Toll-like receptors (TLRs)/NF-κB activation stimulated by lipopolysaccharide (LPS) was associated with diverse biological response in colon cancer, but the underlying mechanism was largely unknown. In the current study, we reported cell proliferation was elevated in adenomatous polyposis coli (APC) mutated- and APC knockdown cell lines, while the proliferation was inhibited in APC wild-type cell lines. Besides, in vivo experiments showed that LPS promoted APC knockdown tumor growth while inhibited proliferation of APC wild type. Further study confirmed that activation of TLRs/NF-κB signaling pathway by LPS cross regulated with APC/GSK-3β/β-catenin pathway, which were depend on APC status of cell lines. Taken together, APC genotypes play a key role in LPS induced different colon cancer biological response by cross-regulating β-catenin and NF-κB, which may provide a novel strategy for carcinogenesis prevention.

PFTK1, also named Cyclin-Dependent Kinase 14 (CDK14), is a member of the cell division cycle 2 (CDC2)-related protein kinase family. It is a serine/threonine-protein kinase involved in the regulation of cell cycle progression and cell proliferation. In this study, we investigated the role of PFTK1 in epithelial ovarian cancer (EOC) development. The expression of PFTK1 was detected by Western blot and immunohistochemistry staining, both of which demonstrated that PFTK1 was overexpressed in EOC tissues and cells. Statistical analysis showed the expression of PFTK1 was associated with multiple clinicopathological factors, including tumor grade, FIGO stage, lymph node metastatis, Ki-67 expression and predicted a poor prognosis of EOC patients. With in vitro studies we found that PFTK1 expression was decreased in serum-starved ovarian cancer cells, and progressively increased after serum-re-feeding. Knocking PFTK1 down by small interfering RNA (siRNA) significantly inhibited ovarian cancer cell proliferation, migration and invasion. Taken together, our study suggested that PFTK1 played an important role in ovarian cancer development.

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.

BACKGROUND The epithelial-mesenchymal transition (EMT) has been shown to be involved in the process of invasion and metastasis of prostate cancer. SIRT1 is the mammalian homologue of the silent information regulator 2 (Sir2) gene, and is abnormally expressed in prostate cancer cells. Therefore, it is hypothesized that SIRT1 mediates the invasion/metastatic ability of prostate cancer via EMT regulation. This study thus investigated the effect of SIRT1 gene on the invasion and migration of prostate cancer cell line PC-3 via the small interference RNA (siRNA) against SIRT1. MATERIAL AND METHODS SiRNA construct was transfected into PC-3 cells, which were tested for the cell migration and invasion ability by scratch assay and Transwell migration assay, respectively. Expression levels of vimentin, E-cadherin, and N-cadherin were further quantified by Western blotting and RT-PCR. RESULTS Both mRNA and protein levels of SIRT1 were depressed after siRNA transfection, along with weakened migration and invasion ability of PC-3 cells. Elevated E-cadherin and suppressed N-cadherin and vimentin were observed in those transfected cells. CONCLUSIONS The silencing of SIRT1 gene in PC-3 cells can suppress the movement, migration, and invasion functions of prostate cancer cells, possibly via the down-regulation of mesenchymal markers vimentin and N-cadherin accompanied with up-regulation of epithelial marker N-cadherin, thus reversing the EMT process.

The -1237T/C polymorphism of the Toll-like receptor 9 (TLR9) gene has been implicated in the susceptibility of inflammatory bowel diseases (IBDs), but the results remain conflicting. We further investigated this association via meta-analysis.

α-synuclein (α-syn) is the main component of intracytoplasmic inclusions deposited in the brains of patients with Parkinson's disease (PD) and certain other neurodegenerative disorders. Recent studies have explored the ability of α-syn to propagate between or across neighboring neurons and supposedly "infect" them with a prion-like mechanism. However, much of this research has used stereotaxic injections of heterologous α-syn fibrils to induce the spreading of inclusions in the rodent brains. Whether α-syn is able to transmit from the host cells to their neighboring cells in vivo is unclear.

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.

Growing evidence suggests that hypoxia-inducible factor-α (HIF-1α) plays an important role in the progression of allergic airway inflammation and remodeling. However, the biochemical mechanisms leading to the activation of HIF-1α and the effects of HIF-1α on the expression of growth factors, including vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), and fibroblast growth factor-2 (FGF-2), in allergic nasal inflammation are not clear. We examined the relationship between HIF-1α activation and production of VEGF, TGF-β1, and FGF-2 in primary cultured nasal epithelial cells (NECs) after stimulation with house dust mite (HDM) extract. Moreover, we evaluated the importance of phosphoinositide3-kinase(PI3K)/Akt signaling in HDM-induced production of these growth factors in vitro and in the nasal mucosa of a murine model of allergic rhinitis (AR). Our results indicate HDM extract induced the expression of VEGF, TGF-β1, and FGF-2 by activating the PI3K/Akt/HIF-1α pathway in human primary cultured NECs and in the nasal mucosa of a murine model. HIF-1α regulated the expression of VEGF, TGF-β1, and FGF-2 in the nasal mucosa through direct and indirect pathways, which suggested that targeting the HIF-1α pathway could be a novel therapeutic approach for reducing nasal airway inflammation and remodeling in AR.

Oxytocin has been suggested as a promising new treatment for neurodevelopmental disorders. However, important gaps remain in our understanding of its mode of action, in particular, to what extent oxytocin modulates social and non-social behaviours and whether its effects are generalizable across both sexes. Here we investigated the effects of a range of oxytocin doses on social and non-social behaviours in C57BL/6N mice of both sexes. As the striatum modulates social and non-social behaviours, and is implicated in neurodevelopmental disorders, we also conducted a pilot exploration of changes in striatal protein expression elicited by oxytocin. Oxytocin increased prepulse inhibition of startle but attenuated the recognition memory in male C57BL/6N mice. It increased social interaction time and suppressed the amphetamine locomotor response in both sexes. The striatum proteome following oxytocin exposure could be clearly discriminated from saline controls. With the caveat that these results are preliminary, oxytocin appeared to alter individual protein expression in directions similar to conventional anti-psychotics. The proteins affected by oxytocin could be broadly categorized as those that modulate glutamatergic, GABAergic or dopaminergic signalling and those that mediate cytoskeleton dynamics. Our results here encourage further research into the clinical application of this peptide hormone, which may potentially extend treatment options across a spectrum of neurodevelopmental conditions.

To develop a novel preimplantation genetic screening (PGS) test using next generation sequencing(NGS) as a alternative to current array comparative genomic hybridization (array CGH) method for detection of small segmental translocations in two patients with repeated implantation failure (RIF) and recurrent miscarriage (RM). Inconsistent results were resolved by validation with fluorescence in situ hybridization (FISH).

To evaluate the diagnostic performance of quantitative analysis as an adjunctive diagnostic tool to contrast-enhanced ultrasound (US) for the differentiation of atypical benign focal liver lesions (FLLs) from malignancies in fatty liver. Twenty-seven benign FLLs and fifty-six malignant FLLs that appeared hyper-enhanced during the arterial phase with washout in the portal or late phase in fatty liver were analyzed. Chi-square tests and logistic regression were applied to identify the specific features. Three sets of criteria were assigned: 1) all FLLs subjected to routine contrast-enhanced US; 2) all FLLs subjected to quantification analysis and contrast-enhanced US; and 3) parts of FLLs that could not be diagnosed using contrast-enhanced US (n = 66, 75.9%) but instead were diagnosed using parametric features. The sensitivity, specificity, accuracy and area under the receiver operating characteristic curve (AUC) of the three sets of criteria were analyzed. The AUCs of the criterion set 2 were significantly higher than those of criterion set 1 (0.904 versus 0.792, P = 0.008). Criterion set 3 showed a relatively high sensitivity (90.2%) with a relatively high AUC (0.845). The quantification analysis offers improved diagnostic performance for the differential identification of atypical benign FLLs from malignancies in fatty liver.

Fibroblasts are rich in the surrounding microenvironment of hepatocellular carcinoma (HCC) because most HCCs occur in fibrotic or cirrhotic livers. However, the role of cancer-associated fibroblasts (CAFs) in HCC metastasis remains obscure. Here, we reported that CAFs promote the migration and invasion of HCC cells in vitro and facilitate the HCC metastasis to the bone, brain and lung in NOD/SCID mice. The RayBio human chemokine antibody array revealed that CAFs secret higher levels of CCL2, CCL5, CCL7 and CXCL16 than peri-tumor fibroblasts. CCL2 and CCL5 increase the migration but not the invasion of HCC cells, while CCL7 and CXCL16 promote both migration and invasion of HCC cells. Moreover, CCL2 and CCL5 stimulate the activation of the hedgehog (Hh) pathway, while CCL7 and CXCL16 enhance the activity of the transforming growth factor-β (TGF-β) pathway in HCC cells. The neutralizing antibodies of chemokines notably attenuate the effect of CAFs on HCC metastasis and compromised the activation of Hh and TGF-β pathways in HCC cells. In summary, CAF-secreted CCL2, CCL5, CCL7 and CXCL16 promote HCC metastasis through the coordinate activation of Hh and TGF-β pathways in HCC cells.

Sleep deprivation during pregnancy is a serious public health problem as it can affect the health of pregnant women and newborns. However, it is not well studied whether sleep deprivation at different stages of pregnancy has similar effects on emotional and cognitive functions of the offspring, and if so, the potential cellular mechanisms also remain poorly understood.

Traditional Chinese Medicine (TCM), with a history of thousands of years of clinical practice, is gaining more and more attention and application worldwide. And TCM-based new drug development, especially for the treatment of complex diseases is promising. However, owing to the TCM's diverse ingredients and their complex interaction with human body, it is still quite difficult to uncover its molecular mechanism, which greatly hinders the TCM modernization and internationalization. Here we developed the first online Bioinformatics Analysis Tool for Molecular mechANism of TCM (BATMAN-TCM). Its main functions include 1) TCM ingredients' target prediction; 2) functional analyses of targets including biological pathway, Gene Ontology functional term and disease enrichment analyses; 3) the visualization of ingredient-target-pathway/disease association network and KEGG biological pathway with highlighted targets; 4) comparison analysis of multiple TCMs. Finally, we applied BATMAN-TCM to Qishen Yiqi dripping Pill (QSYQ) and combined with subsequent experimental validation to reveal the functions of renin-angiotensin system responsible for QSYQ's cardioprotective effects for the first time. BATMAN-TCM will contribute to the understanding of the "multi-component, multi-target and multi-pathway" combinational therapeutic mechanism of TCM, and provide valuable clues for subsequent experimental validation, accelerating the elucidation of TCM's molecular mechanism. BATMAN-TCM is available at http://bionet.ncpsb.org/batman-tcm.

Chemoresistance is common in patients with biliary tract cancer (BTC) including gallbladder cancer (GBC) and cholangiocarcinoma (CC). Therefore, it is necessary to identify effective chemotherapeutic agents for BTC. In the present study, we for the first time tested the effect of farnesoid X receptor (FXR) agonists GW4064 and CDCA (chenodeoxycholic acid) in combination with cisplatin (CDDP) on increasing the chemosensitivity in BTC. Our results show that co-treatment of CDDP with FXR agonists remarkably enhance chemosensitivity of BTC cells. Mechanistically, we found that activation of FXR induced expression of small heterodimer partner (SHP), which in turn inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation and resulted in down-regulation of Bcl-xL expression in BTC cells, leading to increased susceptibility to CDDP. Moreover, the experiments on tumor-bearing mice showed that GW4064/CDDP co-treatment inhibited the tumor growth in vivo by up-regulating SHP expression and down-regulating STAT3 phosphorylation. These results suggest CDDP in combination with FXR agonists could be a potential new therapeutic strategy for BTC.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children, the etiology of which involves a strong genetic component, but much of the underlying genetic determinants still remain unknown. Our aim was to identify novel genetic variants that predispose to JIA.

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.

Multifaceted activities of class I phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 were investigated on human breast cancer cell MCF-7. ZSTK474 inhibited proliferation of MCF-7 cells potently. Flow cytometric analysis indicated that ZSTK474 induced cell cycle arrest at G1 phase, but no obvious apoptosis occurred. Western blot analysis suggested that blockade of PI3K/Akt/GSK-3β/cyclin D1/p-Rb pathway might contribute to the G1 arrest induced. Moreover, we demonstrated that ZSTK474 induced autophagy in MCF-7 cells by use of various assays including monodansylcadaverine (MDC) staining, transmission electron microscopy (TEM), tandem mRFP-GFP-LC3 fluorescence microscopy, and western blot detection of the autophagy protein markers of LC3B II, p62 and Atg 5. Inhibition of class I PI3K and the downstream mTOR might be involved in the autophagy-inducing effect. Combinational use of ZSTK474 and autophagy inhibitors enhanced cell viability, suggesting ZSTK474-induced autophagy might contribute to the antitumor activity. Our report supports the application of ZSTK474, which is being evaluated in clinical trials, for breast cancer therapy.

The neurotransmitter acetylcholine (ACh) promotes the growth and metastasis of several cancers via its M3 muscarinic receptor (M3R). Metastasis-associated in colon cancer-1 (MACC1) is an oncogene that is overexpressed in gastric cancer (GC) and plays an important role in GC progression, though it is unclear how MACC1 activity is regulated in GC. In this study, we demonstrated that ACh acts via M3Rs to promote GC cell invasion and migration as well as expression of several markers of epithelial-mesenchymal transition (EMT). The M3R antagonist darifenacin inhibited GC cell activity in both the presence and absence of exogenous ACh, suggesting GC cells secrete endogenous ACh, which then acts in an autocrine fashion to promote GC cell migration/invasion. ACh up-regulated MACC1 in GC cells, and MACC1 knockdown using siRNA attenuated the effects of ACh on GC cells. AMP-activated protein kinase (AMPK) served as an intermediate signal between ACh and MACC1. These findings suggest that ACh acts via a M3R/AMPK/MACC1 signaling pathway to promote GC cell invasion/migration, which provides insight into the mechanisms underlying GC growth and metastasis and may shed light on new targets for GC treatment.

Human infections with H7 subtype influenza virus have been reported, including an H7N7 outbreak in Netherlands in 2003 and H7N9 infections in China in 2013. Previously, we reported murine monoclonal antibodies (mAbs) that recognize the antigenic site A of H7 hemagglutinin (HA). To better understand protective immunity of H7 vaccines and vaccine candidate selection, we used these mAbs to assess the antigenic relatedness among two H7 HA isolated from past human infections and determine residues that affect susceptibility to neutralization. We found that these mAbs neutralize pseudoviruses bearing HA of A/Shanghai/02/2013(H7N9), but not A/Netherlands/219/2003(H7N7). Glycosylation of the asparagine residue at position 141 (N141) (N133, H3 HA numbering) in the HA of A/Netherlands/219/2003 HA is responsible for this resistance, and it affects the infectivity of HA-pseudoviruses. The presence of threonine at position 143 (T135, H3 HA numbering) in the HA of A/Netherlands/219/2003, rather than an alanine found in the HA of A/Shanghai/02/2013(H7N9), accounts for these differences. These results demonstrate a key role for glycosylation of residue N141 in affecting H7 influenza HA-mediated entry and sensitivity to neutralizing antibodies, which have implications for candidate vaccine design.