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1.  Pharmacological TLR4 Inhibition Protects against Acute and Chronic Fat-Induced Insulin Resistance in Rats 
PLoS ONE  2015;10(7):e0132575.
Aims
To evaluate whether pharmacological TLR4 inhibition protects against acute and chronic fat-induced insulin resistance in rats.
Materials and Methods
For the acute experiment, rats received a TLR4 inhibitor [TAK-242 or E5564 (2x5 mg/kg i.v. bolus)] or vehicle, and an 8-h Intralipid (20%, 8.5 mg/kg/min) or saline infusion, followed by a two-step hyperinsulinemic-euglycemic clamp. For the chronic experiment, rats were subcutaneously implanted with a slow-release pellet of TAK-242 (1.5 mg/d) or placebo. Rats then received a high fat diet (HFD) or a low fat control diet (LFD) for 10 weeks, followed by a two-step insulin clamp.
Results
Acute experiment; the lipid-induced reduction (18%) in insulin-stimulated glucose disposal (Rd) was attenuated by TAK-242 and E5564 (the effect of E5564 was more robust), suggesting improved peripheral insulin action. Insulin was able to suppress hepatic glucose production (HGP) in saline- but not lipid-treated rats. TAK-242, but not E5564, partially restored this effect, suggesting improved HGP. Chronic experiment; insulin-stimulated Rd was reduced ~30% by the HFD, but completely restored by TAK-242. Insulin could not suppress HGP in rats fed a HFD and TAK-242 had no effect on HGP.
Conclusions
Pharmacological TLR4 inhibition provides partial protection against acute and chronic fat-induced insulin resistance in vivo.
doi:10.1371/journal.pone.0132575
PMCID: PMC4510579  PMID: 26196892
2.  Intracoronary infusion of Wharton’s jelly-derived mesenchymal stem cells in acute myocardial infarction: double-blind, randomized controlled trial 
BMC Medicine  2015;13:162.
Background
The use of adult stem cells is limited by the quality and quantity of host stem cells. It has been demonstrated that Wharton’s jelly–derived mesenchymal stem cells (WJMSCs), a primitive stromal population, could integrate into ischemic cardiac tissues and significantly improve heart function. In this randomized, controlled trial, our aim was to assess the safety and efficacy of intracoronary WJMSCs in patients with ST-elevation acute myocardial infarction (AMI).
Methods
In a multicenter trial, 116 patients with acute ST-elevation MI were randomly assigned to receive an intracoronary infusion of WJMSCs or placebo into the infarct artery at five to seven days after successful reperfusion therapy. The primary endpoint of safety: the incidence of adverse events (AEs) within 18 months, was monitored and quantified. The endpoint of efficacy: the absolute changes in myocardial viability and perfusion of the infarcted region from baseline to four months, global left ventricular ejection fraction (LVEF) from baseline to 18 months were measured using F-18-fluorodeoxyglucose positron emission computed tomography (F-18-FDG-PET) and 99mTc-sestamibi single-photon emission computed tomography (99mTc-SPECT), and two-dimensional echocardiography, respectively.
Results
During 18 months follow-up, AEs rates and laboratory tests including tumor, immune, and hematologic indexes were not different between the two groups. The absolute increase in the myocardial viability (PET) and perfusion within the infarcted territory (SPECT) was significantly greater in the WJMSC group [6.9 ± 0.6 % (95 %CI, 5.7 to 8.2)] and [7.1 ± 0.8 % (95 %CI, 5.4 to 8.8) than in the placebo group [3.3 ± 0.7 % (95 %CI, 1.8 to 4.7), P <0.0001] and 3.9 ± 0.6(95 %CI, 2.8 to 5.0), P = 0.002] at four months. The absolute increase in the LVEF at 18 months in the WJMSC group was significantly greater than that in the placebo group [7.8 ± 0.9 (6.0 to approximately 9.7) vs. 2.8 ± 1.2 (0.4 to approximately 5.1), P = 0.001]. Concomitantly, the absolute decreases in LV end-systolic volumes and end-diastolic volumes at 18 months in the WJMSC group were significantly greater than those in the placebo group (P = 0.0004, P = 0.004, respectively).
Conclusions
Intracoronary infusion of WJMSCs is safe and effective in patients with AMI, providing clinically relevant therapy within a favorable time window. This study encourages additional clinical trials to determine whether WJMSCs may serve as a novel alternative to BMSCs for cardiac stem cell-based therapy.
Trial registration
Clinical Trials NCT01291329 (02/05/2011).
doi:10.1186/s12916-015-0399-z
PMCID: PMC4499169  PMID: 26162993
Myocardial infarction; Mesenchymal stem cells; Wharton’s jelly of umbilical cord
3.  Huaier Extract Induces Autophagic Cell Death by Inhibiting the mTOR/S6K Pathway in Breast Cancer Cells 
PLoS ONE  2015;10(7):e0131771.
Huaier extract is attracting increased attention due to its biological activities, including antitumor, anti-parasite and immunomodulatory effects. Here, we investigated the role of autophagy in Huaier-induced cytotoxicity in MDA-MB-231, MDA-MB-468 and MCF7 breast cancer cells. Huaier treatment inhibited cell viability in all three cell lines and induced various large membranous vacuoles in the cytoplasm. In addition, electron microscopy, MDC staining, accumulated expression of autophagy markers and flow cytometry revealed that Huaier extract triggered autophagy. Inhibition of autophagy attenuated Huaier-induced cell death. Furthermore, Huaier extract inhibited the mammalian target of the rapamycin (mTOR)/S6K pathway in breast cancer cells. After implanting MDA-MB-231 cells subcutaneously into the right flank of BALB/c nu/nu mice, Huaier extract induced autophagy and effectively inhibited xenograft tumor growth. This study is the first to show that Huaier-induced cytotoxicity is partially mediated through autophagic cell death in breast cancer cells through suppression of the mTOR/S6K pathway.
doi:10.1371/journal.pone.0131771
PMCID: PMC4489895  PMID: 26134510
4.  Risk of Hospitalization According to Chemotherapy Regimen in Early-Stage Breast Cancer 
Journal of Clinical Oncology  2014;32(19):2010-2017.
Purpose
To compare the risk of hospitalization between patients with early-stage breast cancer who received different chemotherapy regimens.
Patient and Methods
We identified 3,567 patients older than age 65 years from the SEER/Texas Cancer Registry-Medicare database and 9,327 patients younger than age 65 years from the MarketScan database who were diagnosed with early-stage breast cancer between 2003 and 2007. The selection was nonrandomized and nonprospectively collected. We categorized patients according to the regimens they received: docetaxel (T) and cyclophosphamide (C), doxorubicin (A) and C, TAC, AC + T, dose-dense AC + paclitaxel (P) or AC + weekly P. We compared the rates of chemotherapy-related hospitalizations that occurred within 6 months of chemotherapy initiation and used multivariable logistic regression analysis to identify the factors associated with these hospitalizations.
Results
Among patients younger than age 65 years, the hospitalization rates ranged from 6.2% (dose-dense AC + P) to 10.0% (TAC), and those who received TAC and AC + T had significantly higher rates of hospitalization than did patients who received TC. Among patients older than age 65 years, these rates ranged from 12.7% (TC) to 24.2% (TAC) and the rates of hospitalization of patients who received TAC, AC + T, AC, or AC + weekly P were higher than those of patients who received TC.
Conclusion
TAC and AC + T were associated with the highest risk of hospitalization in patients younger than age 65 years. Among patients older than age 65 years, all regimens (aside from dose-dense AC + P) were associated with a higher risk of hospitalization than TC. Results may be affected by selection biases where less aggressive regimens are offered to frailer patients.
doi:10.1200/JCO.2013.49.3676
PMCID: PMC4164758  PMID: 24868022
5.  Analysis of the siRNA-Mediated Gene Silencing Process Targeting Three Homologous Genes Controlling Soybean Seed Oil Quality 
PLoS ONE  2015;10(6):e0129010.
In the past decade, RNA silencing has gained significant attention because of its success in genomic scale research and also in the genetic improvement of crop plants. However, little is known about the molecular basis of siRNA processing in association with its target transcript. To reveal this process for improving hpRNA-mediated gene silencing in crop plants, the soybean GmFAD3 gene family was chosen as a test model. We analyzed RNAi mutant soybean lines in which three members of the GmFAD3 gene family were silenced. The silencing levels of FAD3A, FAD3B and FAD3C were correlated with the degrees of sequence homology between the inverted repeat of hpRNA and the GmFAD3 transcripts in the RNAi lines. Strikingly, transgenes in two of the three RNAi lines were heavily methylated, leading to a dramatic reduction of hpRNA-derived siRNAs. Small RNAs corresponding to the loop portion of the hairpin transcript were detected while much lower levels of siRNAs were found outside of the target region. siRNAs generated from the 318-bp inverted repeat were found to be diced much more frequently at stem sequences close to the loop and associated with the inferred cleavage sites on the target transcripts, manifesting “hot spots”. The top candidate hpRNA-derived siRNA share certain sequence features with mature miRNA. This is the first comprehensive and detailed study revealing the siRNA-mediated gene silencing mechanism in crop plants using gene family GmFAD3 as a test model.
doi:10.1371/journal.pone.0129010
PMCID: PMC4465718  PMID: 26061033
6.  The Prevalence and Associated Risk Factors of Impaired Glucose Regulation in Chinese Adults: A Population-Based Cross-Sectional Study 
The goal of this study was to determine the prevalence and associated risk factors of impaired glucose regulation (IGR) in the population of Tongzhou, China, and to provide scientific basis for preventive interventions. In the study, the overall age-standardized prevalence of IGR (16.0%) in Tongzhou residents was higher than that in the national population (15.0%). There was no significant geographic difference in prevalence of IGR between urban and rural males. Older age, elevated blood pressure, high serum lipids, overweight, and central obesity were significantly associated with increased risk of IGR.
doi:10.1155/2015/731583
PMCID: PMC4468349  PMID: 26136780
7.  Phylogenetic analyses provide the first insights into the evolution of OVATE family proteins in land plants 
Annals of Botany  2014;113(7):1219-1233.
Background and Aims
The OVATE gene encodes a nuclear-localized regulatory protein belonging to a distinct family of plant-specific proteins known as the OVATE family proteins (OFPs). OVATE was first identified as a key regulator of fruit shape in tomato, with nonsense mutants displaying pear-shaped fruits. However, the role of OFPs in plant development has been poorly characterized.
Methods
Public databases were searched and a total of 265 putative OVATE protein sequences were identified from 13 sequenced plant genomes that represent the major evolutionary lineages of land plants. A phylogenetic analysis was conducted based on the alignment of the conserved OVATE domain from these 13 selected plant genomes. The expression patterns of tomato SlOFP genes were analysed via quantitative real-time PCR. The pattern of OVATE gene duplication resulting in the expansion of the gene family was determined in arabidopsis, rice and tomato.
Key Results
Genes for OFPs were found to be present in all the sampled land plant genomes, including the early-diverged lineages, mosses and lycophytes. Phylogenetic analysis based on the amino acid sequences of the conserved OVATE domain defined 11 sub-groups of OFPs in angiosperms. Different evolutionary mechanisms are proposed for OVATE family evolution, namely conserved evolution and divergent expansion. Characterization of the AtOFP family in arabidopsis, the OsOFP family in rice and the SlOFP family in tomato provided further details regarding the evolutionary framework and revealed a major contribution of tandem and segmental duplications towards expansion of the OVATE gene family.
Conclusions
This first genome-wide survey on OFPs provides new insights into the evolution of the OVATE protein family and establishes a solid base for future functional genomics studies on this important but poorly characterized regulatory protein family in plants.
doi:10.1093/aob/mcu061
PMCID: PMC4030818  PMID: 24812252
OVATE family proteins; OFP; land plants; angiosperm; phylogenetic analyses; Arabidopsis thaliana; Oryza sativa; Solanum lycopersicum; segmental duplication; tandem duplication
8.  microRNA-26a suppresses recruitment of macrophages by down-regulating macrophage colony-stimulating factor expression through the PI3K/Akt pathway in hepatocellular carcinoma 
Background
microRNAs (miRNAs) have been reported to modulate macrophage colony-stimulating factor (M-CSF) and macrophages. The aim of this study was to find whether miR-26a can suppress M-CSF expression and the recruitment of macrophages.
Methods
Hepatocellular carcinoma (HCC) cell lines with decreased or increased expression of miR-26a were established in a previous study. M-CSF expression by tumor cells was measured by enzyme-linked immunosorbent assay, and cell migration assays were used to explore the effect of HCC cell lines on macrophage recruitment in vitro. Real-time PCR measured a panel of mRNAs expressed by macrophages. Xenograft models were used to observe tumor growth. Immunohistochemistry was conducted to study the relation between miR-26a expression and M-CSF expression and macrophage recruitment in patients with HCC.
Results
Ectopic expression of miR-26a reduced expression of M-CSF. The conditioned medium (CM) from HepG2 cells that overexpressed miR-26a reduced the migration ability of THP-1 cells stimulated by phorbol myristate acetate (PMA) increased expression of interleukin (IL)-12b or IL-23 mRNA and decreased expression of chemokine (C-C motif) ligand (CCL)22, CCL17, and IL-10 mRNA, in comparison to the medium from the parental HepG2 cells. These effects could be interrupted by the PI3K/Akt pathway inhibitor LY294002. Ectopic expression of miR-26a in HCC cells suppressed tumor growth, M-CSF expression, and infiltration of macrophages in tumors. Similar results were also found when using HCCLM3 cells. Furthermore, the expression of miR-26a was inversely correlated with M-CSF expression and macrophage infiltration in tumor tissues from patients with HCC.
Conclusions
miR-26a expression reduced M-CSF expression and recruitment of macrophages in HCC.
doi:10.1186/s13045-015-0150-4
PMCID: PMC4455972  PMID: 26021873
microRNA-26a; Hepatocellular carcinoma; M-CSF; Macrophages
9.  Activin A expression in esophageal carcinoma and its association with tumor aggressiveness and differentiation 
Oncology Letters  2015;10(1):143-148.
The aim of the present study was to investigate the expression of activin A in esophageal carcinoma and its association with tumor differentiation and metastasis. A total of 57 esophageal carcinoma patients and 36 controls were included in the current study. The mRNA and protein expression levels of activin A in esophageal tumors or normal esophageal tissues were determined by reverse transcription-quantitative polymerase chain reaction and immunohistochemical analysis. In addition, the association of activin A expression with esophageal carcinoma differentiation, metastasis and recurrence postoperatively was analyzed. The mRNA and protein expression levels of activin A in esophageal carcinoma were significantly higher compared with those in normal esophageal tissues (P<0.05). The expression of activin A was higher in poorly-/moderately-differentiated esophageal tumor tissues compared with that of well-differentiated or control tissues (P<0.05). Furthermore, the expression of activin A in poorly-differentiated esophageal tumor tissues was higher compared with that of moderately-differentiated tissues (P<0.05). A positive correlation was also observed between differentiation degree and activin A expression. The expression of activin A was higher in patients with lymph node metastasis compared with those without metastasis (P<0.05). The cumulative survival rate of patients with a high expression of activin A at 1, 2 and 3 years postoperatively was significantly decreased compared with that of patients with a lower expression of activin A (P<0.05); by contrast, the cumulative recurrence rate was significantly higher in patients with a lower activin A expression (P<0.05). In conclusion, abnormal expression of activin A was detected in esophageal tumor tissues, which was correlated with the tumor differentiation, metastasis, survival and recurrence. In conclusion, activin A may be used as an auxiliary index in the diagnosis and prognosis of clinical esophageal carcinoma.
doi:10.3892/ol.2015.3248
PMCID: PMC4487098  PMID: 26170990
activin A; esophageal carcinoma; tumor aggressiveness; cell differentiation
10.  Plasma genistein and risk of prostate cancer in Chinese population 
Objectives
Genistein is one of the main soy isoflavones in our daily diet. There were studies proving that high-dietary intake of genistein may relate to the low morbidity and mortality of prostate cancer (PCa) in the Asian population. Since there were few studies of plasma genistein level in the Chinese population, we performed this study to preliminarily evaluate the associations among plasma genistein, epidemiologic factors and PCa in a Chinese population.
Methods
Between 2012 and 2013, 100 men over the age of 40 underwent prostate biopsy for PCa at Huashan Hospital, Shanghai, China. Clinical information, epidemiologic information and blood samples were collected prior to biopsy for each patient. All patients underwent 10-core ultrasound-guided transperineal prostate biopsy, and the pathology results were collected after biopsy. We measured the plasma genistein concentration of the blood samples and analyzed the results along with the clinical and epidemiologic information.
Results
Among the 100 patients, 46 (46.0 %) were diagnosed with PCa. The median plasma genistein concentration of non-PCa patients (728.6 ng/ml) was significantly higher than that of PCa patients (513.0 ng/ml) (P < 0.05). In the univariate analysis, we found that age and smoking history were related to PCa (P < 0.05). In the multivariate analysis, we found that age, smoking history and plasma genistein were related to PCa (P < 0.05). The age-adjusted odds ratio of PCa risk comparing plasma genistein level above median to that below median was 0.31 (95 % CI 0.13–0.71).
Conclusion
Our study suggested that high concentration of plasma genistein level may contribute to the low incidence of prostate cancer in Chinese population.
doi:10.1007/s11255-015-0981-5
PMCID: PMC4445252  PMID: 25971353
Genistein; Plasma; Prostate; Cancer; China
11.  The impact of demographic and perceptual variables on a young adult’s decision to be covered by private health insurance 
Background
The large number of uninsured individuals in the United States creates negative consequences for those who are uninsured and for those who are covered by health insurance plans. Young adults between the ages of 18 and 24 are the largest uninsured population subgroup. This subgroup warrants analysis. The major aim of this study is to determine why young adults between the ages of 18 and 24 are the largest uninsured population subgroup.
Methods
The present study seeks to determine why young adults between the ages of 18 and 24 are the largest population subgroup that is not covered by private health insurance. Data on perceived health status, perceived need, perceived value, socioeconomic status, gender, and race was obtained from a national sample of 1,340 young adults from the 2005 Medical Expenditure Panel Survey and examined for possible explanatory variables, as well as data on the same variables from a national sample of 1,463 from the 2008 Medical Expenditure Panel Survey.
Results
Results of the structural equation model analysis indicate that insurance coverage in the 2005 sample was largely a function of higher socioeconomic status and being a non-minority. Perceived health status, perceived need, perceived value, and gender were not significant predictors of private health insurance coverage in the 2005 sample. However, in the 2008 sample, these indicators changed. Socioeconomic status, minority status, perceived health, perceived need, and perceived value were significant predictors of private health insurance coverage.
Conclusions
The results of this study show that coverage by a private health insurance plan in the 2005 sample was largely a matter of having a higher socioeconomic status and having a non-minority status.
In 2008 each of the attitudinal variables (perceived health, perceived value, and perceived need) predicted whether subjects carried private insurance. Our findings suggest that among those sampled, the young adult subgroup between the ages of 18 and 24 does not necessarily represent a unique segment of the population, with behaviors differing from the rest of the sample.
doi:10.1186/s12913-015-0848-6
PMCID: PMC4438581  PMID: 25962725
Health insurance coverage; Young adults
12.  High-dose thalidomide increases the risk of peripheral neuropathy in the treatment of ankylosing spondylitis 
Neural Regeneration Research  2015;10(5):814-818.
Thalidomide is an effective drug for the treatment of ankylosing spondylitis but might induce peripheral neuropathy. This major adverse reaction has attracted much concern. The current study aimed to observe the incidence of thalidomide-induced peripheral neuropathy among ankylosing spondylitis patients for 1 year after treatment. In this study, 207 ankylosing spondylitis cases received thalidomide treatment, while 116 ankylosing spondylitis cases received other treatments. Results showed that the incidence of thalidomide-induced peripheral neuropathy in the thalidomide group was higher than that in the non-thalidomide group. There was no significant difference in the incidence of neuropathy between the < 6 months medication and ≥ 6 months medication groups. There were no differences in the mean age, gender, or daily dose between the two groups. The incidence of peripheral neuropathy among patients receiving 25, 50, 75, or 100 mg thalidomide per day was 4.6%, 8.5%, 17.1%, 21.7%, respectively. The incidence was significantly different between the groups receiving 25 mg and 100 mg thalidomide. In conclusion, thalidomide can induce peripheral neuropathy within 1 year after treatment of ankylosing spondylitis; however, age and gender have no obvious impact on the incidence of peripheral neuropathy. The incidence of peripheral neuropathy is associated with increasing daily doses of thalidomide.
doi:10.4103/1673-5374.156988
PMCID: PMC4468777  PMID: 26109960
nerve regeneration; peripheral nerve injury; thalidomide; ankylosing spondylitis; adverse reactions; peripheral neuropathy; prospective study; treatment; dose; treatment time; age; sex; neural regeneration
13.  Complete Genome Sequence of Rhodococcus sp. B7740, a Carotenoid-Producing Bacterium Isolated from the Arctic Sea 
Genome Announcements  2015;3(2):e00333-15.
Rhodococcus sp. B7740 was isolated from Arctic seawater and selected for its capacity to synthesize carotenoids. Here, we report the complete genome sequence of Rhodococcus sp. B7740 to provide the genetic basis for a better understanding of its carotenoid-accumulating capabilities, and we describe the major features of the genome.
doi:10.1128/genomeA.00333-15
PMCID: PMC4417692  PMID: 25931596
14.  Thermodynamic Modeling of Poorly Complexing Metals in Concentrated Electrolyte Solutions: An X-Ray Absorption and UV-Vis Spectroscopic Study of Ni(II) in the NiCl2-MgCl2-H2O System 
PLoS ONE  2015;10(4):e0119805.
Knowledge of the structure and speciation of aqueous Ni(II)-chloride complexes is important for understanding Ni behavior in hydrometallurgical extraction. The effect of concentration on the first-shell structure of Ni(II) in aqueous NiCl2 and NiCl2-MgCl2 solutions was investigated by Ni K edge X-ray absorption (XAS) and UV-Vis spectroscopy at ambient conditions. Both techniques show that no large structural change (e.g., transition from octahedral to tetrahedral-like configuration) occurs. Both methods confirm that the Ni(II) aqua ion (with six coordinated water molecules at RNi-O = 2.07(2) Å) is the dominant species over the whole NiCl2 concentration range. However, XANES, EXAFS and UV-Vis data show subtle changes at high salinity (> 2 mol∙kg-1 NiCl2), which are consistent with the formation of small amounts of the NiCl+ complex (up to 0.44(23) Cl at a Ni-Cl distance of 2.35(2) Å in 5.05 mol∙kg-1 NiCl2) in the pure NiCl2 solutions. At high Cl:Ni ratio in the NiCl2-MgCl2-H2O solutions, small amounts of [NiCl2]0 are also present. We developed a speciation-based mixed-solvent electrolyte (MSE) model to describe activity-composition relationships in NiCl2-MgCl2-H2O solutions, and at the same time predict Ni(II) speciation that is consistent with our XAS and UV-Vis data and with existing literature data up to the solubility limit, resolving a long-standing uncertainty about the role of chloride complexing in this system.
doi:10.1371/journal.pone.0119805
PMCID: PMC4401718  PMID: 25885410
15.  E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma via promoting ubiquitination-mediated degradation of RARα 
Cell Cycle  2014;13(8):1277-1287.
All-trans retinoic acid (ATRA) is a widely used differentiation drug that can effectively induce osteogenic differentiation of osteosarcoma cells, but the underlying mechanism remains elusive, which limits the clinical application for ATRA in osteosarcoma patients. In this study, we identified E2F1 as a novel regulator involved in ATRA-induced osteogenic differentiation of osteosarcoma cells. We observed that osteosarcoma cells are coupled with individual differences in the expression levels of E2F1 in patients, and E2F1 impairs ATRA-induced differentiation of osteosarcoma cells. Moreover, remarkable anti-proliferative and differentiation-inducing effects of ATRA treatment are only observed in E2F1 low to negative expressed primary osteosarcoma cultures. These results strongly suggested that E2F1 may serve as a potent indicator for the effectiveness of ATRA treatment in osteosarcoma. Interestingly, E2F1 is found to downregulate retinoic acid receptor α (RARα), a key factor determines the effectiveness of ATRA. E2F1 specifically binds to RARα and promotes its ubiquitination-mediated degradation; as a consequence, RARα-mediated differentiation is inhibited in osteosarcoma. Therefore, our studies present E2F1 as a potent biomarker, as well as a therapeutic target for ATRA-based differentiation therapeutics, and raise the hope of using differentiation-based approaches for osteosarcoma patients.
doi:10.4161/cc.28190
PMCID: PMC4049964  PMID: 24608861
ATRA; E2F1; RARα; all-trans retinoic acid; osteogenic differentiation; osteosarcoma
16.  Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer 
Gut  2014;64(4):636-645.
Background
Characterisation of colorectal cancer (CRC) genomes by next-generation sequencing has led to the discovery of novel recurrently mutated genes. Nevertheless, genomic data has not yet been used for CRC prognostication.
Objective
To identify recurrent somatic mutations with prognostic significance in patients with CRC.
Method
Exome sequencing was performed to identify somatic mutations in tumour tissues of 22 patients with CRC, followed by validation of 187 recurrent and pathway-related genes using targeted capture sequencing in additional 160 cases.
Results
Seven significantly mutated genes, including four reported (APC, TP53, KRAS and SMAD4) and three novel recurrently mutated genes (CDH10, FAT4 and DOCK2), exhibited high mutation prevalence (6–14% for novel cancer genes) and higher-than-expected number of non-silent mutations in our CRC cohort. For prognostication, a five-gene-signature (CDH10, COL6A3, SMAD4, TMEM132D, VCAN) was devised, in which mutation(s) in one or more of these genes was significantly associated with better overall survival independent of tumor-node-metastasis (TNM) staging. The median survival time was 80.4 months in the mutant group versus 42.4 months in the wild type group (p=0.0051). The prognostic significance of this signature was successfully verified using the data set from the Cancer Genome Atlas study.
Conclusions
The application of next-generation sequencing has led to the identification of three novel significantly mutated genes in CRC and a mutation signature that predicts survival outcomes for stratifying patients with CRC independent of TNM staging.
doi:10.1136/gutjnl-2013-306620
PMCID: PMC4392212  PMID: 24951259
COLONIC NEOPLASMS
17.  Phylogenomic analysis uncovers the evolutionary history of nutrition and infection mode in rice blast fungus and other Magnaporthales 
Scientific Reports  2015;5:9448.
The order Magnaporthales (Ascomycota, Fungi) includes devastating pathogens of cereals, such as the rice blast fungus Pyricularia (Magnaporthe) oryzae, which is a model in host-pathogen interaction studies. Magnaporthales also includes saprotrophic species associated with grass roots and submerged wood. Despite its scientific and economic importance, the phylogenetic position of Magnaporthales within Sordariomycetes and the interrelationships of its constituent taxa, remain controversial. In this study, we generated novel transcriptome data from 21 taxa that represent key Magnaporthales lineages of different infection and nutrition modes and phenotypes. Phylogenomic analysis of >200 conserved genes allowed the reconstruction of a robust Sordariomycetes tree of life that placed the monophyletic group of Magnaporthales sister to Ophiostomatales. Among Magnaporthales, three major clades were recognized: 1) an early diverging clade A comprised of saprotrophs associated with submerged woods; 2) clade B that includes the rice blast fungus and other pathogens that cause blast diseases of monocot plants. These species infect the above-ground tissues of host plants using the penetration structure, appressorium; and 3) clade C comprised primarily of root-associated species that penetrate the root tissue with hyphopodia. The well-supported phylogenies provide a robust framework for elucidating evolution of pathogenesis, nutrition modes, and phenotypic characters in Magnaporthales.
doi:10.1038/srep09448
PMCID: PMC4377577  PMID: 25819715
18.  Classifying Ten Types of Major Cancers Based on Reverse Phase Protein Array Profiles 
PLoS ONE  2015;10(3):e0123147.
Gathering vast data sets of cancer genomes requires more efficient and autonomous procedures to classify cancer types and to discover a few essential genes to distinguish different cancers. Because protein expression is more stable than gene expression, we chose reverse phase protein array (RPPA) data, a powerful and robust antibody-based high-throughput approach for targeted proteomics, to perform our research. In this study, we proposed a computational framework to classify the patient samples into ten major cancer types based on the RPPA data using the SMO (Sequential minimal optimization) method. A careful feature selection procedure was employed to select 23 important proteins from the total of 187 proteins by mRMR (minimum Redundancy Maximum Relevance Feature Selection) and IFS (Incremental Feature Selection) on the training set. By using the 23 proteins, we successfully classified the ten cancer types with an MCC (Matthews Correlation Coefficient) of 0.904 on the training set, evaluated by 10-fold cross-validation, and an MCC of 0.936 on an independent test set. Further analysis of these 23 proteins was performed. Most of these proteins can present the hallmarks of cancer; Chk2, for example, plays an important role in the proliferation of cancer cells. Our analysis of these 23 proteins lends credence to the importance of these genes as indicators of cancer classification. We also believe our methods and findings may shed light on the discoveries of specific biomarkers of different types of cancers.
doi:10.1371/journal.pone.0123147
PMCID: PMC4378934  PMID: 25822500
19.  Construction of a high density SNP linkage map of kelp (Saccharina japonica) by sequencing Taq I site associated DNA and mapping of a sex determining locus 
BMC Genomics  2015;16(1):189.
Background
Kelp (Saccharina japonica) has been intensively cultured in China for almost a century. Its genetic improvement is comparable with that of rice. However, the development of its molecular tools is extremely limited, thus its genes, genetics and genomics. Kelp performs an alternative life cycle during which sporophyte generation alternates with gametophyte generation. The gametophytes of kelp can be cloned and crossed. Due to these characteristics, kelp may serve as a reference for the biological and genetic studies of Volvox, mosses and ferns.
Results
We constructed a high density single nucleotide polymorphism (SNP) linkage map for kelp by restriction site associated DNA (RAD) sequencing. In total, 4,994 SNP-containing physical (tag-defined) RAD loci were mapped on 31 linkage groups. The map expanded a total genetic distance of 1,782.75 cM, covering 98.66% of the expected (1,806.94 cM). The length of RAD tags (85 bp) was extended to 400–500 bp with Miseq method, offering us an easiness of developing SNP chips and shifting SNP genotyping to a high throughput track. The number of linkage groups was in accordance with the documented with cytological methods. In addition, we identified a set of microsatellites (99 in total) from the extended RAD tags. A gametophyte sex determining locus was mapped on linkage group 2 in a window about 9.0 cM in width, which was 2.66 cM up to marker_40567 and 6.42 cM down to marker_23595.
Conclusions
A high density SNP linkage map was constructed for kelp, an intensively cultured brown alga in China. The RAD tags were also extended so that a SNP chip could be developed. In addition, a set of microsatellites were identified among mapped loci, and a gametophyte sex determining locus was mapped. This map will facilitate the genetic studies of kelp including for example the evaluation of germplasm and the decipherment of the genetic bases of economic traits.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1371-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1371-1
PMCID: PMC4369078  PMID: 25887315
Kelp; Saccharina japonica; SNP; RAD; Linkage map; Sex determining locus
20.  Stretchable Polymeric Multielectrode Array for Conformal Neural Interfacing 
Highly stretchable neural interface of concurrent robust electrical and mechanical properties is developed with a conducting polymer film as the sole conductor for both electrodes and leads. This neural interface offers benefits of conducting polymer electrodes in a demanding stretchable format, including low electrode impedance and high charge injection capacity, due to large electroactive surface area of the electrode.
doi:10.1002/adma.201304140
PMCID: PMC4047984  PMID: 24150828
Conducting polymer; polypyrrole; stretchable multielectrode array; conformal; neural interface
21.  Controllable fabrication and magnetic properties of double-shell cobalt oxides hollow particles 
Scientific Reports  2015;5:8737.
Double-shell cobalt monoxide (CoO) hollow particles were successfully synthesized by a facile and effective one-pot solution-based synthetic route. The inner architecture and outer structure of the double-shell CoO hollow particles could be readily created through controlling experimental parameters. A possible formation mechanism was proposed based on the experimental results. The current synthetic strategy has good prospects for the future production of other transition-metal oxides particles with hollow interior. Furthermore, double-shell cobalt oxide (Co3O4) hollow particles could also be obtained through calcinating corresponding CoO hollow particles. The magnetic measurements revealed double-shell CoO and Co3O4 hollow particles exhibit ferromagnetic and antiferromagnetic behaviour, respectively.
doi:10.1038/srep08737
PMCID: PMC4348648  PMID: 25736824
22.  Intravenously delivered neural stem cells migrate into ischemic brain, differentiate and improve functional recovery after transient ischemic stroke in adult rats 
Stem cell transplantation may provide an alternative therapy to promote functional recovery after various neurological disorders including cerebral infarct. Due to the minimal immunogenicity and neuronal differentiation potential of neural stem cells (NSCs), we tested whether intravenous administration of mice-derived C17.2 NSCs could improve neurological function deficit and cerebral infarction volume after ischemic stroke in rats. Additionally, we evaluated the survival, migration, proliferation, and differentiation capacity of transplanted NSCs in the rat brain. Intravenous infusion of NSCs after middle cerebral artery occlusion (MCAO) showed better performance in neurobiological severity scores after MCAO compared to control. However, the volume of cerebral infarction was not different at 7 days after MCAO compared with control. Transplanted NSCs were detected in the ischemic region but not in the contralateral hemisphere. NSCs differentiated into neurons or astrocytes after MCAO. These data suggest that intravenously transplanted NSCs can migrate, proliferate, and differentiate into neurons and astrocytes in the rat brain with focal ischemia and improve functional recovery.
PMCID: PMC4440110  PMID: 26045801
Ischemic stroke; cell transplantation; neural stem cells; intravenous administration
23.  Population pharmacokinetic modeling of the Qishe pill in three major traditional Chinese medicine-defined constitutional types of healthy Chinese subjects: study protocol for a randomized controlled trial 
Trials  2015;16:64.
Background
High incidences of neck pain morbidity are challenging in various situations for populations based on their demographic, physiological and pathological characteristics. Chinese proprietary herbal medicines, as Complementary and Alternative Medicine (CAM) products, are usually developed from well-established and long-standing recipes formulated as tablets or capsules. However, good quantification and strict standardization are still needed for implementation of individualized therapies. The Qishe pill was developed and has been used clinically since 2009. The Qishe pill’s personalized medicine should be documented and administered to various patients according to the ancient TCM system, a classification of personalized constitution types, established to determine predisposition and prognosis to diseases as well as therapy and life-style administration. Therefore, we describe the population pharmacokinetic profile of the Qishe pill and compare its metabolic rate in the three major constitution types (Qi-Deficiency, Yin-Deficiency and Blood-Stasis) to address major challenges to individualized standardized TCM.
Methods/Design
Healthy subjects (N = 108) selected based on constitutional types will be assessed, and standardized pharmacokinetic protocol will be used for assessing demographic, physiological, and pathological data. Laboratory biomarkers will be evaluated and blood samples collected for pharmacokinetics(PK) analysis and second-generation gene sequencing. In single-dose administrations, subjects in each constitutional type cohort (N = 36) will be randomly divided into three groups to receive different Qishe pill doses (3.75, 7.5 and 15 grams).
Multiomics, including next generation sequencing, metabolomics, and proteomics, will complement the Qishe pill’s multilevel assessment, with cytochrome P450 genes as targets. In a comparison with the general population, a systematic population pharmacokinetic (PopPK) model for the Qishe pill will be established and verified.
Trial registration
This study is registered at ClinicalTrials.gov, NCT02294448.15 November 2014.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0568-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13063-015-0568-6
PMCID: PMC4351929  PMID: 25885543
Personalized medicine; Individualized medicine; Traditional Chinese Medicine; Multiomics; Population pharmacokinetics
24.  Dual inhibition of HCV and HIV by ring-expanded nucleosides containing the 5:7-fused imidazo[4,5-e][1,3]diazepine ring System. In vitro results and implications 
Examples of ring-expanded nucleosides (RENs), represented by general structures 1 and 2, exhibited dual anti-HCV and anti-HIV activities in both cell culture systems and the respective target enzyme assays, including HCV NTPase/helicase and human RNA helicase DDX3. Since HCV is a leading co-infection in late stage HIV AIDS patients, often leading to liver cirrhosis and death, the observed dual inhibition of HCV and HIV by the target nucleoside analogues has potentially beneficial implications in treating HIV patients infected with HCV.
doi:10.1016/j.bmcl.2013.12.121
PMCID: PMC3979313  PMID: 24461293
Ring-expanded nucleosides; imidazo[4,5-e][1,3]diazepines; organic synthesis; antiviral compounds; in vitro screening; hepatitis C virus (HCV); human immunodeficiency virus (HIV); dual inhibitors of HCV and HIV; inhibition of HCV NTPase/helicase; inhibition of RNA helicase DDX3
25.  Phosphorylation of Synaptic Vesicle Protein 2A at Thr84 by Casein Kinase 1 Family Kinases Controls the Specific Retrieval of Synaptotagmin-1 
The Journal of Neuroscience  2015;35(6):2492-2507.
Synaptic vesicle protein 2A (SV2A) is a ubiquitous component of synaptic vesicles (SVs). It has roles in both SV trafficking and neurotransmitter release. We demonstrate that Casein kinase 1 family members, including isoforms of Tau–tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1. We show by crystallographic and other analyses that the phosphorylated Thr84 residue binds to a pocket formed by three conserved Lys residues (Lys314, Lys326, and Lys328) on the surface of the synaptotagmin-1 C2B domain. Finally, we observed dysfunctional synaptotagmin-1 retrieval during SV endocytosis by ablating its phospho-dependent interaction with SV2A, knockdown of SV2A, or rescue with a phosphorylation-null Thr84 SV2A mutant in primary cultures of mouse neurons. This study reveals fundamental details of how phosphorylation of Thr84 on SV2A controls its interaction with synaptotagmin-1 and implicates SV2A as a phospho-dependent chaperone required for the specific retrieval of synaptotagmin-1 during SV endocytosis.
doi:10.1523/JNEUROSCI.4248-14.2015
PMCID: PMC4323530  PMID: 25673844
CK1; SV2A; synaptotagmin

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