Immunosensitivity mediated by downregulated AKT1-SKP2 induces anti-PD-1-associated thyroid immune injury.

BACKGROUND: Immune checkpoint inhibitors evoke the immune system, which may cause immune-related adverse effects. The predictors and mechanisms of anti-PD-1-associated thyroid immune injury remain unclear. METHODS: A retrospective analysis is conducted on 518 patients treated with anti PD-1/PD-L1. Firstly, the differences between anti PD-1 and anti PD-L1 are compared on the risk of thyroid immune injury. Then, the predictors of the risk and thyroid function for anti PD-1 related thyroid immune injury are analyzed. Furthermore, the in vitro mechanism of normal thyroid cells (NTHY) is studied. First, the effect of anti PD-1 on the cell viability and immune sensitivity of thyroid cells is observed. Cell viability includes cell proliferation, apoptosis, cell cycle, T4 secretion, while immune sensitivity includes molecular expression and CD8 + T cell aggregation and killing towards NTHY. Then the differentially expressed proteins (DEPs) are screened by protein mass spectrometry. Enrichment of KEGG pathway and annotation of GO function on DEPs are conducted. Human protein-protein interactions are obtained from STRING database. The network is constructed and analyzed using Cytoscape software. In vitro, key proteins and their pathways are validated through overexpression plasmids or inhibitors. The recovery experiment and the immuno-coprecipitation experiment are designed to support the results. In vivo, the key proteins are detected in the thyroid tissue of mice fed with anti PD-1, as well as in the thyroid tissue of patients with Hashimoto's thyroiditis. RESULTS: Thyroid irAE is associated with female, IgG, FT4, TPOAb, TGAb, TSHI, TFQI, and TSH. Peripheral lymphocytes are associated with thyroid function. In vitro, the NIVO group shows prologed G1 phase, decreased FT4, downregulated PD-L1, upregulated IFN-γ, and more CD8 + T cell infiltration and cytotoxicity. AKT1-SKP2 is chosen as the key protein. AKT1 overexpression and SKP2 inhibitor replies to NIVO and AKT1 overexpression, respectively. Immunoprecipitation shows SKP2 and PD-L1 interaction. CONCLUSION: Female, impaired thyroid hormone sensitivity and IgG4 contribute to the risk of thyroid irAE, while peripheral blood lymphocyte characteristics affect thyroid function. Anti-PD-1 induces thyroid irAE by downregulating AKT1-SKP2 to enhance thyroid immunosensitivity.

The relationship between atherosclerotic disease and relapse during ATD treatment.

Background: Clinical relapse is a potential risk for traditional antithyroid drug (ATD) treatment in hyperthyroid patients. Evidence suggests that atherosclerotic disease is closely associated with hyperthyroidism, while the relationship between atherosclerosis and relapse remains unclear. Methods: Two hundred and twenty-five patients with GD who underwent ATD as their first treatment were studied; 88 and 137 patients were categorized as drug reduction relapse and drug reduction remission, respectively. Logistic regression was used to analyze risk factors of drug reduction relapse in patients with GD. Results: During a median of 48 months followed up 88 patients who relapsed. According to multivariate analyses, atherosclerosis related diseases, FT4, goiter, and anxiety rating scores are independent risk factors for drug reduction. According to K-M survival analysis, patients with atherosclerosis related diseases, FT4 > 18.82 pmol/L, anxiety rating scores > 23, and gradation of goiter ≥ Grade II had a higher risk of relapse than those with lower levels. ROC analysis shown atherosclerosis related diseases significantly improved the predictive accuracy of relapse. Conclusions: Atherosclerotic disease is closely related to the relapse of hyperthyroidism, ATD treatment in hyperthyroid patients with atherosclerosis should be given more attention.

Understanding the functional inflammatory factors involved in therapeutic response to immune checkpoint inhibitors for pan-cancer.

Immune checkpoint inhibitors (ICIs) fight tumor progression by activating immune conditions. The inflammatory factors are playing a functional role in programmed death-1 (PD-1) or other immune checkpoints. They are involved in regulating the expression of programmed death ligand-1 (PD-L1), the only predictor recognized by the guidelines in response to ICIs. In addition, abundant components of the tumor microenvironment (TME) all interact with various immune factors contributing to the response to ICIs, including infiltration of various immune cells, extracellular matrix, and fibroblasts. Notably, the occurrence of immune-related adverse events (irAEs) in patients receiving ICIs is increasingly observed in sundry organs. IrAEs are often regarded as an inflammatory factor-mediated positive feedback loop associated with better response to ICIs. It deserves attention because inflammatory factors were observed to be different when targeting different immune checkpoints or in the presence of different irAEs. In the present review, we address the research progresses on regulating inflammatory factors for an intentional controlling anti-cancer response with immune checkpoint inhibitors.

Type 2 diabetes is more closely associated with risk of colorectal cancer based on elevated DNA methylation levels of ADCY5.

Type 2 diabetes mellitus (T2DM) has an increased risk of cancer. In the present study, the relationship between T2DM and 13 types of cancer was analyzed and key methylation genes were searched. First, DNA methylation and mRNA expression were obtained data for T2DM and 13 types of cancer from The Cancer Genome Atlas and Gene Expression Omnibus. The t-test was used to screen the differentially methylated expression overlapping genes (DE-MGs) in T2DM and cancer on both methylation and expression levels. DE-MGs are weighted based on the methylation and projected into the human protein interaction network. The correlation between T2DM and each type of cancer was analyzed, and key genes were identified. The results showed that 293 DE-MGs were related to T2DM and 3307 were related to cancer. The network found that T2DM is more related to colorectal cancer (CRC) compare with the other 12 types of cancer. A total of 5 from 8 candidate genes were associated with CRC. A total of 28 clinical patients were used to validate these 5 genes. A CRC tissue sample was collected from each patient, as well as a paracancerous sample that served as a control. A total of 56 tissue samples were divided into 4 groups: control group, T2DM group, CRC group and T2DM with CRC group (combination group). Compared with the control group, the methylation level of adenylate cyclase 5 (ADCY5), neuregulin 1 and ELAV-like RNA-binding protein 4 in the combination group was significantly upregulated, and the mRNA level was significantly downregulated. Furthermore, based on the methylation level of ADCY5, the correlation coefficient between the combination group and the T2DM group was greater than that of the CRC group. In conclusion, T2DM is most likely to be associated with CRC among 13 common types of cancer based on methylation characteristics. An upregulated methylation of ADCY5 in T2DM may have a higher risk of CRC.

Upregulation Of Protein Tyrosine Phosphatase Receptor Type C Associates To The Combination Of Hashimoto's Thyroiditis And Papillary Thyroid Carcinoma And Is Predictive Of A Poor Prognosis.

INTRODUCTION: PTC is not generally considered a lethal disease, but prone to recurrence as the prognosis. Hashimoto's thyroiditis (HT) is an important factor that affects the prognosis of papillary thyroid carcinoma (PTC). It is crucial to find biomarkers to identify the combination of HT with PTC and to predict the prognosis. METHODS: RNASeq data from the Cancer Genome Atlas (TCGA) database was used to screen differentially expressed genes (DEGs) of PTC with HT via the edgeR package of R software version 3.3.0. Also, the DEGs were applied to the DAVID web-based tool to determine the enrichment of gene functions via Gene Ontology (GO) analysis and to identify associated pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. By constructing protein interaction networks within Cytoscape software, we screened candidate genes and explored possible relationships with the clinical phenotype of PTC. Finally, additional thyroid tissue samples were collected to verify the results above. RESULTS: After analyzing the RNA-Seq data of PTC patients from the Cancer Genomic Atlas, 497 differentially expressed PTC genes were found to be associated with HT, of which protein tyrosine phosphatase receptor type C (PTPRC), KIT, and COL1A1 were associated with tumor size and lymph node metastasis (p < 0.05). Verification of these results with another 30 thyroid tissues of clinical PTC patients revealed that the expression level of PTPRC in the PTC with HT group was higher than that in the PTC without HT group (p < 0.05) and the ROC curve showed a good discrimination (area under the curve = 0.846). However, the correlation with the clinical phenotype was not statistically significant (p > 0.05). DISCUSSION: These data suggest that upregulation of PTPRC enhances the incidence of HT associated with PTC and is also predictive of a poor prognosis.

High iodine effects on the proliferation, apoptosis, and migration of papillary thyroid carcinoma cells as a result of autophagy induced by BRAF kinase.

Papillary thyroid carcinoma (PTC) is a common endocrine tumor. This study found that different iodine concentrations affected the proliferation, apoptosis, and migration of PTC. For this study, we collected clinical information from PTC patients and monitored the levels of urinary iodine, LC3-II, and caspase-3 in cancer tissue, and BRAF kinase in peripheral blood from PTC patients. We also monitored the proliferation, apoptosis and migration ability of human papillary-thyroid carcinoma (BCPAP) cells at different iodine concentrations and their association with changes in autophagy and BRAF kinase activity of BCPAP cells at high iodine levels (10-3 mol/l). We found that the proportion of tumor diameters ≥ 1 cm in the iodine excess group were lower than that in the iodine non-excess group. The proportion of PTC patients with infiltration in the iodine excess group was higher than that in the iodine non-excess group. Levels of the autophagy-related protein LC3-II and the apoptosis-related protein caspase-3 in cancer tissues, and activity of BRAF kinase in peripheral blood, were positively correlated with urinary iodine concentrations from PTC patients. At high iodine levels, the proliferation rate decreased, and apoptosis percentage and migration rates increased compared with the no-iodine group. At high iodine levels, the frequencies of autophagosomes (Aph) and autophagosome-lysosomes (Apl) in BCPAP cells increased significantly, and activities of LC3-II and BRAF kinase increased, respectively. The activity of LC3-II decreased when BRAF kinase was inhibited. The activity of LC3-II and the proliferation and migration rates of BCPAP cells decreased, and the apoptosis percentage increased when autophagy was inhibited at high iodine concentrations. Our results demonstrated that, in the presence of excessive iodine, the mean tumor size of PTC patients was smaller and easier to invade than tumors in patients not supplied with excessive iodine. The levels of autophagy and apoptosis in PTC cancer tissues, and activities of BRAF kinase in peripheral blood increased with increasing urinary iodine concentrations. High iodine levels inhibited cell proliferation and promoted apoptosis and migration of PTC cells. Autophagy induced by BRAF kinase in PTC cells was involved in anti-apoptosis, and promoted proliferation and migration at high iodine concentrations. This study provides a rationale for iodine supplementation in PTC patients.

Combination of serum microRNAs and ultrasound profile as predictive biomarkers of diagnosis and prognosis for papillary thyroid microcarcinoma.

Circulating microRNAs (miRNAs) are promising diagnostic markers in various types of cancers, including papillary thyroid carcinoma (PTC). However, there is sparse information reported with regards to miRNA expression in papillary thyroid microcarcinoma (PTMC) or concerning the role of a combination of miRNAs and ultrasound (US) in the diagnosis of PTMC before surgery. Therefore, we designed a study that aimed to evaluate miRNA expression levels and their potential associations with US findings and determine whether miRNAs could be used as diagnostic and prognostic biomarkers of PTMC. miR­222, miR­221, miR­146b and miR­21 levels were determined using reverse transcription­quantitative polymerase chain reaction (RT­qPCR) in serum from 58 patients with PTMC and 47 with PTC, 35 patients with benign thyroid nodules (BTN) and 40 control subjects. Expression levels of the four miRNAs in serum were evaluated before and after surgery. The results indicated that miR­222, miR­221, miR­146b and miR­21 expression levels were higher in the PTMC samples than in those from the BTN and control groups and the combination of miRNAs and US had a high sensitivity and specificity for discrimination between BTN and PTMC by receiver operating characteristic (ROC) curve analysis and improved the accuracy of diagnosis of PTMC before surgery. In addition, serum miRNA expression levels were significantly related to poor prognostic factors including metastatic lymph nodules (MLNs), multifocal and bilateral lesions, advanced stage and high­risk PTMC patients. The miRNA expression levels in serum from PTMC patients were rapidly reduced after surgery compared with levels before surgery. In addition, we also analyzed the miRNA expression levels in serum from patients who were divided into two groups according to factors indicating a good or poor prognosis associated with PTMC after surgery. The results suggested that after surgery, the miR­222, miR­146b and miR­21 expression levels were significantly higher in the poor prognosis group compared with these levels in the good prognosis group. Serum miRNA expression levels helped distinguish between benign and malignant nodules and were associated with a poor prognosis in PTMC. Circulating miRNAs may be useful as follow­up biomarkers and as diagnostic and prognostic tools.