Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.

In a recent study, we reported that a recombinant protein from fusion expression of flagellin to porcine circovirus type 2 (PCV2) Cap induced robust humoral and cell-mediated immunity that afforded full protection for PCV2 infection using BALB/c mice. Here, we further evaluated the immunogenicity and protection of the recombinant protein using specific pathogen free (SPF) pigs. Twenty-five 3-week-old piglets without passively acquired immunity were divided into 5 groups. All piglets except negative controls were challenged with a virulent PCV2 at 21 days after booster vaccination and necropsied at 21 days post-challenge. Vaccination of piglets with the recombinant protein without adjuvant induced strong humoral and cellular immune responses as observed by high levels of PCV2-specific IgG antibodies and neutralizing antibodies, as well as frequencies of PCV2-specific IFN-γ-secreting cells that conferred good protection against PCV2 challenge, with significant reduced PCV2 viremia, mild lesions, low PCV2 antigen-positive cells, as well as improved body weight gain, comparable to piglets vaccinated with a commercial PCV2 subunit vaccine. These results further demonstrated that the recombinant flagellin-Cap fusion protein is capable of inducing solid protective humoral and cellular immunity when administered to pigs, thereby becoming an effective PCV2 vaccine candidate for control of PCV2 infection.

A cross between the sweet cherry (Prunus avium) cultivars 'Wanhongzhu' and 'Lapins' was performed to create a mapping population suitable for the construction of a linkage map. The specific-locus amplified fragment (SLAF) sequencing technique used as a single nucleotide polymorphism (SNP) discovery platform and generated 701 informative genotypic assays; these, along with 16 microsatellites (SSRs) and the incompatibility (S) gene, were used to build a map which comprised 8 linkage groups (LGs) and covered a genetic distance of 849.0 cM. The mean inter-marker distance was 1.18 cM and there were few gaps > 5 cM in length. Marker collinearity was maintained with the established peach genomic sequence. The map was used to show that trunk diameter (TD) is under the control of 4 loci, mapping to 3 different LGs. Different locus influenced TD at a varying stage of the tree's development. The high density 'W×L' genetic linkage map has the potential to enable high-resolution identification of QTLs of agronomically relevant traits, and accelerate sweet cherry breeding.

Flowering is one of the important defining features of angiosperms. The initiation of flower development and the formation of different floral organs are the results of the interplays among numerous genes. But until now, just fewer genes have been found linked with flower development. And the functions of lots of genes of Arabidopsis thaliana are still unknown. Although, the quartet model successfully simplified the ABCDE model to elaborate the molecular mechanism by introducing protein-protein interactions (PPIs). We still don't know much about several important aspects of flower development. So we need to discriminate even more genes involving in the flower development. In this study, we identified seven differentially modules through integrating the weighted gene co-expression network analysis (WGCNA) and Support Vector Machine (SVM) method to analyze co-expression network and PPIs using the public floral and non-floral expression profiles data of Arabidopsis thaliana. Gene set enrichment analysis was used for the functional annotation of the related genes, and some of the hub genes were identified in each module. The potential floral organ morphogenesis genes of two significant modules were integrated with PPI information in order to detail the inherent regulation mechanisms. Finally, the functions of the floral patterning genes were elucidated by combining the PPI and evolutionary information. It was indicated that the sub-networks or complexes, rather than the genes, were the regulation unit of flower development. We found that the most possible potential new genes underlining the floral pattern formation in A. thaliana were FY, CBL2, ZFN3, and AT1G77370; among them, FY, CBL2 acted as an upstream regulator of AP2; ZFN3 activated the flower primordial determining gene AP1 and AP2 by HY5/HYH gene via photo induction possibly. And AT1G77370 exhibited similar function in floral morphogenesis, same as ELF3. It possibly formed a complex between RFC3 and RPS15 in cytoplasm, which regulated TSO1 and CPSF160 in the nucleus, to control the floral organ morphogenesis. This process might also be fine tuning by AT5G53360 in the nucleus.

Ovarian cancer is the most lethal gynecologic malignancy with an overall cure rate of merely 30%. Most patients experience recurrence within 12-24 months of cure and die of progressively chemotherapy-resistant disease. Thus, more effective anti-ovarian cancer therapies are needed. Here, we investigate the possibility of repurposing antibiotic monensin as an anti-ovarian cancer agent. We demonstrate that monensin effectively inhibits cell proliferation, migration and cell cycle progression, and induces apoptosis of human ovarian cancer cells. Monensin suppresses multiple cancer-related pathways including Elk1/SRF, AP1, NFκB and STAT, and reduces EGFR expression in ovarian cancer cells. Monensin acts synergistically with EGFR inhibitors and oxaliplatin to inhibit cell proliferation and induce apoptosis of ovarian cancer cells. Xenograft studies confirm that monensin effectively inhibits tumor growth by suppressing cell proliferation through targeting EGFR signaling. Our results suggest monensin may be repurposed as an anti-ovarian cancer agent although further preclinical and clinical studies are needed.

RANK/RANKL plays a key role in metastasis of certain malignant tumors, which makes it a promising target for developing novel therapeutic strategies for cancer. However, the prognostic value and pro-metastatic activity of RANK in endometrial cancer (EC) remain to be determined. Thus, the present study investigated the effect of RANK on the prognosis of EC patients, as well as the pro-metastatic activity of EC cells. The results indicated that those with high expression of RANK showed decreased overall survival and progression-free survival. Statistical analysis revealed the positive correlations between RANK/RANKL expression and metastasis-related factors. Additionally, RANK/RANKL significantly promoted cell migration/invasion via activating AKT/β-catenin/Snail pathway in vitro. However, RANK/RANKL-induced AKT activation could be suppressed after osteoprotegerin (OPG) treatment. Furthermore, the combination of medroxyprogesterone acetate (MPA) and RANKL could in turn attenuate the effect of RANKL alone. Similarly, MPA could partially inhibit the RANK-induced metastasis in an orthotopic mouse model via suppressing AKT/β-catenin/Snail pathway. Therefore, therapeutic inhibition of MPA in RANK/RANKL-induced metastasis was mediated by AKT/β-catenin/Snail pathway both in vitro and in vivo, suggesting a potential target of RANK for gene-based therapy for EC.

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH) during transient cessation of breathing, triples the risk for cardiovascular diseases. We used a phage display peptide library as an unbiased approach to investigate whether IH, which is specific to OSA, activates endothelial cells (ECs) in a distinctive manner. The target of a differentially bound peptide on ECs collected from OSA patients was identified as CD59, a major complement inhibitor that protects ECs from the membrane attack complex (MAC). A decreased proportion of CD59 is located on the EC surface in OSA patients compared with controls, suggesting reduced protection against complement attack. In vitro, IH promoted endothelial inflammation predominantly via augmented internalization of CD59 and consequent MAC deposition. Increased internalization of endothelial CD59 in IH appeared to be cholesterol-dependent and was reversed by statins in a CD59-dependent manner. These studies suggest that reduced complement inhibition may mediate endothelial inflammation and increase vascular risk in OSA patients.

Recent studies found that the circulating high-mobility group box 1 (HMGB1) levels could reflect the disease activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). HMGB1 could prime neutrophils by increasing ANCA antigens translocation for ANCA-mediated respiratory burst and degranulation. The current study aimed to investigate whether HMGB1 participates in ANCA-induced neutrophil extracellular traps (NETs) formation, which is one of the most important pathogenic aspects in the development of AAV.

Male moths efficiently recognize conspecific sex pheromones thanks to their highly accurate and specific olfactory system. The Heliothis/Helicoverpa species are regarded as good models for studying the perception of sex pheromones. In this study, we performed a series of experiments to investigate the peripheral mechanisms of pheromone coding in two-closely related species, Helicoverpa armigera and H. assulta. The morphology and distribution patterns of sensilla trichoidea are similar between the two species when observed at the scanning electron microscope, but their performances are different. In H. armigera, three functional types of sensilla trichoidea (A, B and C) were found to respond to different pheromone components, while in H. assulta only two types of such sensilla (A and C) could be detected. The response profiles of all types of sensilla trichoidea in the two species well matched the specificities of the pheromone receptors (PRs) expressed in the same sensilla, as measured in voltage-clamp experiments. The expressions of PRs in neighboring olfactory sensory neurons (OSNs) within the same trichoid sensillum were further confirmed by in situ hybridization. Our results show how the same pheromone components can code for different messages at the periphery of two Helicoverpa species.

Improved therapies are greatly needed for non-small cell lung cancer (NSCLC) that does not harbor targetable kinase mutations or translocations. We previously demonstrated that NSCLC cells that harbor kinase-inactivating BRAF mutations (KIBRAF) undergo senescence when treated with the multitargeted kinase inhibitor dasatinib. Similarly, treatment with dasatinib resulted in a profound and durable response in a patient with KIBRAF NSCLC. However, no canonical pathways explain dasatinib-induced senescence in KIBRAF NSCLC. To investigate the underlying mechanism, we used 2 approaches: gene expression and reverse phase protein arrays. Both approaches showed that DNA repair pathways were differentially modulated between KIBRAF NSCLC cells and those with wild-type (WT) BRAF. Consistent with these findings, dasatinib induced DNA damage and activated DNA repair pathways leading to senescence only in the KIBRAF cells. Moreover, dasatinib-induced senescence was dependent on Chk1 and p21, proteins known to mediate DNA damage-induced senescence. Dasatinib also led to a marked decrease in TAZ but not YAP protein levels. Overexpression of TAZ inhibited dasatinib-induced senescence. To investigate other vulnerabilities in KIBRAF NSCLC cells, we compared the sensitivity of these cells with that of WTBRAF NSCLC cells to 79 drugs and identified a pattern of sensitivity to EGFR and MEK inhibitors in the KIBRAF cells. Clinically approved EGFR and MEK inhibitors, which are better tolerated than dasatinib, could be used to treat KIBRAF NSCLC. Our novel finding that dasatinib induced DNA damage and subsequently activated DNA repair pathways leading to senescence in KIBRAF NSCLC cells represents a unique vulnerability with potential clinical applications.

Human adipose-derived stem cells (hADSCs), widely present in the adult human body, are an emerging and attractive tool for the establishment of stem cell-based therapies for the treatment of liver disease. However, the mechanism underlying hADSCs hepatic differentiation remains to be elucidated. Caveolin-1 (Cav-1), a 21-24 kDa membrane structural protein, is important in liver regeneration and development. In the present study, fluorescence immunocytochemistry and western blotting were used to analyze the expression levels of Cav-1 and evaluate its effects on the hepatic differentiation of hADSCs. The results revealed that primary hADSCs preserved the ability to proliferate and differentiate into hepatocyte-like cells. As demonstrated by semiquantitative reverse transcription-polymerase chain reaction, hepatocyte-inducing factors significantly increased the expression of Cav-1 in a time-dependent manner, as indicated by increased expression levels of the albumin (ALB) and α-fetoprotein (AFP) markers. In addition the expression levels of ALB and HNF1A significantly decreased following small interfering RNA-mediated knockdown of Cav-1. The mitogen-activated protein kinase (MAPK) signaling pathway was activated during hepatic differentiation and inhibited following Cav-1 knockdown. These results suggested that Cav-1 may regulate the hepatocyte-like differentiation of hADSCs by modulating mitogen-activated protein kinase kinase/MAPK signaling. The results of the present study will provide experimental and theoretical basis for further clinical studies on stem cell transplantation in the treatment of liver disease.

Currently, there is limited information about the relationship between manganese superoxide dismutase (sod2) c47t polymorphism and susceptibility to noise-induced hearing loss (NIHL).

New techniques are urgently needed to replace conventional long and costly pre-clinical testing in the new drug administration process. In this study, a laminated microfluidic device was fabricated to mimic the drug ADME response test in vivo. This proposed device was loaded and cultured with functional cells for drug response investigation and organ tissues that are involved in ADME testing. The drug was introduced from the top of the device and first absorbed by the Caco-2 cell layer, and then metabolized by the primary hepatocyte layer. It subsequently interacted with the MCF-7 cell layer, distributed in the lung, heart and fat tissues, and was finally eliminated through the dialysis membrane. Throughout this on-chip ADME process, the proposed device can be used as a reliable tool to simultaneously evaluate the drug anti-tumor activity, hepatotoxicity and pharmacokinetics. Furthermore, this device was proven to be able to reflect the hepatic metabolism of a drug, drug distribution in the target tissues, and the administration method of a drug. Furthermore, this microdevice is expected to reduce the number of drug candidates and accelerate the pre-clinical testing process subject to animal testing upon adaptation in new drug discovery.

This study aimed to develop and evaluate barium and calcium microcapsules as candidates for scaffolding in artificial dermal papilla. Dermal papilla cells (DPCs) were isolated and cultured by one-step collagenase treatment. The DPC-Ba and DPC-Ca microcapsules were prepared by using a specially designed, high-voltage, electric-field droplet generator. Selected microcapsules were assessed for long-term inductive properties with xenotransplantation into Sprague-Dawley rat ears. Both barium and calcium microcapsules maintained xenogenic dermal papilla cells in an immunoisolated environment and induced the formation of hair follicle structures. Calcium microcapsules showed better biocompatibility, permeability, and cell viability in comparison with barium microcapsules. Before 18 weeks, calcium microcapsules gathered together, with no substantial immune response. After 32 weeks, some microcapsules were near inflammatory cells and wrapped with fiber. A few large hair follicles were found. Control samples showed no marked changes at the implantation site. Barium microcapsules were superior to calcium microcapsules in structural and mechanical stability. The cells encapsulated in hydrogel barium microcapsules exhibited higher short-term viability. This study established a model to culture DPCs in 3D culture conditions. Barium microcapsules may be useful in short-term transplantation study. Calcium microcapsules may provide an effective scaffold for the development of artificial dermal papilla.

Increasing evidence supports that ELL (eleven-nineteen lysine-rich leukaemia) is a key regulator of transcriptional elongation, but the physiological function of Ell in mammals remains elusive. Here we show that ELL functions as an E3 ubiquitin ligase and targets c-Myc for proteasomal degradation. In addition, we identify that UbcH8 serves as a ubiquitin-conjugating enzyme in this pathway. Cysteine 595 of ELL is an active site of the enzyme; its mutation to alanine (C595A) renders the protein unable to promote the ubiquitination and degradation of c-Myc. ELL-mediated c-Myc degradation inhibits c-Myc-dependent transcriptional activity and cell proliferation, and also suppresses c-Myc-dependent xenograft tumour growth. In contrast, the ELL(C595A) mutant not only loses the ability to inhibit cell proliferation and xenograft tumour growth, but also promotes tumour metastasis. Thus, our work reveals a previously unrecognized function for ELL as an E3 ubiquitin ligase for c-Myc and a potential tumour suppressor.

Previous studies have suggested a positive link between serum uric acid (UA) and bone mineral density (BMD). In this study, we re-examined the association between UA and BMD and further explored whether this was mediated by skeletal muscle mass in a general Chinese population.

As a novel oral drug delivery system, proliposome was applied to improve the solubility of active components of Ginkgo biloba extract (GbE). There are currently few reports focusing on the pharmacokinetic characteristics of proliposome of GbE (GbP). A rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous quantification of active components of GbP and a commercial tablet product (Ginaton) in rat plasma was developed and successfully validated. The method was applied to the comparative pharmacokinetic evaluation of GbP and Ginaton in rat plasma. The results indicated that GbP has a significant effect on absorption, elimination and bioavailability of flavonoids and terpenoid lactones in comparison with Ginaton. The obtained results would be helpful for evaluating the absorption mechanism in the gastrointestinal tract in pharmacokinetic level and guiding the development of the novel oral drug delivery system.

Clinical guidelines define obesity in terms of excess body weight adjusted for height (i.e., bodymass index [BMI] categories) and/or gender-specific waist circumference (WC) cut-point values. Since body composition, particularly fat mass, is the most variable among individuals due to differences by gender, age, and race, and total percent body fat (%BF) can be estimated accurately using dual-energy X-ray absorptiometry (DXA), the purpose of this study was to develop and compare two field-based body fat prediction equations suitable for a nationally representative sample of the US adult population. Data were analyzed from subjects 20+ years of age (n = 11,907) with BMI and WC values, and that participated in DXA scans as part of the 1999-2004 National Health and Nutrition Examination Survey (NHANES). Multiple linear regression was used to develop and compare DXA-estimated %BF as the dependent variable versus BMI or WC, gender, age, and race as predictor variables. Mean values for age, BMI, WC, and %BF among the sample were 46.84 ± 0.30 years, 28.17 ± 0.11 kg/m2, 96.69 ± 0.27 cm, and 34.19 ± 0.14 %, respectively. Both equations were similar in terms of explained variance, with R2 values of 0.82 for the BMI and WC equations, respectively. Both equations are easy to use, and could easily be developed as an application on a smartphone or other handheld device, or simply integrated into a spreadsheet for use as an additional tool for health professionals to assess the current health status of individuals based on predicted body fat from BMI, WC, and demographics.

Epigallocatechin gallate (EGCG) is the most abundant component of green tea catechins and has strong physiological activities. In this study, two novel EGCG glycosides (EGCG-G1 and EGCG-G2) were chemoselectively synthesized by a chemical modification strategy. Each of these EGCG glycosides underwent structure identification, and the structures were assigned as follows: epigallocatechin gallate-4''-O-β-d-glucopyranoside (EGCG-G1, 2) and epigallocatechin gallate-4',4''-O-β-d-gluco-pyranoside (EGCG-G2, 3). The EGCG glycosides were evaluated for their anticancer activity in vitro against two human breast cell lines (MCF-7 and MDA-MB-231) using MTT assays. The inhibition rate of EGCG glycosides (EGCG-G1 and EGCG-G2) is not obvious. The EGCG glycosides are more stable than EGCG in aqueous solutions, but exhibited decreasing antioxidant activity in the DPPH radical-scavenging assay (EGCG > EGCG-G2 > EGCG-G1). Additionally, the EGCG glycosides exhibited increased water solubility: EGCG-G2 and EGCG-G1 were 15 and 31 times as soluble EGCG, respectively. The EGCG glycosides appear to be useful, and further studies regarding their biological activity are in progress.

Esophageal cancer is a common and aggressive malignant tumor. This study aimed to investigate the association between human papillomavirus (HPV) Types 16 and 18 and esophageal carcinoma (EC) in the world population by conducting a meta-analysis.