The weekly protocol of iv methylprednisolone therapy is more efficient and safer than the daily protocol for patients with active moderate-to-severe GO.

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.

This study sought to evaluate the potential of circulating long non-coding RNAs (lncRNAs) as biomarkers for acute myocardial infarction (AMI). We measured the circulating levels of 15 individual lncRNAs, known to be relevant to cardiovascular disease, using the whole blood samples collected from 103 AMI patients, 149 non-AMI subjects, and 95 healthy volunteers. We found that only two of them, Zinc finger antisense 1 (ZFAS1) and Cdr1 antisense (CDR1AS), showed significant differential expression between AMI patients and control subjects. Circulating level of ZFAS1 was significantly lower in AMI (0.74 ± 0.07) than in non-AMI subjects (1.0 ± 0.05, P < 0.0001), whereas CDR1AS showed the opposite changes with its blood level markedly higher in AMI (2.18 ± 0.24) than in non-AMI subjects (1.0 ± 0.05, P < 0.0001). When comparison was made between AMI and non-AMI, the area under ROC curve was 0.664 for ZFAS1 alone or 0.671 for CDR1AS alone, and 0.691 for ZFAS1 and CDR1AS combination. Univariate and multivariate analyses identified these two lncRNAs as independent predictors for AMI. Similar changes of circulating ZFAS1 and CDR1AS were consistently observed in an AMI mouse model. Reciprocal changes of circulating ZFAS1 and CDR1AS independently predict AMI and may be considered novel biomarkers of AMI.Acute myocardial infarction (AMI) is the worst threat to human lives and the quality of human life. Early detection of AMI with noninvasive and reliable biomarkers is the foremost step for minimizing ischemic damage to the myocardium. Clinically validated biomarkers like creatine kinase MB (CKMB) and cardiac troponin I (cTnI), currently considered as "gold standard" for AMI diagnosis [1][2][3][4] , have a number of pitfalls. Search for new biomarkers of AMI, particularly those for early diagnosis, is therefore a top-urgent mission and has actually been an endless effort from fundamental and clinical researchers worldwide.In addition to protein biomarkers, recent studies have suggested the potential value of RNA biomarkers for AMI, e.g., microRNAs (miRNAs) [5][6][7] . More recently, long non-coding RNAs (lncRNAs), a new class of functional

Steroid receptor coactivator 3 (SRC-3/AIB1/ACTR/NCoA-3) is a transcriptional coactivator for nuclear receptors including vitamin D receptor (VDR). Growth hormone (GH) regulates insulin-like growth factor I (IGF-I) expression, and IGF-I forms complexes with acid-labile subunit (ALS) and IGF-binding protein 3 (IGFBP-3Nuclear receptors are hormone-inducible transcription factors that require coactivators to mediate their transcriptional activities (34). Most nuclear receptor coactivators exist in cells at limiting concentrations, and their transcriptional activities are regulated by various signaling pathway-triggered posttranslational modifications (3,32,34). Accordingly, regulation of coactivator concentrations and activities appears to be one of the major means to control gene expression and metabolic homeostasis regulated by hormones and their cognate receptors. Conversely, coactivator dysfunction may cause a number of developmental and physiological disorders and life-threatening diseases (11, 34). In the p160 steroid receptor coactivator (SRC) family (34), disruption of the SRC-1 gene in mice results in partial resistance to steroid and thyroid hormones (31, 36); disruption of SRC-2 (TIF2 or GRIP1) impairs both male and female reproductive functions (5, 17); and disruption of SRC-3 (AIB1, RAC3, p/CIP, ACTR, or TRAM-1) retards somatic and mammary gland growth, reduces female reproductive function, and suppresses oncogene-and carcinogeninduced mammary tumorigenesis (9,10,30,35). In addition, SRC-3 is overexpressed in human breast cancers, and overexpression of SRC-3 in the mouse mammary epithelium is sufficient to induce ductal carcinomas (1, 29). Therefore, studies to understand the biological functions and molecular mechanisms of nuclear receptor coactivators have been a recent focus in the field of molecular endocrinology.The p160 SRC coactivators interact with nuclear receptors in a hormone-dependent manner and recruit protein acetyltransferases such as CBP, p300, and p/CAF and protein methyltransferases such as CARM1 and PRMT1 to the promoter of hormone-responsive genes. These SRC-recruited histone modification enzymes change the chromatin topology, facilitate general transcription factor assembly, and potentiate transcription (34). In cultured cells, overexpression of each SRC member increases most nuclear receptor-mediated transactivation, suggesting that each SRC can serve as a coactivator for multiple nuclear receptors (34). This notion is further supported by our findings showing partial redundancy of function between SRC-1 and SRC-2 in promoting Purkinje cell development in the cerebellum, spermatogenesis in the testis, and postnatal viability (17,21). On the other hand, the distinct phenotypes observed in mice lacking SRC-1, SRC-2, or SRC-3 indicate that each SRC member has a specific biological function, presumably due to its preference for specific transcription factors and/or its temporal and spatial expression patterns (6,7,34,35,39). One of the unique phenotypes observed in SRC-3 Ϫ/Ϫ mice is th...