Roles of four targets in the pathogenesis of graves' orbitopathy.

Graves' orbitopathy (GO) is an autoimmune disease that involves complex immune systems. The mainstays of clinical management for this disease are surgery, targeted drugs therapy, and no-targeted drugs drug therapy. targeted drugs can improve therapeutic efficacy and enhance the quality of life for GO patients. However, as a second-line treatment for GO, targeted drugs such as tocilizumab and rituximab have very limited therapeutic effects and may be accompanied by side effects. The introduction of Teprotumumab, which targets IGF-IR, has made significant progress in the clinical management of GO. The pathophysiology of GO still remains uncertain as it involves a variety of immune cells and fibroblast interactions as well as immune responses to relevant disease targets of action. Therfore, learning more about immune response feedback pathways and potential targets of action will assist in the treatment of GO. In this discussion, we explore the pathogenesis of GO and relevant work, and highlight four potential targets for GO: Interleukin-23 receptor (IL-23 R), Leptin receptor (LepR), Orbital fibroblast activating factors, and Plasminogen activator inhibitor-1 (PAI-1). A deeper understanding of the pathogenesis of GO and the role of potential target signaling pathways is crucial for effective treatment of this disease.

Regulation of Notch Signaling Pathway to Innate Lymphoid Cells in Patients with Acute Myocardial Infarction.

The Notch signaling pathway is an important regulator in fate decisions and immune responses of innate lymphoid cells (ILCs). However, the function of Notch signaling in ILCs in acute coronary syndrome is still not fully elucidated. Thirty-one unstable angina pectoris (UAP) patients, 21 acute myocardial infarction (AMI) patients, and 20 controls were included in this study. Peripheral blood mononuclear cells (PBMCs) were isolated. The mRNA expression levels of Notch receptors and ligands were measured by real-time PCR, while ILC subsets were measured by flow cytometry. Lin- cells were purified and stimulated with γ-secretase inhibitor (GSI). ILC subsets, transcription factors, and secreted cytokines were assessed. Notch receptor and ligand mRNA levels were elevated in PBMCs and peripheral lin- cells from AMI patients. There was no significant difference in total lin-CD45+CD161+CD127+ ILC frequency among three groups. The CRTH2-CD117- ILC1 subset was down-regulated, while the CRTH2+ ILC2 subset was up-regulated in AMI patients. The CRTH2-CD117+ ILC3 subpopulation was comparable among the three groups. ILC1% was negatively correlated with Notch1 and Notch2 in AMI patients. Inhibition of Notch signaling pathway by GSI induced elevations in ILC1 frequency, T-bet mRNA expression, and interferon-γ secretion and reduced ILC2 frequency, GATA3 mRNA levels, and interleukin-5/interleukin-13 production by lin- cells from AMI patients. The current data indicated that activation of Notch signaling pathway might contribute to ILC1-to-ILC2 shift in peripheral blood in AMI patients.

Coumarins ameliorate diabetogenic action of dexamethasone via Akt activation and AMPK signaling in skeletal muscle.

Glucocorticoids are widely prescribed for lots of pathological conditions, however, can produce 'Cushingoid' side effects including central obesity, glucose intolerance, insulin resistance and so forth. Our study is intended to investigate the improving effects of coumarins on diabetogenic action of dexamethasone in vivo and in vitro and elucidate potential mechanisms. ICR mice treated with dexamethasone for 21 days exhibited decreased body weight, increased blood glucose and impaired glucose tolerance, which were prevented by fraxetin (40 mg/kg/day), esculin (40 mg/kg/day) and osthole (20 mg/kg/day), respectively. Esculin, fraxetin and osthole also could promote glucose uptake in normal C2C12 myotubes, and improve insulin resistance in myotubes induced by dexamethasone. Western blotting results indicated that esculin, fraxetin and osthole could boost Akt activation, stimulate GLUT4 translocation, thus alleviate insulin resistance. Esculin and osthole also could activate AMPK, thereby phosphorylate TBC1D1 at Ser237, and consequently ameliorate diabetogenic action of dexamethasone. Our study indicates coumarins as potential anti-diabetic candidates or leading compounds for drug development.

A Porous Organic Poly(triphenylimidazole) Decorated with Palladium Nanoparticles for the Cyanation of Aryl Iodides.

A new porous organic poly(triphenylimidazole), PTPI-Me, was prepared through a Yamamoto self-coupling reaction of 2,4,5-tris-(4-bromophenyl)-1-methyl-1H-imidazole (TPI-Me) in the presence of bis(1,5-cyclooctadiene)nickel(0). The polymer was subsequently decorated with Pd nanoparticles (NPs) to afford a heterogeneous cyanation catalyst, Pd@PTPI-Me. Pd NPs with an average diameter of 2.7 nm were grown within the PTPI-Me framework, owing to the coordination of the imidazole rings to the Pd species. The resultant Pd@PTPI-Me catalyst, with a Pd loading of 0.13 mmol g-1 , exhibited superior catalytic activity for the cyanation of aryl iodides. More importantly, the heterogeneous catalyst was also readily recycled and displayed negligible deactivation after five cycles.

Breast cancer stem cells characterized by CD70 expression preferentially metastasize to the lungs.

BACKGROUND: Cancer stem cells (CSCs) are believed to form metastases. We sought to determine whether CD70 + subpopulation in human breast cancers represents the CSCs accounting for distant metastasis. METHODS: We measured the expression levels of CD70 in breast cancer cell lines and 122 primary breast cancer samples. We characterized the functional roles of CD70 + subpopulation in distant metastasis of breast cancers. RESULTS: We observed a distinct pattern of CD70 expression in a panel of primary breast carcinoma samples, indicating that CD70 serves as a biomarker of lung-specific metastasis. CD70- and CD70+ cell populations isolated from breast cancer cell lines exhibited epithelial and mesenchymal phenotypes, respectively. CD70+ cells, but not CD70- cells, possessed self-renewal and differentiation potentials. Tumorsphere formation in suspension cultures and in vivo tumorigenicity were significantly greater in CD70+ cells than in CD70- cells. Furthermore, the development of lung metastases induced by orthotopic injection was markedly increased in mice inoculated with CD70 + cells. CD70 contributed to the promotion of lung metastases by enhancing self-renewal potential of CD70 + cells. CONCLUSIONS: We isolated CSCs from primary human breast cancers and found that CD70 + subpopulations mediate lung-specific metastasis. These findings might be used to aid in selection of patients for postoperative adjuvant therapy.

Chronic vagus nerve stimulation improves left ventricular function in a canine model of chronic mitral regurgitation.

BACKGROUND: Autonomic dysfunction, characterized by sympathetic activation and vagal withdrawal, contributes to the progression of heart failure (HF). We hypothesized that chronic vagus nerve stimulation (VNS) could prevent left ventricular (LV) remodeling and dysfunction in a canine HF model induced by chronic mitral regurgitation (MR). METHODS AND RESULTS: After the MR inducing procedure, 12 survived canines were randomly divided into the control (n = 6) and the VNS (n = 6) groups. At month 2, a VNS stimulator system was implanted in all canines. From month 3 to month 6, VNS therapy was applied in the VNS group but not in the control group. At month 6, compared with the control group, the canines in VNS group had significantly higher cardiac output (2.3 ± 0.3 versus 2.9 ± 0.4 L/min, P < 0.05, LV forward stroke volume (20.1 ± 3.7 versus 24.8 ± 3.9 ml, P < 0.05), and end-systolic stiffness constant (2.2 ± 0.3 versus 2.7 ± 0.3, P < 0.05). NT-proBNP and C-reactive protein were decreased significantly in the VNS group. However, no statistical difference was found in LV ejection fraction, LV end-diastolic dimension, LV end-diastolic volume, myocyte cross-sectional area, or collagen volume fraction between two groups. CONCLUSIONS: Chronic VNS therapy may ameliorate MR-induced LV contractile dysfunction and improve the expression of biomarkers, but has less effect in improving LV chamber remodeling.

[Establishment and preliminary validation of warfarin maintenance dose algorithm in Chinese Han Population].

OBJECTIVES: To establish an algorithm to predict the warfarin maintenance dose in Chinese Han population and validate the accuracy of this algorithm. METHODS: A total of 488 Chinese Han patients, hospitalized in Fuwai hospital and had a stable dose of warfarin and a target international normalized ratio (INR) of 1.5 to 3.0, were recruited. Indications for warfarin use included prosthetic heart valve, atrial fibrillation and pulmonary embolism. These patients were divided into derivation group (n = 323) and validation group (n = 165) according to the enrollment time. A warfarin maintenance dose algorithm was established based on genetic information, demographic characteristics and concomitant medications by multiple linear regression analysis in derivation group. In the validation group, we evaluated the accuracy of our algorithm by comparing the predicted dose with the actual dose. RESULTS: Our algorithm included VKORC1-1639G > A, CYP2C9*3 and CYP4F2 genotype, age, Body hight, body weight, amiodarone and digoxin use (R(2) = 0.652, P < 0.001) .In the validation group, the average predicted dose by our algorithm had no statistical difference with the actual dose [(3.51 ± 1.03) mg vs. (3.53 ± 1.41) mg, P = 0.779]. Our algorithm identified 100 out of 165 (60.6%) patients in the validation group, whose predicted dose of warfarin was within 20% of the actual dose, and predicted warfarin dose was underestimated in 17.6% (29/165) patients and overestimated in 21.8% (36/165) patients. CONCLUSION: Our algorithm based on VKORC1, CYP2C9 and CYP4F2 polymorphisms can help to predict the warfarin maintenance dose in Chinese Han Population.

[Impact of six genetic polymorphisms on Warfarin maintenance dose variation in Chinese Han population].

OBJECTIVE: To evaluate the effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms on Warfarin maintenance dose variation in Chinese Han Population. METHODS: Four hundred eighty-eight patients with prosthetic heart valves, atrial fibrillation or pulmonary thromboembolism and achieved stable Warfarin dose were enrolled. TaqMan probe or direct sequencing were used to genotype Y9VKORC1, CYP2C9, GGCX, EPHX1 and CYP4F2 gene polymorphisms. Demographic characteristics, stable therapeutic dose of Warfarin and concomitant medications were collected for all patients. The effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms, demographic characteristics and concomitant medications on Warfarin daily maintenance dose were analyzed with statistical method. RESULTS: VKORC1 and CYP2C9 gene polymorphisms could explain more than 50% Warfarin maintenance dose variation in recruited patients, while CYP4F2 gene polymorphisms could only explain 1%. GGCX, PROC and EPHX1 gene polymorphisms had no impact no Warfarin maintenance dose. VKORC1 and CYP2C9 gene polymorphisms have a greater impact on Warfarin maintenance dose compared with demographic characteristics and concomitant medications. CONCLUSION: VKORC1 and CYP2C9 gene polymorphisms have a significant impact on Warfarin maintenance dose in Chinese Han population.

Outcome of gallbladder preservation in surgical management of primary bile duct stones.

AIM: To evaluate the methods and outcome of gallbladder preservation in surgical treatment of primary bile duct stones. METHODS: Thirty-five patients with primary bile duct stones and intact gallbladders received stone extraction by two operative approaches, 23 done through the intrahepatic duct stump (RBD-IDS, the RBD-IDS group) after partial hepatectomy and 12 through the hepatic parenchyma by retrograde puncture (RBD-RP, the RBD-RP group). The gallbladders were preserved and the common bile duct (CBD) incisions were primarily closed. The patients were examined postoperatively by direct cholangiography and followed up by ultrasonography once every six months. RESULTS: In the RBD-IDS group, residual bile duct stones were found in three patients, which were cleared by a combination of fibrocholedochoscopic extraction and lithotripsy through the drainage tracts. The tubes were removed on postoperative day 22 (range: 16-42 days). In the RBD-RP group, one patient developed hemobilia and was cured by conservative therapy. The tubes were removed on postoperative day 8 (range: 7-11 days). Postoperative cholangiography showed that all the gallbladders were well opacified, contractile and smooth. During 54 (range: 6-120 months) months of follow-up, six patients had mildly thickened cholecystic walls without related symptoms and further changes, two underwent laparotomies because of adhesive intestinal obstruction and gastric cancer respectively, three died of cardiopulmonary diseases. No stones were found in all the preserved gallbladders. CONCLUSION: The intact gallbladders preserved after surgical extraction of primary bile duct stones will not develop gallstones. Retrograde biliary drainage is an optimal approach for gallbladder preservation.