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1.  Hybrid Dielectric-loaded Nanoridge Plasmonic Waveguide for Low-Loss Light Transmission at the Subwavelength Scale 
Scientific Reports  2017;7:40479.
The emerging development of the hybrid plasmonic waveguide has recently received significant attention owing to its remarkable capability of enabling subwavelength field confinement and great transmission distance. Here we report a guiding approach that integrates hybrid plasmon polariton with dielectric-loaded plasmonic waveguiding. By introducing a deep-subwavelength dielectric ridge between a dielectric slab and a metallic substrate, a hybrid dielectric-loaded nanoridge plasmonic waveguide is formed. The waveguide features lower propagation loss than its conventional hybrid waveguiding counterpart, while maintaining strong optical confinement at telecommunication wavelengths. Through systematic structural parameter tuning, we realize an efficient balance between confinement and attenuation of the fundamental hybrid mode, and we demonstrate the tolerance of its properties despite fabrication imperfections. Furthermore, we show that the waveguide concept can be extended to other metal/dielectric composites as well, including metal-insulator-metal and insulator-metal-insulator configurations. Our hybrid dielectric-loaded nanoridge plasmonic platform may serve as a fundamental building block for various functional photonic components and be used in applications such as sensing, nanofocusing, and nanolasing.
doi:10.1038/srep40479
PMCID: PMC5238436  PMID: 28091583
2.  Targeting ornithine decarboxylase by α-difluoromethylornithine inhibits tumor growth by impairing myeloid-derived suppressor cells 
α-difluoromethylornithine (DFMO) is currently used in chemopreventive regimens primarily for its conventional direct anti-carcinogenesis activity. However, little is known about the effect of decarboxylase (ODC) inhibition by DFMO on antitumor immune responses. We showed here that pharmacologic blockade of ODC by DFMO inhibited tumor growth in intact immunocompetent mice, but abrogated in the immunodeficient Rag1−/− mice, suggesting that antitumor effect of DFMO is dependent on the induction of adaptive anti-tumor T cell immune responses. Depletion of CD8+ T cells impeded the tumor-inhibiting advantage of DFMO. Moreover, DFMO treatment enhanced antitumor CD8+ T cell infiltration and IFN-γ production, and augmented the efficacy of adoptive T cell therapy. Importantly, DFMO impaired Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs) suppressive activity through at least two mechanisms, including reducing arginase expression and activity, and inhibiting CD39/CD73-mediated pathway. MDSCs were one primary cellular target of DFMO as indicated by both adoptive transfer and MDSC depletion analyses. Our findings establish a new role of ODC inhibition by DFMO as a viable and effective immunological adjunct in effective cancer treatment, thereby adding to the growing list of chemoimmunotherapeutic applications of these agents.
doi:10.4049/jimmunol.1500729
PMCID: PMC4707077  PMID: 26663722
3.  Clinicopathological indices to predict hepatocellular carcinoma molecular classification 
Background & Aims
Hepatocellular carcinoma (HCC) is the second most lethal cancer due to lack of effective therapies. Although promising, HCC molecular classification, which enriches potential responders to specific therapies, has not yet been assessed in clinical trials of anti-HCC drugs. We aimed to overcome these challenges by developing clinicopathological surrogate indices of HCC molecular classification.
Methods
HCC classification defined in our previous transcriptome meta-analysis (S1, S2, and S3 subclasses) was implemented in an FDA-approved diagnostic platform (Elements assay, NanoString). Ninety-six HCC tumors (training set) were assayed to develop molecular subclass-predictive indices based on clinicopathological features, which were independently validated in 99 HCC tumors (validation set). Molecular deregulations associated with the histopathological features were determined by pathway analysis. Sample sizes for HCC clinical trials enriched with specific molecular subclasses were determined.
Results
HCC subclass-predictive indices were: steatohepatitic (SH)-HCC variant and immune cell infiltrate for S1 subclass, macrotrabecular/compact pattern, lack of pseudoglandular pattern, and high serum alpha-fetoprotein (>400 ng/mL) for S2 subclass, and microtrabecular pattern, lack of SH-HCC and clear cell variants, and lower histological grade for S3 subclass. Macrotrabecular/compact pattern, a predictor of S2 subclass, was associated with activation of therapeutically targetable oncogene YAP and stemness markers EPCAM/KRT19. BMP4 was associated with pseudoglandular pattern. Subclass-predictive indices-based patient enrichment reduced clinical trial sample sizes from 121, 184, and 53 to 30, 43, and 22 for S1, S2, and S3 subclass-targeting therapies, respectively.
Conclusions
HCC molecular subclasses can be enriched by clinicopathological indices tightly associated with deregulation of therapeutically targetable molecular pathways.
doi:10.1111/liv.12889
PMCID: PMC4674393  PMID: 26058462
Histopathology; molecular subclass; predictive index; gene expression; clinical diagnostic
4.  18F-FDG PET-CT: a powerful tool for the diagnosis and treatment of relapsing polychondritis 
The British Journal of Radiology  2015;89(1057):20150695.
Objective:
This study aimed to evaluate fluorine-18 fludeoxyglucose positron emission tomography-CT (18F-FDG PET-CT) for the diagnosis, targeted biopsy and therapy of relapsing polychondritis (RP).
Methods:
The literature pertaining to the use of 18F-FDG PET-CT in patients with RP was retrieved from the Cochrane Library, PubMed, Excerpta Medica Database (EMBASE), China National Knowledge Infrastructure (CNKI) and Wanfang databases until July 2015. Clinical characteristics, auxiliary examination results, chest CT findings, tracheoscopy and biopsy findings, high metabolic activity lesions, maximum standardized uptake values, 18F-FDG PET-CT-guided biopsy site, pathologic results of biopsy samples and alteration in high 18F-FDG-uptake lesions after treatment were retrospectively analysed.
Results:
18 publications with 26 cases were enrolled. The five most common symptoms of patients with RP diagnosed with 18F-FDG PET-CT were cough, fever, chest tightness, sore throat and arthralgia. Of the 26 patients, 23 patients had multiple and symmetric cartilage lesions with high metabolic activity, revealed by 18F-FDG PET-CT. The disease mainly affected organs such as the bronchus, trachea, throat, costicartilage and auricle. The maximum standardized uptake values ranged from 1.93 to 13.03 (mean, 4.94). 18F-FDG PET-CT revealed that patients with RP with tracheal and bronchial involvement had a close correlation with cough (χ2 = 6.80, p = 0.006). 18F-FDG PET-CT showed a significantly higher positive biopsy rate compared with bronchoscopy (χ2 = 12.91, p < 0.001) for targeted lesions with high metabolic activity. Post-treatment re-examinations with 18F-FDG PET-CT showed obvious subsidence or complete disappearance of high 18F-FDG-uptake lesions in 13 cases, showing highly consistent symptom improvements.
Conclusion:
18F-FDG PET-CT is likely to become a valuable imaging tool in the diagnosis and treatment of RP.
Advances in knowledge:
The presence of symmetrically distributed high FDG-uptake lesions may be a criterion for the diagnosis of RP. 18F-FDG PET-CT is useful for targeting biopsy sites, which remarkably increase the positive biopsy rate. Therefore, 18F-FDG PET-CT may be of great value in the diagnosis and treatment of RP.
doi:10.1259/bjr.20150695
PMCID: PMC4985965  PMID: 26529231
5.  Third-generation CD28/4-1BB chimeric antigen receptor T cells for chemotherapy relapsed or refractory acute lymphoblastic leukaemia: a non-randomised, open-label phase I trial protocol 
BMJ Open  2016;6(12):e013904.
Introduction
There is no curative treatment available for patients with chemotherapy relapsed or refractory CD19+ B cells-derived acute lymphoblastic leukaemia (r/r B-ALL). Although CD19-targeting second-generation (2nd-G) chimeric antigen receptor (CAR)-modified T cells carrying CD28 or 4-1BB domains have demonstrated potency in patients with advanced B-ALL, these 2 signalling domains endow CAR-T cells with different and complementary functional properties. Preclinical results have shown that third-generation (3rd-G) CAR-T cells combining 4-1BB and CD28 signalling domains have superior activation and proliferation capacity compared with 2nd-G CAR-T cells carrying CD28 domain. The aim of the current study is therefore to investigate the safety and efficacy of 3rd-G CAR-T cells in adults with r/r B-ALL.
Methods and analysis
This study is a phase I clinical trial for patients with r/r B-ALL to test the safety and preliminary efficacy of 3rd-G CAR-T cells. Before receiving lymphodepleting conditioning regimen, the peripheral blood mononuclear cells from eligible patients will be leukapheresed, and the T cells will be purified, activated, transduced and expanded ex vivo. On day 6 in the protocol, a single dose of 1 million CAR-T cells per kg will be administrated intravenously. The phenotypes of infused CAR-T cells, copy number of CAR transgene and plasma cytokines will be assayed for 2 years after CAR-T infusion using flow cytometry, real-time quantitative PCR and cytometric bead array, respectively. Moreover, several predictive plasma cytokines including interferon-γ, interleukin (IL)-6, IL-8, Soluble Interleukin (sIL)-2R-α, solubleglycoprotein (sgp)130, sIL-6R, Monocyte chemoattractant protein (MCP1), Macrophage inflammatory protein (MIP1)-α, MIP1-β and Granulocyte-macrophage colony-stimulating factor (GM-CSF), which are highly associated with severe cytokine release syndrome (CRS), will be used to forecast CRS to allow doing earlier intervention, and CRS will be managed based on a revised CRS grading system. In addition, patients with grade 3 or 4 neurotoxicities or persistent B-cell aplasia will be treated with dexamethasone (10 mg intravenously every 6 hours) or IgG, respectively. Descriptive and analytical analyses will be performed.
Ethics and dissemination
Ethical approval for the study was granted on 10 July 2014 (YLJS-2014-7-10). Written informed consent will be taken from all participants. The results of the study will be reported, through peer-reviewed journals, conference presentations and an internal organisational report.
Trial registration number
NCT02186860.
doi:10.1136/bmjopen-2016-013904
PMCID: PMC5223707  PMID: 28039295
IMMUNOLOGY; chimeric antigen receptor; acute lymphoblastic leukemia; Third-generation
7.  Exosomes from Human Umbilical Cord Mesenchymal Stem Cells: Identification, Purification, and Biological Characteristics 
Stem Cells International  2016;2016:1929536.
Our and other groups have discovered that mesenchymal stem cells (MSCs) derived exosomes are a novel therapeutical modality for many diseases. In this study, we summarized a method to extract and purify hucMSCs-exosomes using ultrafiltration and gradient centrifugation in our laboratory and proved that hucMSCs-exosomes prepared according to our procedure were stable and bioactive. Results showed that exosomes derived from hucMSC were 40~100 nm and CD9 and CD81 positive. Functionally, hucMSCs-exosomes promoted cell proliferation and protected against oxidative stress-induced cell apoptosis in vitro by activation of ERK1/2 and p38. Interestingly, UV exposure abrogated the regulatory roles of exosomes under oxidative stress, indicating that hucMSCs-exosomes may regulate cell growth and apoptosis by exosomal shuttle of RNA. Furthermore, cytokine profile analysis revealed that hucMSCs-exosomes contained high dose of IL-6, IL-8, and other cytokines. The established method is practical and efficient, which provides a basis for further evaluating the potential of hucMSCs-exosomes as therapeutic agents.
doi:10.1155/2016/1929536
PMCID: PMC5220513
8.  The transcriptional repressor Hes1 attenuates inflammation via regulating transcriptional elongation 
Nature immunology  2016;17(8):930-937.
Most of the known regulatory mechanisms that curb inflammatory gene expression target pre-transcription initiation steps and evidence for regulation of inflammatory gene expression post initiation remains scarce. Here we show that transcription repressor hairy and enhancer of split 1 (Hes1) suppresses production of CXCL1, a chemokine crucial for recruiting neutrophils. Hes1 negatively regulates neutrophil recruitment in vivo in a manner that is dependent on macrophage-produced CXCL1 and attenuates severity of inflammatory arthritis. Mechanistically, inhibition of Cxcl1 expression by Hes1 does not involve modification of transcription initiation. Instead, Hes1 inhibits signal-induced recruitment of positive transcription elongation complex P-TEFb, thereby preventing phosphorylation of RNA polymerase II on serine-2 and productive elongation. Thus, our results identify Hes1 as a homeostatic suppressor of inflammatory responses which exerts its suppressive function by regulating transcription elongation.
doi:10.1038/ni.3486
PMCID: PMC4955730  PMID: 27322654
9.  Study of in vitro RBCs membrane elasticity with AOD scanning optical tweezers 
Biomedical Optics Express  2016;8(1):384-394.
The elasticity of red cell membrane is a critical physiological index for the activity of RBC. Study of the inherent mechanism for RBCs membrane elasticity transformation is attention-getting all along. This paper proposes an optimized measurement method of erythrocytes membrane shear modulus incorporating acousto-optic deflector (AOD) scanning optical tweezers system. By use of this method, both membrane shear moduli and sizes of RBCs with different in vitro times were determined. The experimental results reveal that the RBCs membrane elasticity and size decline with in vitro time extension. In addition, semi quantitative measurements of S-nitrosothiol content in blood using fluorescent spectrometry during in vitro storage show that RBCs membrane elasticity change is positively associated with the S-nitrosylation level of blood. The analysis considered that the diminished activity of the nitric oxide synthase makes the S-nitrosylation of in vitro blood weaker gradually. The main reason for worse elasticity of the in vitro RBCs is that S-nitrosylation effect of spectrin fades. These results will provide a guideline for further study of in vitro cells activity and other clinical applications.
doi:10.1364/BOE.8.000384
PMCID: PMC5231307
(000.1430) Biology and medicine; (350.4855) Optical tweezers or optical manipulation
10.  MiR-150 promotes cellular metastasis in non-small cell lung cancer by targeting FOXO4 
Scientific Reports  2016;6:39001.
Previous studies have shown that dysregulation of microRNA-150 (miR-150) is associated with aberrant proliferation of human non-small cell lung cancer (NSCLC) cells. However, whether miR-150 has a critical role in NSCLC cell metastasis is unknown. Here, we reveal that the critical pro-metastatic role of miR-150 in the regulation of epithelial-mesenchymal-transition (EMT) through down-regulation of FOXO4 in NSCLC. In vitro, miR-150 targets 3′UTR region of FOXO4 mRNA, thereby negatively regulating its expression. Clinically, the expression of miR-150 was frequently up-regulated in metastatic NSCLC cell lines and clinical specimens. Contrarily, FOXO4 was frequently down-regulated in NSCLC cell lines and clinical specimens. Functional studies show that ectopic expression of miR-150 enhanced tumor cell metastasis in vitro and in a mouse xenograft model, and triggered EMT-like changes in NSCLC cells (including E-cadherin repression, N-cadherin and Vimentin induction, and mesenchymal morphology). Correspondingly, FOXO4 knockdown exhibited pro-metastatic and molecular effects resembling the effect of miR-150 over-expression. Moreover, NF-κB/snail/YY1/RKIP circuitry regulated by FOXO4 were likely involved in miR-150-induced EMT event. Simultaneous knockdown of miR-150 and FOXO4 abolished the phenotypic and molecular effects caused by individual knockdown of miR-150. Therefore, our study provides previously unidentified pro-metastatic roles and mechanisms of miR-150 in NSCLC.
doi:10.1038/srep39001
PMCID: PMC5157020  PMID: 27976702
11.  Global analysis of regulatory divergence in the evolution of mouse alternative polyadenylation 
Molecular Systems Biology  2016;12(12):890.
Abstract
Alternative polyadenylation (APA), which is regulated by both cis‐elements and trans‐factors, plays an important role in post‐transcriptional regulation of eukaryotic gene expression. However, comparing to the extensively studied transcription and alternative splicing, the extent of APA divergence during evolution and the relative cis‐ and trans‐contribution remain largely unexplored. To directly address these questions for the first time in mammals, by using deep sequencing‐based methods, we measured APA divergence between C57BL/6J and SPRET/EiJ mouse strains as well as allele‐specific APA pattern in their F1 hybrids. Among the 24,721 polyadenylation sites (pAs) from 7,271 genes expressing multiple pAs, we identified 3,747 pAs showing significant divergence between the two strains. After integrating the allele‐specific data from F1 hybrids, we demonstrated that these events could be predominately attributed to cis‐regulatory effects. Further systematic sequence analysis of the regions in proximity to cis‐divergent pAs revealed that the local RNA secondary structure and a poly(U) tract in the upstream region could negatively modulate the pAs usage.
doi:10.15252/msb.20167375
PMCID: PMC5199128  PMID: 27932516
alternative polyadenylation; evolution; regulatory divergence; Chromatin, Epigenetics, Genomics & Functional Genomics; Genome-Scale & Integrative Biology; Transcription
12.  Residency as a Social Network: Burnout, Loneliness, and Social Network Centrality 
Background
Burnout is typically viewed as an individual condition, and no link has been identified between burnout and loneliness.
Objective
To investigate the association of burnout with loneliness and social network degree and centrality.
Methods
A survey containing the Maslach Burnout Inventory (MBI), a 3-question loneliness scale, and a social connectivity component was sent to residents in a large urban academic medical center internal medicine residency program.
Results
The response rate was 77% (95 of 124 residents). We defined significant burnout as MBI subscores of ≥ 27 for emotional exhaustion (EE), ≥ 10 for depersonalization (DP), or both. This was met by 43 (45%), 47 (49%), and 31 (33%) out of 95 respondents, respectively. Those with significant burnout had higher loneliness scores: 5.6 versus 4.5 for EE (P = .002; OR = 1.50; 95% CI 1.15–1.95); 5.4 versus 4.6 for DP (P = .024; OR = 1.33; 95% CI 1.03–1.71); and 5.8 versus 4.6 for both EE and DP (P = .001; OR = 1.54; 95% CI 1.17–2.02). Rating a larger number of coresidents as closer connections on a 5-point Likert scale was not associated with lower burnout scores. No measures of centrality were associated with burnout scores for EE and/or DP. High personal accomplishment subscores on the MBI did correlate significantly with several measures of centrality.
Conclusions
Burnout was associated with loneliness in a dose-dependent fashion. Greater sense of personal accomplishment was associated with greater network centrality.
doi:10.4300/JGME-D-15-00038.1
PMCID: PMC4675420  PMID: 26692975
13.  Multi-locus phylogeny using topotype specimens sheds light on the systematics of Niviventer (Rodentia, Muridae) in China 
Background
Niviventer is a genus of white-bellied rats that are among the most common rodents in the Indo-Sundaic region. The taxonomy of the genus has undergone extensive revisions and remains controversial. The current phylogeny is unresolved and was developed primarily on the basis of mitochondrial genes. Identification is extremely difficult, and a large number of GenBank sequences seem to be problematic. We extensively sampled specimens of Niviventer in China and neighboring northern Vietnam, including topotypes of the most reported species (n = 6), subspecies (n = 8), and synonyms (n = 4). We estimated phylogenetic relationships on the basis of one mitochondrial and three nuclear genes, using concatenation and coalescent-based approaches. We also employed molecular species delimitation approaches to test the existence of cryptic and putative new species.
Results
Our phylogeny was finely resolved, especially for the N. confucianus-like species. Our data provided the first support for N. brahma and N. eha as sister species, an assignment that is congruent with their morphological similarities. Species delimitation analyses provided new insight into species diversity and systematics. Three geographic populations of N. confucianus and one of N. fulvescens were supported as genetically distinct in our species delimitation analyses, while three recognized species (N. coninga, N. huang, and N. lotipes) were not strongly supported as distinct.
Conclusions
Our results suggested that several genetically distinct species may be contained within the species currently known as N. confucianus and N. fulvescens. In addition, the results of Bayesian Phylogenetics and Phylogeography (BPP) for N. coninga, N. huang, and N. lotipes indicated that either inter-specific gene flow had occurred or imperfect taxonomy was present. Morphological examinations and morphometric analyses are warranted to examine the molecular results.
Electronic supplementary material
The online version of this article (doi:10.1186/s12862-016-0832-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12862-016-0832-8
PMCID: PMC5133754  PMID: 27905886
Cryptic species; Species delimitation; Niviventer; Phylogenetics; Taxonomy; Topotype
14.  DiseaseMeth version 2.0: a major expansion and update of the human disease methylation database 
Nucleic Acids Research  2016;45(Database issue):D888-D895.
The human disease methylation database (DiseaseMeth, http://bioinfo.hrbmu.edu.cn/diseasemeth/) is an interactive database that aims to present the most complete collection and annotation of aberrant DNA methylation in human diseases, especially various cancers. Recently, the high-throughput microarray and sequencing technologies have promoted the production of methylome data that contain comprehensive knowledge of human diseases. In this DiseaseMeth update, we have increased the number of samples from 3610 to 32 701, the number of diseases from 72 to 88 and the disease–gene associations from 216 201 to 679 602. DiseaseMeth version 2.0 provides an expanded comprehensive list of disease–gene associations based on manual curation from experimental studies and computational identification from high-throughput methylome data. Besides the data expansion, we also updated the search engine and visualization tools. In particular, we enhanced the differential analysis tools, which now enable online automated identification of DNA methylation abnormalities in human disease in a case-control or disease–disease manner. To facilitate further mining of the disease methylome, three new web tools were developed for cluster analysis, functional annotation and survival analysis. DiseaseMeth version 2.0 should be a useful resource platform for further understanding the molecular mechanisms of human diseases.
doi:10.1093/nar/gkw1123
PMCID: PMC5210584  PMID: 27899673
15.  Association of pre-pregnancy body mass index, gestational weight gain with cesarean section in term deliveries of China 
Scientific Reports  2016;6:37168.
China has one of the highest rates of cesarean sections in the world. However, limited epidemiological studies have evaluated the risk factors for cesarean section among Chinese women. Thus, the aim of this cohort study was to investigate the associations between pre-pregnancy BMI, gestational weight gain (GWG) and the risk of cesarean section in China. A total of 57,891 women with singleton, live-born, term pregnancies were included in this analysis. We found that women who were overweight or obese before pregnancy had an elevated risk of cesarean section. Women with a total GWG above the Institute of Medicine (IOM) recommendations had an adjusted OR for cesarean section of 1.45 (95% CI, 1.40–1.51) compared with women who had GWG within the IOM recommendations. Women with excessive BMI gain during pregnancy also had an increased risk of cesarean section. When stratified by maternal pre-pregnancy BMI, there was a significant association between excessive GWG and increased odds of cesarean section across all pre-pregnancy BMI categories. These results suggest that weight control efforts before and during pregnancy may help to reduce the rate of cesarean sections.
doi:10.1038/srep37168
PMCID: PMC5181837  PMID: 27872480
16.  Comparison of rabbit rib defect regeneration with and without graft 
Rib segment, as one of the most widely used autologous boneresources for bone repair, is commonly isolated with an empty left in the defect. Although defective rib repair is thought to be unnecessary traditionally, it’s of vital importance actually to promote rib regeneration for patients with better postoperative recovery and higher life quality. Comparative investigations on rabbit rib bone regeneration with and without graft were reported in this article. A segmental defect was performed on the 8th rib of 4-month-old male New Zealand rabbits. The mineralized collagen bone graft (MC) was implanted into the defect and evaluated for up to 12 weeks. The rib bone repair was investigated by using X-ray at 4, 8 and 12 weeks and histological examinations at 12 weeks after surgery, which showed a higher bone remodeling activity in the groups with MC implantation in comparison with blank control group, especially at the early stage of remodeling.
doi:10.1007/s10856-016-5807-1
PMCID: PMC5116313  PMID: 27866345
17.  DGCA: A comprehensive R package for Differential Gene Correlation Analysis 
BMC Systems Biology  2016;10:106.
Background
Dissecting the regulatory relationships between genes is a critical step towards building accurate predictive models of biological systems. A powerful approach towards this end is to systematically study the differences in correlation between gene pairs in more than one distinct condition.
Results
In this study we develop an R package, DGCA (for Differential Gene Correlation Analysis), which offers a suite of tools for computing and analyzing differential correlations between gene pairs across multiple conditions. To minimize parametric assumptions, DGCA computes empirical p-values via permutation testing. To understand differential correlations at a systems level, DGCA performs higher-order analyses such as measuring the average difference in correlation and multiscale clustering analysis of differential correlation networks. Through a simulation study, we show that the straightforward z-score based method that DGCA employs significantly outperforms the existing alternative methods for calculating differential correlation. Application of DGCA to the TCGA RNA-seq data in breast cancer not only identifies key changes in the regulatory relationships between TP53 and PTEN and their target genes in the presence of inactivating mutations, but also reveals an immune-related differential correlation module that is specific to triple negative breast cancer (TNBC).
Conclusions
DGCA is an R package for systematically assessing the difference in gene-gene regulatory relationships under different conditions. This user-friendly, effective, and comprehensive software tool will greatly facilitate the application of differential correlation analysis in many biological studies and thus will help identification of novel signaling pathways, biomarkers, and targets in complex biological systems and diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12918-016-0349-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12918-016-0349-1
PMCID: PMC5111277  PMID: 27846853
Differential correlation; Differential coexpression; Multiscale clustering analysis; R package; RNA-Seq; TP53; Breast cancer; Triple negative breast cancer
18.  Pulmonary Artery Dissection: A Fatal Complication of Pulmonary Hypertension 
Case Reports in Medicine  2016;2016:4739803.
Pulmonary artery dissection is extremely rare but it is a really life-threatening condition when it happens. Most patients die suddenly from major bleeding or tamponade caused by direct rupture into mediastinum or retrograde into the pericardial sac. What we are reporting is a rare case of a 46-year-old female patient whose pulmonary artery dissection involves both the pulmonary valve and right pulmonary artery. The patient had acute chest pain and severe dyspnea, and the diagnosis of pulmonary artery dissection was confirmed by ultrasonography and CT angiography. Moreover, its etiology, clinical manifestations, and management are also discussed in this article.
doi:10.1155/2016/4739803
PMCID: PMC5126397  PMID: 27974894
19.  Antitumor effects of recombinant human adenovirus-p53 against human cutaneous squamous cell carcinoma in mice 
The present study was conducted to identify the anti-tumor effects of rAd/p53, which is a recombinant human serotype 5 adenovirus, in cutaneous squamous cell carcinoma (cSCC). Mouse models of human cSCC were constructed by injecting human cutaneous squamous cell carcinoma cells into both flanks of nude mice. Subsequently, the 75 nude mice with cSCC xenograft tumors were randomly divided into recombinant human serotype 5 adenovirus (rAd)/p53, rAd/p53 + 5-fluorouracil (5-Fu) and 5-Fu groups. One side of the tumors was administered the therapeutic agents as the therapeutic group, whereas the remaining side was treated with medical saline as the control. At 24, 48, 72, 120 and 168 h post-intratumoral injection, alterations in tumor volume, tumor necrosis and the expression of several tumor-associated genes, including Smad4, Brca1 and matrix metalloproteinase (MMP-2), were analyzed. Compared with its control group, the rAd/P53 group exhibited a significantly increased tumor necrosis ratio. In addition, Smad4 and Brca1 expression levels increased significantly at various time points (P<0.05), and MMP-2 expression decreased significantly (P<0.05). In the rAd/p53 + 5-Fu group, the tumor necrosis ratio, and Smad4 and Brca1 expression levels also significantly increased at various time points (P<0.05). MMP-2 gene transcription gradually decreased, high expression of Smad4 was prolonged, and high expression of Brca1 was observed in the early period following treatment compared with the rAd/P53 group. In addition, p53 expression exhibited a positive correlation with the tumor necrosis ratio and Smad4 expression, and showed a negative correlation with MMP-2 gene transcription (P<0.05). These findings indicate that rAd/p53 has a potent anti-tumor effect in cSCC via the promotion of tumor necrosis and regulating the expression of various tumor-associated genes.
doi:10.3892/etm.2016.3901
PMCID: PMC5228342
human cutaneous squamous cell carcinoma; xenograft model; mice; recombinant human serotype 5 adenovirus/p53; 5-fluorouracil
20.  Association between Myocardial Infarction and Periodontitis: A Meta-Analysis of Case-Control Studies 
Background and Objective: Many clinical researches have been carried out to investigate the relationship between myocardial infarction (MI) and periodontitis. Despite most of them indicated that the periodontitis may be associated with an increased risk of MI, the findings and study types of these studies have been inconsistent. The goal of this meta-analysis was to critically assess the strength of the association between MI and periodontitis in case-control studies.
Methods: PubMed and the Cochrane Library were searched for eligible case-control studies reporting relevant parameters that compared periodontal status between MI and control subjects. The odds ratios (ORs) and 95% confidence intervals (CIs) from each study were pooled to estimate the strength of the association between MI and periodontitis. The mean differences and 95% CIs for periodontal-related parameters were calculated to determine their overall effects.
Results: Seventeen studies including a total of 3456 MI patients and 3875 non-MI control subjects were included. The pooled OR for the association between MI and periodontitis was 2.531 (95% CI: 1.927–3.324). The mean differences (95% CIs) for clinical attachment loss, probing depth, bleeding on probing, plaque index, and the number of missing teeth were 1.000 (0.726–1.247), 1.209 (0.538–1.880), 0.342 (0.129–0.555), 0.383 (0.205–0.560), and 4.122 (2.012–6.232), respectively.
Conclusion: With the current evidence, the results support the presence of a significant association between MI and periodontitis. Moreover, MI patients had worse periodontal and oral hygiene status and fewer teeth than did control subjects. More high-quality and well-designed studies focusing on the casual relationship between MI and periodontitis should be conducted in the future.
doi:10.3389/fphys.2016.00519
PMCID: PMC5095113  PMID: 27867362
periodontitis; myocardial infarction; periodontal examination; risk factor; case-control study; meta-analysis
21.  Mergeomics: multidimensional data integration to identify pathogenic perturbations to biological systems 
BMC Genomics  2016;17:874.
Background
Complex diseases are characterized by multiple subtle perturbations to biological processes. New omics platforms can detect these perturbations, but translating the diverse molecular and statistical information into testable mechanistic hypotheses is challenging. Therefore, we set out to create a public tool that integrates these data across multiple datasets, platforms, study designs and species in order to detect the most promising targets for further mechanistic studies.
Results
We developed Mergeomics, a computational pipeline consisting of independent modules that 1) leverage multi-omics association data to identify biological processes that are perturbed in disease, and 2) overlay the disease-associated processes onto molecular interaction networks to pinpoint hubs as potential key regulators. Unlike existing tools that are mostly dedicated to specific data type or settings, the Mergeomics pipeline accepts and integrates datasets across platforms, data types and species. We optimized and evaluated the performance of Mergeomics using simulation and multiple independent datasets, and benchmarked the results against alternative methods. We also demonstrate the versatility of Mergeomics in two case studies that include genome-wide, epigenome-wide and transcriptome-wide datasets from human and mouse studies of total cholesterol and fasting glucose. In both cases, the Mergeomics pipeline provided statistical and contextual evidence to prioritize further investigations in the wet lab. The software implementation of Mergeomics is freely available as a Bioconductor R package.
Conclusion
Mergeomics is a flexible and robust computational pipeline for multidimensional data integration. It outperforms existing tools, and is easily applicable to datasets from different studies, species and omics data types for the study of complex traits.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-016-3198-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-016-3198-9
PMCID: PMC5097440  PMID: 27814671
Mergeomics; Integrative genomics; Multidimensional data integration; Functional genomics; Gene networks; Key drivers; Cholesterol; Blood glucose
22.  Prenatal exposure to lead in relation to risk of preterm low birth weight: a matched case-control study in China 
We investigated the association between prenatal exposure to lead (Pb) and the risk of preterm low birth weight (PLBW). Pb concentrations in maternal urine collected at birth from 408 subjects (102 cases and 306 matched controls) were analyzed and adjusted by creatinine. The median Pb concentration in the PLBW cases (10.60 μg Pb/g creatinine) was higher than that of the controls (7.28 μg Pb/g creatinine). An adjusted odds ratio (OR) of 2.96 (95% CI = 1.49-5.87) for PLBW was observed when the highest tertile was compared to the lowest tertile of Pb levels. The association was more pronounced among female infants (adjusted OR = 3.67 for the highest tertile; 95% CI = 1.35-9.93) than male infants (adjusted OR = 1.91 for the highest tertile; 95% CI = 0.74-4.95). Our study suggests that prenatal exposure to levels of Pb encountered today in China is associated with an elevated risk of PLBW.
doi:10.1016/j.reprotox.2015.06.051
PMCID: PMC4843791  PMID: 26122562
Lead; Preterm birth; Prenatal exposure; Maternal urine
23.  Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease 
Genome Medicine  2016;8:104.
Background
Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration. However, despite extensive clinical and genomic studies, the molecular basis of AD development and progression remains elusive.
Methods
To elucidate molecular systems associated with AD, we developed a large scale gene expression dataset from 1053 postmortem brain samples across 19 cortical regions of 125 individuals with a severity spectrum of dementia and neuropathology of AD. We excluded brain specimens that evidenced neuropathology other than that characteristic of AD. For the first time, we performed a pan-cortical brain region genomic analysis, characterizing the gene expression changes associated with a measure of dementia severity and multiple measures of the severity of neuropathological lesions associated with AD (neuritic plaques and neurofibrillary tangles) and constructing region-specific co-expression networks. We rank-ordered 44,692 gene probesets, 1558 co-expressed gene modules and 19 brain regions based upon their association with the disease traits.
Results
The neurobiological pathways identified through these analyses included actin cytoskeleton, axon guidance, and nervous system development. Using public human brain single-cell RNA-sequencing data, we computed brain cell type-specific marker genes for human and determined that many of the abnormally expressed gene signatures and network modules were specific to oligodendrocytes, astrocytes, and neurons. Analysis based on disease severity suggested that: many of the gene expression changes, including those of oligodendrocytes, occurred early in the progression of disease, making them potential translational/treatment development targets and unlikely to be mere bystander result of degeneration; several modules were closely linked to cognitive compromise with lesser association with traditional measures of neuropathology. The brain regional analyses identified temporal lobe gyri as sites associated with the greatest and earliest gene expression abnormalities.
Conclusions
This transcriptomic network analysis of 19 brain regions provides a comprehensive assessment of the critical molecular pathways associated with AD pathology and offers new insights into molecular mechanisms underlying selective regional vulnerability to AD at different stages of the progression of cognitive compromise and development of the canonical neuropathological lesions of AD.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-016-0355-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13073-016-0355-3
PMCID: PMC5088659  PMID: 27799057
Alzheimer’s disease; Dementia; Differential expression; Gene co-expression network; Gene module; Systems biology; Selective vulnerability; Demyelination; Brain cell types
24.  Mapping patterns of nodal metastases in esophageal carcinoma: rethinking the clinical target volume for supraclavicular nodal irradiation 
Journal of Thoracic Disease  2016;8(11):3132-3138.
Background
To map detail distribution of metastatic supraclavicular (SCV) lymph nodes (LN) in esophageal cancer (EC) patients and determine the precise radiation therapy clinical target volume (CTV).
Methods
A total of 101 thoracic esophageal carcinoma patients after surgery experienced SCV LN metastasis were retrospectively examined. The SCV region is further divided into four subgroups. Using hand drawings registration, nodes were mapped to a template computed tomogram to provide a visual impression of nodal frequencies and anatomic distribution.
Results
In all, 158 nodes were considered to be clinical metastatic in the SCV region in the 101 patients, 74 on the left and 84 on the right. Seven of 158 (4.4%) positive LN were located in group I, 78 of 158 (49.37%) were located in group II, 72 of 158 nodes (45.6%) were located in group III, 1 of 158 (0.63%) located in group IV.
Conclusions
According to our results, the SCV group II and group III are considered to be the high risk regions of esophageal squamous cell carcinoma (ESCC) LN metastasis, which were defined as elective nodal irradiation (ENI) areas.
doi:10.21037/jtd.2016.11.96
PMCID: PMC5179466  PMID: 28066592
Esophageal cancer (EC); postoperative radiotherapy; target volume definition; supraclavicular region (SCV region)
25.  Molecular and biological compatibility with host alpha-synuclein influences fibril pathogenicity 
Cell reports  2016;16(12):3373-3387.
Summary
The accumulation and propagation of misfolded α-Synuclein (α-Syn) is a central feature of Parkinson’s disease (PD) and other synucleinopathies. Molecular compatibility between a fibrillar seed and its native protein state is a major determinant of amyloid self-replication. We show that cross-seeded aggregation of human (Hu) and mouse (Ms) α-Syn is bidirectionally restricted. Although fibrils formed by Hu-Ms-α-Syn chimeric mutants can overcome this inhibition in cell-free systems, sequence homology poorly predicts their efficiency in inducing α-Syn pathology in primary neurons or after intracerebral injection into wildtype mice. Chimeric α-Syn fibrils demonstrate enhanced or reduced pathogenicities compared to wildtype Hu- or Ms-α-Syn fibrils. Furthermore, α-Syn mutants induced to polymerize by fibrillar seeds inherit the functional properties of their template, suggesting transferable pathogenic and non-pathogenic states likely influence the initial engagement between exogenous α-Syn seeds with endogenous neuronal α-Syn. Thus, transmission of synucleinopathies is regulated by biological processes in addition to molecular compatibility.
Graphical abstract
doi:10.1016/j.celrep.2016.08.053
PMCID: PMC5087609  PMID: 27653697

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