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1.  Phosphorylated Mammalian Target of Rapamycin p-mTOR Is a Favorable Prognostic Factor than mTOR in Gastric Cancer 
PLoS ONE  2016;11(12):e0168085.
Aims
The mammalian target of rapamycin (mTOR) and phosphorylated mTOR (p-mTOR) occurring downstream in the PI3K/Akt/mTOR pathway, are regarded as potential prognostic markers for gastric cancer (GC). However, the prognostic value of mTOR/p-mTOR expression remains controversial. In this study, we determined the expression of mTOR, p-mTOR, p70S6k, and p-p70S6K in GC, and investigated the correlation between their overexpression, clinicopathological parameters, and overall survival (OS).
Methods
The expression of mTOR, p-mTOR, p70S6k, and p-p70S6K was examined in 120 GC patients by immunohistochemistry (IHC). The association of protein expression with clinicopathological features and OS was explored. The p-mTOR expression was detected in normal, adjacent, and GC tissues using Western blot. Eligible studies retrieved from PubMed, Ovid, Web of Science and Cochrane databases, were reviewed in this meta-analysis.
Results
IHC showed that the rates of expression of the signal transduction molecules mTOR, p-mTOR, p70S6k and p-p70S6K in GC were 60.8%, 54.2%, 53.3% and 53.3%, respectively. Overexpression of mTOR and p70S6K showed no significant association with clinical variables. Expression of p-mTOR was significantly associated with differentiation (P < 0.01), depth of invasion (P < 0.01), lymph node metastasis (P = 0.04) and TNM stage (P = 0.02). Expression of p-p70S6K was associated with differentiation (P = 0.006), depth of invasion (P < 0.001), and TNM stage (P = 0.02). In survival analysis, differentiation, depth of invasion, lymph node metastasis and TNM stage were not related to OS (all P > 0.05). Furthermore, p-mTOR and p-p70S6K expression, but not mTOR and p70S6K, were tightly associated with OS of GC patients (P = 0.006 and P < 0.001, respectively). In Western blot, p-mTOR was significantly higher in GC tissues than in normal and adjacent tissues. In the present meta-analysis, mTOR overexpression showed no relationship with any clinicopathological variables. However, p-mTOR was correlated with depth of invasion, and TNM stage (all P < 0.05), and its overexpression was associated with a shorter survival time (P < 0.001).
Conclusion
The results suggest that p-mTOR is a more valuable prognostic factor than mTOR in GC.
doi:10.1371/journal.pone.0168085
PMCID: PMC5179011  PMID: 28005970
2.  One-pot synthesis of carbon supported calcined-Mg/Al layered double hydroxides for antibiotic removal by slow pyrolysis of biomass waste 
Scientific Reports  2016;6:39691.
A biochar supported calcined-Mg/Al layered double hydroxides composite (CLDHs/BC) was synthesized by a one-pot slow pyrolysis of LDHs preloaded bagasse biomass. Multiple characterizations of the product illustrated that the calcined-Mg/Al layered double hydroxides (CLDHs) were successfully coated onto the biochar in slow pyrolysis of pre-treated biomass. The as-synthesized CLDHs/BC could efficiently remove antibiotic tetracycline from aqueous solutions. The coating of CLDHs significantly increased the adsorption ability of biochar, and CLDHs/BC exhibited more than 2 times higher adsorption capacity than that of the pristine biochar (BC) in the tested pH range. The maximum adsorption capacity of CLDHs/BC for tetracycline was 1118.12 mg/g at 318 K. The experimental results suggested that the interaction with LDHs on biochar played a dominant role in tetracycline adsorption, accompanied with π–π interaction and hydrogen bond. This study provides a feasible and simple approach for the preparation of high-performance material for antibiotics contaminated wastewater treatment in a cost-effective way.
doi:10.1038/srep39691
PMCID: PMC5175202  PMID: 28000759
3.  Microneedles with Controlled Bubble Sizes and Drug Distributions for Efficient Transdermal Drug Delivery 
Scientific Reports  2016;6:38755.
Drug loaded dissolving microneedles (DMNs) fabricated with water soluble polymers have received increasing attentions as a safe and efficient transdermal drug delivery system. Usually, to reach a high drug delivery efficiency, an ideal drug distribution is gathering more drugs in the tip or the top part of DMNs. In this work, we introduce an easy and new method to introduce a bubble with controlled size into the body of DMNs. The introduction of bubbles can prevent the drug diffusion into the whole body of the MNs. The heights of the bubbles are well controlled from 75 μm to 400 μm just by changing the mass concentrations of polymer casting solution from 30 wt% to 10 wt%. The drug-loaded bubble MNs show reliable mechanical properties and successful insertion into the skins. For the MNs prepared from 15 wt% PVA solution, bubble MNs achieve over 80% of drug delivery efficiency in 20 seconds, which is only 10% for the traditional solid MNs. Additionally, the bubble microstructures in the MNs are also demonstrated to be consistent and identical regardless the extension of MN arrays. These scalable bubble MNs may be a promising carrier for the transdermal delivery of various pharmaceuticals.
doi:10.1038/srep38755
PMCID: PMC5144082  PMID: 27929104
4.  Pretreatment Hematocrit Is Superior to Hemoglobin as a Prognostic Factor for Triple Negative Breast Cancer 
PLoS ONE  2016;11(11):e0165133.
Background
Anemia usually refers to low hemoglobin (Hb) levels. Previous studies indicated that anemia negatively influence the survival in various cancers. Hematocrit (HCT) is the volume percentage of red blood cells in blood, which could indicate anemia in both individuals and populations. This study compared the value of HCT with that of Hb for predicting outcomes of patients who underwent treatment for triple negative breast cancer (TNBC).
Methods
A retrospective study of 293 triple negative breast cancer patients, accepting treatment from January 2004 to December 2009 at Sun Yat-sen University Cancer Center, was conducted. Kaplan-Meier curves and multivariate Cox proportional models were used to calculate disease free survival (DFS) and overall survival (OS).
Results
The cut-off value of HCT was 35.9% determined by X-tile software analysis. The cut-off value of Hb was 12.0 g/dl based on the World Health Organization (WHO) criteria. In univariate analysis, low HCT and low Hb were both significantly associated with decreased DFS and OS. In multivariate analysis, HCT (HR: 0.570; 95% CI: 0.331–0.981, P = 0.042 for DFS; HR: 0.456; 95% CI: 0.256–0.813, P = 0.008 for OS) was still identified as independent predictor of outcome, but not Hb.
Conclusion
Pretreatment low HCT is independently associated with poor prognosis in TNBC patients. However, HCT was found to be superior to Hb in terms of predicting breast cancer mortality. In the future, large-scale prospective studies or validation studies are needed to verify our findings.
doi:10.1371/journal.pone.0165133
PMCID: PMC5112796  PMID: 27851755
5.  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
6.  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
7.  Current status and future prospects of mesenchymal stem cell therapy for liver fibrosis*  
Liver fibrosis is the end-stage of many chronic liver diseases and is a significant health threat. The only effective therapy is liver transplantation, which still has many problems, including the lack of donor sources, immunological rejection, and high surgery costs, among others. However, the use of cell therapy is becoming more prevalent, and mesenchymal stem cells (MSCs) seem to be a promising cell type for the treatment of liver fibrosis. MSCs have multiple differentiation abilities, allowing them to migrate directly into injured tissue and differentiate into hepatocyte-like cells. Additionally, MSCs can release various growth factors and cytokines to increase hepatocyte regeneration, regress liver fibrosis, and regulate inflammation and immune responses. In this review, we summarize the current uses of MSC therapies for liver fibrosis and suggest potential future applications.
doi:10.1631/jzus.B1600101
PMCID: PMC5120225  PMID: 27819130
Liver fibrosis; Cell therapy; Mesenchymal stem cells
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  Safety and efficacy profile of lenvatinib in cancer therapy: a systematic review and meta-analysis 
Oncotarget  2016;7(28):44545-44557.
To systematically review the safety and efficacy of lenvatinib in the treatment of patients, we retrieved all the relevant clinical trials on the adverse events (AEs) and survival outcomes of lenvatinib through PubMed, Medline, Embase, Web of Science and Cochrane Collaboration's Central register of controlled trial. Fourteen eligible studies involving a total of 978 patients were included in our analysis. The most common all-grade AEs observed in patients treated with lenvatinib were hematuria (56.6%), fatigue (52.2%) and decreased appetite (50.5%). The most frequently observed grade ≥3 AEs were thrombocytopenia (25.4%), hypertension (17.7%) and edema peripheral (15.5%). The incidences of both all-grade and high-grade hypertension were significantly increased. Meanwhile, the controlled trial suggested that progression free survival (PFS) was significantly longer in the lenvatinib group than the placebo group. Subgroup analyses showed that mean PFS for renal cell carcinoma was 10.933±1.828 months (95% CI 7.350-14.515, p < 0.001), and that for thyroid cancer was 18.344±0.083 months (95% CI 18.181-18.506, p < 0.001). In conclusion, lenvatinib is an effective agent in thyroid cancer. Early monitoring and effective management of side effects are crucial for the safe use of this drug.
doi:10.18632/oncotarget.10019
PMCID: PMC5190117  PMID: 27329593
safety; efficacy; lenvatinib; cancer; meta-analysis
23.  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
24.  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
25.  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

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