequencing except for one case with 0.14 copies/uL of the fusion. CONCLUSION: The accurate and sensitive ddPCR method reported here is powerful to detection CCDC6::RET fusion in PTC samples, application of this method would benefit more RET fusion-positive patients in the clinic.

Retrospective Analysis of Carotid Body Tumor Surgical Management: Roles of Preoperative Image Investigation and Preoperative Embolization.

BACKGROUND: Carotid body tumors (CBT) surgery is a challenging procedure, and the role of embolization (EMB) in CBT surgery has remained unclear. This study is performed to analyze the management of CBTs, particularly the use of preoperative EMB and image features in minimizing surgical complications. METHODS: A total of 200 CBTs were identified among 184 medical records involving CBT surgery. Regression analysis was used to explore the prognostic predictors of cranial nerve deficit (CND), including image features. In addition, blood loss, operation times, and complication rates were compared between patients who had surgery only versus patients who had surgery along with preoperative EMB. RESULTS: Overall, 96 males and 88 females were identified for inclusion in the study, with a median age of 37.0 years. Computed tomography angiography (CTA) showed the presence of a tiny gap adjacent to the encasement of carotid vessels, which could help minimize carotid arterial injury. High-lying tumors that encased the cranial nerve were usually managed with synchronous cranial nerve resection. Regression analysis revealed that the incidence of CND was positively associated with Shamblin Ⅲ, high-lying, and a maximal CBT diameter of ≥ 5 cm. Among 146 EMB cases, 2 cases of intracranial arterial EMB occurred. No statistical difference was found between the EBM and non-EBM groups in terms of bleeding volume, operation time, blood loss, blood transfusion requirement, stroke, and permanent CND. Subgroup analysis revealed that EMB decreased CND in Shamblin III and low-lying tumors. CONCLUSIONS: CBT surgery should be performed with preoperative CTA to identify favorable factors for minimizing surgical complications. Shamblin Ⅲ or high-lying tumors, as well as CBT diameter, are predictors of permanent CND. EBM does not reduce blood loss or shorten operation time.

Ticlopidine induces embryonic development toxicity and hepatotoxicity in zebrafish by upregulating the oxidative stress signaling pathway.

Ticlopidine exerts its anti-platelet effects mainly by antagonizing platelet p2y12 receptors. Previously, a few studies have shown that ticlopidine can induce liver injury, but the exact mechanism of hepatotoxicity remains unclear. Oxidative stress, metabolic disorders, hepatocyte apoptosis, lipid peroxidation, and inflammatory responses can all lead to hepatic liver damage, which can cause hepatotoxicity. In this study, in order to deeply explore the potential molecular mechanisms of ticlopidine -induced hepatotoxicity, we used zebrafish as a model organism to comprehensively evaluate the hepatotoxicity of ticlopidine and its associated mechanism. Three days post-fertilization, zebrafish larvae were exposed to varying concentrations (1.5, 1.75 and 2 µg/mL) of ticlopidine for 72 h, in contrast, adult zebrafish were exposed exposure to 4 µg/mL of ticlopidine for 28 days. Ticlopidine-exposed zebrafish larvae showed changes in liver morphology, shortened body length, and delayed development of the swim bladder development. Liver tissues of ticlopidine-exposed zebrafish larvae and adults stained with Hematoxylin & Eosin revealed vacuolization and increased cellular interstitial spaces in liver tissues. Furthermore, using Oil Red O and periodic acid-Schiff staining methods and evaluating different metabolic enzymes of ticlopidine-exposed zebrafish larvae and adults suggested abnormal liver metabolism and liver injury in both ticlopidine-exposed zebrafish larvae and adults. Ticlopidine also significantly elevated inflammation and oxidative stress and reduced hepatocyte proliferation. During the rescue intervention using N-acetylcysteine, we observed significant improvement in ticlopidine-induced morphological changes in the liver, shortened body length, delayed swim bladder development, and proliferation of liver tissues showed significant improvement. In conclusion, ticlopidine might inhibit normal development and liver proliferation in zebrafish by upregulation of oxidative stress levels, thus leading to embryonic developmental toxicity and hepatotoxicity. In this study, we used zebrafish as a model organism to elucidate the developmental toxicity and hepatotoxicity induced by ticlopidine upregulation of oxidative stress signaling pathway in zebrafish, providing a theoretical basis for clinical application.

Intervention time decides the status of autophagy, NLRP3 activity and apoptosis in macrophages induced by ox-LDL.

BACKGROUND: It has been determined through extensive studies that autophagy, the Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome and apoptotic responses in macrophages jointly contribute to atherogenesis and its development in the presence of lipid abnormalities. Few studies have investigated in full-scale if the intervention time for lipids abnormality or NLRP3 activation have a significant effect on autophagy, NLRP3 or the apoptotic status in macrophages. METHODS: Human THP-1 monocyte-derived macrophages were established by challenging THP-1 monocytes with 80 µg/ml oxidized low-density lipoprotein (ox-LDL) for specific durations. Foam cell formation was observed by Oil Red O (ORO) staining. Western blots were employed to determine protein expression. Transmission electron microscope (TEM) and immunofluorescence microscopy were applied to observe the autophagic status of cells. Cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). RESULTS: The cells were treated with ox-LDL for 12 h and 36 h, which were considered to represent early and advanced stages of atherogenesis for this study. The results showed that inhibition of ox-LDL phagocytosis by cytochalasin D in the early stage improved autophagic status, reduced NLRP3 activation and the apoptotic response significantly. In contrast, cytochalasin D had little effect on blocking the detrimental effect of ox-LDL at the advanced stage. Moreover, the changes in autophagy, apoptosis and NLRP3 expression after treatment with small interfering (si) RNA targeting NLRP3 in the early and advanced stages of atherogenesis were consistent with the above data. CONCLUSIONS: Interventions against lipid disorders or inflammatory reactions in the early or advanced stages of atherogenesis may have different results depending on when they are applied during the process of atherosclerotic pathogenesis. These results may help improve therapeutic strategies for atherosclerosis prevention. Furthermore, a healthy lifestyle should still be recommended as the most important and inexpensive measure to prevent atherogenesis.

Ticlopidine induces cardiotoxicity in zebrafish embryos through AHR-mediated oxidative stress signaling pathway.

Ticlopidine has inhibitory effects on platelet aggregation via ADP (adenosine diphosphate), platelet release reaction and depolymerization. In clinical practice, it is commonly used to prevent heart, cerebrovascular and other thromboembolic diseases. However, ticlopidine has also been reported to have teratogenic effects on the heart, though its specific molecular mechanism remains unclear. In this study, zebrafish embryos were used as model organisms to examine the toxicity effect of ticlopidine. Zebrafish embryos exposed to 6, 7.5, and 9 mg/L ticlopidine solutions manifested several abnormalities, including body curvature, smaller eyes, slower absorption of the vitella sac, pericardial edema, slower heart rate, increased mortality, longer venous sinus - arterial ball (SV-BA) distance, and increased oxidative stress, which indicated developmental and cardiac toxicity. Abnormal expression of key genes related to heart development was observed, and the level of apoptotic gene expression was up-regulated. Further experiments revealed up-regulation of embryonic oxidative stress following ticlopidine exposure, leading to a decrease in cardiomyocyte proliferation. Conversely, the aromatic hydrocarbon receptor (AHR) inhibitor CH223191 protected embryos from the cardiotoxicity effect of ticlopidine, confirming further the role of up-regulated oxidative stress as the molecular mechanism of ticlopidine-induced cardiotoxicity in zebrafish. In conclusion, ticlopidine exposure leads to developmental and cardiotoxicity in zebrafish embryos. Therefore, further studies are warranted to ascertain such potential harms of ticlopidine in humans, which are vital in providing guidance in the safe use of drugs in clinical practice.

CircCD44 plays oncogenic roles in triple-negative breast cancer by modulating the miR-502-5p/KRAS and IGF2BP2/Myc axes.

BACKGROUND: Emerging studies have revealed the potent functions of circRNAs in breast cancer tumorigenesis. However, the biogenesis, biofunction and mechanism of circRNAs in triple-negative breast cancer (TNBC) are largely unknown. METHODS: High-throughput RNA sequencing was applied to identify dysregulated circRNAs in TNBCs and paired normal tissues. RNA pulldown and luciferase assays were performed to investigate the interaction between circular CD44 (circCD44, also annotated as hsa_circ_0021735) and miR-502-5p. RNA pulldown and RIP assays were used to investigate the interaction between circCD44 and IGF2BP2. Cell viability, colony formation, migration/invasion assays and in vivo tumorigenesis were used to investigate circCD44 biological functions. RESULTS: CircCD44 is an uncharacterized circRNA, which is highly expressed in TNBC, and its expression is negatively correlated with the prognosis of TNBC patients. CircCD44 promotes TNBC proliferation, migration, invasion and tumorigenesis at least partially by sponging miR-502-5p and interacting with IGF2BP2. CONCLUSION: Our data suggested that overexpressed circCD44 promotes TNBC progression. CircCD44 is potentially a novel diagnostic and therapeutic marker for TNBC patients.

Screening and the epidemic of thyroid cancer in China: An analysis of national representative inpatient and commercial insurance databases.

Reasons behind the rapid increase of thyroid cancer (TC) in China are uncertain. We assessed the burden of TC and the role of access to screening and salt iodization. We analyzed two national databases in China: Hospital Quality Monitoring System (HQMS) and China Reinsurance Company (CRC) database. HQMS covered 1037 (44.3%) Class 3 hospitals and 76 263 617 Class 3 hospital inpatients in 2013 to 2017 and CRC covered 93 123 018 clients in 2000 to 2016. The proportion of TC inpatients among inpatients in HQMS and TC incidence in critical illness insurance buyers were used to evaluate the association with screening and iodine status. Between 2013 and 2017, the proportion of TC patients in HQMS with urban employee medical insurance and good access to screening increased sharply while there was little change among those with the other two forms of medical insurance. Across provinces, the proportion of TC inpatients in HQMS was positively correlated with per capita disposable income but not with median urinary iodine. Similar findings were observed in the CRC database. In 2017, approximately 1000 individuals were overdiagnosed with TC daily. We conservatively forecast that 5.1 million healthy individuals would become TC patients unnecessarily between 2019 and 2030. Our findings suggested the epidemic of TC in China was substantially underestimated. It was associated with screening but not with salt iodization.

Apolipoprotein A1 is negatively associated with male papillary thyroid cancer patients: a cross-sectional study of single academic center in China.

BACKGROUND: Papillary thyroid cancer (PTC) is the most common type of thyroid cancer and the incidence of PTC has continued to increase over the past decades. Many studies have shown that obesity is an independent risk factor for PTC and obese PTC patients tend to have a relative larger tumor size and higher grade of tumor stage. Obesity is associated with disordered lipid metabolism and the relationship between serum lipids and PTC remains unclear. Therefore, this study aimed to investigate the association between serum lipid level and PTC. METHODS: We retrospectively analyzed 1018 PTC patients diagnosed and treated in our hospital, all these cases were first diagnosed with PTC and had complete clinical information including ultrasound reports before surgery, serum lipid (CHOL, TG, HDL-c, LDL-c, Apo-A1, Apo-B, Apo-E) results, surgical records and pathological reports. RESULTS: None of these lipid markers were associated with tumor size in the whole cohort and in the female group. In the male group, on crude analysis, Apo-A1 showed a marginally association with tumor size, [OR = 0.158 (0.021-1.777)], p = 0.072. After adjusting for age and multifocality, Apo-A1 showed a significant association with tumor size [OR = 0.126 (0.016-0.974)], p = 0.047. This association become more apparent in a young male subgroup, [OR = 0.051 (0.005-0.497)], p = 0.009. CHOL, TG, HDL-c, LDL-c, Apo-B, Apo-E did not show significant association with tumor size. As for LNM, neither in the male group nor in the female group were found to be associated with any serum lipid biomarkers. CONCLUSION: As PTC incidences continues to increase, our findings demonstrated a negatively association between PTC and apoA-1 in male PTC patients, which may contribute to further investigation concerning diagnosing and preventing this most common type of thyroid cancer.

Circular HER2 RNA positive triple negative breast cancer is sensitive to Pertuzumab.

BACKGROUND: Triple negative breast cancer (TNBC) remains the most challenging breast cancer subtype so far. Specific therapeutic approaches have rarely achieved clinical improvements in treatment of TNBC patients and effective molecular biomarkers are largely unknown. METHODS: We used paired TNBC samples and high throughput RNA sequencing to identify differentially expressed circRNAs. Sucrose gradient polysome fractionation assay, antibody and Mass spectra were used to validate active circRNA translation. The novel protein function was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by immunoprecipitation analyses and kinase activity assay. RESULTS: Circular HER2 RNA (circ-HER2) encoded a novel protein, HER2-103. Unexpectedly, while HER2 mRNA and protein were barely detected, circ-HER2/HER2-103 was expressed in ~ 30% TNBC clinical samples. Circ-HER2/HER2-103 positive TNBC patients harbored worse overall prognosis than circ-HER2/HER2-103 negative patients. Knockdown circ-HER2 inhibited TNBC cells proliferation, invasion and tumorigenesis in vitro and in vivo, suggesting the critical role of circ-HER2/HER2-103 in TNBC tumorigenicity. Mechanistically, HER2-103 promoted homo/hetero dimerization of epidermal growth factor receptor (EGFR)/HER3, sustained AKT phosphorylation and downstream malignant phenotypes. Furthermore, HER2-103 shared most of the same amino acid sequences as HER2 CR1 domain which could be antagonized by Pertuzumab, a clinical used HER2 antibody. Pertuzumab markedly attenuated in vivo tumorigenicity of circ-HER2/HER2-103 expressing TNBC cells but showed no effects in circ-HER2/HER2-103 negative TNBC cells. CONCLUSION: Our results not only demonstrated that certain TNBCs were not truly 'HER2 negative' but also highlighted the clinical implications of Pertuzumab in circ-HER2/HER2-103 expressing TNBC patients.

miR-17-5p suppresses cell proliferation and invasion by targeting ETV1 in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is the malignancy with the worst outcome among all breast cancer subtypes. We reported that ETV1 is a significant oncogene in TNBC tumourigenesis. Consequently, investigating the critical regulatory microRNAs (miRNAs) of ETV1 may be beneficial for TNBC targeted therapy. METHODS: We performed in situ hybridization (ISH) and immunohistochemistry (IHC) to detect the location of miR-17-5p and ETV1 in TNBC patient samples, respectively. miR-17-5p expression in TNBC tissues and cell lines was assessed by quantitative real-time PCR (qRT-PCR). ETV1 expression was evaluated by qRT-PCR, western blotting and IHC. Cell Counting Kit-8 (CCK-8), colony formation, Transwell and wound closure assays were utilized to determine the TNBC cell proliferation and migration capabilities. In vivo tumour metastatic assays were performed in a zebra fish model. RESULTS: The abundance of miR-17-5p was significantly decreased in TNBC cell lines and clinical TNBC tissues. The miR-17-5p expression levels were closely correlated with tumour size (P < 0.05) and TNM stage (P < 0.05). By contrast, the expression of ETV1 was significantly up-regulated in TNBC cell lines and tissues. There is an inverse correlation between the expression status of miR-17-5p and ETV1 (r = -0.28, P = 3.88 × 10-3). Luciferase reporter assay confirmed that ETV1 was a direct target of miR-17-5p. Forced expression of miR-17-5p in MDA-MB-231 or BT549 cells significantly decreased ETV1 expression and suppressed cell proliferation, migration in vitro and tumour metastasis in vivo. However, rescuing the expression of ETV1 in the presence of miR-17-5p significantly recovered the cell phenotype. High miR-17-5p expression was associated with a significantly favourable prognosis, in either the ETV1-positive or ETV1-negative groups (log-rank test, P < 0.001; P < 0.001). Both univariate and multivariate analyses showed that miR-17-5p and ETV1 were independent risk factors in the prognosis of TNBC patient. CONCLUSIONS: Our data indicate that miR-17-5p acts as a tumour suppressor in TNBC by targeting ETV1, and a low-abundance of miR-17-5p may be involved in the pathogenesis of TNBC. These findings indicate that miR-17-5p may be a therapeutic target for TNBC.

MCP-1 stimulates MMP-9 expression via ERK 1/2 and p38 MAPK signaling pathways in human aortic smooth muscle cells.

OBJECTIVE: We investigated the molecular mechanism underlying the role of monocyte chemoattractant protein-1 (MCP-1) in the formation and development of human abdominal aortic aneurysm (AAA). METHODS: We examined protein expression profiles using a protein array and found that MCP-1 was the most highly expressed protein in AAA tissues compared with normal aortas. To investigate the potential mechanism of MCP-1 involvement in the pathogenesis of AAA, we treated human aortic smooth muscle cells (HASMCs) with human recombinant MCP-1. RESULTS: MCP-1 was the most highly expressed protein in AAA tissues compared with normal aorta; matrix metalloproteinase-9 (MMP-9) expression was also significantly increased. Treatment with MCP-1 significantly increased the expression and activation of MMP-9 and activated the three major mitogen activated protein kinases (MAPKs) extracellular signal regulated kinase (ERK), c-Jun amino terminal kinase (JNK1/2) and p38 MAPK. Furthermore, MCP-1-induced secretion of MMP-9 was inhibited by U0126 (inhibitor of the ERK 1/2 pathway) and SB203580 (inhibitor of the p38 MAPK pathway), but not SP600125 (inhibitor of the JNK1/2 pathway). CONCLUSION: These data demonstrate that MCP-1 stimulates secretion of MMP-9 directly through the ERK1/2 and p38 MAPK mediated pathways in HASMCs. Thus, inhibition of this molecular mechanism might be a potential therapeutic target in the non-surgical treatment of AAA.

The ERK inhibitor GDC-0994 selectively inhibits growth of BRAF mutant cancer cells.

BRAF or RAS mutation-induced aberrant activation of the mitogen-activated protein kinase (MAPK) pathway is frequently observed in human cancers. As the key downstream node of MAPK pathway, ERK1/2 is as an important therapeutic target. GDC-0994 (ravoxertinib), an orally bioavailable, highly selective small-molecule inhibitor of ERK1/2, showed acceptable safety and pharmacodynamic profile in a recent phase I clinical trial. In this study, we investigated dependence of the anti-tumor effect of ERK inhibitor GDC-0994 on genetic alterations in the MAPK pathway. The results showed that GDC-0994 sharply inhibited cell proliferation and colony formation and induced remarkable G1 phase cell-cycle arrest in cancer cells harboring BRAF mutation but had little effect on cell behaviors in most RAS mutant or wild-type cell lines. The expression of a large number of genes, particularly the genes in the cell cycle pathway, were significantly changed after GDC-0994 treatment in BRAF mutant cells, while no remarkable expression change of such genes was observed in wild-type cells. Moreover, GDC-0994 selectively inhibited tumor growth in a BRAF mutant xenograft mice model. Our findings demonstrate a BRAF mutation-dependent anti-tumor effect of GDC-0994 and provide a rational strategy for patient selection for ERK1/2 inhibitor treatment.

Multi-Level Switching of Spin-Torque Ferromagnetic Resonance in 2D Magnetite.

2D magnetic materials hold substantial promise in information storage and neuromorphic device applications. However, achieving a 2D material with high Curie temperature (TC), environmental stability, and multi-level magnetic states remains a challenge. This is particularly relevant for spintronic devices, which require multi-level resistance states to enhance memory density and fulfil low power consumption and multi-functionality. Here, the synthesis of 2D non-layered triangular and hexagonal magnetite (Fe3O4) nanosheets are proposed with high TC and environmental stability, and demonstrate that the ultrathin triangular nanosheets show broad antiphase boundaries (bAPBs) and sharp antiphase boundaries (sAPBs), which induce multiple spin precession modes and multi-level resistance. Conversely, the hexagonal nanosheets display slip bands with sAPBs associated with pinning effects, resulting in magnetic-field-driven spin texture reversal reminiscent of "0" and "1" switching signals. In support of the micromagnetic simulation, direct explanation is offer to the variation in multi-level resistance under a microwave field, which is ascribed to the multi-spin texture magnetization structure and the randomly distributed APBs within the material. These novel 2D magnetite nanosheets with unique spin textures and spin dynamics provide an exciting platform for constructing real multi-level storage devices catering to emerging information storage and neuromorphic computing requirements.

Exploring the Association Between Thyroid Function and Oral Microbiome Diversity: An NHANES Analysis.

Objective: To investigate the association between thyroid functions and the oral microbiome diversity. Method: Data from the US National Health and Nutrition Examination Survey (NHANES; 2009-2012) were analyzed. Thyroid functions were defined using thyroid hormones and related biomarkers. Oral microbiome was measured using the observed number of amplicon sequence variants (ASVs) and the Bray-Curtis dissimilarity. Linear regression was used to estimate the average change (ß) and 95% CI for the number of ASVs against thyroid functions, adjusted for sociodemographic variables, health conditions, urinary iodine status, and periodontitis. Non-metric multidimensional scaling (NMDS) was used to analyze the Bray-Curtis dissimilarity. Results: A total of 2943 participants were analyzed. The observed number of ASVs has a weighted mean of 128.9. Self-reported thyroid disease was associated with reduced number of ASVs (ß = -9.2, 95% CI: -17.2, -1.2), if only adjusted for sociodemographic variables and health conditions. In the fully adjusted model, compared to normal thyroid function, both subclinical and clinical hyperthyroidism were associated with reduced number of ASVs (ß = -59.6, 95% CI: -73.2, -46.0; ß = -28.2, 95% CI: -50.0, -6.5, respectively). Thyroid peroxidase antibody level higher than the reference range was associated with higher observed ASV (ß= 9.0, 95% CI: 1.2, 16.9). NMDS analysis suggested significant difference in oral microbiome composition between free triiodothyronine groups (P = .002), between free thyroxine groups (P = .015), and between thyroglobulin groups (P = .035). Conclusion: Hyperthyroidism was associated with reduced oral microbiome diversity. Free triiodothyronine, free thyroxine, and thyroglobulin levels may alter the oral microbiome composition.

CircGLIS3 inhibits thyroid cancer invasion and metastasis through miR-146b-3p/AIF1L axis.

PURPOSE: Studies have shown that circRNA is involved in the occurrence and development of human cancers. However, it remains unclear that the contribution of circRNA in thyroid carcinoma and its role in the process of tumorigenesis. METHODS: The expression profile of circRNA-miRNA-mRNA in thyroid carcinoma was detected by RNA sequencing and verified by qRT-PCR. The characteristics of circGLIS3 were verified by RNase R and actinomycin assays, subcellular fractionation, and fluorescence in situ hybridization. The functions of circGLIS3 and AIF1L were detected by wound healing, transwell, 3D culture and Western blot. RNA Immunoprecipitation (RIP), RNA pulldown and dual-luciferase reporter assays were used to verify the target genes of circGLIS3 and downstream miRNAs. Functional rescue experiments were performed by transfecting miRNA mimics or siRNA of target genes. Finally, metastatic mouse models were used to investigate circGLIS3 function in vivo. RESULTS: In this study, we discovered a novel circRNA (has_circ_0007368, named as circGLIS3) by RNA sequencing. CircGLIS3 was down-regulated in thyroid carcinoma tissues and cells line, and was negatively associated with malignant clinical features of thyroid carcinoma. Functional studies found that circGLIS3 could inhibit the migration and invasion of thyroid carcinoma cells, and was related to the EMT process. Mechanistically, circGLIS3 can upregulate the expression of the AIF1L gene by acting as a miR-146b-3p sponge to inhibit the progression of thyroid carcinoma. CONCLUSION: Our study identified circGLIS3 as a novel tumor suppressor in thyroid cancer, indicating the potential of circGLIS3 as a promising diagnostic and prognostic marker for thyroid cancer.

The interference between effects of PFAS exposure on thyroid hormone disorders and cholesterol levels: an NHANES analysis.

Studies have documented that per- and polyfluoroalkyl substance (PFAS) exposures are associated with thyroid hormones (TH) and lipid levels. This study investigates whether these effects interfere with each other. We analyzed data on 3954 adults in the US National Health and Nutrition Examination Survey (NHANES; 2007-2012). TH disorder was defined using thyroid hormones. Serum high-density lipoprotein (HDL) cholesterol, total cholesterol, and six types of PFAS were included. Weighted quantile sum (WQS) regression was used to estimate the overall effect of PFAS mixture on TH disorder and cholesterols, respectively. Potential confounders, including age, race, gender, education, household poverty, smoking, and alcohol drinking, were adjusted. PFAS mixture was associated increased risk for TH disorder (odds ratio = 1.21, 95% confidence interval (CI): 1.02, 1.43), higher HDL cholesterol (linear coefficient = 1.31, 95% CI: 0.50, 2.11), and higher total cholesterol (linear coefficient = 5.30, 95% CI: 3.40, 7.21). TH disorder was associated with higher HDL cholesterol (linear coefficient = 2.30, 95% CI: 0.50, 2.11), but not total cholesterol. When adjusted for TH disorder, the effect estimates of PFAS mixture remain roughly unchanged on HDL cholesterol (linear coefficient = 1.13, 95% CI: 0.28, 1.98) and total cholesterol (linear coefficient = 5.61, 95% CI: 3.58, 7.63). Sex modified the effect of PFAS mixture on HDL cholesterol (P for interaction: 0.04) but did not change the interaction between PFAS and TH disorder on cholesterols. We corroborated the adverse health effects of PFAS exposure on TH and lipids; however, these two effects appear to be independent of and not interfere with each other.

Enhanced spin-orbit torque and field-free switching in Au/TMDs/Ni hybrid structures.

Spin-orbit torque (SOT) plays a significant role in spintronic logic and memory devices. However, due to the limited spin Hall angle and SOT symmetry in a heavy-metal-ferromagnet bilayer, further improving SOT efficiency and all-electric magnetization manipulation remain a challenge. Here we report enhanced SOT efficiency and all-electric switching in Au based magnetic structures, by inserting two-dimensional transition metal dichalcogenides (2D TMDs) with large spin-orbit coupling. With the TMD spacer insert, both damping-like and field-like SOTs are improved, and an unconventional out-of-plane damping-like SOT is induced, due to the interface orbital hybridization, modified spin-mixing conductance and orbital current. Moreover, current induced field-free magnetization switching is demonstrated in Au/WTe2/Ni and Au/MoS2/Ni devices, and it shows multiple intermediate states and can be efficiently controlled by an electric current. Our results open a path for increasing torques and expand the application of 2D TMDs in spintronic devices for neuromorphic computing.

Methylation-Mediated Silencing of ATF3 Promotes Thyroid Cancer Progression by Regulating Prognostic Genes in the MAPK and PI3K/AKT Pathways.

Background: Aberrant expression of oncogenes and/or tumor suppressor genes (TSGs) drives the tumorigenesis and development of thyroid cancer. We investigated the expression and function of a member of the activating transcription factor (ATF)/cAMP-responsive element-binding protein (CREB) transcription factor (TF) family, ATF3, in thyroid cancer. Methods: Data from 80 patients with papillary thyroid cancer (PTC) in the First Affiliated Hospital of Sun Yat-sen University and 510 PTC samples in The Cancer Genome Atlas thyroid cancer database were utilized for gene expression and prognosis analyses. The survival data were analyzed by Kaplan-Meier curves and Cox regression with adjustment for age, sex, multilocality, extrathyroidal extension, lymph metastases, and history of neoadjuvant treatment. DNA methylation was analyzed by methylation-specific polymerase chain reaction (PCR) and bisulfite sequencing PCR. TFs binding to ATF3 promoter were identified by DNA pull-down combined with mass spectrum assay, and confirmed by quantitative PCR (qPCR), luciferase reporter assay, and chromatin immunoprecipitation (ChIP)-qPCR. We conducted functional assays in vitro and in a xenograft mouse model to evaluate the function of ATF3 in thyroid cancer. Integrated analyses based on RNA sequencing, ChIP-seq, and CUT&Tag assays were performed to explore the mechanisms underlying the function of ATF3. Results: ATF3 was significantly downregulated in PTC and patients with low ATF3 expression had reduced progression-free survival (adjusted hazard ratio = 0.50 [CI 0.26-0.98], p = 0.043). DNA hypermethylation in ATF3 promoter disrupted the binding of SP1 and MYC-MAX, leading to inactivation of the gene. ATF3 functioned as a TSG by inhibiting the proliferation and mobility of thyroid cancer cells. And ATF3 regulated the expression of a number of genes by binding to the regulatory elements of them, particularly for genes in MAPK and PI3K/AKT pathways. Among these target genes, filamin C was positively regulated by ATF3 and associated with a more favorable thyroid cancer prognosis, while dual specificity phosphatase 10, fibronectin-1, tenascin C, and CREB5 were negatively regulated by ATF3 and associated with a poorer prognosis. Conclusions: We observed that the promoter DNA hypermethylation decreased the expression of ATF3, which in turn promoted the progression of thyroid cancer, at least partially, by directly regulating prognosis-related genes in the MAPK and PI3K/AKT pathways.

STRA6 Promotes Thyroid Carcinoma Progression via Activation of the ILK/AKT/mTOR Axis in Cells and Female Nude Mice.

BACKGROUND: Metastasis has emerged to be an important cause for poor prognosis of thyroid carcinoma (TC) and its molecular mechanisms are not fully understood. STRA6 is a multifunctional membrane protein widely expressed in embryonic and adult tissues. The function and mechanism of STRA6 in TC remain elusive. OBJECTIVE: We aimed to explore the role of STRA6 in TC progression and provide a therapeutic target for TC. METHODS: The expression and clinicopathological relevance of STRA6 were explored in TC. Stable STRA6-knockdown TC cells were established and used to determine the biological function of STRA6 in vitro and in vivo. RNA sequencing and co-immunoprecipitation were performed to unveil the molecular mechanism of STRA6 in TC progression. The potential of STRA6 as a therapeutic target was evaluated by lipid nanoparticles (LNPs) containing siRNA. RESULTS: STRA6 was upregulated in TC and correlated with aggressive clinicopathological features, including extrathyroidal extension and lymph node metastasis, which contributed to the poor prognosis of TC. STRA6 facilitated TC progression by enhancing proliferation and metastasis in vitro and in vivo. Mechanistically, STRA6 could interact with integrin-linked kinase (ILK) and subsequently activate the protein kinase B/mechanistic target of rapamycin (AKT/mTOR) signaling pathway. We further unveiled that STRA6 reprogrammed lipid metabolism through SREBP1, which was crucial for the metastasis of TC. Moreover, STRA6 siRNA delivered by LNPs significantly inhibited cell growth in xenograft tumor models. CONCLUSIONS: Our study demonstrates the critical roles of STRA6 contributing to TC progression via the ILK/AKT/mTOR axis, which may provide a novel prognostic marker as well as a promising therapeutic target for aggressive TC.