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1.  1HNMR-based metabolomic profile of rats with experimental acute pancreatitis 
BMC Gastroenterology  2014;14:115.
Background
Acute pancreatitis (AP) is a common inflammatory disease of the pancreas accompanied by serious metabolic disturbances. Nevertheless, the specific metabolic process of this disease is still unclear. Characterization of the metabolome may help identify biomarkers for AP. To identify potential biomarkers, this study therefore investigated the 1H-nuclear magnetic resonance (NMR)-based metabolomic profile of AP.
Methods
Fourteen male adult Sprague–Dawley rats were randomized into two groups: the AP group, in which AP was induced by retrograde ductal infusion of 3.5% sodium taurocholate; and the sham operation group (SO), in which rats were infused with 0.9% saline. Blood samples were obtained 12 hours later and a 600 MHz superconducting NMR spectrometer was used to detect plasma metabolites. Principal components analysis (PCA) and partial least squares-discriminant analysis after orthogonal signal correction (OSC-PLS-DA) were used to analyze both longitudinal Eddy-delay (LED) and Carr–Purcell–Meiboom–Gill (CPMG) spectra.
Results
Differences in plasma metabolites between the two groups were detected by PCA and PLS-DA of 1HNMR spectra. Compared with the SO group, plasma levels of lactate (δ 1.3, 1.34, 4.1), valine (δ 0.98, 1.02), succinic acid (δ 2.38), 3-hydroxybutyric acid (3-HB, δ 1.18), high density lipoprotein (HDL, δ 0.8), and unsaturated fatty acid (UFA, δ 2.78, 5.3) were elevated in the AP group, while levels of glycerol (δ 3.58, 3.66), choline (δ 3.22), trimethylamine oxide (TMAO, δ 3.26), glucose (δ 3–4), glycine (δ 3.54), very low density lipoprotein (VLDL, δ 1.34) and phosphatidylcholine (Ptd, δ 2.78) were decreased.
Conclusions
AP has a characteristic metabolic profile. Lactate, valine, succinic acid, 3-HB, HDL, UFA, glycerol, choline, TMAO, glucose, glycine, VLDL, and Ptd may be potential biomarkers of early stage AP.
doi:10.1186/1471-230X-14-115
PMCID: PMC4100530  PMID: 24975214
Metabolomics; Acute pancreatitis; 1HNMR; PCA analysis; PLS-DA analysis
2.  A pilot study on acute inflammation and cancer: a new balance between IFN-γ and TGF-β in melanoma 
Recent data have redefined the concept of inflammation as a critical component of tumor progression. However, there has been little development on cases where inflammation on or near a wound and a tumor exist simultaneously. Therefore, this pilot study aims to observe the impact of a wound on a tumor, to build a new mouse tumor model with a manufactured surgical wound representing acute inflammation, and to evaluate the relationship between acute inflammation or wound healing and the process of tumor growth. We focus on the two phases that are present when acute inflammation influences tumor. In the early phase, inhibitory effects are present. The process that produces these effects is the functional reaction of IFN-γ secretions from a wound inflammation. In the latter phase, the inhibited tumor is made resistant to IFN-γ through the release of TGF-β to balance the inflammatory factor effect on the tumor cells. A pair of cytokines IFN-γ/TGF-β established a new balance to protect the tumor from the interference effect of the inflammation. The tumor was made resistant to IFN-γ through the release of TGF-β to balance the inflammatory effect on the tumor cells. This balance mechanism that occurred in the tumor cells increased proliferation and invasion. In vitro and in vivo experiments have confirmed a new view of clinical surgery that will provide more detailed information on the evaluation of tumors after surgery. This study also provides a better understanding of the relationship between tumor and inflammation, as well as tumor cell attacks on inflammatory factors.
doi:10.1186/1756-9966-28-23
PMCID: PMC2683570  PMID: 19228418
3.  TREM-2 promotes acquired cholesteatoma-induced bone destruction by modulating TLR4 signaling pathway and osteoclasts activation 
Scientific Reports  2016;6:38761.
Triggering receptor expressed on myeloid cells (TREM) has been broadly studied in inflammatory disease. However, the expression and function of TREM-2 remain undiscovered in acquired cholesteatoma. The expression of TREM-2 was significantly higher in human acquired cholesteatoma than in normal skin from the external auditory canal, and its expression level was positively correlated with the severity of bone destruction. Furthermore, TREM-2 was mainly expressed on dendritic cells (DCs). In human acquired cholesteatoma, the expression of proinflammatory cytokines (IL-1β, TNF-α and IL-6) and matrix metalloproteinases (MMP-2, MMP-8 and MMP-9) were up-regulated, and their expression levels were positively correlated with TREM-2 expression. Osteoclasts were activated in human acquired cholesteatoma. In an animal model, TREM-2 was up-regulated in mice with experimentally acquired cholesteatoma. TREM-2 deficiency impaired the maturation of experimentally acquired cholesteatoma and protected against bone destruction induced by experimentally acquired cholesteatoma. Additional data showed that TREM-2 up-regulated IL-1β and IL-6 expression via TLR4 instead of the TLR2 signaling pathway and promoted MMP-2 and MMP-8 secretion and osteoclast activation in experimentally acquired cholesteatoma. Therefore, TREM-2 might enhance acquired cholesteatoma-induced bone destruction by amplifying the inflammatory response via TLR4 signaling pathways and promoting MMP secretion and osteoclast activation.
doi:10.1038/srep38761
PMCID: PMC5146948  PMID: 27934908
4.  Magneto-Plasmonic Janus Vesicles for Magnetic Field-Enhanced Photoacoustic and Magnetic Resonance Imaging of Tumors 
Magneto-plasmonic Janus vesicles (JVs) integrated with gold nanoparticles (AuNPs) and magnetic NPs (MNPs) were prepared asymmetrically in the membrane for in vivo cancer imaging. The hybrid JVs were produced by coassembling a mixture of hydrophobic MNPs, free amphiphilic block copolymers (BCPs), and AuNPs tethered with amphiphilic BCPs. Depending on the size and content of NPs, the JVs acquired spherical or hemispherical shapes. Among them, hemispherical JVs containing 50 nm AuNPs and 15 nm MNPs showed a strong absorption in the near-infrared (NIR) window and enhanced the transverse relaxation (T2) contrast effect, as a result of the ordering and dense packing of AuNPs and MNPs in the membrane. The magneto-plasmonic JVs were used as drug delivery vehicles, from which the release of a payload can be triggered by NIR light and the release rate can be modulated by a magnetic field. Moreover, the JVs were applied as imaging agents for in vivo bimodal photoacoustic (PA) and magnetic resonance (MR) imaging of tumors by intravenous injection. With an external magnetic field, the accumulation of the JVs in tumors was significantly increased, leading to a signal enhancement of approximately 2–3 times in the PA and MR imaging, compared with control groups without a magnetic field.
Graphical Abstract
Magneto-plasmonic Janus vesicles, with controlled shape and nanoparticle organization in the membrane, were prepared by coassembly of amphiphilic block copolymers ( ). The copolymers were subsequently tethered to gold ( ) and magnetic ( ) nanoparticles. The Janus vesicles allowed for magnetic field-enhanced bimodal photoacoustic and magnetic resonance imaging, as well as magnetic manipulation and near-infrared light triggered release of therapeutic agents.
doi:10.1002/anie.201608338
PMCID: PMC5131874  PMID: 27862808
Janus vesicles; magnetic resonance imaging; nanoparticles; photoacoustic imaging; self-assembly
5.  A dynamic protein interaction landscape of the human centrosome-cilium interface 
Cell  2015;163(6):1484-1499.
Summary
Centrioles coordinate the primary microtubule organizing center of the cell and template the formation of cilia, thereby operating at a nexus of critical cellular functions. Here we use proximity-dependent biotinylation (BioID) to map the centrosome-cilium interface; with 58 bait proteins we generate a protein topology network comprising >7000 interactions. Analysis of interaction profiles coupled with high resolution phenotypic profiling implicates a number of new protein modules in centriole duplication, ciliogenesis and centriolar satellite biogenesis, and highlights extensive interplay between these processes. By monitoring dynamic changes in the centrosome-cilium protein interaction landscape during ciliogenesis, we also identify satellite proteins that support cilia formation. Systematic profiling of proximity interactions combined with functional analysis thus provides a rich resource for better understanding human centrosome and cilia biology. Similar strategies may be applied to other complex biological structures or pathways.
Graphical abstract
We use in vivo proximity-dependent biotinylation(BioID) to generate a protein interaction map of the human centrosome-cilium interface. Avast and functionally rich interaction space is characterized, allowing us to uncover protein modules critical for centrosome and cilium biogenesis. We demonstrate pervasive interplay between centriole duplication, centriolar satellite biogenesis and ciliogenesis, anddiscover pronounced dynamic modulation of the protein interaction landscape during the ciologenesis program. Our work thus provides a rich resource for better understanding human centrosome and cilia biology.
doi:10.1016/j.cell.2015.10.065
PMCID: PMC5089374  PMID: 26638075
6.  Software to Facilitate Remote Sensing Data Access for Disease Early Warning Systems 
Satellite remote sensing produces an abundance of environmental data that can be used in the study of human health. To support the development of early warning systems for mosquito-borne diseases, we developed an open-source, client based software application to enable the Epidemiological Applications of Spatial Technologies (EASTWeb). Two major design decisions were full automation of the discovery, retrieval and processing of remote sensing data from multiple sources, and making the system easily modifiable in response to changes in data availability and user needs. Key innovations that helped to achieve these goals were the implementation of a software framework for data downloading and the design of a scheduler that tracks the complex dependencies among multiple data processing tasks and makes the system resilient to external errors. EASTWeb has been successfully applied to support forecasting of West Nile virus outbreaks in the United States and malaria epidemics in the Ethiopian highlands.
doi:10.1016/j.envsoft.2015.07.006
PMCID: PMC4669966  PMID: 26644779
Software architecture; workflows; remote sensing; early warning; malaria; West Nile virus
7.  Obscured hemorrhagic pancreatitis after orthotopic heart transplantation complicated with acute right heart failure and hepatic dysfunction: a case report 
Background
Pancreatitis is a serious complication after cardiac surgery and can lead to significant morbidities and mortality. The incidence of pancreatitis is even higher in patients undergoing heart transplantation than in those undergoing other cardiac surgeries. Nevertheless, the clinical presentations of pancreatitis are frequently atypical in these patients.
Case presentation
We report a heart recipient who was complicated with acute right heart failure initially after orthotopic heart transplantation and developed devastating unanticipated hemorrhagic pancreatitis 1 month after the transplantation. This crypto-symptomatic pancreatitis was not diagnosed until massive internal bleeding and hemorrhagic shock occurred, because the typical presentations of acute pancreatitis were masked by the intra-abdominal manifestations caused by right heart failure and congestive liver dysfunction. The patient underwent a successful transarterial embolization.
Conclusions
The causes of pancreatitis after heart transplantation include low cardiac output, immunosuppressant use and cytomegalovirus infection. The typical symptoms of pancreatitis might be not apparent in patients after heart transplantation because of their immunosuppressive status. Furthermore, in patients complicated with right heart failure after transplantation, the manifestation of pancreatitis could be even more obscure. The prompt diagnosis is highly depended on the clinician’s astuteness.
doi:10.1186/s13019-016-0562-4
PMCID: PMC5134229  PMID: 27908284
Heart transplantation; Pancreatitis; Right heart failure; Case report
8.  The design, rationale, and baseline characteristics of a nationwide cohort registry in China: blood pressure and clinical outcome in TIA or ischemic stroke 
Patient preference and adherence  2016;10:2419-2427.
Background
The relationship between poststroke blood pressure (BP) and clinical outcomes in ischemic stroke (IS) is still controversial. However, there is no large BP database for IS or transient ischemic attack (TIA) in China. This study aims to describe the rationale, study design, and baseline characteristics of a nationwide BP database in IS or TIA patients in China.
Materials and methods
The BOSS (blood pressure and clinical outcome in TIA or ischemic stroke) study was a hospital-based, prospective cohort study aiming to assess BP parameters and clinical outcome in IS/TIA patients. BP parameters were based on office BP, ambulatory BP, and home BP. Clinical outcomes included stroke recurrence, combined vascular events, and disability. Electronic case-report forms were used to record baseline and follow-up data. The patients were followed up for clinical outcomes at 3 months through face-to-face interview and at 12 months by telephone.
Results
Between October 2012 and February 2014, the BOSS registry recruited 2,608 patients from 61 hospitals, with a mean age of 62.5 years, 32.4% of whom were female, 88.9% with an entry diagnosis of IS, and 86% diagnosed with hypertension. The rates of patients lost-to-follow-up were 3.1% at 3 months and 5.1% at 1 year; 93% of patients completed ambulatory BP monitoring during hospitalization and 94.7% finished a 3-month BP diary.
Conclusion
The BOSS registry will provide important evidence about BP management in the acute phase and secondary prevention for IS/TIA patients.
doi:10.2147/PPA.S119825
PMCID: PMC5138037  PMID: 27942205
blood pressure; ischemic stroke; transient ischemic attack
9.  Glucocorticoid receptor and Histone deacetylase 6 mediate the differential effect of dexamethasone during osteogenesis of mesenchymal stromal cells (MSCs) 
Scientific Reports  2016;6:37371.
Lineage commitment and differentiation of mesenchymal stromal cells (MSCs) into osteoblasts in vitro is enhanced by a potent synthetic form of glucocorticoid (GC), dexamethasone (Dex). Paradoxically, when used chronically in patients, GCs exert negative effects on bone, a phenomenon known as glucocorticoid-induced osteoporosis in clinical practice. The mechanism on how GC differentially affects bone precursor cells to become mature osteoblasts during osteogenesis remains elusive. In this study, the dose and temporal regulation of Dex on MSC differentiation into osteoblasts were investigated. We found that continuous Dex treatment led to a net reduction of the maturation potential of differentiating osteoblasts. This phenomenon correlated with a decrease in glucocorticoid receptor (GR) expression, hastened degradation, and impaired sub cellular localization. Similarly, Histone Deacetylase 6 (HDAC6) expression was found to be regulated by Dex, co-localized with GR and this GR-HDAC6 complex occupied the promoter region of the osteoblast late marker osteocalcin (OCN). Combinatorial inhibition of HDAC6 and GR enhanced OCN expression. Together, the cross-talk between the Dex effector molecule GR and the inhibitory molecule HDAC6 provided mechanistic explanation of the bimodal effect of Dex during osteogenic differentiation of MSCs. These findings may provide new directions of research to combat glucocorticoid-induced osteoporosis.
doi:10.1038/srep37371
PMCID: PMC5128810  PMID: 27901049
10.  Ratio of lymph node to primary tumor SUVmax multiplied by maximal tumor diameter on positron emission tomography/integrated computed tomography may be a predictor of mediastinal lymph node malignancy in lung cancer 
Medicine  2016;95(46):e5457.
Abstract
Positron emission tomography/integrated computed tomography (PET/CT) provides the most accurate imaging modality for preoperative lung cancer staging. However, the diagnostic accuracy of maximum standardized uptake value (SUVmax) for mediastinal (N2) lymph nodes (LN) is unclear. We compared SUVmax, the ratio of LN to primary tumor SUVmax (SUVn/t), and SUVn/t multiplied by maximal tumor diameter (SUVindex) in terms of their abilities to predict mediastinal LN malignancy.
We retrospectively analyzed 170 mediastinal LN stations from 73 consecutive patients who underwent systemic LN resection and PET/CT within 27 days. The SUVmax of the primary tumors was >2.0 and the SUVmax of the mediastinal LN stations ranged from 2.0 to 7.0 on PET/CT. Receiver-operating characteristic curves (ROCs) of SUVmax, SUVn/t, and SUVindex were calculated separately and the areas under the curves (AUCs) were used to assess the abilities of the parameters to predict LN malignancy. The optimal cutoff values were calculated from each ROC curve and the diagnostic abilities were also compared. The diagnostic accuracies of the 3 methods were also assessed separately in smoking and nonsmoking patients.
Twenty-eight LN stations were malignancy-positive and the remaining 142 were malignancy-negative. The AUCs for SUVindex, SUVn/t, and SUVmax were 0.709, 0.590, and 0.673, respectively, and the optimal cutoff values for SUVindex, SUVn/t, and SUVmax were 1.11, 0.34, and 3.6, respectively. The differences between SUVindex and SUVn/t were significant, but there was no significant difference between SUVindex and SUVmax. There were no significant differences between smokers and nonsmokers in the AUCs for any of the methods for predicting LN malignancy (P values >0.05).
SUVindex may be a predictor of mediastinal LN malignancy in lung cancer patients.
doi:10.1097/MD.0000000000005457
PMCID: PMC5120955  PMID: 27861398
diagnosis; lung neoplasms; mediastinal lymph node; neoplasm staging; positron emission tomography
11.  A Systems Approach to Reverse Engineer Lifespan Extension by Dietary Restriction 
Cell metabolism  2016;23(3):529-540.
Summary
Dietary restriction (DR) is the most powerful natural means to extend lifespan. Although several genes can mediate responses to alternate DR regimens, no single genetic intervention has recapitulated the full effects of DR, and no unified system is known for different DR regimens. Here we obtain temporally resolved transcriptomes during calorie restriction and intermittent fasting in Caenorhabditis elegans, and find that early and late responses involve metabolism and cell cycle/DNA damage, respectively. We uncover three network modules of DR regulators by their target specificity. By genetic manipulations of nodes representing discrete modules, we induce transcriptomes that progressively resemble DR as multiple nodes are perturbed. Targeting all three nodes simultaneously results in extremely long-lived animals that are refractory to DR. These results and dynamic simulations demonstrate that extensive feedback controls among regulators may be leveraged to drive the regulatory circuitry to a younger steady state, recapitulating the full effect of DR.
doi:10.1016/j.cmet.2016.02.002
PMCID: PMC5110149  PMID: 26959186
12.  Modeling of hydrogen atom diffusion and response behavior of hydrogen sensors in Pd–Y alloy nanofilm 
Scientific Reports  2016;6:37043.
To detect hydrogen gas leakage rapidly, many types of hydrogen sensors containing palladium alloy film have been proposed and fabricated to date. However, the mechanisms and factors that determine the response rate of such hydrogen sensor have not been established theoretically. The manners in which response time is forecasted and sensitive film is designed are key issues in developing hydrogen sensors with nanometer film. In this paper, a unilateral diffusion model of hydrogen atoms in Pd alloy based on Fick’s second law is proposed to describe the Pd–H reaction process. Model simulation shows that the hydrogen sensor response time with Pd alloy film is dominated by two factors (film thickness and hydrogen diffusion coefficient). Finally, a series of response rate experiments with varying thicknesses of Pd–Y (yttrium) alloy film are implemented to verify model validity. Our proposed model can help researchers in the precise optimization of film thickness to realize a simultaneously speedy and sensitive hydrogen sensor. This study also aids in evaluating the influence of manufacturing errors on performances and comparing the performances of sensors with different thicknesses.
doi:10.1038/srep37043
PMCID: PMC5109211  PMID: 27845408
13.  Fasting and Feeding Signals Control the Oscillatory Expression of Angptl8 to Modulate Lipid Metabolism 
Scientific Reports  2016;6:36926.
Emerging evidence implies a key role of angiopoietin-like protein 8 (Angptl8) in the metabolic transition between fasting and feeding, whereas much less is known about the mechanism of its own expression. Here we show that hepatic Angptl8 is rhythmically expressed, which involving the liver X receptor alpha (LXRα) and glucocorticoid receptor (GR) modulation during feeding and fasting periods, respectively. In addition, Angptl8 mRNA is very unstable, which contributes to the nature of its daily rhythmicity by rapidly responding to fasting/feeding transition. To explore its pathological function in dexamethasone (DEX)-induced fatty liver, we reversed its suppression by glucocorticoids through adenoviral delivery of Angptl8 gene in mouse liver. Surprisingly, hepatic overexpression of Angptl8 dramatically elevated plasma triglyceride (TG) and non-esterified fatty acid (NEFA) levels in DEX-treated mice, suggesting a metabolic interaction between Angptl8 and glucocorticoid signaling. Moreover, intracellular hepatic Angptl8 is implicated in the regulation of lipid homeostasis by the experiments with ectopic expression of a nonsecreted Angptl8 mutant (Δ25-Angptl8). Altogether, our data demonstrate the molecular mechanism of the diurnal rhythm of Angptl8 expression regulated by glucocorticoid signaling and LXRα pathway, and provide new evidence to understand the role of Angptl8 in maintaining plasma TG homeostasis.
doi:10.1038/srep36926
PMCID: PMC5109406  PMID: 27845381
14.  The Relationship between MC1R Mutation and Plumage Color Variation in Pigeons 
BioMed Research International  2016;2016:3059756.
The polymorphisms of MC1R gene play a crucial role in coat color variation in mammals; however, the relationship is still unclear in pigeons. In this study, we sequenced 741 bp fragment of the MC1R for 39 individuals with five plumage color patterns (gray plumage, n = 12; black plumage, n = 9; white plumage, n = 3; spotted plumage, n = 12; red plumage, n = 3). A total of three single nucleotide polymorphisms (SNPs) were detected, including G199A, G225A, and A466G, which subsequently determined four haplotypes (H1–H4). Among them, H1 is the predominant haplotype. Association analysis revealed that H1 and H3 were significantly associated with the black plumage trait (P < 0.05), while the H4 was significantly associated with gray plumage trait (P < 0.05). Furthermore, only diplotype H1H1 was significantly associated with black and gray traits of pigeons. Collectively, our study suggested an association between genetic variation of MC1R and plumage color in pigeon.
doi:10.1155/2016/3059756
PMCID: PMC5124481  PMID: 27957493
15.  Relationship between traditional Chinese medicine constitutional types with chemotherapy-induced nausea and vomiting in patients with breast cancer: an observational study 
Background
The theory of traditional Chinese medicine (TCM) constitution involves genetic characteristics, psychological factors, organ functions, and many other aspects. Studies have shown that TCM constitution is associated with HLA polymorphisms and has a genetic basis. A large number of Chinese studies have suggested that the clinical evolution of breast cancer may differ among patients with different TCM constitutions. In addition, patients with breast cancer and different TCM constitutions may have different degrees of myelosuppression after chemotherapy. Some studies have revealed that some constitutions may become predictive factors for death and morbidity of some diseases. The study was to investigate the risk factors among TCM constitutions for chemotherapy-induced nausea and vomiting (CINV) in patients with primary breast cancer undergoing chemotherapy.
Methods
From September 2008 to January 2014, 612 patients who underwent surgery and chemotherapy for breast cancer in three hospitals in Xi’an, Shanxi province, underwent TCM constitution assessment using the Nine Basic Constitutions in Chinese Medicine Questionnaire before chemotherapy. CINV was monitored during treatments. Patients were asked to complete the Functional Living Index-Emesis (FLIE) questionnaire. The most severe CINV grade during chemotherapy was recorded according to the WHO standard. The relationships between TCM constitutions, CINV, and clinical and pathological characteristics of the cancers were assessed.
Results
There were no differences in the incidence of CINV among breast cancer patients receiving different chemotherapy regimens, and among patients with different TCM constitutions. The wetness-heat score was an independent risk factor for severe CINV (grade III-IV) (OR = 1.012, 95 % CI: 1.007–1.021, P < 0.001). In-depth analyses of the wetness-heat constitution showed that bitter taste/smelly mouth was an independent risk factor for severe CINV (OR = 1.209, 95 % CI: 1.035–1.412, P = 0.017), as well as progesterone receptor-positive cancer (OR = 1.429, 95 % CI: 1.030–1.981, P = 0.032). Vomiting history was a protective factor against CINV (OR = 0.548, 95 % CI: 0.353–0.849, P = 0.007).
Conclusion
Risk of grade III-IV nausea and vomiting was higher in breast cancer patients with TCM constitution of wetness-heat, especially bitter taste or smelly mouth.
doi:10.1186/s12906-016-1415-3
PMCID: PMC5103454  PMID: 27829423
Traditional Chinese medicine; Constitution; Breast cancer; Chemotherapy; Nausea and vomiting
16.  Estimating long-term clinical effectiveness and cost-effectiveness of HPV 16/18 vaccine in China 
BMC Cancer  2016;16:848.
Background
Human papillomavirus (HPV) 16 and 18 are the two most common HPV oncogenic types that can be prevented by vaccination. This study aimed at assessing the cost-effectiveness of 3 doses of the bivalent HPV vaccine in rural and urban settings in China.
Methods
A Markov model was adapted to reflect the lifetime of a modelled 100,000 12-year-old girls cohort in rural and urban settings in China. Input parameters were obtained from published literature, official reports and a two-round expert review panel. Clinical and economic outcomes of vaccination at age 12 with screening was compared to screening only. In the base case analysis, a 3 % discount rate, the vaccine cost of 247 CNY (US$ 39, PAHO vaccine cost in 2013), two rounds of screening in a life time and 70 % coverage for both screening and vaccination were used. One-way, two-way and probabilistic sensitivity analyses were performed. We used different thresholds of cost-effectiveness to reflect the diversity of economic development in China.
Results
Vaccination in addition to screening could prevent 60 % more cervical cancer cases and deaths than screening only. The incremental cost effectiveness ratio varied largely when changing cost of vaccination and discount in one way analysis. Vaccination was very cost-effective when the vaccine cost ranged 87-630 CNY (US$ 13.8-100) in rural and 87-750 CNY (US$ 13.8–119) in urban; and remained cost-effective when the vaccine cost ranged 630–1,700 CNY (US$ 100–270) in rural and 750–1,900 CNY (US$ 119–302) in urban in two way analysis. Probabilistic sensitivity analyses showed that model results were robust.
Conclusions
In both rural and urban, the vaccination cost and discounting are important factors determining the cost-effectiveness of HPV vaccination; policy makers in China should take these into account when making a decision on the introduction of HPV vaccine. In areas with a high burden of cervical cancer and limited screening activities, HPV vaccination should be prioritized. However, the vaccine cost needs to be reduced in order to make it very cost-effective and affordable as well, in particular in poverty areas with high disease burden.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2893-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-016-2893-x
PMCID: PMC5097411  PMID: 27814703
Cervical cancer; HPV vaccine; Cost-effectiveness
17.  Comparisons of oncological and functional outcomes among radical retropubic prostatectomy, high dose rate brachytherapy, cryoablation and high-intensity focused ultrasound for localized prostate cancer 
SpringerPlus  2016;5(1):1905.
Purpose
To conduct a retrospective, single institutional and comparative study for radical retropubic prostatectomy (RRP), high dose rate brachytherapy (HDRBT), cryoablation and high-intensity focused ultrasound (HIFU) in localized prostate cancer with respect to oncological and functional outcomes.
Methods
We reviewed 97, 161, 114 and 120 patients of RRP, HDRBT, cryoablation and HIFU respectively for localized prostate cancer from May 2008 to December 2013. PSA biochemical recurrence, salvage treatment-free rate, metastasis-free rate, and biochemical recurrence-free survival were analyzed for oncological outcomes. Functional outcomes included complications and serial IIEF-5 scores, IPSS and related QoL scores.
Results
During nearly 3 years of follow-up, the patients of HDRBT experienced higher PSA biochemical recurrence rate overall (54.7%), as well as D’Amico intermediate-risk (34.4%) and high-risk (61.8%) groups, lower salvage treatment-free rate (46.7%), and metastasis-free rate (90.7%). Besides, the patients of RRP demonstrated higher urethral stricture (29.9%) and urinary incontinence (11.3%). The patients of HIFU revealed lower de novo erectile dysfunction rate at 1 year (65.6%), higher serial IIEF-5 scores, lower IPSS and related QoL scores.
Conclusions
The patients of HDRBT demonstrated worse oncological outcomes in D’Amico intermediate and high-risk groups. Besides, the patients of RRP had more complications rate in urethral stricture and urinary incontinence. Moreover, the patients of HIFU experienced better urinary function improvement and more possible sexual function preservation. In consideration of trifecta, HIFU may provide equivalent cancer control and better quality of life for patients of localized prostate cancer.
doi:10.1186/s40064-016-3584-4
PMCID: PMC5095104  PMID: 27867812
Brachytherapy; Cryoablation; High-intensity focused ultrasound; Localized prostate cancer; Radical prostatectomy
18.  NIR-responsive on-demand release of CO from metal carbonyl-caged graphene oxide nanomedicine 
On-demand release of CO is realized through a novel NIR-responsive nanomedicine in favor of the enhancement of therapy efficacy and bio-safety of CO therapy.
doi:10.1002/adma.201502762
PMCID: PMC4921239  PMID: 26401893
drug delivery; controlled release; nanomedicine; graphene; CO therapy
19.  Hydrostatic Compress Force Enhances the Viability and Decreases the Apoptosis of Condylar Chondrocytes through Integrin-FAK-ERK/PI3K Pathway 
Reduced mechanical stimuli in many pathological cases, such as hemimastication and limited masticatory movements, can significantly affect the metabolic activity of mandibular condylar chondrocytes and the growth of mandibles. However, the molecular mechanisms for these phenomena remain unclear. In this study, we hypothesized that integrin-focal adhesion kinase (FAK)-ERK (extracellular signal–regulated kinase)/PI3K (phosphatidylinositol-3-kinase) signaling pathway mediated the cellular response of condylar chondrocytes to mechanical loading. Primary condylar chondrocytes were exposed to hydrostatic compressive forces (HCFs) of different magnitudes (0, 50, 100, 150, 200, and 250 kPa) for 2 h. We measured the viability, morphology, and apoptosis of the chondrocytes with different treatments as well as the gene, protein expression, and phosphorylation of mechanosensitivity-related molecules, such as integrin α2, integrin α5, integrin β1, FAK, ERK, and PI3K. HCFs could significantly increase the viability and surface area of condylar chondrocytes and decrease their apoptosis in a dose-dependent manner. HCF of 250 kPa resulted in a 1.51 ± 0.02-fold increase of cell viability and reduced the ratio of apoptotic cells from 18.10% ± 0.56% to 7.30% ± 1.43%. HCFs could significantly enhance the mRNA and protein expression of integrin α2, integrin α5, and integrin β1 in a dose-dependent manner, but not ERK1, ERK2, or PI3K. Instead, HCF could significantly increase phosphorylation levels of FAK, ERK1/2, and PI3K in a dose-dependent manner. Cilengitide, the potent integrin inhibitor, could dose-dependently block such effects of HCFs. HCFs enhances the viability and decreases the apoptosis of condylar chondrocytes through the integrin-FAK-ERK/PI3K pathway.
doi:10.3390/ijms17111847
PMCID: PMC5133847  PMID: 27827993
integrin; FAK; ERK; PI3K; mandibular condyle; chondrocyte; apoptosis
20.  A Novel Inflammation-Based Stage (I Stage) Predicts Overall Survival of Patients with Nasopharyngeal Carcinoma 
Recent studies have indicated that inflammation-based prognostic scores, such as the Glasgow Prognostic Score (GPS), modified GPS (mGPS) and C-reactive protein/Albumin (CRP/Alb) ratio, platelet–lymphocyte ratio (PLR), and neutrophil–lymphocyte ratio (NLR), have been reported to have prognostic value in patients with many types of cancer, including nasopharyngeal carcinoma (NPC). In this study, we proposed a novel inflammation-based stage, named I stage, for patients with NPC. A retrospective study of 409 newly-diagnosed cases of NPC was conducted. The prognostic factors (GPS, mGPS, CRP/Alb ratios, PLR, and NLR) were evaluated using univariate and multivariate analyses. Then, according to the results of the multivariate analyses, we proposed a I stage combination of independent risk factors (CRP/Alb ratio and PLR). The I stage was calculated as follows: patients with high levels of CRP/Alb ratio (>0.03) and PLR (>146.2) were defined as I2; patients with one or no abnormal values were defined as I1 or I0, respectively. The relationships between the I stage and clinicopathological variables and overall survival (OS) were evaluated. In addition, the discriminatory ability of the I stage with other inflammation-based prognostic scores was assessed using the AUCs (areas under the curves) analyzed by receiver operating characteristics (ROC) curves. The p value of <0.05 was considered to be significant. A total of 409 patients with NPC were enrolled in this study. Multivariate analyses revealed that only the CRP/Alb ratio (Hazard ratio (HR) = 2.093; 95% Confidence interval (CI): 1.222–3.587; p = 0.007) and PLR (HR: 2.003; 95% CI: 1.177–3.410; p = 0.010) were independent prognostic factors in patients with NPC. The five-year overall survival rates for patients with I0, I1, and I2 were 92.1% ± 2.9%, 83.3% ± 2.6%, and 63.1% ± 4.6%, respectively (p < 0.001). The I stage had a higher area under the curve value (0.670) compared with other systemic inflammation-based prognostic scores (p < 0.001). The I stage is a novel and useful predictive factor for OS in patients with NPC.
doi:10.3390/ijms17111900
PMCID: PMC5133899  PMID: 27854304
nasopharyngeal carcinoma; inflammation-based stage; survival; prognosis
21.  Antileukemic Scalarane Sesterterpenoids and Meroditerpenoid from Carteriospongia (Phyllospongia) sp., Induce Apoptosis via Dual Inhibitory Effects on Topoisomerase II and Hsp90 
Scientific Reports  2016;6:36170.
Two new scalarane sesterterpenoids, 12β-(3′β-hydroxybutanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (1) and 12β-(3′β-hydroxypentanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (2), along with one known tetraprenyltoluquinol-related metabolite (3), were isolated from the sponge Carteriospongia sp. In leukemia Molt 4 cells, 1 at 0.0625 μg/mL (125 nM) triggered mitochondrial membrane potential (MMP) disruption and apoptosis showing more potent effect than 2 and 3. The isolates inhibited topoisomerase IIα expression. The apoptotic-inducing effect of 3 was supported by the in vivo experiment through suppressing the volume of xenograft tumor growth (47.58%) compared with the control. Compound 1 apoptotic mechanism of action in Molt 4 cells was further elucidated through inducing ROS generation, calcium release and ER stress. Using the molecular docking analysis, 1 exhibited more binding affinity to N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. The expression of Hsp90 client proteins, Akt, p70S6k, NFκB, Raf-1, p-GSK3β, and XIAP, MDM 2 and Rb2, and CDK4 and Cyclin D3, HIF 1 and HSF1 were suppressed by the use of 1. However, the expression of Hsp70, acetylated tubulin, and activated caspase 3 were induced after 1 treatment. Our results suggested that the proapoptotic effect of the isolates is mediated through the inhibition of Hsp90 and topoisomerase activities.
doi:10.1038/srep36170
PMCID: PMC5086919  PMID: 27796344
22.  Nasal Airflow Measured by Rhinomanometry Correlates with FeNO in Children with Asthma 
PLoS ONE  2016;11(10):e0165440.
Background
Rhinitis and asthma share similar immunopathological features. Rhinomanometry is an important test used to assess nasal function and spirometry is an important tool used in asthmatic children. The degree to which the readouts of these tests are correlated has yet to be established. We sought to clarify the relationship between rhinomanometry measurements, fractional exhaled nitric oxide (FeNO), and spirometric measurements in asthmatic children.
Methods
Patients’ inclusion criteria: age between 5 and 18 years, history of asthma with nasal symptoms, and no anatomical deformities. All participants underwent rhinomanometric evaluations and pulmonary function and FeNO tests.
Results
Total 84 children were enrolled. By rhinomanometry, the degree of nasal obstruction was characterized as follows: (1) no obstruction in 33 children, (2) slight obstruction in 29 children, and (3) moderate obstruction in 22 children. FeNO was significantly lower in patients without obstruction than those with slight or moderate obstruction. Dividing patients according to ATS Clinical Practice Guidelines regarding FeNO, patients < 12 years with FeNO > 20 ppb had a lower total nasal airflow rate than those with FeNO < 20 ppb. Patients ≥ 12 years with FeNO > 25 ppb had a lower total nasal airflow rate than those with FeNO < 25 ppb.
Conclusions
Higher FeNO was associated with a lower nasal airflow and higher nasal resistance. This supports a relationship between upper and lower airway inflammation, as assessed by rhinomanometry and FeNO. The results suggest that rhinomanometry may be integrated as part of the functional assessment of asthma.
doi:10.1371/journal.pone.0165440
PMCID: PMC5085031  PMID: 27792747
23.  Aptamer-based microchip electrophoresis assays for amplification detection of carcinoembryonia antigen 
Background
Carcinoembryonic antigen (CEA) as one of the most widely used tumor marker is used in the clinical diagnosis of colorectal, pancreatic, gastric, and cervical carcinomas. We developed an aptamer-based microchip electrophoresis assay technique for assaying CEA in human serum for cancer diagnosis.
Methods
The magnetic beads (MBs) are employed as carriers of double strand DNA that is formed by an aptamer of target and a complementary DNA of aptamer. After the aptamer in MB-dsDNA conjugate binds with target, the complementary DNA was released from MB-dsDNA conjugate. The released complementary DNA hybridizes with a fluorescein amidite (FAM) labeled DNA, and forms DNA duplex, which triggers the selective cleavage of FAM labeled DNA by nicking endonuclease Nb.BbvCI, and generating FAM labeled DNA segment. The released complementary DNA hybridizes with another FAM labeled DNA, resulting in a continuous cleavage of FAM labeled DNA, and the generation of large numbers of FAM labeled DNA segments. In MCE laser induced fluorescence detection (LIF), FAM labeled DNA segment is separated and detected.
Results
The linear range for CEA was 130 pg/ml~8.0 ng/ml with a correlation coefficient of 0.9916 and a detection limit of 68 pg/ml. The CEA concentration in the serum samples from healthy subjects was found be in the range 1.3 ng/ml to 3.2 ng/ml. The CEA concentration in the samples from cancer patients was found to be >15 ng/ml.
Conclusions
This method may become a useful tool for rapid analysis of CEA and other tumor markers in biomedical analysis and clinical diagnosis.
doi:10.1016/j.cca.2015.09.002
PMCID: PMC4609300  PMID: 26344338
aptamer; carcinoembryonic antigen; microchip electrophoresis; cancer
24.  The Role of H. pylori CagA in Regulating Hormones of Functional Dyspepsia Patients 
Helicobacter pylori (H. pylori, Hp) colonizes the stomachs of approximately 20%–80% of humans throughout the world. The Word Healthy Organization (WHO) classified H. pylori as a group 1 carcinogenic factor in 1994. Recently, an increasing number of studies has shown an association between H. pylori infection and various extragastric diseases. Functional dyspepsia (FD) is considered a biopsychosocial disorder with multifactorial pathogenesis, and studies have shown that infection with CagA-positive H. pylori strains could explain some of the symptoms of functional dyspepsia. Moreover, CagA-positive H. pylori strains have been shown to affect the secretion of several hormones, including 5-HT, ghrelin, dopamine, and gastrin, and altered levels of these hormones might be the cause of the psychological disorders of functional dyspepsia patients. This review describes the mutual effects of H. pylori and hormones in functional dyspepsia and provides new insight into the pathogenesis of functional dyspepsia.
doi:10.1155/2016/7150959
PMCID: PMC5093276  PMID: 27840636
25.  A novel variant on chromosome 6p21.1 is associated with the risk of developing colorectal cancer: a two-stage case-control study in Han Chinese 
BMC Cancer  2016;16:807.
Background
Genes in inflammatory pathways play a pivotal role in the development of colorectal cancer. We conducted a two-stage case-control study and aimed at screening the colorectal cancer-associated genetic variations in inflammatory genes.
Methods
Twenty-three candidate variants were genotyped in 952 primary colorectal cancer cases and 875 cancer-free controls from eastern China. Promising single nucleotide polymorphisms were further genotyped in 518 cases and 554 controls from middle China. Expression quantitative trait loci and differential gene expression analyses were performed for the associated gene.
Results
rs2282151 presented consistently significant associations with the risk of colorectal cancer in both stages (odds ratio (95 % confidence interval) = 1.30 (1.16–1.46), risk allele = C, P combined = 8.9E-6). Gene expression quantitative trait loci analyzes uncovered consistent cis-regulatory signals which showed that the C allele of rs2282151 was associated with increased expression level of heat shock protein 90 alpha family class B member 1 (HSP90AB1). Then we found that the mRNA expression levels of HSP90AB1 were significantly higher in tumor tissues than normal tissues (fold-change = 1.83) in 28 pairs of colorectal tissue samples. The expression difference was consistent with data from online datasets. Additionally, we observed notable peaks of H3K27ac and H3K4me3 near the first intron of HSP90AB1 using ChIP-seq data from multiple cell lines (including HCT116).
Conclusions
Our findings indicate that the C allele of the novel colorectal cancer-associated variant rs2282151 is associated with increased expression levels of HSP90AB1, which is expressed higher in colorectal tumor tissues than in normal tissues.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2843-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-016-2843-7
PMCID: PMC5069896  PMID: 27756247
Colorectal cancer; Genetic variant; Inflammation; HSP90

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