Graves’ disease (GD) is one of the most common autoimmune diseases. The immune dysfunction in GD involves the generation of thyroid-stimulating hormone receptor (TSHR) autoantibodies that presumably arise consequent to interactions among dendritic cells (DCs), T cells, and regulatory T (Treg) cells. However, the immunological mechanisms of interactions between them that lead to the induction and regulation of this autoimmune disease are poorly defined. In this study, we investigated whether DCs are the main cause of the defective activity of Treg cells in GD patients. We found a significant decrease in the percentage of circulating CD4+CD25+FOXP3+ Treg cells in untreated GD patients (uGD), which was negatively correlated with the concentration of TSHR autoantibodies. uGD-derived DCs were polarized to increase the number of plasmacytoid DCs (pDCs) and conferred the ability to abrogate the suppressive function of Treg cells through inducing apoptosis of CD4+CD25+ Treg cells in an IFN-α–dependent manner, and elevated thyroid hormones further exacerbated the effect. The nucleotide UDP, which inhibits IFN-α secretion of pDCs through P2Y6 receptor signaling, restored the suppressive function of CD4+CD25+ Treg cells. Collectively, uGD-derived DCs through pDC polarization and elevated thyroid hormones act in concert to impair the regulatory capacity of Treg cells, facilitating the production of TSHR autoantibodies in the pathogenesis of GD.

Fibrinogen and D-dimer levels after two cycles of chemotherapy are predictors for response on chemotherapy and prognosis in SCLC patients.

Previous studies have suggested an association between preoperative plasma fibrinogen and D-dimer levels and prognosis in patients with non-small cell lung cancer (NSCLC) who underwent surgery. In this study, we evaluate the value of pre- and post-operative plasma fibrinogen and D-dimer levels and changes in the levels of the two markers between before and after operation in predicting tumor recurrence and metastasis in NSCLC patients who undergoing radical surgery. One hundred and eighty-four patients with I-IIIA NSCLC were enrolled in this study, and plasma fibrinogen and D-dimer levels were measured in these patients before and after surgery, respectively. The results showed that pre- and post-operative plasma fibrinogen and D-dimer levels were significantly higher in NSCLC patients than in control group. Pre- and post-operative plasma fibrinogen and D-dimer positivities were significantly correlated with tumor recurrence (P = 0.020 and P = 0.001 for fibrinogen, and P = 0.027 and P = 0.001 for D-dimer). Moreover, there was a significant link between the decrease in fibrinogen and D-dimer levels after surgery and tumor recurrence (P = 0.014 and P = 0.018). Patients with pre- and post-operative fibrinogen and D-dimer positivities had a shorter disease-free survival (DFS) than those without (P = 0.002 and P < 0.001 for fibrinogen, and P = 0.003 and P = 0.001 for D-dimer). Multivariate Cox regression analyses revealed that pre- and post-operative fibrinogen and D-dimer positivities were independent predictors for unfavorable DFS. Our results indicate that pre- and post-operative plasma fibrinogen and D-dimer levels may be useful biomarkers in predicting tumor recurrence and metastasis for patients who undergo curative surgery.

The positivity of D-dimer before and during chemotherapy is a predictor of treatment response and worse PFS in patients with advanced NSCLC. D-dimer levels provide prognostic information in addition to that of imaging studies.

The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) protects a variety of cell types against neuronal apoptosis by binding to apolipoprotein E receptor 2 (ApoER2). The present study aimed to determine the association between PCSK9/ApoER2 signaling and neuronal apoptosis following middle cerebral artery occlusion (MCAO) injury in hyperlipidemic mice. For this purpose, C57BL/6 mice fed with a high-fat diet (HFD) for 6 weeks were exposed to MCAO. Subsequently, PCSK9 was inhibited by a lentiviral vector harboring short-hairpin RNA (shRNA) targeting PCSK9, which was stereotaxically injected into the cerebral cortex of mice. At 48 h post-ischemia, hematoxylineosin staining and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay were performed to determine cerebral tissue injury and apoptosis. PCSK9 and ApoER2 expression levels were assessed by reverse transcription-quantitative polymerase chain reaction, immunohistochemistry and western blotting. The results indicated that hyperlipidemia and increased PCSK9 expression were evident in HFD mice. Cerebral histological injury and neuronal apoptosis, as well as PCSK9 and ApoER2 levels, which were increased upon ischemia in hyperlipidemic mice, were attenuated by PCSK9 shRNA treatment. These protective effects of PCSK9 shRNA interference were associated with decreased neuronal apoptosis and a reduced level of ApoER2 expression in the hippocampus and cortex. The data of the present study demonstrated that the PCSK9 shRNA-mediated anti-apoptotic effect induced by MCAO in hyperlipidemic mice is associated with ApoER2 downregulation, which may be a potential new therapy for stroke treatment in patients with hyperlipidemia.