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Background Obesity worsens asthma control partly through enhanced airway neutrophilia, altered lung mechanics and comorbidities, including obstructive sleep apnea syndrome, gastroesophageal reflux disease and depression. Although controversial, obesity may also cause poorer outcomes in acute asthma. IL-17 is associated with neutrophilic inflammation, steroid resistance and severe asthma, but its importance in the association between asthma and obesity is unknown. Objective To investigate the role of IL-17 in obese asthma in both acute and stable settings. Methods Both stable (n = 177) and acute (n = 78) asthmatics were recruited and categorized into lean (n = 77 and 39 respectively), overweight (n = 41 and 17 respectively) and obese (n = 59 and 22 respectively) groups and compared for clinical characteristics, including sputum and plasma IL-17 protein concentrations, sputum cellularity, spirometry and comorbidities. Correlations of IL-17 expression with other measures were explored. Results In stable subjects, airway neutrophilia and IL-17 concentrations were most prominent in the obese, and correlated positively with each other. Significant increase in plasma IL-17 levels was also noted and associated with elevated depressive symptoms in obesity. In acute asthma, IL-17 expression, like most other clinical measures, was similar among lean, overweight and obese groups, but was higher in acute versus stable asthma subjects, with sputum IL-17 correlating positively with sputum neutrophils and negatively with FEV 1 and plasma IL-17 showing a positive connection to airway eosinophilia during exacerbation. Conclusions IL-17 contributes to worse disease control in obese asthma through enhancing airway neutrophilia and depression, and may implicate in asthma exacerbations. Effects of adiposity on acute asthma remain uncertain.

Background The optimal timing of renal replacement therapy (RRT) initiation in patients undergoing cardiac surgery remains controversial. This study aimed to determine whether preemptive RRT or standard RRT was associated with hospital mortality in cardiac surgical patients with acute kidney injury (AKI). Methods Data were retrospectively collected from patients who underwent cardiac surgery and experienced postoperative AKI requiring RRT at Zhongshan Hospital of Fudan University from September 1, 2006 to December 31, 2013. The patients were divided into two groups according to the RRT strategy applied. Results A total of 213 patients were enrolled in this study; 59 patients were categorized into the preemptive RRT group and 154 into the standard RRT group. The preemptive RRT group exhibited significantly lower mortality (33.90% versus 51.95%, P = 0.018) and time to recovery of renal function than the standard RRT group (15.34 ± 14.46 versus 22.88 ± 14.08 d, P = 0.022). Moreover, the preemptive RRT group showed significantly lower serum creatinine levels and higher proportions of recovery of renal function and weaning from RRT at death or discharge than the standard RRT group. There was no significant difference in the duration of mechanical ventilation, RRT, intensive care unit stay, or hospital stay between the two groups. Conclusions In patients after cardiac surgery, preemptive RRT was associated with lower hospital mortality and faster and more frequent recovery of renal function than standard RRT. However, preemptive RRT did not affect other patient-centered outcomes including mechanical ventilation time, RRT time, or length of intensive care unit or hospital stay.

Background This study will assess the effect of high-quality nursing intervention (HQNI) on anxiety and depression in patients with chronic heart failure companied malnutrition (CHFM). Methods We will retrieve electronic databases from the respective dates to February 29, 2020 without language and publication status restrictions: Cochrane Library, Web of Science, MEDLINE, EMBASE, Scopus, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. All potential randomized controlled trials (RCTs), which examined the effect of HQNI on anxiety and depression in patients with CHFM will be included. Two team members will separately perform article retrieval, duplicates excluding, scanning, data collection, and study quality assessment. In addition, this study will carry out data analysis by RevMan 5.3 software. Results This study will provide high-quality synthesis and/or descriptive analysis of the latest evidence to assess the effect of HQNI on anxiety and depression in patients with CHFM. Conclusion The findings of this study will exert evidence to judge whether or not HQNI is effective on anxiety and depression in patients with CHFM. Registration number INPLASY202040069.

Nanotechnology is an emerged field to develop the plant mediated metal based nanodrugs by green method. In this current study, the zinc oxide metal based nanoparticles were developed using (Clausena lansium (Lour.) Skeels) Peel aqueous extracts and zinc nitrate. The C.L extract zinc nanoparticleswere indicated by the sharp peak seen at 350 nm utilizing the Ultraviolet–Visible spectroscopy (UV–Vis). The high peaks indicate the presence of phytochemicals and its functional groups in ZnONPs were studied by the Fourier Transform Infrared Spectroscopy (FT-IR). The X-Ray Diffraction analysis (XRD) explores the pattern and structure of ZnONPs as spherical and base-centered monoclinic crystalline shapes. The C.L extract with Zn nanoparticles were spherical in nature and the size of the synthesized particles were about 28.42 nm respectively. The autophagy (Beclin-1, LC3-I, LC3-II and ATG4B) and apoptotic (Bax, Bcl-2 and Caspase-3) proteins were regulated by the treatment with ZnONPs in SH-SY5Y neuroblastoma cells. The DNA loss or damage was occurred in the ZnONPs treatment and it was performed using Comet assay. The ZnONPs treatment generates the ROS in the cells and decreased its stability and viability. Addition of NAC prevents ROS in the cultured SH-SY5Y cells and prevents the cells from the apoptosis. We concluded that the ZnONPs potentially kills the neuroblastoma cells by producing the intracellular ROS.

Background Histone modifications are critical in regulating neuronal processes. However, the impacts of individual histone modifications on learning and memory are elusive. Here, we investigated the contributions of histone H3 lysine modifications to learning and memory in Drosophila by using histone lysine-to-alanine mutants. Results Behavioural analysis indicated that compared to the H3WT group, mutants overexpressing H3K23A displayed impaired courtship learning. Chromatin immunoprecipitation analysis of H3K23A mutants showed that H3K23 acetylation (H3K23ac) levels were decreased on learning-related genes. Knockdown of CREB-binding protein (CBP) decreased H3K23ac levels, attenuated the expression of learning-related genes, led to a courtship learning defect and altered development of the mushroom bodies. A decline in courtship learning ability was observed in both larvae and adult treatments with ICG-001. Furthermore, treatment of Drosophila overexpressing mutated H3K23A with a CBP inhibitor did not aggravate the learning defect. Conclusions H3K23ac, catalysed by the acetyltransferases dCBP, contributes to Drosophila learning, likely by controlling the expression of specific genes. This is a novel epigenetic regulatory mechanism underlying neuronal behaviours. Electronic supplementary material The online version of this article (10.1186/s12861-018-0179-z) contains supplementary material, which is available to authorized users.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis.The Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism.GABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce CaOverexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.

Purpose: Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP–P2RY2 axis could be a potential therapeutic approach for PDAC treatment. Experimental Design: Expression of P2RY2 was determined in 264 human PDAC samples and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity, and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression. Results: P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT–mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevated expression of c-Myc and HIF1α, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacologic inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. In addition, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice. Conclusions: These findings reveal the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.

Ovarian cancer is one of the three most deadly gynecological cancers, with the highest mortality rate. As the main cause of death, metastasis is considered to be a crucial factor that reduces the survival time of ovarian carcinoma patients. YWHAZ (also known as 14‑3‑3ζ) influences diverse vital cellular processes such as metabolism, signal transduction, apoptosis and cell cycle regulation. In the present study, we determined that YWHAZ is upregulated in ovarian cancers in contrast to normal tissues by immunohistochemical staining. High YWHAZ expression was found to be associated with TNM stage and metastasis‑free prognosis of ovarian cancer patients. Silencing of YWHAZ inhibited the proliferation and facilitated serum starvation‑induced apoptosis of ovarian cancer cells. Cell migration was also suppressed by YWHAZ silencing. Furthermore, using an in vivo metastatic model, we found that YWHAZ silence also inhibited ovarian cancer metastasis in vivo. Notably, glycolysis was clearly inhibited in YWHAZ‑silenced ovarian cancer cells as determined by lactate production assay and Seahorse XF analysis. YWHAZ also regulated the PI3K/Akt1/vimentin signaling pathway in ovarian cancer cells as detected by western blot analysis. Taken together, our results demonstrated that YWHAZ plays an important role in the progression of ovarian cancer and can be used as a potential target for the diagnosis and treatment of epithelial ovarian cancer.

Integrin subunit alpha 9 (ITGA9) mediates cell-cell and cell-matrix adhesion, cell migration, and invasion through binding different kinds of extracellular matrix (ECM) components. However, its potential role and underlying molecular mechanisms remain unclear in hepatocellular carcinoma (HCC). Here, we found that ITGA9 expression was obviously decreased in patients with HCC, which was negatively correlated with HCC growth and metastasis. ITGA9 overexpression significantly inhibited cell proliferation and migration in vitro as well as tumor growth and metastasis in vivo. Our data demonstrated that the inhibitory effect of ITGA9 on HCC cell motility was associated with reduced phosphorylation of focal adhesion kinase (FAK) and c-Src tyrosine kinase (Src), disrupted focal adhesion reorganization, and decreased Rac1 and RhoA activity. Our data suggest ITGA9, as a suppressor of HCC, prevents tumor cell migration and invasiveness through FAK/Src-Rac1/RhoA signaling.

Dysregulation of the homeostatic balance of histone H3 di- and tri-methyl lysine 27 (H3K27me2/3) levels caused by the mis-sense mutation of histone H3 (H3K27M) is reported to be associated with various types of cancers. In this study, we found that reduction in H3K27me2/3 caused by H3.1K27M, a mutation of H3 variants found in patients with diffuse intrinsic pontine glioma (DIPG), dramatically attenuated the presence of 53BP1 (also known as TP53BP1) foci and the capability of non-homologous end joining (NHEJ) in human dermal fibroblasts. H3.1K27M mutant cells showed increased rates of genomic insertions/deletions and copy number variations, as well as an increase in p53-dependent apoptosis. We further showed that both hypo-H3K27me2/3 and H3.1K27M interacted with FANCD2, a central player in the choice of DNA repair pathway. H3.1K27M triggered the accumulation of FANCD2 on chromatin, suggesting an interaction between H3.1K27M and FANCD2. Interestingly, knockdown of FANCD2 in H3.1K27M cells recovered the number of 53BP1-positive foci, NHEJ efficiency and apoptosis rate. Although these findings in HDF cells may differ from the endogenous regulation of the H3.1K27M mutant in the specific tumor context of DIPG, our results suggest a new model by which H3K27me2/3 facilitates NHEJ and the maintenance of genome stability.This article has an associated First Person interview with the first author of the paper.

Dysregulation of the homeostatic balance of histone H3 di- and tri-methyl lysine 27 (H3K27me2/3) levels caused by the mis-sense mutation of histone H3 (H3K27M) is reported to be associated with various types of cancers. In this study, we found that reduction in H3K27me2/3 caused by H3.1K27M, a mutation of H3 variants found in patients with diffuse intrinsic pontine glioma (DIPG), dramatically attenuated the presence of 53BP1 (also known as TP53BP1) foci and the capability of non-homologous end joining (NHEJ) in human dermal fibroblasts. H3.1K27M mutant cells showed increased rates of genomic insertions/deletions and copy number variations, as well as an increase in p53-dependent apoptosis. We further showed that both hypo-H3K27me2/3 and H3.1K27M interacted with FANCD2, a central player in the choice of DNA repair pathway. H3.1K27M triggered the accumulation of FANCD2 on chromatin, suggesting an interaction between H3.1K27M and FANCD2. Interestingly, knockdown of FANCD2 in H3.1K27M cells recovered the number of 53BP1-positive foci, NHEJ efficiency and apoptosis rate. Although these findings in HDF cells may differ from the endogenous regulation of the H3.1K27M mutant in the specific tumor context of DIPG, our results suggest a new model by which H3K27me2/3 facilitates NHEJ and the maintenance of genome stability.This article has an associated First Person interview with the first author of the paper.

Integrin subunit alpha 9 (ITGA9) mediates cell-cell and cell-matrix adhesion, cell migration, and invasion through binding different kinds of extracellular matrix (ECM) components. However, its potential role and underlying molecular mechanisms remain unclear in hepatocellular carcinoma (HCC). Here, we found that ITGA9 expression was obviously decreased in patients with HCC, which was negatively correlated with HCC growth and metastasis. ITGA9 overexpression significantly inhibited cell proliferation and migration in vitro as well as tumor growth and metastasis in vivo. Our data demonstrated that the inhibitory effect of ITGA9 on HCC cell motility was associated with reduced phosphorylation of focal adhesion kinase (FAK) and c-Src tyrosine kinase (Src), disrupted focal adhesion reorganization, and decreased Rac1 and RhoA activity. Our data suggest ITGA9, as a suppressor of HCC, prevents tumor cell migration and invasiveness through FAK/Src-Rac1/RhoA signaling.

Chromatin is a highly organized and dynamic structure in eukaryotic cells. The change of chromatin structure is essential in many cellular processes, such as gene transcription, DNA damage repair and others. Anti-silencing function 1 (ASF1) is a histone chaperone that participates in chromatin higher-order organization and is required for appropriate chromatin assembly. In this study, we identified the E2 ubiquitin-conjugating enzyme RAD6 as an evolutionary conserved interacting protein of ASF1 in D. melanogaster and H. sapiens that promotes the turnover of ASF1A by cooperating with a well-known E3 ligase, MDM2, via ubiquitin-proteasome pathway in H. sapiens. Further functional analyses indicated that the interplay between RAD6 and ASF1A associates with tumorigenesis. Together, these data suggest that the RAD6-MDM2 ubiquitin ligase machinery is critical for the degradation of chromatin-related proteins.

Hormones and their corresponding receptors are vital in controlling metabolism under normal physiologic and pathologic conditions, but less is known about their roles in the metabolism of cancer. Using a small interfering RNA screening approach, we examined the effects of silencing 20 well‐known hormone receptors on the Warburg effect, specifically by measuring the production of lactate in four established hepatocellular carcinoma (HCC) cell lines. We found that silencing a variety of hormone receptors had effects on the production of this metabolite. Unexpectedly silencing of mineralocorticoid receptor (MR) significantly increased lactate production in all these HCC cell lines. Subsequent in vitro and in vivo studies showed that gain‐ and loss‐of‐function of MR significantly influenced HCC cellular proliferation, cell cycle distribution, and apoptosis. Furthermore, mechanistic studies revealed that MR as a transcriptional factor directly regulated the expression of miR‐338‐3p, suppressing the Warburg effects of HCC cells by targeting a key enzyme of glycolysis: pyruvate kinase, liver and red blood cells. Moreover, MR expression was significantly down‐regulated in 81% of HCC patient tissues, caused by both chromosome deletion and histone deacetylation. Low expression of MR in tumor tissues was associated with poor patient prognosis. The expression level of miR‐338‐3p was found to positively correlate with the expression of MR in HCC tissues and to inversely correlate with expression of the enzyme pyruvate kinase, liver and red blood cells. Conclusion: MR affects HCC development by modulating the miR‐338‐3p/pyruvate kinase, liver and red blood cells axis with an ability to suppress the Warburg effect. (Hepatology 2015;62:1145‐1159)

The aim of this study was to determine the mechanisms driving the protective effects of squid ink polysaccharide (SIP) against cyclophosphamide (CP)-induced testicular damage, focusing on germ cells. In the testes of mice exposed to CP and/or SIP, the present study examined the levels of reactive oxygen species (ROS) and malondialdehyde, activity of superoxide dismutase levels, protein expression levels of B-cell lymphoma 2 (Bcl2), Bcl2-associated X protein (Bax), and total Caspase 3, activation of p-p38 and p-Akt proteins, and tissue morphology. The findings indicated that CP induced ROS production and oxidative stress, resulting in testicular damage. However, under administration of SIP, oxidative stress was impaired and the testicular toxicity induced by CP was weakened, which implied that SIP may have an important role in preventing chemotherapeutic damage to the male reproductive system via promoting antioxidant ability. Furthermore, the altered expression levels, including the upregulation of Bax and Caspase 3, downregulation of Bcl-2 and the increased Bax/Bcl-2 ratio, indicated that apoptosis occurred in CP exposed testes of mice; however, the alterations were reversed in mice treated with SIP. Moreover, in CP-exposed testes, p38 and Akt proteins were significantly phosphorylated (P

Cervical cancer is an infectious cancer and the most common gynecologic cancer worldwide. E6/E7, the early genes of the high-risk mucosal human papillomavirus type, play key roles in the carcinogenic process of cervical cancer. However, little was known about its roles in modulating tumor microenvironment, particular extracellular matrix (ECM). In this study, we found that E6/E7 could regulate multiple ECM proteins, especially collagen triple helix repeat containing 1 (CTHRC1). CTHRC1 is highly expressed in cervical cancer tissue and serum and closely correlated with clinicopathological parameters. CTHRC1 promotes cervical cancer cell migration and invasion in vitro and metastasis in vivo. E6/E7 regulates the expression of CTHRC1 in cervical cancer by E6/E7-p53-POU2F1 (POU class 2 homeobox 1) axis. Futhermore, CTHRC1 activates Wnt/PCP signaling pathway. Take together, E6/E7-p53-POU2F1-CTHRC1 axis promotes cervical cancer cell invasion and metastasis and may act as a potential therapeutic target for interventions against cervical cancer invasion and metastasis.

Polycyclic tetramate macrolactams (PTMs) were identified as distinct secondary metabolites of the mangrove-derived Streptomyces xiamenensis 318. Together with three known compounds—ikarugamycin (1), capsimycin (2) and capsimycin B (3)—two new compounds, capsimycin C (4) with trans-diols and capsimycin D (5) with trans-configurations at C-13/C-14, have been identified. The absolute configurations of the tert/tert-diols moiety was determined in 4 by NMR spectroscopic analysis, CD spectral comparisons and semi-synthetic method. The post-modification mechanism of the carbocyclic ring at C-14/C-13 of compound 1 in the biosynthesis of an important intermediate 3 was investigated. A putative cytochrome P450 superfamily gene, SXIM_40690 (ikaD), which was proximally localized to the ikarugamycin biosynthetic pathway, was characterized. In vivo gene inactivation and complementation experiment confirmed that IkaD catalysed the epoxide-ring formation reaction and further hydroxylation of ethyl side chain to form capsimycin G (3′). Binding affinities and kinetic parameters for the interactions between ikarugamycin (1) and capsimycin B (3) with IkaD were measured with Surface Plasmon Resonance. The intermediate compound 3′ was isolated and identified as 30-hydroxyl-capsimycin B. The caspimycins 2 and 3, were transferred to methoxyl derivatives, 6 and 7, under acidic and heating conditions. Compounds 1–3 exhibited anti-proliferative activities against pancreatic carcinoma with IC50 values of 1.30–3.37 μM.

Exemestane (EXE) is an irreversible steroidal aromatase inhibitor mainly used as an adjuvant endocrine therapy for postmenopausal women suffering from breast cancer. Besides inhibiting aromatase activity, EXE has multiple biological functions, such as antiproliferation, anti-inflammatory, and antioxidant activities which are all involved in hepatic fibrosis. Therefore, we investigated the role of EXE during the progress of hepatic fibrosis. The effect of EXE on liver injury and fibrosis were assessed in two hepatic fibrosis rat models, which were induced by either carbon tetrachloride (CCl4) or bile duct ligation (BDL). The influence of EXE treatment on activation and proliferation of primary rat hepatic stellate cells (HSCs) was observedin vitro. The results showed that EXE attenuated the liver fibrosis by decreasing the collagen deposition andα-SMA expressionin vivoand inhibited the activation and proliferation of primary rat HSCsin vitro. Additionally, EXE promoted the secretion of antifibrotic and anti-inflammatory cytokine IL-10in vivoand in HSC-T6 culture media. In conclusion, our findings reveal a new function of EXE on hepatic fibrosis and prompted its latent application in liver fibrotic-related disease.

Lysyl oxidase-like 4 (LOXL4) has been found up-regulated in a variety of human malignancies, but its clinical significance and functional roles in gastric cancer (GC) remain unknown.Lysyl oxidase-like 4 (LOXL4) expression level in tumor tissues and human GC cell lines was evaluated by quantitative real-time polymerase chain reaction, Western blotting and immunohistochemical analyses. Its clinical significance was inferred from the analysis of 379 tissue samples of patients with GC using tissue microarray. The roles of LOXL4 in cell proliferation, migration and invasion in vitro were analyzed by gene over-expression, RNA interference and recombinant protein. Effects of LOXL4 on regulation of focal adhesion kinase/Src kinase (FAK/Src) pathway were examined by Western blotting.Lysyl oxidase-like 4 (LOXL4) was up-regulated in GC tissues relative to paired non-tumor tissues, and this over-expression was significantly associated with tumor size, depth of tumor invasion, lymph node metastasis, tumor-node-metastasis (TNM) stages and poorer overall survival. Over-expression of LOXL4 has promotive effects on GC cell proliferation, migration and invasion in vitro, consistent with this, LOXL4 knockdown has inhibitive effects on GC cell proliferation, migration and invasion. Furthermore, recombinant human LOXL4 protein also promoted GC cell proliferation and migration. Subsequent mechanistic studies showed that LOXL4 could activate FAK/Src pathway to enhance cell-extracellular matrix adhesion.Taken together, our data reveal that up-regulation of LOXL4 expression is a frequent event in GC progression, contributes to tumor cell proliferation and metastasis, and LOXL4 may be a potential independent prognostic marker and therapeutic target for GC.

Background & Aims Monoamine oxidase A (MAOA), a catecholamine neurotransmitter degrading enzyme, is closely associated with neurological and psychiatric disorders. However, its role in cancer progression remains unknown. Methods Hepatocellular carcinoma (HCC) tissue arrays (n=254) were used to investigate the correlation between MAOA expression and clinicopathological findings. In vitro invasion and anoikis assays, and in vivo intrahepatic and lung metastasis models were used to determine the role of MAOA in HCC metastasis. Quantitative real-time PCR, western blotting, immunohistochemical staining and HPLC analysis were performed to uncover the mechanism of MAOA in HCC. Results We found that MAOA expression was significantly downregulated in 254 clinical HCC samples and was closely correlated with cancer vasoinvasion, metastasis, and poor prognoses. We then demonstrated that MAOA suppressed norepinephrine/epinephrine (NE/E)-induced HCC invasion and anoikis inhibition, and uncovered that the effects of NE/E on HCC behaviors were primarily mediated through alpha 1A (ADRA1A) and beta 2 adrenergic receptors (ADRB2). In addition to the canonical signaling pathway, which is mediated via adrenergic receptors (ADRs), we found that ADR-mediated EGFR transactivation was also involved in NE-induced HCC invasion and anoikis inhibition. Notably, we found that MAOA could synergize with EGFR inhibitors or ADR antagonists to abrogate NE-induced HCC behaviors. Conclusions Taken together, the results of our study may provide insights into the application of MAOA as a novel predictor of clinical outcomes and indicate that increasing MAOA expression or enzyme activity may be a new approach that can be used for HCC treatment.

In this work, we reported the preparation and chemical analysis of novel polyhedral oligomeric silsesquioxane (POSS)-based porous materials, which were prepared according to Friedel-Crafts chloromethylation by using aluminum chloride as the catalyst and dichloromethane as the solvent. Through controlling the treatment solvent (water or methanol) and kinds of POSS, several materials with different morphologies were conveniently obtained. The chemical structure of porous materials was systematically characterized by Fourier-transform infrared (FTIR) spectra, 29Si Nuclear Magnetic Resonance (NMR), 13C NMR, and X-ray photoelectron spectroscopy (XPS). The samples were further characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and thermogravimetric analysis (TGA) to study their crystallinity, morphology, and thermal properties, respectively. The work systematically demonstrated the chemical structure of the porous materials. Moreover, the advantages and disadvantages of the preparation method and typical properties of the material were evaluated through a comparative analysis with other related research works.

This article causes for the different sub-word ambiguity problem, the sub-word dictionary based on the design of the traditional mechanical segmentation algorithm improvements, according to "priority" and "a maximum of sub-word" the principle of long-term, proposed the dynamic maximum points word algorithm and up Segmentation in communication material. And use of open source code java word segmentation algorithm to achieve the design in communication material.

Hypertrophic scarring is a common disease affecting millions of people around the world, but there are currently no satisfactory drugs to treat the disease. Exaggerated inflammation and mechanical stress have been shown to be two main mechanisms of excessive fibrotic diseases. Here we found that a benzopyran natural product, xiamenmycin, could significantly attenuate hypertrophic scar formation in a mechanical stretch-induced mouse model. The compound suppressed local inflammation by reducing CD4+ lymphocyte and monocyte/macrophage retention in fibrotic foci and blocked fibroblast adhesion with monocytes. Both in vivo and in vitro studies found that the compound inhibited the mechanical stress-induced profibrotic effects by suppressing proliferation, activation, fibroblast contraction, and inactivating FAK, p38, and Rho guanosine triphosphatase signaling. Taken together, the compound could simultaneously suppress both the inflammatory and mechanical stress responses, which are the two pivotal pathological processes in hypertrophic scar formation, thus suggesting that xiamenmycin can serve as a potential agent for treating hypertrophic scar formation and other excessive fibrotic diseases.

The AB2 type bulk polymerization of 3,5-bis(trimethylsiloxy)benzoyl chloride is studied by the reactive 3d bond fluctuation lattice model (3d-BFLM). Through tuning the reactivity parameters, the experimental data are fitted well via an iterative dichotomy method. By using the optimized reactivity parameters, the number-average degree of polymerization and degree of branching obtained in simulation are very close to experimental data. Meanwhile, the information about the weightaverage degree of polymerization and the polydispersity index is provided, and the internal structural properties of hyperbranched polyesters are investigated. Simulation results demonstrate that the 3d-BFLM can be used to study specific hyperbranched polymerizations semi-quantitatively which is helpful to deep understand the kinetics of reactions and make predictions for specific polymerization systems.

In our recent reports, a squid ink polysaccharide (SIP) was found having preventive activity against cyclophosphamide induced damage in mouse testis and ovary. Here we further reveal the regulative mechanism of SIP against chemical toxicity on testis. Leydig cells exposed to acrolein (ACR) underwent apoptosis at 12h and 24h. Before apoptosis, cells occurred autophagy that was confirmed by high autophagic rate and Beclin-1 protein content at 3h. PI3K/Akt and p38 MAPK signal pathways involved in the regulatory mechanisms. These outcomes of ACR were recovered completely by SIP, which was demonstrated by attenuated disruption of redox equilibrium and increased testosterone production, through suppressing ACR-caused autophagy and apoptosis regulated by PI3K/Akt and p38 MAPK signal pathways in Leydig cells. Summarily, autophagy occurred before apoptosis caused by ACR-activated p38 MAPK and PI3K/Akt pathways were blocked by SIP, resulting in survival and functional maintenance of Leydig cells.

3β-Hydroxysteroid-Δ24 reductase (DHCR24), the final enzyme of the cholesterol biosynthetic pathway, has been associated with urogenital neoplasms. However, the function of DHCR24 in endometrial cancer (EC) remains largely elusive. Here, we analyzed the expression profile of DHCR24 and the progesterone receptor (PGR) in our tissue microarray of EC (n = 258), the existing EC database in GEO (Gene Expression Omnibus), and TCGA (The Cancer Genome Atlas). We found that DHCR24 was significantly elevated in patients with EC, and that the up-regulation of DHCR24 was associated with advanced clinical stage, histological grading, vascular invasion, lymphatic metastasis, and reduced overall survival. In addition, DHCR24 expression could be induced by insulin though STAT3, which directly binds to the promoter elements of DHCR24, as demonstrated by ChIP-PCR and luciferase assays. Furthermore, genetically silencing DHCR24 inhibited the metastatic ability of endometrial cancer cells and up-regulated PGR expression, which made cells more sensitive to progestin. Taken together, we have demonstrated for the first time the crucial role of the insulin/STAT3/DHCR24/PGR axis in the progression of EC by modulating the metastasis and progesterone response, which could serve as potential therapeutic targets for the treatment of EC with progesterone receptor loss.

Gastrointestinal stromal tumor (GIST) is the most major mesenchymal neoplasm of the digestive tract. Up to now, imatinib mesylate has been used as a standard first-line treatment for irresectable and metastasized GIST patients or adjuvant treatment for advanced GIST patients who received surgical resection. However, secondary resistance to imatinib usually happens, resulting in a major obstacle in GIST successful therapy. In this study, we first found that collagen and calcium binding EGF domains 1 (CCBE1) expression gradually elevated along with the risk degree of NIH classification, and poor prognosis emerged in the CCBE1-positive patients. In vitro experiments showed that recombinant CCBE1 protein can enhance angiogenesis and neutralize partial effect of imatinib on the GIST-T1 cells. In conclusion, these data indicated that CCBE1 may be served as a new predictor of prognosis in post-operative GIST patients and may play an important role in stimulating GIST progression.

Epithelial ovarian cancer (EOC) is the major cause of deaths from gynecologic malignancies, and metastasis is the main cause of cancer related death. Collagen triple helix repeat containing-1 (CTHRC1) is a secreted protein that has the ability to inhibit collagen matrix synthesis. In this study, we found that high CTHRC1 expression was associated with poor prognosis of EOC. In vitro experiments showed that CTHRC1 promoted migration and invasion of ovarian cancer cells. CTHRC1 had no effect on ovarian cancer cells viability. Additionally, EGFR inhibitors reduced the promotion effects of CTHRC1 on EOC cell invasion. After silencing of CTHRC1, downregulated expression of phosphorylation of EGFR/ERK1/2/AKT was observed in ovarian cancer cells. Taken together, our results suggest a role for CTHRC1 in the progression of ovarian cancer and identified CTHRC1 as a potentially important predictor for human ovarian cancer prognosis.

Stem-cell-derived hepatocyte transplantation is considered as a potential method for the therapy of acute and chronic liver failure. However, the low efficiency of differentiation into mature and functional hepatocytes remains a major challenge for clinical applications. By using polyethyleneimine-modified silica nanoparticles, this study develops a system for sustained delivery of growth factors, leading to induce hepatocyte-like cells (iHeps) from mouse embryonic stem cells (mESCs) and improve the expression of endoderm and hepatocyte-specific genes and proteins significantly, thus producing a higher population of functional hepatocytes in vitro. When transplanted into liver-injured mice after four weeks, mESC-derived definitive endoderm cells treated with this delivery system show higher integration efficiency into the host liver, differentiated into iHeps in vivo and significantly restored the injured liver. Therefore, these findings reveal the multiple advantages of functionalized nanoparticles to serve as efficient delivery platforms to promote stem cell differentiation in the regenerative medicine.

Thyroid hormone receptor β1 (TRβ1) is a ligand‑dependent transcription factor that belongs to the superfamily of nuclear receptors. TRβ1 has been found to act as a tumor suppressor in many solid tumors including breast cancer and hepatocellular carcinoma, but its role in the progression of human colorectal cancer (CRC) remains unclear. In this study, microarray data analysis revealed that TRβ1 mRNA was downregulated in CRC tumors compared with that in the normal counterparts in both The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Using a CRC tissue microarray (TMA), we confirmed that the expression of TRβ1 was decreased in human CRC tumor tissues in contrast to normal colorectal mucosal tissues. Notably, the TRβ1 expression was strongly correlated with tumor size (p=0.045). Furthermore, we found that CRC cell proliferation and migration were significantly inhibited by TRβ1 overexpression in vitro. Mechanistic studies indicated that activated phosphorylated Akt was clearly suppressed by TRβ1 in the CRC tissues and cells. In conclusion, this study provides evidence that TRβ1 plays a critical role in the progression of CRC via the PI3K/Akt pathway, and the TRβ1 gene may represent a novel target for CRC therapeutics.

A wideband slot antenna for mobile phone applications is proposed. The antenna has two slots with open ends etched on the opposite edges of the ground plane. The main slot, of total length of 59 mm, is composed of a rectangle connected to a circle having radius of 5 mm. Another slot, having a rectangular shape with width of 2.8 mm and length of 26 mm, is employed to enhance the antenna bandwidth. The slots are fed by means of a rectangular monopole connected to a circular patch joined to a bent 50 Ω microstrip transmission line forming two right angles. To obtain a wideband impedance matching, the upper edge of the monopole and a part of the feeding line evolve along the top edge of the two slots. To reduce the antenna size, the upper part of the board above the slot (just 3 mm from the slot) is folded vertically to the ground plane. The measured bandwidth of the antenna is 0.698–1.10 GHz and 1.64–2.83 GHz covering LTE700/2300/2500, GSM850/900/1800/1900, and UMTS bands.

Sortases catalyze the covalent attachment of proteins with a C-terminal LPxTG motif to the cell walls of Gram-positive bacteria. Here, we show that deletion of the srtA genes of Staphylococcus aureus and Staphylococcus epidermidis resulted in the dislocation of several LPxTG proteins from the cell wall to the growth medium. Nevertheless, proteomics and Western blotting analyses revealed that substantial amounts of the identified proteins remained cell wall bound through noncovalent interactions. The protein dislocation phenotypes of srtA mutants of S. aureus and S. epidermidis were reverted by ectopic expression of srtA genes of either species. Interestingly, S. epidermidis contains a second sortase A, which was previously annotated as ``SrtC.'' Ectopic expression of this SrtC in srtA mutant cells reverted the dislocation of some, but not all, cell wall associated proteins. Similarly, defects in biofilm formation were reverted by ectopic expression of SrtC in some, but not all, tested srtA mutant strains. Finally, overexpression of SrtA resulted in increased levels of biofilm formation in some tested strains. Taken together, these findings show that the substrate specificities of SrtA and SrtC overlap partially, and that sortase levels may be limiting for biofilm formation in some staphylococci.

To solve the problem of embryonic lethality in conventional gene knockouts, site-specific recombinase (SSR) systems (Cre-loxP, Flp-FRT, and ΦC31) have been used for tissue-specific gene knockout. With the combination of an SSR system and inducible gene expression systems (tetracycline and tamoxifen), stage-specific knockout and transgenic expression can be achieved. The application of this “SSR+inducible” conditional tool to genomic manipulation can be extended in various ways. Alternatives to conditional gene targeting, such as conditional gene trapping, multipurpose conditional alleles, and conditional gene silencing, have been developed. SSR systems can also be used to construct precise disease models with point mutations and chromosomal abnormalities. With these exciting achievements, we are moving towards a new era in which the whole genome can be manipulated as we wish.

Measurements of methane (CH(4)) and nitrous oxide (N(2)O) fluxes have been extensively taken following rice seedlings transplanted into paddy fields, while little is known about CH(4) and N(2)O fluxes from rice seedling nurseries. Fluxes of CH(4) and N(2)O were simultaneously measured in rice seedling nurseries under the water regimes of continuous flooding and moist irrigation without waterlogging in Southeast China in 2010. Fluxes of CH(4) and N(2)O from continuously flooded nurseries averaged 10.33-14.84 mg m(-2) h(-1) and 28.64-34.35 μg N(2)O-Nm(-2) h(-1) for the different fertilizer applied plots, respectively. Relative to continuous flooding, moist irrigation decreased total CH(4) by 14-50% but increased N(2)O by 72-186%, dependent on the fertilizer types. Compared with inorganic N fertilizer, organic manure application increased CH(4) by 44% and 148% in the continuously flooded and moist irrigation nurseries, respectively. Rice seedling growth parameters were the greatest in moist irrigation nurseries with inorganic N fertilizer application. Moist irrigation instead of continuous waterlogging and shifts from organic manure to combined organic/inorganic N fertilizer inputs have been increasingly experienced in Chinese rice seedling nurseries, which would benefit for mitigating the combined global warming potentials of CH(4) and N(2)O from rice seedling nurseries in China.

In this paper, an eight-node solid hybrid-stabilized element for general piezoelectric laminate plate analysis is formulated based on the electromechanical Hellinger-Reissner functional. The independent field variables in the functional include the displacement, electric potential, stress and electric displacement. The non-constant electromechanical stress modes are contravariant in nature and chosen to be orthogonal with respect to the constant ones. The othogonality and the practice put forward in the admissible matrix formulation allow the electromechanical flexibility matrices to be block diagonal. As a result, the computational cost for inverting the electromechanical flexibility matrices can be greatly reduced. Numerical examples indicate that the proposed hybrid piezoelectric element is more accurate than their conventional counterpart.

Objective The purpose of this study is to determine how to disclose bad news to patients with cancer in China. Methods One hundred fifty pairs of hospitalized patients and their family members were investigated using a self-designed questionnaire. Results More patients than their families believed that patients should be informed of their illnesses (98.0% vs 66.7%, p

An attempt is made to extend the double superposition hypothesis for elastic laminate analysis to piezoelectric laminate structure analysis. In addition to the displacement, the double superposition technique is also applied to the electric potential. The double-superposition hypothesis for piezoelectric laminate analysis can predict the zigzag feature of the field variables along the transverse direction in piezoelectric laminates. Moreover, the elastic field computational cost of double superposition assumption is no more than that of high-order shear theories for global coordinates, and the degrees of freedom by double superposition assumption for electric potential are much fewer than those by layerwise models for electric potential. It will be seen from the numerical examples that the good accuracy and lower computational cost can be presented by the double-superposition assumption for piezoelectric laminate beams.

In this paper, we consider the application of the ensemble Kalman filter for some nonlinear operator equations. According to the structural feature of the nonlinear operator, we construct an iteration process and the corresponding linear observation operator. This construction puts our problem into the frame of 3DVar. Based on the linear observation operator, the ensemble Kalman filter approach is adopted to blend the data into the dynamics to obtain an approximation of the unknown parameter. The method is applied to an inverse potential problem and a nonlinear Fredholm integral equation. The numerical results are compared with Bayesian approach, classical regularization methods including Tikhonov regularization and Landweber iteration, which shows that the proposed algorithm is effective and competitive.

Background & Aims Agents designed to block or alter cytokinesis can kill or stop proliferation of cancer cells. We aimed to identify cytokinesis-related proteins that are overexpressed in hepatocellular carcinoma (HCC) cells and might be targeted to slow liver tumor growth. Methods Using the Oncomine database, we compared the gene expression patterns in 16 cancer microarray datasets and assessed gene enrichment sets using gene ontology. We performed immunohistochemical analysis of an HCC tissue microarray and identified changes in protein levels that are associated with patient survival times. Candidate genes were overexpressed or knocked down with small hairpin RNAs in SMMC7721, MHCC97H, or HCCLM3 cell lines; we analyzed their proliferation, viability, and clone-formation ability and their growth as subcutaneous or orthotopic xenograft tumors in mice. We performed microarray analyses to identify alterations in signaling pathways and immunoblot and immunofluorescence assays to detect and localize proteins in tissues. Yeast 2-hybrid screens and mass spectrometry combined with co-immunoprecipitation experiments were used to identify binding proteins. Protein interactions were validated with co-immunoprecipitation and proximity ligation assays. Chromatin immunoprecipitation, promoter luciferase activity, and quantitative real-time polymerase chain reaction analyses were used to identify factors that regulate transcription of specific genes. Results The genes that were most frequently overexpressed in different types of cancer cells were involved in cell division processes. We identified 3 cytokinesis-regulatory proteins among the 10 genes most frequently overexpressed by all cancer cell types. Rac GTPase activating protein 1 (RACGAP1) was the cytokinesis-regulatory protein that was most highly overexpressed in multiple cancers. Increased expression of RACGAP1 in tumor tissues was associated with shorter survival times of patients with cancer. Knockdown of RACGAP1 in HCC cells induced cytokinesis failure and cell apoptosis. In microarray analyses, we found knockdown of RACGAP1 in SMMC7721 cells to reduce expression of genes regulated by yes-associated protein (YAP) and WW domain containing transcription regulator 1 (WWTR1 or TAZ). RACGAP1 reduced activation of the Hippo pathway in HCC cells by increasing activity of RhoA and polymerization of filamentous actin. Knockdown of YAP reduced phosphorylation of RACGAP1 and redistribution at the anaphase central spindle. We found transcription of the translocated promoter region, nuclear basket protein (TPR) to be regulated by YAP and coordinately expressed with RACGAP1 to promote proliferation of HCC cells. TPR redistributed upon nuclear envelope breakdown and formed complexes with RACGAP1 during mitosis. Knockdown of TPR in HCC cells reduced phosphorylation of RACGAP1 by aurora kinase B and impaired their redistribution at the central spindle during cytokinesis. STAT3 activated transcription of RACGAP in HCC cells. Conclusions In an analysis of gene expression patterns of multiple tumor types, we found RACGAP1 to be frequently overexpressed, which is associated with shorter survival times of patients. RACGAP1 promotes proliferation of HCC cells by reducing activation of the Hippo and YAP pathways and promoting cytokinesis in coordination with TPR.