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1.  Defective autophagy leads to the suppression of stem-like features of CD271+ osteosarcoma cells 
Background
As an important stress-response mechanism, autophagy plays crucial role in the tumor formation and drug resistance of cancer cells including osteosarcoma (OS). OS cancer stem cells (CSCs) also are considered a key factor of tumorigenesis, drug resistance and tumor recurrence. However, the relationship between autophagy and OS CSCs still remains unclear.
Methods
CD271+ OS CSCs and CD271- OS cells were isolated by magnetic activated cell sorting. The autophagy level was evaluated by the mRNA expression of autophagy genes, the protein level of LC3II and p62, and the mean number of GFP-LC3 dot per cell. Lentivirus-delivered specific shRNA was utilized to inhibit the corresponding gene expression. The cell viability was examined with CCK8 assay. The cell proliferation level was detected with BrdU staining assay. Cell death was determined by Annexin V/PI double staining of fluorescence activated cell sorting, lactate dehydrogenase release and caspase-3 activity. Tumorigenicity ability was evaluated by colony and sphere formation assay, the protein expression of stemness markers and tumor formation in nude mice.
Results
Our data indicated that CD271+ OS CSCs had a similar basic autophagy level with CD271- OS cells. Autophagy deficiency had no observable effects on the levels of cell proliferation and death both in CD271+ and CD271- OS cells under normal condition. However, CD271+ OS cells showed a higher autophagy activity than CD271- OS cells under hypoxia and low nutrient (LH) condition. Moreover, autophagy-deficient CD271+ OS cells lost the advantage of tolerance to LH condition compared to CD271- OS cells. Meanwhile, autophagy deficiency enhanced the sensitivity to chemotherapeutics in the CD271+ cells to the comparable level in the CD271- cells. More importantly, deficient-autophagy decreased the protein expression of stemness markers and caused the disappearance of the superiority in tumorigenicity in vitro and vivo in CD271+ OS cells.
Conclusion
The results above demonstrated that autophagy contributes to the stem-like features of CD271+ OS CSCs. Inhibition of autophagy is a promising strategy in the CSCs-targeting OS therapy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12929-016-0297-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12929-016-0297-5
PMCID: PMC5116184  PMID: 27863492
Osteosarcoma; Autophagy; Cancer stem cells; CD271
2.  Illumina Miseq platform analysis caecum bacterial communities of rex rabbits fed with different antibiotics 
AMB Express  2016;6:100.
Antibiotics have been widely used for the prevention and the treatment of diseases to humans and animals, and they have fed additives for agricultural animals to promote growth. However, there is a growing concern over the practice due to its side effects on intestinal microbial communities which plays a vital role in animals’ health. To investigate the effect of antibiotics on the bacterial population of the caecum in rex rabbits, 80 rex rabbits were randomly divided into four groups: control group (B, basal diet), chlortetracycline group (C, 50 mg/kg), colistin sulfate group (S, 20 mg/kg) and zinc bacitracin group (Z, 40 mg/kg). Caecum microbial communities of rex rabbits from the four groups were analyzed through Illumina Miseq platform after being fed 28 days. The results showed that most obtained sequences belongs to Firmicutes followed by Bacteroidetes, and the ratio of Bacteroidetes/Firmicutes in C group (42.31 %) was higher than that in Z group (21.84 %). Zinc bacitracin supplementation caused a significant decreased of the Proteobacteria phylum and Lactobacillus spp. (P < 0.05), while the Lactobacillus spp. significantly increased in S group (P < 0.05). In addition, Ruminococcus spp., especially Ruminococcus albus were the predominant bacterial species found in both S and Z groups. The proportion of Coprococcus spp. significantly increased in Z group (P < 0.05). These findings suggested that the antibiotics used may cause significant changes in the caecum microbiota of rex rabbits, and we also found C group had a similarity caecum bacteria structure with B group which was probably due to the high levels of chlortetracycline resistance.
Electronic supplementary material
The online version of this article (doi:10.1186/s13568-016-0273-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13568-016-0273-1
PMCID: PMC5074941  PMID: 27770389
Illumina Miseq platform; Rex rabbit; Chlortetracycline; Colistin sulfate; Zinc bacitracin; Caecum microflora
4.  A Microchip for Integrated Single-Cell Gene Expression Profiling and Genotoxicity Detection 
Sensors (Basel, Switzerland)  2016;16(9):1489.
Microfluidics-based single-cell study is an emerging approach in personalized treatment or precision medicine studies. Single-cell gene expression holds a potential to provide treatment selections with maximized efficacy to help cancer patients based on a genetic understanding of their disease. This work presents a multi-layer microchip for single-cell multiplexed gene expression profiling and genotoxicity detection. Treated by three drug reagents (i.e., methyl methanesulfonate, docetaxel and colchicine) with varied concentrations and time lengths, individual human cancer cells (MDA-MB-231) are lysed on-chip, and the released mRNA templates are captured and reversely transcribed into single strand DNA. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), cyclin-dependent kinase inhibitor 1A (CDKN1A), and aurora kinase A (AURKA) genes from single cells are amplified and real-time quantified through multiplex polymerase chain reaction. The microchip is capable of integrating all steps of single-cell multiplexed gene expression profiling, and providing precision detection of drug induced genotoxic stress. Throughput has been set to be 18, and can be further increased following the same approach. Numerical simulation of on-chip single cell trapping and heat transfer has been employed to evaluate the chip design and operation.
doi:10.3390/s16091489
PMCID: PMC5038763  PMID: 27649175
single-cell analysis; integrated multiplex RT-qPCR; microfluidics
5.  Interleukin-6 enhances cancer stemness and promotes metastasis of hepatocellular carcinoma via up-regulating osteopontin expression 
American Journal of Cancer Research  2016;6(9):1873-1889.
Interleukin-6 (IL-6), one of the most important inflammatory cytokines, plays a pivotal role in metastasis and stemness of solid tumors. However, the underlying mechanisms of IL-6 in HCC metastasis remain unclear. In the present study, we demonstrated that stemness and metastatic potential of HCC cells were significantly enhanced after IL-6 stimulation. IL-6 could induce expression of osteopontin (OPN), along with other stemness-related genes, including HIF1α, BMI1, and HEY1. Block of OPN induction could significantly abrogate the effect of IL-6 on stemness and metastasis of HCC cells. Furthermore, IL-6 level was positively correlated with OPN in HCC. Patients with high plasma IL-6 or OPN level had poorer prognosis. In multivariate analysis, IL-6 and OPN were demonstrated to be independent prognostic indicators for HCC patients, and their combination had a better prognostic performance than IL-6 or OPN alone. Collectively, our findings indicate that IL-6 could enhance stemness and promote metastasis of HCC via up-regulating OPN expression, which can be a potential therapeutic target for combating HCC metastasis, and the combination of IL-6 and OPN serves as a promising prognostic predictor for HCC.
PMCID: PMC5043100  PMID: 27725896
Liver cancer; cancer stem cell; inflammatory factor; prognosis
6.  A Comprehensive and System Review for the Pharmacological Mechanism of Action of Rhein, an Active Anthraquinone Ingredient 
Rhein is a major medicinal ingredient isolated from several traditional Chinese medicines, including Rheum palmatum L., Aloe barbadensis Miller, Cassia angustifolia Vahl., and Polygonum multiflorum Thunb. Rhein has various pharmacological activities, such as anti-inflammatory, antitumor, antioxidant, antifibrosis, hepatoprotective, and nephroprotective activities. Although more than 100 articles in PubMed are involved in the pharmacological mechanism of action of rhein, only a few focus on the relationship of crosstalk among multiple pharmacological mechanisms. The mechanism of rhein involves multiple pathways which contain close interactions. From the overall perspective, the pathways which are related to the targets of rhein, are initiated by the membrane receptor. Then, MAPK and PI3K-AKT parallel signaling pathways are activated, and several downstream pathways are affected, thereby eventually regulating cell cycle and apoptosis. The therapeutic effect of rhein, as a multitarget molecule, is the synergistic and comprehensive result of the involvement of multiple pathways rather than the blocking or activation of a single signaling pathway. We review the pharmacological mechanisms of action of rhein by consulting literature published in the last 100 years in PubMed. We then summarize these pharmacological mechanisms from a comprehensive, interactive, and crosstalk perspective. In general, the molecular mechanism of action of drug must be understood from a systematic and holistic perspective, which can provide a theoretical basis for precise treatment and rational drug use.
doi:10.3389/fphar.2016.00247
PMCID: PMC4987408  PMID: 27582705
rhein; pharmacological mechanism; signaling pathways; precise treatment; crosstalk network
7.  Association between body mass index and mortality in a prospective cohort of Chinese adults 
Medicine  2016;95(32):e4327.
Supplemental Digital Content is available in the text
Abstract
Obesity is associated with an increased risk of diabetes mellitus, hypertension, and coronary artery disease; however, the relation between body mass index (BMI) and the risk of all-cause mortality is controversial. We prospectively examined the relationship between BMI and all-cause mortality in 123,384 Chinese men and women who participated in the Kailuan health examination study from 2006 to 2007 and 2008 to 2009. Cases included 6218 deaths (5770 men and 448 women) that occurred during a mean follow-up period of 7.39 years. Relative risk was adjusted for factors such as age, serum lipid levels (ie, triglyceride, high-density lipoprotein, and low-density lipoprotein cholesterol), history of smoking and drinking, and physical activity, as well as a medical history of hypertension, diabetes, myocardial infarction, and stroke. Within the cohort, the lowest risk of all-cause mortality was seen among persons with a BMI of 24 to 28 kg/m2 in male, and the risk was elevated among persons with BMI levels lower or higher than that range. Moreover, all-cause mortality was greatest in the group with a BMI of <18.5 kg/m2. In contrast, in female, a high BMI was associated with increased mortality, and a BMI of <18.5 kg/m2 was associated with the lowest risk. Further, a U-shaped association was seen between BMI and the risk of death from any cause among men and women, even after adjusting for confounding factors. In conclusion, underweight was associated with a substantially increased risk of all-cause mortality in males. The excess risk of all-cause mortality with a high BMI, however, was seen among females.
doi:10.1097/MD.0000000000004327
PMCID: PMC4985299  PMID: 27512844
all-cause mortality; body mass index; Chinese; obesity; obesity paradox
8.  Lysine-specific histone demethylase 1 inhibition promotes reprogramming by facilitating the expression of exogenous transcriptional factors and metabolic switch 
Scientific Reports  2016;6:30903.
Lysine-specific histone demethylase 1 (LSD1) regulates histone methylation and influences the epigenetic state of cells during the generation of induced pluripotent stem cells (iPSCs). Here we reported that LSD1 inhibition via shRNA or specific inhibitor, tranylcypromine, promoted reprogramming at early stage via two mechanisms. At early stage of reprogramming, LSD1 inhibition increased the retrovirus-mediated exogenous expression of Oct4, Klf4, and Sox2 by blocking related H3K4 demethylation. Since LSD1 inhibition still promoted reprogramming even when iPSCs were induced with small-molecule compounds in a virus-free system, additional mechanisms should be involved. When RNA-seq was used for analysis, it was found that LSD1 inhibition reversed some gene expression changes induced by OKS, which subsequently promoted reprogramming. For example, by partially rescuing the decreased expression of Hif1α, LSD1 inhibition reversed the up-regulation of genes in oxidative phosphorylation pathway and the down-regulation of genes in glycolysis pathway. Such effects facilitated the metabolic switch from oxidative phosphorylation to glycolysis and subsequently promoted iPSCs induction. In addition, LSD1 inhibition also promoted the conversion from pre-iPSCs to iPSCs by facilitating the similar metabolic switch. Therefore, LSD1 inhibition promotes reprogramming by facilitating the expression of exogenous transcriptional factors and metabolic switch.
doi:10.1038/srep30903
PMCID: PMC4969595  PMID: 27481483
9.  Long noncoding RNAs in DNA methylation: new players stepping into the old game 
Cell & Bioscience  2016;6:45.
Long non-coding RNAs (lncRNAs) are being discovered as a novel family of regulators of gene expression at the epigenetic level. Emerging lines of evidence demonstrate that interplays between lncRNAs and DNA methylation machinery are an important layer of epigenetic regulation. Here in this mini-review we summarize the current findings in the field and focus particularly on the interactions mediated through direct physical association between lncRNAs and DNA methyltransferases (DNMTs).
doi:10.1186/s13578-016-0109-3
PMCID: PMC4940868  PMID: 27408682
lncRNAs; Dnmt; Methylation; Epigenetics
10.  Integrated long non‐coding RNA analyses identify novel regulators of epithelial‐mesenchymal transition in the mouse model of pulmonary fibrosis 
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease characterized by aberrant accumulation of fibroblast population and deposition of extra cellular matrix. Increasing evidence support that epithelial‐mesenchymal transition (EMT) of alveolar epithelial cells is a critical process in the pathogenesis of IPF. Although delivery of bleomycin to induce acute lung injury is the most well‐studied animal model of pulmonary fibrosis, there is considerable interest to pursue other models to understand the common and/or specific pathological mechanisms. In this study, we established a mouse model of pulmonary injury and progressive interstitial fibrosis via intraperitoneal injection of paraquat, a widely used herbicide known to cause pulmonary fibrosis in human. Using transcriptome sequencing and microarray analysis, we profiled expression of long non‐coding RNAs (lncRNAs) and identified 513 up‐regulated and 204 down‐regulated lncRNAs in paraquat‐induced fibrotic lung tissues. Gene ontology analysis revealed that the differentially expressed lncRNAs are implicated in cell differentiation, epithelium morphogenesis and wound healing, pathways closely associated with EMT. Furthermore, we identified the evolutionally conserved target genes of two up‐regulated lncRNAs, uc.77 and 2700086A05Rik, as Zeb2 and Hoxa3, respectively, both of which are important modulators of EMT. Consistently, overexpression of uc.77 or 2700086A05Rik in human lung epithelial cells induced EMT as demonstrated by changes in gene and protein expression of various EMT markers and cell morphology. Collectively, our results uncovered a crucial role of lncRNA in the regulation of EMT during lung fibrosis and provide potential avenues for the discovery of novel molecular markers and therapeutic targets for IPF.
doi:10.1111/jcmm.12783
PMCID: PMC4929291  PMID: 26824344
pulmonary fibrosis; epithelial–mesenchymal transition; paraquat; long non‐coding RNA
11.  Long-term prognosis of patients with acute myocardial infarction due to unprotected left main coronary artery disease: a single-centre experience over 14 years 
Singapore Medical Journal  2016;57(7):396-400.
INTRODUCTION
Acute myocardial infarction (AMI) due to unprotected left main coronary artery (ULMCA) disease is clinically catastrophic although it has a low incidence. Studies on the long-term prognosis of these patients are rare.
METHODS
From January 1999 to September 2013, 55 patients whose infarct-related artery was the ULMCA were enrolled. Clinical, angiographic and interventional data was collected. Short-term and long-term clinical follow-up results as well as prognostic determinants during hospitalisation and follow-up were analysed.
RESULTS
Cardiogenic shock (CS) occurred in 30 (54.5%) patients. During hospitalisation, 22 (40.0%) patients died. Multivariate logistic regression analysis showed that CS (odds ratio [OR] 5.86; p = 0.03), collateral circulation of Grade 2 or 3 (OR 0.14; p = 0.02) and final flow of thrombolysis in myocardial infarction (TIMI) Grade 3 (OR 0.05; p = 0.03) correlated with death during hospitalisation. 33 patients survived to discharge; another seven patients died during the follow-up period of 44.6 ± 31.3 (median 60, range 0.67–117.00) months. The overall mortality rate was 52.7% (n = 29). Kaplan-Meier analysis showed that the total cumulative survival rate was 30.7%. Cox multivariate regression analysis showed that CS during hospitalisation was the only predictor of overall mortality (hazard ratio 4.07, 95% confidence interval 1.40–11.83; p = 0.01).
CONCLUSION
AMI caused by ULMCA lesions is complicated by high incidence of CS and mortality. CS, poor collateral blood flow and failure to restore final flow of TIMI Grade 3 correlated with death during hospitalisation. CS is the only predictor of long-term overall mortality.
doi:10.11622/smedj.2016121
PMCID: PMC4958717  PMID: 27439434
acute myocardial infarction; cardiogenic shock; infarct-related artery; percutaneous coronary intervention; unprotected left main coronary artery
12.  An excellent navigation system and experience in craniomaxillofacial navigation surgery: a double-center study 
Scientific Reports  2016;6:28242.
Numerous problems regarding craniomaxillofacial navigation surgery are not well understood. In this study, we performed a double-center clinical study to quantitatively evaluate the characteristics of our navigation system and experience in craniomaxillofacial navigation surgery. Fifty-six patients with craniomaxillofacial disease were included and randomly divided into experimental (using our AccuNavi-A system) and control (using Strker system) groups to compare the surgical effects. The results revealed that the average pre-operative planning time was 32.32 mins vs 29.74 mins between the experimental and control group, respectively (p > 0.05). The average operative time was 295.61 mins vs 233.56 mins (p > 0.05). The point registration orientation accuracy was 0.83 mm vs 0.92 mm. The maximal average preoperative navigation orientation accuracy was 1.03 mm vs 1.17 mm. The maximal average persistent navigation orientation accuracy was 1.15 mm vs 0.09 mm. The maximal average navigation orientation accuracy after registration recovery was 1.15 mm vs 1.39 mm between the experimental and control group. All patients healed, and their function and profile improved. These findings demonstrate that although surgeons should consider the patients’ time and monetary costs, our qualified navigation surgery system and experience could offer an accurate guide during a variety of craniomaxillofacial surgeries.
doi:10.1038/srep28242
PMCID: PMC4910165  PMID: 27305855
13.  microRNA-802/Rnd3 pathway imposes on carcinogenesis and metastasis of fine particulate matter exposure 
Oncotarget  2016;7(23):35026-35043.
Recent studies have linked ambient fine particulate matter (PM2.5) to increased lung cancer mortality and morbidity. However, the underlying mechanism causing the adverse effects of PM2.5 is less clear. In the present study, post-transcriptional profiling was used to explore biological pathways involved in PM2.5-induced pulmonary disorders. The carcinogenesis and metastasis of PM2.5 exposure were evaluated by long-term PM2.5 exposure tests. We observed dysregulation of actin in A549 cells line and dysplasia in the lungs of mice exposed to PM2.5. Both PM2.5-exposed cells and animals showed increased Rnd3 expression levels. Moreover, miR-802 mimics rescued actin disorganization in vitro and alveolitis in vivo. Long-term exposure to PM2.5 promoted carcinogenesis and metastasis of pulmonary cells. Decreased miR-802 expression levels in the serum samples of PM2.5-treated mice and individuals from moderately polluted cities were observed. Increased Rnd3 expression levels in lung cancers tissues have been identified by a genome database TCGA, and have been linked to less overall survival probabilities of lung cancer patients. Our findings suggest that dysregulation of actin cytoskeleton and down-regulation of miR-802 expression might be the underlying mechanism involved in the adverse effects of PM2.5 exposure. In addition, long-term exposure to PM2.5 demonstrated strong associations with malignant pulmonary disorders.
doi:10.18632/oncotarget.9019
PMCID: PMC5085207  PMID: 27144337
PM2.5; microRNA; lung cancer; carcinogenesis; actin
14.  Meta-Analysis of EMT Datasets Reveals Different Types of EMT 
PLoS ONE  2016;11(6):e0156839.
As a critical process during embryonic development, cancer progression and cell fate conversions, epithelial-mesenchymal transition (EMT) has been extensively studied over the last several decades. To further understand the nature of EMT, we performed meta-analysis of multiple microarray datasets to identify the related generic signature. In this study, 24 human and 17 mouse microarray datasets were integrated to identify conserved gene expression changes in different types of EMT. Our integrative analysis revealed that there is low agreement among the list of the identified signature genes and three other lists in previous studies. Since removing the datasets with weakly-induced EMT from the analysis did not significantly improve the overlapping in the signature-gene lists, we hypothesized the existence of different types of EMT. This hypothesis was further supported by the grouping of 74 human EMT-induction samples into five distinct clusters, and the identification of distinct pathways in these different clusters of EMT samples. The five clusters of EMT-induction samples also improves the understanding of the characteristics of different EMT types. Therefore, we concluded the existence of different types of EMT was the possible reason for its complex role in multiple biological processes.
doi:10.1371/journal.pone.0156839
PMCID: PMC4892621  PMID: 27258544
15.  Hyper-SUMOylation of the Kv7 Potassium Channel Diminishes the M-Current Leading to Seizures and Sudden Death 
Neuron  2014;83(5):1159-1171.
SUMMARY
Sudden unexplained death in epilepsy (SUDEP) is the most common cause of premature mortality in epilepsy and was linked to mutations in ion channels; however, genes within the channel protein interactome might also represent pathogenic candidates. Here we show that mice with partial deficiency of Sentrin/SUMO-specific protease 2 (SENP2) develop spontaneous seizures and sudden death. SENP2 is highly enriched in the hippocampus, often the focus of epileptic seizures. SENP2 deficiency results in hyper-SUMOylation of multiple potassium channels known to regulate neuronal excitability. We demonstrate that the depolarizing M-current conducted by Kv7 channel is significantly diminished in SENP2-deficient hippocampal CA3 neurons, primarily responsible for neuronal hyperexcitability. Following seizures, SENP2-deficient mice develop atrioventricular conduction blocks and cardiac asystole. Both seizures and cardiac conduction blocks can be prevented by retigabine, a Kv7 channel opener. Thus, we uncover a disease-causing role for hyper-SUMOylation in the nervous system and establish an animal model for SUDEP.
doi:10.1016/j.neuron.2014.07.042
PMCID: PMC4877174  PMID: 25189211
16.  A microfluidic approach to parallelized transcriptional profiling of single cells 
Microfluidics and nanofluidics  2015;19(6):1429-1440.
The ability to correlate single-cell genetic information with cellular phenotypes is of great importance to biology and medicine, as it holds the potential to gain insight into disease pathways that is unavailable from ensemble measurements. We present a microfluidic approach to parallelized, rapid, quantitative analysis of messenger RNA from single cells via RT-qPCR. The approach leverages an array of single-cell RT-qPCR analysis units formed by a set of parallel microchannels concurrently controlled by elastomeric pneumatic valves, thereby enabling parallelized handling and processing of single cells in a drastically simplified operation procedure using a relatively small number of microvalves. All steps for single-cell RT-qPCR, including cell isolation and immobilization, cell lysis, mRNA purification, reverse transcription and qPCR, are integrated on a single chip, eliminating the need for off-chip manual cell and reagent transfer and qPCR amplification as commonly used in existing approaches. Additionally, the approach incorporates optically transparent microfluidic components to allow monitoring of single-cell trapping without the need for molecular labeling that can potentially alter the targeted gene expression and utilizes a polycarbonate film as a barrier against evaporation to minimize the loss of reagents at elevated temperatures during the analysis. We demonstrate the utility of the approach by the transcriptional profiling for the induction of the cyclin-dependent kinase inhibitor 1a and the glyceraldehyde 3-phosphate dehydrogenase in single cells from the MCF-7 breast cancer cell line. Furthermore, the methyl methanesulfonate is employed to allow measurement of the expression of the genes in individual cells responding to a genotoxic stress.
doi:10.1007/s10404-015-1657-2
PMCID: PMC4868186  PMID: 27194954
Single-cell analysis; Microfluidics; Integrated transcriptional profiling; Parallelized RT-qPCR
17.  Draft Genome Sequence of Bacillus megaterium BHG1.1, a Strain Isolated from Bar-Headed Goose (Anser indicus) Feces on the Qinghai-Tibet Plateau 
Genome Announcements  2016;4(3):e00317-16.
Bacillus megaterium is a soil-inhabiting Gram-positive bacterium that is routinely used in industrial applications for recombinant protein production and bioremediation. Studies involving Bacillus megaterium isolated from waterfowl are scarce. Here, we report a 6.26-Mbp draft genome sequence of Bacillus megaterium BHG1.1, which was isolated from feces of a bar-headed goose.
doi:10.1128/genomeA.00317-16
PMCID: PMC4866837  PMID: 27174262
18.  Electrospun silk fibroin/poly(lactide-co-ε-caprolactone) nanofibrous scaffolds for bone regeneration 
Background
Tissue engineering has become a promising therapeutic approach for bone regeneration. Nanofibrous scaffolds have attracted great interest mainly due to their structural similarity to natural extracellular matrix (ECM). Poly(lactide-co-ε-caprolactone) (PLCL) has been successfully used in bone regeneration, but PLCL polymers are inert and lack natural cell recognition sites, and the surface of PLCL scaffold is hydrophobic. Silk fibroin (SF) is a kind of natural polymer with inherent bioactivity, and supports mesenchymal stem cell attachment, osteogenesis, and ECM deposition. Therefore, we fabricated hybrid nanofibrous scaffolds by adding different weight ratios of SF to PLCL in order to find a scaffold with improved properties for bone regeneration.
Methods
Hybrid nanofibrous scaffolds were fabricated by blending different weight ratios of SF with PLCL. Human adipose-derived stem cells (hADSCs) were seeded on SF/PLCL nanofibrous scaffolds of various ratios for a systematic evaluation of cell adhesion, proliferation, cytotoxicity, and osteogenic differentiation; the efficacy of the composite of hADSCs and scaffolds in repairing critical-sized calvarial defects in rats was investigated.
Results
The SF/PLCL (50/50) scaffold exhibited favorable tensile strength, surface roughness, and hydrophilicity, which facilitated cell adhesion and proliferation. Moreover, the SF/PLCL (50/50) scaffold promoted the osteogenic differentiation of hADSCs by elevating the expression levels of osteogenic marker genes such as BSP, Ocn, Col1A1, and OPN and enhanced ECM mineralization. In vivo assays showed that SF/PLCL (50/50) scaffold improved the repair of the critical-sized calvarial defect in rats, resulting in increased bone volume, higher trabecular number, enhanced bone mineral density, and increased new bone areas, compared with the pure PLCL scaffold.
Conclusion
The SF/PLCL (50/50) nanofibrous scaffold facilitated hADSC proliferation and osteogenic differentiation in vitro and further promoted new bone formation in vivo, suggesting that the SF/PLCL (50/50) nanofibrous scaffold holds great potential in bone tissue regeneration.
doi:10.2147/IJN.S97445
PMCID: PMC4833379  PMID: 27114708
human adipose-derived mesenchymal stem cells; silk fibrin; poly(lactide-co-ε-caprolactone); proliferation; osteogenesis
19.  Dexmedetomidine versus midazolam for sedation during endoscopy: A meta-analysis 
Patients undergoing endoscopy frequently require sedation, which commonly includes the administration of midazolam or dexmedetomidine. Previous meta-analyses have mainly focused on comparing the effects of these two drugs in intensive care unit patients. In the present study, randomized controlled trials (RCTs) that compared the sedative and clinical effectiveness of these two drugs in patients undergoing endoscopy were searched in a number of databases. The meta-analysis showed that dexmedetomidine demonstrated a significantly lower rate of respiratory depression and adverse events compared with those presented upon midazolam administration. A significant difference was also observed in the sedation potency of the sedatives. The current controlled data suggest that dexmedetomidine may be an alternative to midazolam in the sedation for endoscopy. However, more high-quality and well-designed studies are required to further evaluate this conclusion.
doi:10.3892/etm.2016.3186
PMCID: PMC4887952  PMID: 27284342
dexmedetomidine; midazolam; sedation; endoscopy; meta-analysis
20.  Opioid doses required for pain management in lung cancer patients with different cholesterol levels: negative correlation between opioid doses and cholesterol levels 
Background
Pain management has been considered as significant contributor to broad quality-of-life improvement for cancer patients. Modulating serum cholesterol levels affects analgesia abilities of opioids, important pain killer for cancer patients, in mice system. Thus the correlation between opioids usages and cholesterol levels were investigated in human patients with lung cancer.
Methods
Medical records of 282 patients were selected with following criteria, 1) signed inform consent, 2) full medical records on total serum cholesterol levels and opioid administration, 3) opioid-naïve, 4) not received/receiving cancer-related or cholesterol lowering treatment, 5) pain level at level 5–8. The patients were divided into different groups basing on their gender and cholesterol levels. Since different opioids, morphine, oxycodone, and fentanyl, were all administrated at fixed low dose initially and increased gradually only if pain was not controlled, the percentages of patients in each group who did not respond to the initial doses of opioids and required higher doses for pain management were determined and compared.
Results
Patients with relative low cholesterol levels have larger percentage (11 out of 28 in female and 31 out of 71 in male) to not respond to the initial dose of opioids than those with high cholesterol levels (0 out of 258 in female and 8 out of 74 in male). Similar differences were obtained when patients with different opioids were analyzed separately. After converting the doses of different opioids to equivalent doses of oxycodone, significant correlation between opioid usages and cholesterol levels was also observed.
Conclusions
Therefore, more attention should be taken to those cancer patients with low cholesterol levels because they may require higher doses of opioids as pain killer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12944-016-0212-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12944-016-0212-9
PMCID: PMC4782347  PMID: 26952011
Cholesterol level; Opioid; Analgesia; Lung cancer patients
21.  Diagnostic Value of Soluble Suppression of Tumorigenicity-2 for Heart Failure 
Chinese Medical Journal  2016;129(5):570-577.
Background:
Many studies have explored the diagnostic performance of soluble suppression of tumorigenicity-2 (sST2) for heart failure (HF), but the results are inconsistent. Here, we performed a meta-analysis to assess the role of sST2 in the diagnosis of HF.
Methods:
We searched PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Database from inception to April 2015. Studies that investigated the diagnostic role of sST2 for HF were reviewed. The numbers of true-positive, false-positive, false-negative, and true-negative results were extracted to calculate pooled diagnostic odds ratio (DOR) with 95% confidence interval (CI) and the summary receiver operating characteristic curve and area under the curve (AUC). The Spearman correlation coefficient was used to check the threshold effect. The Cochran Q statistic (P < 0.05) and the inconsistency index (I2 > 50%) were used to assess the nonthreshold effect. Meta-regression was conducted to explore the source of heterogeneity; subgroup analysis showed the results in different subgroups. Finally, the Deeks’ test was performed to assess the publication bias.
Results:
Nine articles including 10 studies were included in the meta-analysis. The pooled sensitivity was 0.84 (95% CI: 0.81–0.86), and pooled specificity was 0.74 (95% CI: 0.72–0.76). The summary DOR was 8.49 (95% CI: 4.54–15.86), and AUC was 0.81 (standard error: 0.03). The Spearman correlation coefficient identified the nonsignificant threshold effect (coefficient = 0.49, P = 0.148), but the nonthreshold effect heterogeneity was significant (Cochran Q = 58.52, P < 0.0001; I2 = 84.6%). Meta-regression found that characteristics of controls might be the suggestive source of nonthreshold effect heterogeneity (P = 0.095). Subgroup analysis found that DOR was 5.65 and 7.86, respectively for the controls of hospital patients and healthy populations. Deeks’ test demonstrated that there was no publication bias (P = 0.616).
Conclusion:
The meta-analysis illustrated that sST2 might play a role in diagnosing HF.
doi:10.4103/0366-6999.177000
PMCID: PMC4804439  PMID: 26904992
Biomarker; Diagnosis; Heart Failure; Meta-analysis; Soluble Suppression of Tumorigenicity-2
22.  LncRNA Dum interacts with Dnmts to regulate Dppa2 expression during myogenic differentiation and muscle regeneration 
Cell Research  2015;25(3):335-350.
Emerging studies document the roles of long non-coding RNAs (LncRNAs) in regulating gene expression at chromatin level but relatively less is known how they regulate DNA methylation. Here we identify an lncRNA, Dum (developmental pluripotency-associated 2 (Dppa2) Upstream binding Muscle lncRNA) in skeletal myoblast cells. The expression of Dum is dynamically regulated during myogenesis in vitro and in vivo. It is also transcriptionally induced by MyoD binding upon myoblast differentiation. Functional analyses show that it promotes myoblast differentiation and damage-induced muscle regeneration. Mechanistically, Dum was found to silence its neighboring gene, Dppa2, in cis through recruiting Dnmt1, Dnmt3a and Dnmt3b. Furthermore, intrachromosomal looping between Dum locus and Dppa2 promoter is necessary for Dum/Dppa2 interaction. Collectively, we have identified a novel lncRNA that interacts with Dnmts to regulate myogenesis.
doi:10.1038/cr.2015.21
PMCID: PMC4349245  PMID: 25686699
LncRNA; Dum; myogenesis; Dppa2; DNA methylation
23.  Relationships among three popular measures of differential risks: relative risk, risk difference, and odds ratio 
The relative risk, risk difference, and odds ratio are the three most commonly used measures for comparing the risk of disease between different groups. Although widely popular in biomedical and psychosocial research, the relationship among the three measures has not been clarified in the literature. Many researchers incorrectly assume a monotonic relationship, such that higher (or lower) values in one measure are associated with higher (or lower) values in the other measures. In this paper we discuss three theorems and provide examples demonstrating that this is not the case; there is no logical relationship between any of these measures. Researchers must be very cautious when implying a relationship between the different measures or when combining results of studies that use different measures of risk.
doi:10.11919/j.issn.1002-0829.216031
PMCID: PMC4984606  PMID: 27688647
odds ratio; relative risk; risk difference
24.  CT Imaging Biomarkers Predict Clinical Outcomes After Pancreatic Cancer Surgery 
Medicine  2016;95(5):e2664.
Abstract
This study aimed to determine whether changes in contrast-enhanced computed tomography (CT) parameters could predict postsurgery overall and progression-free survival (PFS) in pancreatic cancer patients. Seventy-nine patients with a final pathological diagnosis of pancreatic adenocarcinoma were included in this study from June 2008 to August 2012. Dynamic contrast-enhanced (DCE) CT of tumors was obtained before curative-intent surgery. Absolute enhancement change (AEC) and relative enhancement change (REC) were evaluated on DCE-CT. PFS and overall survival (OS) were compared based on CT enhancement patterns. The markers of fibrogenic alpha-smooth muscle antigen (α-SMA) and periostin in tumor specimens were evaluated by immunohistochemical staining. The χ2 test was performed to determine whether CT enhancement patterns were associated with α-SMA-periostin expression levels (recorded as positive or negative). Lower REC (<0.9) was associated with shorter PFS (HR 0.51, 95% CI: 0.31–0.89) and OS (HR 0.44, 95% CI: 0.25–0.78). The α-SMA and periostin expression level were negatively correlated with REC (both P = 0). Among several CT enhancement parameters, REC was the best predictor of patient postsurgery survival. Low REC was associated with a short progression-free time and poor survival. The pathological studies suggested that REC might be a reflection of cancer fibrogenic potential.
doi:10.1097/MD.0000000000002664
PMCID: PMC4748912  PMID: 26844495
25.  Genome-wide RNA-seq and ChIP-seq reveal Linc-YY1 function in regulating YY1/PRC2 activity during skeletal myogenesis 
Genomics Data  2016;7:247-249.
Little is known how lincRNAs are involved in skeletal myogenesis. Here we describe the discovery and functional annotation of Linc-YY1, a novel lincRNA originating from the promoter of the transcription factor (TF) Yin Yang 1 (YY1). Starting from whole transcriptome shotgun sequencing (a.k.a. RNA-seq) data from muscle C2C12 cells, a series of bioinformatics analysis was applied towards the identification of hundreds of high-confidence novel lincRNAs. Genome-wide approaches were then employed to demonstrate that Linc-YY1 functions to promote myogenesis through associating with YY1 and regulating YY1/PRC2 transcriptional activity in trans. Here we describe the details of the ChIP-seq, RNA-seq experiments, and data analysis procedures associated with the study published by Zhou and colleagues in the Nature Communications Journal in 2015 Zhou et al. (2015) [1]. The data was deposited on NCBI's Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) with accession number GSE74049.
doi:10.1016/j.gdata.2016.01.022
PMCID: PMC4778671  PMID: 26981420
Linc-YY1; Myogenesis; RNA-seq; ChIP-seq; C2C12 cells

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