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1.  Neuroprotection Mediated through GluN2C-Containing N-methyl-D-aspartate (NMDA) Receptors Following Ischemia 
Scientific Reports  2016;6:37033.
Post-ischemic activation of NMDA receptors (NMDARs) has been linked to NMDAR subunit-specific signaling that mediates pro-survival or pro-death activity. Although extensive studies have been performed to characterize the role of GluN2A and GluN2B following ischemia, there is less understanding regarding the regulation of GluN2C. Here, we show that GluN2C expression is increased in acute hippocampal slices in response to ischemia. Strikingly, GluN2C knockout mice, following global cerebral ischemia, exhibit greater neuronal death in the CA1 area of the hippocampus and reduced spatial working memory compared to wild-type mice. Moreover, we find that GluN2C-expressing hippocampal neurons show marked resistance to NMDA-induced toxicity and reduced calcium influx. Using both in vivo and in vitro experimental models of ischemia, we demonstrate a neuroprotective role of GluN2C, suggesting a mechanism by which GluN2C is upregulated to promote neuronal survival following ischemia. These results may provide insights into development of NMDAR subunit-specific therapeutic strategies to protect neurons from excitotoxicity.
doi:10.1038/srep37033
PMCID: PMC5109474  PMID: 27845401
2.  Acupuncture with different acupoint combinations for chemotherapy-induced nausea and vomiting: study protocol for a randomized controlled trial 
Background
Acupuncture is beneficial for controlling chemotherapy-induced nausea and vomiting (CINV). However, the effect of different acupoint combinations on controlling CINV remains unknown. This study aims to compare the effects of distal-proximal point association and local distribution point association on controlling CINV.
Methods/design
The study is a single-center, randomized controlled trial. A total of 240 participants will be randomly divided into four groups. The control group will receive standard antiemetic only, whereas three acupuncture groups will receive four electro-acupuncture treatments once a day with the standard antiemetic. Acupuncture group I and II will receive distal-proximal point association (“Neiguan (PC6) and Zhongwan (CV12)”, and “Zusanli (ST36) and CV12”, respectively); Acupuncture group III will receive local distribution point association (“Shangwan (CV13) and CV12”). The primary outcome measures are the frequency and distress of nausea and vomiting. The secondary outcome measures are the grade of constipation and diarrhea, electrogastrogram, quality of life, etc. Assessment is scheduled from the day before chemotherapy to the fifth day of chemotherapy. Follow-ups are performed from the sixth day to the twenty-first day of chemotherapy.
Discussion
Results of this trial will help in evaluating the efficacy and safety of electro-acupuncture with different acupoint combinations in the management of CINV.
Trial registration
ClinicalTrials.gov identifier: NCT02478047.
doi:10.1186/s12906-016-1425-1
PMCID: PMC5100267  PMID: 27821107
Acupuncture; Chemotherapy-induced nausea and vomiting; Acupoint combination; Randomized controlled trial
3.  A fully functionalized metamaterial perfect absorber with simple design and implementation 
Scientific Reports  2016;6:36244.
Broadband perfect metamaterial absorbers have been drawing significant attention in recent years. A close-to-unity absorption over a broad spectral range is established and this facilitates many photonic applications. A more challenging goal is to construct a broadband absorber with a tailored spectral absorption. The spectral absorption control and spectral shaping are very critical in many applications, such as thermal-photovoltaic, thermal emitters, spectrum imaging system, biomedical and extraterrestrial sensing, and refractive index sensor. In this work, one-dimensional (1D) planar stacking structure is designed to achieve the ultimate goal of a functionalized absorber with a fully tailorable spectral absorption. The lithography and etching process are totally eliminated in this proposed structure, and the fabrication is fully compatible with the regular silicon IC processing. By using ~2 nm ultra-thin metallic layers with a 10-pair (10X) SiO2/Si3N4 integrated dielectric filter, we can achieve decent spectral response shaping. The planar configuration of the ultra-thin-metal metamaterial perfect absorber (MPA) is the key to the easy design/integration of the dielectric filters on top of the MPA. Specifically, band-rejected, high-pass, low-pass and band-pass structure are constructed successfully. Finally, experimental evidence to support our simulation result is also provided, which proves the feasibility of our proposal.
doi:10.1038/srep36244
PMCID: PMC5080586  PMID: 27782181
4.  Wnt regulates proliferation and neurogenic potential of Müller glial cells through a Lin28/let-7 miRNA-dependent pathway in adult mammalian retina 
Cell reports  2016;17(1):165-178.
In cold-blooded vertebrates such as zebrafish, Müller glial cells (MGs) readily proliferate to replenish lost retinal neurons. In mammals, however, MGs lack regenerative capability as they do not spontaneously re-enter the cell cycle unless the retina is injured. Here, we show that gene transfer of β-catenin in adult mouse retina activates Wnt signaling and MG proliferation without retinal injury. Upstream of Wnt, deletion of GSK3β stabilizes β-catenin and activates MG proliferation. Downstream of Wnt, β-catenin binds to the Lin28 promoter and activates transcription. Deletion of Lin28 abolishes β-catenin-mediated effects on MG proliferation, and Lin28 gene transfer stimulates MG proliferation. We further demonstrate that let-7 miRNAs are critically involved in Wnt/Lin28-regulated MG proliferation. Intriguingly, a subset of cell cycle reactivated MGs express markers for amacrine cells. Together, these results reveal a key role of Wnt-Lin28-let7 miRNA signaling in regulating proliferation and neurogenic potential of MGs in adult mammalian retina.
In Brief
Müller glial cells (MGs) are a source of retinal stem cells. To overcome proliferation quiescence of MGs in adult mammalian retina, Yao et al. report that modulation of Wnt/Lin28/let-7 miRNA signaling stimulates MG proliferation without retinal injury. A subset of cell cycle reactivated MGs express markers for retinal interneurons.
doi:10.1016/j.celrep.2016.08.078
PMCID: PMC5076887  PMID: 27681429
5.  Early Development of Definitive Erythroblasts from Human Pluripotent Stem Cells Defined by Expression of Glycophorin A/CD235a, CD34, and CD36 
Stem Cell Reports  2016;7(5):869-883.
Summary
The development of human erythroid cells has been mostly examined in models of adult hematopoiesis, while their early derivation during embryonic and fetal stages is largely unknown. We observed the development and maturation of erythroblasts derived from human pluripotent stem cells (hPSCs) by an efficient co-culture system. These hPSC-derived early erythroblasts initially showed definitive characteristics with a glycophorin A+ (GPA+) CD34lowCD36− phenotype and were distinct from adult CD34+ cell-derived ones. After losing CD34 expression, early GPA+CD36− erythroblasts matured into GPA+CD36low/+ stage as the latter expressed higher levels of β-globin along with a gradual loss of mesodermal and endothelial properties, and terminally suppressed CD36. We establish a unique in vitro model to trace the early development of hPSC-derived erythroblasts by serial expression of CD34, GPA, and CD36. Our findings may provide insight into the understanding of human early erythropoiesis and, ultimately, therapeutic potential.
Highlights
•The hPSC/AGM-S3 co-culture system generates considerable definitive erythroblasts•hPSC-derived erythroblasts initiate from a unique GPA+CD34lowCD36− fraction•Human early erythropoiesis can be traced by serial expression of CD34, GPA, and CD36
In this article, Ma and colleagues show that considerable definitive erythroblasts could be generated from hPSCs by co-culturing with AGM-S3 cells. Tracing through serial expression of CD34, GPA, and CD36 on hPSC-derived erythroblasts revealed that they arose from a unique GPA+CD34lowCD36− cell fraction sharing both erythroid and mesodermal endothelium characteristics.
doi:10.1016/j.stemcr.2016.09.002
PMCID: PMC5106477  PMID: 27720903
hESC; hiPSC; hematopoiesis; development; erythroblasts; erythropoiesis; endothelial cells; GPA; CD36; CD34
6.  The Antipancreatic Cancer Activity of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2 
DNA and Cell Biology  2015;34(10):610-617.
In the present study, we investigated the potential activity of OSI-027, a potent and selective mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells both in vitro and in vivo. We demonstrated that OSI-027 inhibited survival and growth of both primary and transformed (PANC-1 and MIA PaCa-2 lines) human pancreatic cancer cells. Meanwhile, OSI-027 induced caspase-dependent apoptotic death of the pancreatic cancer cells. On the other hand, caspase inhibitors alleviated cytotoxicity by OSI-027. At the molecular level, OSI-027 treatment blocked mTORC1 and mTORC2 activation simultaneously, without affecting ERK–mitogen-activated protein kinase activation. Importantly, OSI-027 activated cytoprotective autophagy in the above cancer cells. Whereas pharmacological blockage of autophagy or siRNA knockdown of Beclin-1 significantly enhanced the OSI-027-induced activity against pancreatic cancer cells. Specifically, a relatively low dose of OSI-027 sensitized gemcitabine-induced pancreatic cancer cell death in vitro. Further, administration of OSI-027 or together with gemcitabine dramatically inhibited PANC-1 xenograft growth in severe combined immunodeficiency mice, leading to significant mice survival improvement. In summary, the preclinical results of this study suggest that targeting mTORC1/2 synchronously by OSI-027 could be further investigated as a valuable treatment for pancreatic cancer.
doi:10.1089/dna.2015.2886
PMCID: PMC4593879  PMID: 26284306
7.  Cell Shape Dependent Regulation of Nuclear Morphology 
Biomaterials  2015;67:129-136.
Recent studies suggest that actin filaments are essential in how a cell controls its nuclear shape. However, little is known about the relative importance of membrane tension in determining nuclear morphology. In this study, we used adhesive micropatterned substrates to alter the cellular geometry (aspect ratio, size, and shape) that allowed direct membrane tension or without membrane lateral contact with the nucleus and investigate nuclear shape remodeling and orientation on a series of rectangular shapes. Here we showed that at low cell aspect ratios the orientation of the nucleus was regulated by actin filaments while cells with high aspect ratios can maintain nuclear shape and orientation even when actin polymerization was blocked. A model adenocarcinoma cell showed similar behavior in the regulation of nuclear shape in response to changes in cell shape but actin filaments were essential in maintaining cell shape. Our results highlight the two distinct mechanisms to regulate nuclear shape through cell shape control and the difference between fibroblasts and a model cancerous cell in cell adhesion and cell shape control.
doi:10.1016/j.biomaterials.2015.07.017
PMCID: PMC4626019  PMID: 26210179
Micropatterned materials; Nuclear morphology; Actin filaments; Cell shape
8.  Upregulation of retinoic acid receptor-β reverses drug resistance in cholangiocarcinoma cells by enhancing susceptibility to apoptosis 
Molecular Medicine Reports  2016;14(4):3602-3608.
Retinoic acid receptor β (RARβ), a known tumor suppressor gene, is frequently silenced in numerous malignant types of tumor. Recent reports have demonstrated that loss of RARβ expression may be responsible, in part, for the drug resistance observed in clinical trials. However, little is known about the role of RARβ in regulating drug sensitivity in patients with cholangiocarcinoma (CCA) with a high risk of mortality and poor outcomes. In the present study, low RARβ expression was observed in the majority of CCA tissues investigated (28/33, 84.8%). In addition, the CCA cell line QBC939, which exhibits low RARβ expression, was found to be significantly resistant to chemotherapeutic agents compared with SK-ChA-1, MZ-ChA-1 and Hccc9810 CCA cell lines, which exhibit high RARβ expression. Furthermore, upregulation of RARβ significantly enhanced the sensitivity of QBC939 cells to common chemotherapeutic agents both in vitro and in vivo. Upregulation of RARβ was shown to increase the expression of proapoptotic genes bax, bak and bim, in addition to caspase-3 activity, and decrease the expression of antiapoptotic genes bcl-2, bcl-xL and mcl-1. As a result, CCA cells were more susceptible to caspase-dependent apoptosis. Taken together, these data suggest that RARβ upregulation rendered CCA cells more sensitive to chemotherapeutic agents by increasing the susceptibility of cells to caspase-dependent apoptosis. These results support the hypothesis that RARβ may be an ideal chemosensitization target for the treatment of patients with drug-resistant CCA.
doi:10.3892/mmr.2016.5701
PMCID: PMC5042735  PMID: 27599527
retinoic acid receptor β; drug resistance; caspase-3; apoptosis; cholangiocarcinoma
9.  Recent advances of sonodynamic therapy in cancer treatment 
Cancer Biology & Medicine  2016;13(3):325-338.
Sonodynamic therapy (SDT) is an emerging approach that involves a combination of low-intensity ultrasound and specialized chemical agents known as sonosensitizers. Ultrasound can penetrate deeply into tissues and can be focused into a small region of a tumor to activate a sonosensitizer which offers the possibility of non-invasively eradicating solid tumors in a site-directed manner. In this article, we critically reviewed the currently accepted mechanisms of sonodynamic action and summarized the classification of sonosensitizers. At the same time, the breath of evidence from SDT-based studies suggests that SDT is promising for cancer treatment.
doi:10.20892/j.issn.2095-3941.2016.0068
PMCID: PMC5069838  PMID: 27807500
Sonodynamic therapy; Sonosensitizer; Cancer; Ultrasound; Reactive oxygen species
10.  Response of plasmaspheric configuration to substorms revealed by Chang’e 3 
Scientific Reports  2016;6:32362.
The Moon-based Extreme Ultraviolet Camera (EUVC) of the Chang’e 3 mission provides a global and instantaneous meridian view (side view) of the Earth’s plasmasphere. The plasmasphere is one inner component of the whole magnetosphere, and the configuration of the plasmasphere is sensitive to magnetospheric activity (storms and substorms). However, the response of the plasmaspheric configuration to substorms is only partially understood, and the EUVC observations provide a good opportunity to investigate this issue. By reconstructing the global plasmaspheric configuration based on the EUVC images observed during 20–22 April 2014, we show that in the observing period, the plasmasphere had three bulges which were located at different geomagnetic longitudes. The inferred midnight transit times of the three bulges, using the rotation rate of the Earth, coincide with the expansion phase of three substorms, which implies a causal relationship between the substorms and the formation of the three bulges on the plasmasphere. Instead of leading to plasmaspheric erosion as geomagnetic storms do, substorms initiated on the nightside of the Earth cause local inflation of the plasmasphere in the midnight region.
doi:10.1038/srep32362
PMCID: PMC5006020  PMID: 27576944
11.  Nomograms for Predicting the Prognostic Value of Pre-Therapeutic CA15-3 and CEA Serum Levels in TNBC Patients 
PLoS ONE  2016;11(8):e0161902.
Previous studies have indicated that carcinoembryonic antigen (CEA) and cancer antigen 15–3 (CA15-3) levels are both independent prognostic factors in breast cancer. However, the utility of CEA and CA15-3 levels as conventional cancer biomarkers in patients with triple-negative breast cancer (TNBC) remains controversial. The current study was performed to explore the predictive value of pre-therapeutic serum CEA and CA15-3 levels, and nomograms were developed including these serum cancer biomarkers to improve the prognostic evaluation of TNBC patients. Pre-therapeutic CA15-3 and CEA concentrations were measured in 247 patients with stage I–IV TNBC. Kaplan-Meier analysis showed that TNBC patients with high levels of both CEA and CA15-3 had shorter overall survival (OS) and disease-free survival (DFS) rates than those in the low-level groups (p<0.05). Multivariate analysis suggested that pre-therapeutic CA15-3 and CEA levels are independent predictive elements for OS (p = 0.022 and p = 0.040, respectively) and DFS (p = 0.023 and p = 0.028, respectively). In addition, novel nomograms were established and validated to provide personal forecasts of OS and DFS for patients with TNBC. These novel nomograms may help physicians to select the optimal treatment plans to ensure the best outcomes for TNBC patients.
doi:10.1371/journal.pone.0161902
PMCID: PMC4999206  PMID: 27561099
12.  HER3, but Not HER4, Plays an Essential Role in the Clinicopathology and Prognosis of Gastric Cancer: A Meta-Analysis 
PLoS ONE  2016;11(8):e0161219.
Background and Aim
Human epidermal growth factor receptor (HER) family plays an important role in gastric cancer (GC), especially HER2. Too much attention has been paid to HER2; however, the functions of HER3 and HER4 overexpression in GC are always ignored. The clinicopathological and prognostic roles of HER3 and HER4 in GC are controversial. In this study, a systematic review and meta-analysis was conducted to evaluate the use of HER3 or HER4 as a predictor of clinicopathology and survival time in GC patients.
Methods
Eligible studies were searched on PubMed, Ovid, Web of Science, and Cochrane databases through multiple search strategies. Data collection and statistical analysis were carried out by the Revman 5.3 software. The Newcastle-Ottawa scale was used to assess the quality of included studies.
Results
A total of 448 studies about HER3 overexpression and GC, and 398 studies about HER4 overexpression and GC were searched. Of these, 5 eligible studies about HER3 including 1016 GC patients and 3 eligible studies about HER4 including 793 GC patients met the inclusion criteria. The results showed that HER3 and HER4 overexpression were significantly associated with depth of tumor invasion (OR = 0.44, 95%CI 0.29–0.67, P = 0.0002 and OR = 0.50, 95%CI 0.38–0.86, P = 0.007) and lymph node metastasis (OR = 0.40, 95%CI 0.20–0.77, P = 0.007 and OR = 0.57, 95%CI 0.38–0.86, P = 0.007), and HER3 overexpression reveals a tendency of later tumor node metastases (TNM) stage (OR = 0.50, 95%CI 0.22–1.15, P = 0.10) and predicts a worse survival time (RR = 0.71, 95%CI 0.61–0.84, P<0.00001), while HER4 overexpression had no correlation with TNM stage (OR = 0.60, 95%CI 0.20–1.78) and survival time (RR = 1.09, 95%CI 0.91–1.30).
Conclusions
This meta-analysis indicated that HER3 plays an essential role in the clinicopathology and prognosis of GC. However, HER4 may not be an ideal prognostic factor for GC.
doi:10.1371/journal.pone.0161219
PMCID: PMC4990181  PMID: 27536774
13.  RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals 
B-lineage cells reconcile the competing needs of proliferation and genome stability.
DNA double-strand breaks (DSBs) activate a canonical DNA damage response, including highly conserved cell cycle checkpoint pathways that prevent cells with DSBs from progressing through the cell cycle. In developing B cells, pre–B cell receptor (pre–BCR) signals initiate immunoglobulin light (Igl) chain gene assembly, leading to RAG-mediated DNA DSBs. The pre–BCR also promotes cell cycle entry, which could cause aberrant DSB repair and genome instability in pre–B cells. Here, we show that RAG DSBs inhibit pre–BCR signals through the ATM- and NF-κB2–dependent induction of SPIC, a hematopoietic-specific transcriptional repressor. SPIC inhibits expression of the SYK tyrosine kinase and BLNK adaptor, resulting in suppression of pre–BCR signaling. This regulatory circuit prevents the pre–BCR from inducing additional Igl chain gene rearrangements and driving pre–B cells with RAG DSBs into cycle. We propose that pre–B cells toggle between pre–BCR signals and a RAG DSB-dependent checkpoint to maintain genome stability while iteratively assembling Igl chain genes.
doi:10.1084/jem.20151048
PMCID: PMC4749927  PMID: 26834154
14.  Gender Difference on the Association between Dietary Patterns and Obesity in Chinese Middle-Aged and Elderly Populations 
Nutrients  2016;8(8):448.
Dietary patterns are linked to obesity, but the gender difference in the association between dietary patterns and obesity remains unclear. We explored this gender difference in a middle-aged and elderly populations in Shanghai. Residents (n = 2046; aged ≥45 years; 968 men and 1078 women) who participated in the Shanghai Food Consumption Survey were studied. Factor analysis of data from four periods of 24-h dietary recalls (across 2012–2014) identified dietary patterns. Height, body weight, and waist circumference were measured to calculate the body mass index. A log binominal model examined the association between dietary patterns and obesity, stratified by gender. Four dietary patterns were identified for both genders: rice staple, wheat staple, snacks, and prudent patterns. The rice staple pattern was associated positively with abdominal obesity in men (prevalence ratio (PR) = 1.358; 95% confidence interval (CI) 1.132–1.639; p = 0.001), but was associated negatively with general obesity in women (PR = 0.745; 95% CI: 0.673–0.807; p = 0.031). Men in the highest quartile of the wheat staple pattern had significantly greater risk of central obesity (PR = 1.331; 95% CI: 1.094–1.627; p = 0.005). There may be gender differences in the association between dietary patterns and obesity in middle-aged and elderly populations in Shanghai, China.
doi:10.3390/nu8080448
PMCID: PMC4997363  PMID: 27455322
dietary patterns; obesity; gender difference; factor analysis; middle-aged and elderly Chinese people
15.  Autocrine activity of BDNF induced by the STAT3 signaling pathway causes prolonged TrkB activation and promotes human non-small-cell lung cancer proliferation 
Scientific Reports  2016;6:30404.
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin superfamily, which has been implicated in the pathophysiology of the nervous system. Recently, several studies have suggested that BDNF and/or its receptor, tropomyosin related kinase B (TrkB), are involved in tumor growth and metastasis in several cancers, including prostate cancer, neuroblastoma, pancreatic ductal carcinoma, hepatocellular carcinoma, and lung cancer. Despite the increasing emphasis on BDNF/TrkB signaling in human tumors, how it participates in primary tumors has not yet been determined. Additionally, little is known about the molecular mechanisms that elicit signaling downstream of TrkB in the progression of non-small-cell lung cancer (NSCLC). In this study, we report the significant expression of BDNF in NSCLC samples and show that BDNF stimulation increases the synthesis of BDNF itself through activation of STAT3 in lung cancer cells. The release of BDNF can in turn activate TrkB signaling. The activation of both TrkB and STAT3 contribute to downstream signaling and promote human non-small-cell lung cancer proliferation.
doi:10.1038/srep30404
PMCID: PMC4960652  PMID: 27456333
16.  Rapid Quantification of Melamine in Different Brands/Types of Milk Powders Using Standard Addition Net Analyte Signal and Near-Infrared Spectroscopy 
Multivariate calibration (MVC) and near-infrared (NIR) spectroscopy have demonstrated potential for rapid analysis of melamine in various dairy products. However, the practical application of ordinary MVC can be largely restricted because the prediction of a new sample from an uncalibrated batch would be subject to a significant bias due to matrix effect. In this study, the feasibility of using NIR spectroscopy and the standard addition (SA) net analyte signal (NAS) method (SANAS) for rapid quantification of melamine in different brands/types of milk powders was investigated. In SANAS, the NAS vector of melamine in an unknown sample as well as in a series of samples added with melamine standards was calculated and then the Euclidean norms of series standards were used to build a straightforward univariate regression model. The analysis results of 10 different brands/types of milk powders with melamine levels 0~0.12% (w/w) indicate that SANAS obtained accurate results with the root mean squared error of prediction (RMSEP) values ranging from 0.0012 to 0.0029. An additional advantage of NAS is to visualize and control the possible unwanted variations during standard addition. The proposed method will provide a practically useful tool for rapid and nondestructive quantification of melamine in different brands/types of milk powders.
doi:10.1155/2016/9256102
PMCID: PMC4971385  PMID: 27525154
17.  Expression and clinical significance of Apollon in esophageal squamous cell carcinoma 
Molecular Medicine Reports  2016;14(3):1933-1940.
Apollon, an unusually large member of the inhibitors of apoptosis protein family, may be important for oncogenesis development. The aim of the present study was to assess the association between esophageal squamous cell carcinoma (ESCC) and Apollon expression levels, and to highlight the association between Apollon and the occurrence, development and prognosis of ESCC. Apollon expression was detected by immunohistochemical staining and reverse transcription-quantitative polymerase chain reaction in ESCC tissues, adjacent non-cancerous tissues and paired normal tissues respectively, in order to analyze the association between Apollon expression and the clinicopathological features of ESCC. Survival analysis was used to assess the prognostic significance of Apollon expression. It was determined that the mRNA and protein expression levels of Apollon were significantly higher in the carcinoma tissues compared with the adjacent non-cancerous tissues and normal control tissues (P<0.001). There was a significant difference in lymph node involvement and the tumor, nodes, and metastases stage in patients categorized according to different Apollon expression levels. The prognostic significance of Apollon was also determined using the log-rank method. The overexpression of Apollon was associated with shorter overall survival and disease-free survival rates. The present study indicates that Apollon expression is associated with the biological characteristics of ESCC, and may be a valuable prognostic factor and a novel chemotherapeutic target for ESCC treatment.
doi:10.3892/mmr.2016.5473
PMCID: PMC4991688  PMID: 27432467
esophageal squamous cell carcinoma; Apollon; apoptosis; inhibitors of apoptosis protein; prognosis
18.  Conpair: concordance and contamination estimator for matched tumor–normal pairs 
Bioinformatics  2016;32(20):3196-3198.
Motivation: Sequencing of matched tumor and normal samples is the standard study design for reliable detection of somatic alterations. However, even very low levels of cross-sample contamination significantly impact calling of somatic mutations, because contaminant germline variants can be incorrectly interpreted as somatic. There are currently no sequence-only based methods that reliably estimate contamination levels in tumor samples, which frequently display copy number changes. As a solution, we developed Conpair, a tool for detection of sample swaps and cross-individual contamination in whole-genome and whole-exome tumor–normal sequencing experiments.
Results: On a ladder of in silico contaminated samples, we demonstrated that Conpair reliably measures contamination levels as low as 0.1%, even in presence of copy number changes. We also estimated contamination levels in glioblastoma WGS and WXS tumor–normal datasets from TCGA and showed that they strongly correlate with tumor–normal concordance, as well as with the number of germline variants called as somatic by several widely-used somatic callers.
Availability and Implementation: The method is available at: https://github.com/nygenome/conpair.
Contact: egrabowska@gmail.com or mczody@nygenome.org
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btw389
PMCID: PMC5048070  PMID: 27354699
19.  Palladium/N-heterocyclic carbene catalysed regio and diastereoselective reaction of ketones with allyl reagents via inner-sphere mechanism 
Nature Communications  2016;7:11806.
The palladium-catalysed allylic substitution reaction is one of the most important reactions in transition-metal catalysis and has been well-studied in the past decades. Most of the reactions proceed through an outer-sphere mechanism, affording linear products when monosubstituted allyl reagents are used. Here, we report an efficient Palladium-catalysed protocol for reactions of β-substituted ketones with monosubstituted allyl substrates, simply by using N-heterocyclic carbene as ligand, leading to branched products with up to three contiguous stereocentres in a (syn, anti)-mode with excellent regio and diastereoselectivities. The scope of the protocol in organic synthesis has been examined preliminarily. Mechanistic studies by both experiments and density functional theory (DFT) calculations reveal that the reaction proceeds via an inner-sphere mechanism—nucleophilic attack of enolate oxygen on Palladium followed by C–C bond-forming [3,3']-reductive elimination.
Palladium catalyzed allylic substitution reactions typically proceed via an outer sphere mechanism, yielding predominately linear products. Here, the authors report an inner sphere process for the allylic substitution of ketone enolates, giving branched products with up to three contiguous stereocentres.
doi:10.1038/ncomms11806
PMCID: PMC4906412  PMID: 27283477
20.  Multiple Patterns of Regulation and Overexpression of a Ribonuclease-Like Pathogenesis-Related Protein Gene, OsPR10a, Conferring Disease Resistance in Rice and Arabidopsis 
PLoS ONE  2016;11(6):e0156414.
An abundant 17 kDa RNase, encoded by OsPR10a (also known as PBZ1), was purified from Pi-starved rice suspension-cultured cells. Biochemical analysis showed that the range of optimal temperature for its RNase activity was 40–70°C and the optimum pH was 5.0. Disulfide bond formation and divalent metal ion Mg2+ were required for the RNase activity. The expression of OsPR10a::GUS in transgenic rice was induced upon phosphate (Pi) starvation, wounding, infection by the pathogen Xanthomonas oryzae pv. oryzae (Xoo), leaf senescence, anther, style, the style-ovary junction, germinating embryo and shoot. We also provide first evidence in whole-plant system, demonstrated that OsPR10a-overexpressing in rice and Arabidopsis conferred significant level of enhanced resistance to infection by the pathogen Xoo and Xanthomona campestris pv. campestris (Xcc), respectively. Transgenic rice and Arabidopsis overexpressing OsPR10a significantly increased the length of primary root under phosphate deficiency (-Pi) condition. These results showed that OsPR10a might play multiple roles in phosphate recycling in phosphate-starved cells and senescing leaves, and could improve resistance to pathogen infection and/or against chewing insect pests. It is possible that Pi acquisition or homeostasis is associated with plant disease resistance. Our findings suggest that gene regulation of OsPR10a could act as a good model system to unravel the mechanisms behind the correlation between Pi starvation and plant-pathogen interactions, and also provides a potential application in crops disease resistance.
doi:10.1371/journal.pone.0156414
PMCID: PMC4892481  PMID: 27258121
21.  Structural dynamics of ribosome subunit association studied by mixing-spraying time-resolved cryo-EM 
Structure (London, England : 1993)  2015;23(6):1097-1105.
Ribosomal subunit association is a key checkpoint in translation initiation, but its structural dynamics are poorly understood. Here, we used a recently developed mixing-spraying, time-resolved, cryogenic electron microscopy (cryo-EM) method to study ribosomal subunit association in the sub-second time range. We have improved this method and increased the cryo-EM data yield by tenfold. Pre-equilibrium states of the association reaction were captured by reacting the mixture of ribosomal subunits for 60 ms and 140 ms. We also identified three distinct ribosome conformations in the associated ribosomes. The observed proportions of these conformations are the same in these two time points, suggesting that ribosomes equilibrate among the three conformations within less than 60 ms upon formation. Our results demonstrate that the mixing-spraying method can capture multiple states of macromolecules during a sub-second reaction. Other fast processes, such as translation initiation, decoding and ribosome recycling, are amenable to study with this method.
doi:10.1016/j.str.2015.04.007
PMCID: PMC4456197  PMID: 26004440
time-resolved; cryo-EM; mixing-spraying; ribosome subunit association; structural dynamics
22.  Clinicopathological Characteristics of Mucinous Breast Cancer: A Retrospective Analysis of a 10-Year Study 
PLoS ONE  2016;11(5):e0155132.
Background
Mucinous breast carcinoma (MC) is a special type of breast cancer that presents with a large amount of extracellular mucin. MC comprises approximately 4% of all invasive breast cancers. This type of tumor has a better prognosis and higher incidence in peri- and post-menopausal patients. Pathologically, there are two main subtypes of MC: pure and mixed. In this study, we describe 10 years of experience with MC at the Zhejiang Cancer Hospital in China, specifically, clinical data, histological findings and immunohistochemical features.
Methods
We identified MC patients who were diagnosed as operable and completed clinical treatment from January 2001 to January 2011. The clinicopathological data included the age at diagnosis, tumor size, TNM stage, presence and number of lymph node (LN) metastases, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) status and p53 expression. If the tumor was defined as mixed mucinous carcinoma (MMC), IHC was performed on a non-mucinous part, such as invasive ductal and lobular cancer. We evaluated the clinical characteristics of all MC patients using chi-square, one-way ANOVA and LSD tests. We also studied the correlations between all of the clinical parameters and LN metastasis in a binary logistic regression analysis. We used ten consecutive years of data that were collected at Zhejiang Cancer Hospital.
Results
We identified 48 cases of pure mucinous carcinoma (PMC) and 77 cases of MMC. The 48 PMC cases consisted of 38 PMC-A and 10 PMC-B subtypes. The MMCs were divided into two groups, those with partial mixed mucinous breast carcinoma (pMMC, 58 cases) and those with main mixed mucinous breast carcinoma (mMMC, 19 cases). pMMC was defined by tumors with less than 50% mucinous components, while mMMC was defined by tumors where the mucinous component accounted for 50% to 90% of the tumor. No significant differences in the clinicopathological characteristics were noted between the patients with PMC-A and those with PMC-B. The tumor size was larger in the mMMC than PMC cases (44.84 mm vs. 30.06 mm, p = 0.021). The number of positive LN metastases was greater in pMMC than PMC patients (p = 0.024). The clinical stages were significantly different among the three groups, with the pMMC group having more stage III-IV patients than the other two groups (p = 0.005). The incidence of LN metastasis was also higher in the pMMC cases (pMMC vs. mMMC and PMC, 50% vs. 31.58% and 18.75%, p = 0.003). The PMC patients had much lower p53 expression than the other two groups (PMC vs. pMMC and mMMC, 27.08% vs. 55.17% and 57.89%, p = 0.007). The tumor size (>30mm), p53 expression and less proportion of the mucinous component are associated with risk of LN metastasis.
Conclusion
Based on the results of this study, we conclude that the tumor size, status of LN metastasis, clinical stage, and p53 mutation rate may differ between MMC and PMC patients. The tumor size (>30mm), p53 mutation and less proportion of the mucinous component should be considered risk factors of LN metastasis in MC patients.
doi:10.1371/journal.pone.0155132
PMCID: PMC4883756  PMID: 27232881
23.  Correlation Between Interleukin-1β-511 C/T Polymorphism and Gastric Cancer in Chinese Populations: A Meta-Analysis 
Background
Several studies have indicated that interleukin (IL)-1β-511 C/T polymorphism may contribute to individual susceptibility to gastric cancer, but the results vary among regions and races. No relevant meta-analysis has been conducted in a Chinese population. Therefore, we performed the current meta-analysis to investigate the possible correlation between IL-1β-511 C/T polymorphism and gastric cancer susceptibility in Chinese subjects.
Material/Methods
PubMed, EmBase, Cochrane Library, Chinese Biology Medicine (CBM), Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases were searched for case-control studies published before 21 January 2015 and investigating a correlation between IL-1β-511 C/T polymorphism and gastric cancer susceptibility. Two investigators independently screened the studies, extracted data, and evaluated the quality of included studies with the Newcastle-Ottawa scale. Meta-analysis was conducted with STATA 12.0.
Results
A total of 27 articles from 28 case-control studies were collected. Meta-analysis showed that IL-1β-511C/T polymorphism was related to increased susceptibility to gastric cancer in Chinese subjects [T vs. C: OR=1.21, 95%CI (1.07–1.37), P<0.01; TT vs. CC: OR=1.41, 95%CI (1.11–1.80), P<0.01; CT vs. CC: OR=1.26, 95% CI (1.05–1.50), P<0.01; TT+CT vs. CC: OR=1.31, 95%CI (1.08–1.58), P<0.01; and TT vs. CT+CC: OR=1.24, 95%CI (1.05–1.47), P<0.01]. Subgroup analysis showed a significant correlation between IL-1β-511C/T polymorphism and susceptibility to gastric cancer in residents of southern China and in patients with intestinal-type gastric cancer, but not in residents of northern China or in patients with diffuse gastric cancer. Moreover, H. pylori-infected subjects carrying T (CT+TT) exhibited a relatively higher risk of GC [OR=2.4, 95% CI (1.2–5.1), P=0.02].
Conclusions
IL-1β-511C/T polymorphism is significantly associated with increased susceptibility to gastric cancer in residents of southern China and in intestinal-type gastric cancer. We also found a synergistic interaction between IL-1β-511C/T polymorphism and H. pylori infection in the development of GC.
doi:10.12659/MSM.895771
PMCID: PMC4915325  PMID: 27215350
China; Interleukin-1beta; Meta-Analysis; Polymorphism, Single-Stranded Conformational; Stomach Neoplasms
24.  GPCR dimerization in brainstem nuclei contributes to the development of hypertension 
British Journal of Pharmacology  2015;172(10):2507-2518.
Background and Purpose
μ-Opioid receptors, pro-opiomelanocortin and pro-enkephalin are highly expressed in the nucleus tractus solitarii (NTS) and μ receptor agonists given to the NTS dose-dependently increased BP. However, the molecular mechanisms of this process remain unclear. In vitro, μ receptors heterodimerize with α2A-adrenoceptors. We hypothesized that α2A-adrenoceptor agonists would lose their depressor effects when their receptors heterodimerize in the NTS with μ receptors.
Experimental Approach
We microinjected μ-opioid agonists and antagonists into the NTS of rats and measured changes in BP. Formation of μ receptor/α2A-adrenoceptor heterodimers was assessed with immunofluorescence and co-immunoprecipitation methods, along with proximity ligation assays.
Key Results
Immunofluorescence staining revealed colocalization of α2A-adrenoceptors and μ receptors in NTS neurons. Co-immunoprecipitation revealed interactions between α2A-adrenoceptors and μ receptors. In situ proximity ligation assays confirmed the presence of μ receptor/α2A-adrenoceptor heterodimers in the NTS. Higher levels of endogenous endomorphin-1 and μ receptor/α2A-adrenoceptor heterodimers were found in the NTS of hypertensive rats, than in normotensive rats. Microinjection of the μ receptor agonist [D-Ala2, MePhe4, Gly5-ol]-enkephalin (DAMGO), but not that of the α2A-adrenoceptor agonist guanfacine, into the NTS of normotensive rats increased μ receptor/α2A-adrenoceptor heterodimer formation and BP elevation. The NO-dependent BP-lowering effect of α2A-adrenoceptor agonists was blunted following increased formation of μ receptor/α2A-adrenoceptor heterodimers in the NTS of hypertensive rats and DAMGO-treated normotensive rats.
Conclusions and Implications
Increases in endogenous μ receptor agonists in the NTS induced μ receptor/α2A-adrenoceptor heterodimer formation and reduced the NO-dependent depressor effect of α2A-adrenoceptor agonists. This process could contribute to the pathogenesis of hypertension.
doi:10.1111/bph.13074
PMCID: PMC4409903  PMID: 25573074
25.  Echocardiographic Diagnosis of Incidentally Found Left Coronary Artery to Pulmonary Artery Fistula in an 11-Year-Old Girl  
Acta Cardiologica Sinica  2016;32(3):359-362.
We report on a healthy 11-year-old girl who presented to our facility with sudden onset of fainting in a strenuous running course. Transthoracic echocardiography at short-axis view showed a diastolic flow into the main pulmonary artery (PA). The diagnosis of left anterior descending artery (LAD) to PA fistula was documented by cardiac computed tomography and catheterization. Interventional therapy of LAD to the main PA fistula was not performed because of no evidence of myocardial ischemia or significant hemodynamic change. Presently, the patient remains asymptomatic. Coronary fistula with an incidence of about 0.1-0.8% is very rare and may be undetected, particularly in pediatric patients without cardiac murmur. We herein describe the diagnostic approach and discuss the current treatment modalities.
PMCID: PMC4884765  PMID: 27274178
Coronary angiography; Coronary artery fistula; Echocardiography

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