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Dysregulation of gene amplification, cell-signaling-pathway transduction, epigenetic and transcriptional regulation, and protein interactions drives tumor-cell proliferation and invasion, while ion channels also play an important role in the generation and development of tumor cells. Overexpression of Ca

Aims Tetrahydrobiopterin (BH4) is a critical determinant of the biological function of endothelial nitric oxide synthase. The present study was to investigate the role of valvular endothelial cell (VEC)-derived BH4 in aortic valve calcification. Methods and results Plasma and aortic valve BH4 concentrations and the BH4:BH2 ratio were significantly lower in calcific aortic valve disease patients than in controls. There was a significant decrease of the two key enzymes of BH4 biosynthesis, guanosine 5′-triphosphate cyclohydrolase I (GCH1) and dihydrofolate reductase (DHFR), in calcified aortic valves compared with the normal ones. Endothelial cell-specific deficiency of Gch1 in Apoe −/− (Apoe −/− Gch1 fl/fl Tie2 Cre) mice showed a marked increase in transvalvular peak jet velocity, calcium deposition, runt-related transcription factor 2 (Runx2), dihydroethidium (DHE), and 3-nitrotyrosine (3-NT) levels in aortic valve leaflets compared with Apoe −/− Gch1 fl/fl mice after a 24-week western diet (WD) challenge. Oxidized LDL (ox-LDL) induced osteoblastic differentiation of valvular interstitial cells (VICs) co-cultured with either si-GCH1- or si-DHFR-transfected VECs, while the effects could be abolished by BH4 supplementation. Deficiency of BH4 in VECs caused peroxynitrite formation increase and 3-NT protein increase under ox-LDL stimulation in VICs. SIN-1, the peroxynitrite generator, significantly up-regulated alkaline phosphatase (ALP) and Runx2 expression in VICs via tyrosine nitration of dynamin-related protein 1 (DRP1) at Y628. Finally, folic acid (FA) significantly attenuated aortic valve calcification in WD-fed Apoe −/− mice through increasing DHFR and salvaging BH4 biosynthesis. Conclusion The reduction in endothelial-dependent BH4 levels promoted peroxynitrite formation, which subsequently resulted in DRP1 tyrosine nitration and osteoblastic differentiation of VICs, thereby leading to aortic valve calcification. Supplementation of FA in diet attenuated hypercholesterolaemia-induced aortic valve calcification by salvaging BH4 bioavailability.

Anoctamin 1 (ANO1) or TMEM16A gene encodes a member of Ca2+ activated Cl– channels (CaCCs) that are critical for physiological functions, such as epithelial secretion, smooth muscle contraction and sensory signal transduction. The attraction and interest in ANO1/TMEM16A arise from a decade long investigations that abnormal expression or dysfunction of ANO1 is involved in many pathological phenotypes and diseases, including asthma, neuropathic pain, hypertension and cancer. However, the lack of specific modulators of ANO1 has impeded the efforts to validate ANO1 as a therapeutic target. This review focuses on the recent progress made in understanding of the pathophysiological functions of CaCC ANO1 and the current modulators used as pharmacological tools, hopefully illustrating a broad spectrum of ANO1 channelopathy and a path forward for this target validation., Graphical abstract The abnormal expression or dysfunction of Ca2+ activated Cl– channel anoctamin 1 (ANO1) is involved in pathological phenotypes and diseases, suggesting that pharmacological modulation of ANO1 may serve as therapeutic potential and strategy.Image 1

The development of dopant-free carrier-selective layer demonstrates the potential to overcome parasitic absorption and doping-related recombination caused by heavy doping to realize both low recomb...

Dopant-free passivating contacts for photovoltaics have the potential to be deposited at low costs while providing excellent surface passivation and low contact resistance. However, one pressing is...

Objectives: This study amied to whether IL-21 promotes osteoblast transdifferentiation of cultured human Valvular interstitial cells (VICs). Methods: We first confirmed that IL-21 alters gene expression between CAVD aortic valve tissue and normal samples by immunohistochemistry, qPCR, and western blotting. VICs were cultured and treated with IL-21. Gene and protein expression levels of the osteoblastic markers ALP and Runx2, which can be blocked by specific JAK3 inhibitors and/or siRNA of STAT3, were measured. Results: IL-21 expression was upregulated in calcified aortic valves and promotes osteogenic differentiation of human VICs. IL-21 accelerated VIC calcification through the JAK3/STAT3 pathway. Conclusion: Our data suggest that IL-21 is a key factor in valve calcification and a promising candidate for targeted therapeutics for CAVD.

Digital advertising is a critical part of many e-commerce platforms such as Taobao and Amazon. While in recent years a lot of attention has been drawn to the consumer side including canonical problems like ctr/cvr prediction, the advertiser side, which directly serves advertisers by providing them with marketing tools, is now playing a more and more important role. When speaking of sponsored search, bid keyword recommendation is the fundamental service. This paper addresses the problem of keyword matching, the primary step of keyword recommendation. Existing methods for keyword matching merely consider modeling relevance based on a single type of relation among ads and keywords, such as query clicks or text similarity, which neglects rich heterogeneous interactions hidden behind them. To fill this gap, the keyword matching problem faces several challenges including: 1) how to learn enriched and robust embeddings from complex interactions among various types of objects; 2) how to conduct high-quality matching for new ads that usually lack sufficient data. To address these challenges, we develop a heterogeneous-graph-neural-network-based model for keyword matching named HetMatch, which has been deployed both online and offline at the core sponsored search platform of Alibaba Group. To extract enriched and robust embeddings among rich relations, we design a hierarchical structure to fuse and enhance the relevant neighborhood patterns both on the micro and the macro level. Moreover, by proposing a multi-view framework, the model is able to involve more positive samples for cold-start ads. Experimental results on a large-scale industrial dataset as well as online AB tests exhibit the effectiveness of HetMatch., Comment: 10 pages

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With the increasing volume of cardiovascular surgeries and the rising adoption rate of new methodologies that serve as a bridge to cardiac transplantation and that require multiple surgical interventions, the formation of postoperative intrapericardial adhesions has become a challenging problem that limits future surgical procedures, causes serious complications, and increases medical costs. To prevent this pathology, we developed a nanotechnology-based self-healing drug delivery hydrogel barrier composed of silicate nanodisks and polyethylene glycol with the ability to coat the epicardial surface of the heart without friction and locally deliver dexamethasone, an anti-inflammatory drug. After the fabrication of the hydrogel, mechanical characterization and responses to shear, strain, and recovery were analyzed, confirming its shear-thinning and self-healing properties. This behavior allowed its facile injection (5.75 ± 0.15 to 22.01 ± 0.95 N) and subsequent mechanical recovery. The encapsulation of dexamethasone within the hydrogel system was confirmed by 1H NMR, and controlled release for 5 days was observed. In vitro, limited cellular adhesion to the hydrogel surface was achieved, and its anti-inflammatory properties were confirmed, as downregulation of ICAM-1 and VCAM-1 was observed in TNF-α activated endothelial cells. In vivo, 1 week after administration of the hydrogel to a rabbit model of intrapericardial injury, superior efficacy was observed when compared to a commercial adhesion barrier, as histological and immunohistochemical examination revealed reduced adhesion formation and minimal immune infiltration of CD3+ lymphocytes and CD68+ macrophages, as well as NF-κβ downregulation. We presented a novel nanostructured drug delivery hydrogel system with unique mechanical and biological properties that act synergistically to prevent cellular infiltration while providing local immunomodulation to protect the intrapericardial space after a surgical intervention.

ANO1 is a calcium-activated chloride channel protein that has been used to diagnose GISTs after tissue biopsy. Recently, ANO1 mRNA amplification in the blood has received considerable attention as a useful method for the diagnosis of GISTs. The aim of this study was to evaluate the diagnostic ability of ANO1 mRNA in distinguishing GIST patients from healthy subjects. We constructed a logistic regression model for examining the diagnostic ability of ANO1 mRNA in comparison with conventional tumor markers, including CEA, CA199, and CA724. Our results showed that ANO1 mRNA was significantly amplified in PBMCs, the average expression level and range of ANO1 mRNA in the blood were increased along with the expression of ANO1 in the tissues, and the extent of amplification of ANO1 was associated with tumor size. In addition, ROC curve analysis showed that ANO1 mRNA in the blood had the highest specificity when compared with conventional tumor markers. Moreover, a combined analysis with ANO1 mRNA and conventional tumor markers had the highest sensitivity in diagnosing GISTs. Our study indicated that detection of ANO1 mRNA in PBMCs is a promising method for diagnosis of GISTs in vitro.

Most common ovarian cancers are epithelial carcinoma in which the etiology for carcinogenesis remains elusive. ANO1/TMEM16A, a member of Ca2+ -activated Cl- channels (CaCCs), has been demonstrated to promote epithelium-originated cancers and whether it plays a role in the pathogenesis of ovarian cancer is unknown. In our study we found that ANO1 proteins were overexpressed in human epithelial ovarian cancer cells and tissue samples. ANO1 protein upregulation was correlated with the clinical FIGO (International Federation of Gynecology and Obstetrics) staging and poor grade in ovarian cancer tissues. Interestingly, the upregulation of ANO1 gene expression was also detected in the peripheral blood mononuclear cells (PBMCs) from preoperative patients with ovarian tumors, and the down-regulation of ANO1 in the PBMCs from postoperative patients. Silencing of ANO1 inhibited proliferation and invasion of ovarian cancer cells. Mechanistically, ANO1 knockdown attenuated phosphorylation of PI3K/Akt, and inhibition of PI3K/Akt signaling by specific inhibitor LY294002 resulted in suppression of ovarian cancer cells growth promoted by ANO1 expression. Furthermore, intratumoral injection of ANO1 siRNA suppressed subcutaneous xenograft tumor growth in nude mice implanted with ovarian cancer SKOV3 cells. Taken together, our findings demonstrate that ANO1 overexpression is involved in the pathogenesis of human epithelial ovarian cancer. Inhibition of ANO1 upregulation or inactivating PI3K/Akt signaling may have therapeutic potential for epithelial ovarian cancer, and the detection of ANO1 expression level in PBMCs from patients may also serve as a biomarker for diagnosis and prognosis of epithelial ovarian cancers.

Glutaraldehyde‐fixed porcine heart valve (GPHV) calcify and deteriorate over time. The aim of this study was to explore the roles macrophages play in mediating calcification and degeneration of the valve's connective tissue matrix. GPHV were implanted subcutaneously in the abdomens of C57BL/6 mice. The mice were equally divided into two study groups: (a) GPHV +phosphate buffered saline (PBS) liposomes, and (b) GPHV +clodronate liposomes. GPHV were collected for further analyses at 4 weeks post implant. Macrophages were almost depleted from the spleens of mice injected with clodronate liposomes as indicated by immunohistochemical staining. Furthermore, the expression of matrix metalloproteinase‐2 (MMP‐2), MMP‐9, and proinflammatory cytokines like IL‐1β, IL‐6, MCP‐1, MIP‐1a, MIP‐1b, were downregulated in the GPHV +Clodronate liposomal group compared with the GPHV+PBS liposomal group. Clodronate liposomal treatment led to significant decreases in the expression of RUNX2, ALP and OPN as well as less calcium deposits in GPHVs compared with PBS liposomal treatment. This finding indicated that infiltrating macrophages are critically involved in the development of calcification and deterioration in GPHVs. Macrophage depletion by clodronate liposomes decreased the extent of GPHV’s calcification and deterioration., The application scope of bioprosthetic valve is limited due to the early degeneration. Although progress has been accomplished in the fixation, pre‐implantation, and anti‐calcification treatment of GBHV, structural valve degeneration (SVD) remains an important limitation of this type of prosthesis. Based on these reported observations, we hypothesized that the infiltration of peripheral macrophages was possibly detrimental for GBHV in vivo, and macrophage elimination could prevent GBHV calcification and degradation.

BACKGROUND: To evaluate circulating T follicular helper (cTfh) cells and characterize their function in chronic-phase recipients after heart transplantation. METHODS: Participants were divided into healthy control (HC, n=40), preoperative (Pre, n=40), and post-transplantation chronic-phase recipient (1-year, n=40) groups. The percentages of cTfh cell subsets and CD19(+) B cell subsets were measured using flow cytometry. In vitro co-culture experiments were performed using cTfh cells and B cells isolated by fluorescence-activated cell sorting. Plasma concentrations of IL-21, chemokine ligand 13 (CXCL13), immunoglobulin G1 (IgG1), and immunoglobulin G3 (IgG3) were quantified using enzyme-linked immunosorbent assays (ELISA). RESULTS: cTfh and programmed cell death protein 1-positive (PD-1(+)) cTfh cells, the cTfh17/cTfh ratio, and class-switched memory B cells in peripheral blood were significantly increased in the 1-year group versus the HC and Pre groups (P

Background: Anoctamin-1 (ANO1) plays a pivotal role in cancer progression. A meta-analysis was conducted to assess the potential prognostic role of ANO1 in cancers. Methods: A total of 1760 patients from 7 eligible studies were included into the analysis. Pooled hazard ratios or odds ratios were extracted and calculated with a random-effects model, and analyses of heterogeneity bias were conducted. Results: Our results showed that over expression of ANO1 was significantly correlated with poor overall survival in all cancers (HR = 1.52; 95% CI: 1.19–1.92; P = .0006). Subgroup analysis indicated that there was a significant association between over expression of ANO1 and poor prognosis breast cancer (HR = 3.24; 95% CI: 1.74–6.04), head and neck squamous cell carcinoma (HR = 1.14; 95% CI: 1.00–1.30), esophageal squamous cell carcinoma (HR = 1.93; 95% CI: 1.07–3.50), gastric cancer (HR = 1.62; 95% CI: 1.12–2.34) and colorectal cancer (HR = 1.38; 95% CI: 1.03–1.85). In addition, over expression of ANO1 was not associated with TNM stage, histological grade, lymph node metastasis, tumor size, age and gender. However, ANO1 was significantly associated with human epidermal growth factor receptor 2, but not associated with progesterone receptor or estrogen receptor in breast cancer. Conclusions: Our results indicate that ANO1 can be a predictive factor for prognosis of cancer.

Background The purpose of this study is to explore the combined diagnostic value of anti-cyclic citrullinated peptide antibody (A-CCP), rheumatoid factor (RF) and imaging result in early rheumatoid arthritis, and the role of A-CCP and RF in prediction for radiological outcomes. Methods 101 patients with rheumatoid arthritis and 97 control individuals were detect their A-CCP, RF and radiological joint changes, the diagnostic efficacy of the respective indicators and the combined indicators was analyzed by logistic regression model. Results Our results showed that values of A-CCP and RF were significantly higher in the RA group than in the normal group. Receiver operating characteristic curve results show that the sensitivity of RF is higher than A-CCP and radiological outcome, and specificity of CCP is higher than RA and radiological outcome, and the diagnostic ability of combination of RF, A-CCP and radiological outcome is the strongest. Furthermore, RF and A-CCP had high significant OR for radiological joint damage and progression. Conclusions Our study indicated that the combined diagnosis of RF and A-CCP with radiological outcome can improve the diagnostic efficacy of RA, and RF and A-CCP are independent predictors of radiological damage and progression.

Aims To investigate the role of PP2A in calcified aortic valve disease (CAVD). Materials and methods The expressions of PP2A subunits were detected by real-time polymerase chain reaction (RT-PCR) and western blot in aortic valves from patients with CAVD and normal controls, the activities of PP2A were analyzed by commercial assay kit at the same time. Aortic valve calcification of mice was evaluated through histological and echocardiographic analysis. ApoE−/− mice and ApoE−/− mice injected intraperitoneally with PP2A inhibitor LB100 were fed a high-cholesterol diet for 24 weeks. Immunofluorescent staining was used to locate the cell-type in which PP2A activity was decreased, the PP2A activity of valvular interstitial cells (VICs) treated with osteogenic induction medium was assessed by western blot and commercial assay kit. After changing the activity of VICs through pharmacologic and genetic intervention, the osteoblast differentiation and mineralization were assessed by western blot and Alizarin Red staining. Finally, the mechanism was clarified by using several specific inhibitors. Key findings PP2A activity was decreased both in calcified aortic valves and human VICs under osteogenic induction. The PP2A inhibitor LB100 aggravated the aortic valve calcification of mice. Furthermore, PPP2CA overexpression inhibited osteogenic differentiation of VICs, whereas PPP2CA knockdown promoted the process. Further study revealed that the ERK/p38 MAPKs signaling pathways mediated the osteogenic differentiation of VICs induced by PP2A inactivation. Significance This study demonstrated that PP2A plays an important role in CAVD pathophysiology, PP2A activation may provide a novel strategy for the pharmacological treatment of CAVD.

The purpose of the present study was to evaluate the diagnostic role of CRP in ovarian cancer and to assess whether CRP can be combined with tumor markers to enhance the diagnostic efficacy toward ovarian cancer. Area under the curve, sensitivity, and specificity were calculated to access the diagnostic ability of each singly and combined as markers for ovarian cancer. The CRP cut-off value was then calculated to evaluate the diagnostic efficacy of CRP for ovarian cancer. Our results showed that values for all markers were significantly higher in the cancer group than in the control group. Receiver operating characteristic curve results showed that CA125 had the highest diagnostic efficacy for ovarian cancer, while the sensitivity for CRP was higher than for CA125, and the specificity for CRP was equal to that of CA125. The combination of CRP, CA125, and HE4, however, provided the strongest diagnostic capability. Furthermore, the diagnostic cut-off value for CRP with regard to ovarian cancer was 9.8 mg/L, and high levels of CRP were correlated with stage and tumor size of ovarian cancer. Our study indicated that CRP is valuable in the diagnosis of ovarian cancer, and that combining CRP with CA125 and HE4 improved the diagnostic efficacy with respect to ovarian cancer.

The dopant-free back contact solar cells are demonstrated based on hole selective contact material, chromium trioxide (CrO x , x x is first applied in silicon based solar cell as the emitter. Integrating 5 nm CrO x and 2 nm LiF x into solar cell as the emitter and the back surface filed, resulted in a device efficiency of 13.6%. For further improvement, the back contact solar cell reaching an efficiency of 15.8% was fabricated, by implementing the multilayer films of CrO x (5 nm)/Au (4 nm)/ CrO x (5 nm) as the emitter. The formation of Cr(OH) 3 in ambient condition, resulted in a lower work function (4.8 eV) of the CrO x film. Furthermore, the multilayer back contact solar cell demonstrated a high stability due to CrO x covered with 500 nm Ag, when stored in ambient air longer than 170 days.

The present study investigated the anticancer functions of ursolic acid (UA) and its novel derivatives, with a nitrogen-containing heterocyclic scaffold and the privileged fragment at the C-28 position on apoptosis induction, cell proliferation and cell cycle in human BC lines. UA was chemically modified in the present study to increase its antitumor activity and bioavailability. A novel UA derivative, FZU3010, was synthesized using a nitrogen-containing heterocyclic scaffold and a privileged fragment at the C-28 position. Sulforhodimine B assays were used to measure the effect of UA and different concentrations of FZU3010 on the viability of breast cancer (BC) SUM149PT and HCC1937 cells. FZU3010 significantly repressed the proliferation of the two cancer cell lines in a dose-dependent manner, with a half-maximal inhibitory concentration of 4-6 µM, and exhibited decreased cytotoxicity compared with vehicle-treated cell lines. The effect of FZU3010 on cell cycle distribution and cellular apoptosis was also investigated. The results of this investigation indicated that FZU3010 significantly increased the number of SUM149PT and breast cancer HCC1937 cells in the G0/G1 phase in a dose-dependent manner. Additionally, at a concentration of 5 µM, the capability of FZU3010 to induce BC apoptosis was significantly higher than the capability of UA. Thus, the results of the current study indicated that FZU3010 induced apoptosis in BC cells, together with induction of cell cycle arrest at the S and G0/G1 phase. FZU3010 may therefore be considered as a potential therapeutic agent for the treatment of BC.