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2.  Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer 
OncoTargets and therapy  2014;7:1653-1661.
Purpose
The primary aim of this research was to investigate the association between uridine diphosphate glucuronosyltransferase (UGT)1A1 gene polymorphisms and the toxicities of irinotecan-based regimens in Chinese patients with metastatic colorectal cancer.
Methods
The study analyzed the distribution of UGT1A1*28/*6 gene polymorphisms by polymerase chain reaction amplification and pyrosequencing. The adverse reactions and tumor response were evaluated according to National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 3.0, and Response Evaluation Criteria In Solid Tumors, Version 1.0, criteria, respectively. The correlation between UGT1A1 gene polymorphisms and severe delayed diarrhea or neutropenia was analyzed. The influences of UGT1A1*6/*28 polymorphisms on response rate and progression-free survival were also analyzed. Survival analysis was performed by the Kaplan–Meier method, and we used the log-rank test to analyze the effect of genotypes on progression-free survival, the logistic regression model for multivariate analysis, and the Cox regression model for multivariate survival analysis.
Results
A total of 167 patients with metastatic colorectal cancer who were treated with irinotecan-based regimens and with detected UGT1A1 gene polymorphisms were enrolled in this research. The rate of UGT1A1*28 homozygous wild-type TA6/6, heterozygous mutant-type TA6/7, and homozygous mutant-type TA7/7 was 65.3% (109/167), 32.3% (54/167), and 2.4% (4/167), respectively; the incidence of UGT1A1*6 wild-type G/G was 67.1% (112/167), heterozygous mutant-type G/A accounted for 28.7% (48/167), and seven cases were homozygous mutant-type A/A (4.2%; 7/167). The incidence of grade 3 or 4 delayed diarrhea in patients carrying UGT1A1*6 (G/A and A/A) was higher than that in the wild-type (G/G) (P=0.021). The rate was significantly lower in patients with the UGT1A1*28 TA6/6 wide-type genotype than those with TA6/7 and TA7/7 mutant-type genotypes (P=0.027). However, neither UGT1A1*6 (P=0.34) nor UGT1A1*28 (P=0.232) variants were significantly associated with severe neutropenia. Our study found no significant differences of severe neutropenia in patients with different numbers of mutational alleles (P=0.354), but patients with two alleles or single allele variants had more chances to develop severe diarrhea than patients with wild-type (P=0.027). No significant differences of either response rate or progression-free survival were found among different genotypes (P>0.05).
Conclusion
For irinotecan-based regimens in metastatic colorectal cancer, the UGT1A1*28 and UGT1A1*6 locus mutations can be regarded as predictors for irinotecan-associated severe delayed diarrhea, whereas no association between UGT1A1 gene polymorphisms and severe neutropenia was observed. We also found that neither clinical response nor prognosis were significantly associated with UGT1A1 gene polymorphisms.
doi:10.2147/OTT.S67867
PMCID: PMC4181635  PMID: 25285015
uridine diphosphate glucuronosyltransferase 1A1; gene polymorphism; metastatic colorectal cancer; irinotecan
3.  Multicenter phase ii study of a combination of cyclosporine a, methotrexate and mycophenolate mofetil for GVHD prophylaxis: results of the Chinese Bone Marrow Transplant Cooperative Group (CBMTCG) 
Background
Improvement of current GVHD prophylactic therapies remains an important goal in the allo-HSCT. We have described a novel prophylaxis regimen in a single institution trial. The Chinese Bone Marrow Transplant Cooperative Group (CBMTCG) initiated a phase II multicenter study.
Methods
The study was designed as a prospective, single arm phase II open-label, multicenter clinical trial. The primary endpoint was improvement of aGVHD by 25% over historical control (40%) in Chinese patients. 508 patients were enrolled. All of the patients received cyclosporine A (CsA), methotrexate (MTX) and mycophenolate mofetil (MMF) (0.5-1.0 g daily for 30 days) as GVHD prophylaxis regimen.
Results
The primary endpoint was met with cumulative incidences of grades 2 to 4 and grades 3 to 4 aGVHD of 23.2% and 10.3%, respectively. Incidence for cGVHD was 67.4%. The non-relapse mortality (NRM) rate was 18.4% at 2 years. The probabilities of leukemia free survival (LFS) for non-advanced stage and advanced stage patients at 2 years were 69.7% and 44.8% respectively (p = 0.000). Recipient age ≥ 40 years, advanced stage and Busulfan-Fludarabine(BuFlu) conditioning regimen were identified as major risk factors for aGVHD. Recipient age ≥ 40 years, BuFlu conditioning regimens, female donor/male recipient and prior aGVHD were associated with cGVHD. Despite lower RM (relapse mortality), patients with grade 2–4 aGVHD had higher NRM and worse OS and LFS compared to patients with grade 0–1 aGVHD. In contrast, patients with cGVHD had better OS and LFS and lower RM compared to patients without cGVHD.
Conclusion
The novel GVHD regimen decreased the risk for aGVHD by 42% without improving the risk for cGVHD compared to historical controls. Development of aGVHD was associated with worse OS and LFS as well as higher NRM. In contrast, cGVHD was associated with improved OS and LFS likely attributed to a GVL effect.
doi:10.1186/s13045-014-0059-3
PMCID: PMC4237802  PMID: 25139202
Allogeneic hematopoietic stem cell transplantation (allo-HSCT); Graft-versus-host disease (GVHD) prophylaxis; Mycophenolate mofetil (MMF)
4.  Correlation between EGFR mutation status and response to first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer 
OncoTargets and therapy  2014;7:1185-1193.
Background
The purpose of this research was to investigate the relationship between epidermal growth factor receptor (EGFR) mutations and the response to first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).
Methods
A total of 266 patients with stage IIIB or IV NSCLC who received platinum-based doublet therapies as first-line chemotherapy were investigated retrospectively, and their clinical data were assessed according to EGFR mutation.
Results
EGFR mutations were identified in 45.5% of patients. There was no significant difference in response rate between EGFR mutation carriers and EGFR wild-type carriers (P=0.484). Among the patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type, however, those with EGFR mutations responded better to treatment than EGFR wild-type patients (46.2% versus 20.8%, P=0.043). The disease control rate associated with pemetrexed-based treatments was higher than for vinorelbine-based therapies in EGFR mutation patients (P=0.001). EGFR mutation was found in patients with longer progression-free survival and median survival time, and improved 1-year and 2-year overall survival when compared with EGFR wild-type patients (6.1 versus 5.0 months, P=0.004; 18.9 versus 13.8 months, P=0.001; 81.0% versus 63.4%, P=0.002; and 33.9% versus 22.8% P=0.044, respectively). Patients with the EGFR exon 19 mutation had longer progression-free survival than those with EGFR exon 21 mutation (P=0.007). Multivariate analysis showed that the response to first-line chemotherapy and the presence of EGFR mutations were independent prognostic factors in patients with advanced NSCLC.
Conclusion
Our data showed that the presence of EGFR mutations meant longer survival times for patients with advanced NSCLC who received platinum-based doublet first-line chemotherapy, especially in those with the exon 19 deletion mutation. Among KRAS wild-type patients, those with EGFR mutation responded better to first-line chemotherapy than EGFR wild-type patients.
doi:10.2147/OTT.S63665
PMCID: PMC4085297  PMID: 25061320
non-small cell lung cancer; chemotherapeutic agents; epidermal growth factor receptor mutation; targeted therapy; prognosis
5.  Amplified voltammetric detection of glycoproteins using 4-mercaptophenylboronic acid/biotin-modified multifunctional gold nanoparticles as labels 
Ultrasensitive detection of protein biomarkers is essential for early diagnosis and therapy of many diseases. Glycoproteins, differing from other types of proteins, contain carbohydrate moieties in the oligosaccharide chains. Boronic acid can form boronate ester covalent bonds with diol-containing species. Herein, we present a sensitive and cost-effective electrochemical method for glycoprotein detection using 4-mercaptophenylboronic acid (MBA)/biotin-modified gold nanoparticles (AuNPs) (MBA-biotin-AuNPs) as labels. To demonstrate the feasibility and sensitivity of this method, recombinant human erythropoietin (rHuEPO) was tested as a model analyte. Specifically, rHuEPO was captured by the anti-rHuEPO aptamer-covered electrode and then derivatized with MBA-biotin-AuNPs through the boronic acid–carbohydrate interaction. The MBA-biotin-AuNPs facilitated the attachment of streptavidin-conjugated alkaline phosphatase for the production of electroactive p-aminophenol from p-aminophenyl phosphate substrate. A detection limit of 8 fmol L−1 for rHuEPO detection was achieved. Other glycosylated and non-glycosylated proteins, such as horseradish peroxidase, prostate specific antigen, metallothionein, streptavidin, and thrombin showed no interference in the detection assay.
doi:10.2147/IJN.S62343
PMCID: PMC4043723  PMID: 24920899
electrochemical biosensor; boronic acid; signal amplification; alkaline phosphatase
8.  Correction: Telomere Reprogramming and Maintenance in Porcine iPS Cells 
PLoS ONE  2013;8(11):10.1371/annotation/f5e4554b-18cc-46ef-ac39-73ac4d6750ae.
doi:10.1371/annotation/f5e4554b-18cc-46ef-ac39-73ac4d6750ae
PMCID: PMC3829974  PMID: 24250774
9.  Discovery of 2-Alkyl-1-arylsulfonylprolinamides as 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors 
ACS Medicinal Chemistry Letters  2012;3(10):793-798.
On the basis of scaffold hopping, a novel series of 2-alkyl-1-arylsulfonylprolinamides was discovered as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) inhibitors. A representative compound 4ek, obtained through SAR and structure optimization studies, demonstrates excellent in vitro potency against 11β-HSD-1 and dose-dependent in vivo inhibition of 11β-HSD-1 in a prednisone/prednisolone transformation biomarker study in mice.
doi:10.1021/ml300144n
PMCID: PMC4025654  PMID: 24900382
metabolic syndrome; enzyme inhibitor; 11β-hydroxysteroid dehydrogenase type 1; sulfonamide; 2-alkylproline; prolinamide
10.  Telomere Reprogramming and Maintenance in Porcine iPS Cells 
PLoS ONE  2013;8(9):e74202.
Telomere reprogramming and silencing of exogenous genes have been demonstrated in mouse and human induced pluripotent stem cells (iPS cells). Pigs have the potential to provide xenotransplant for humans, and to model and test human diseases. We investigated the telomere length and maintenance in porcine iPS cells generated and cultured under various conditions. Telomere lengths vary among different porcine iPS cell lines, some with telomere elongation and maintenance, and others telomere shortening. Porcine iPS cells with sufficient telomere length maintenance show the ability to differentiate in vivo by teratoma formation test. IPS cells with short or dysfunctional telomeres exhibit reduced ability to form teratomas. Moreover, insufficient telomerase and incomplete telomere reprogramming and/or maintenance link to sustained activation of exogenous genes in porcine iPS cells. In contrast, porcine iPS cells with reduced expression of exogenous genes or partial exogene silencing exhibit insufficient activation of endogenous pluripotent genes and telomerase genes, accompanied by telomere shortening with increasing passages. Moreover, telomere doublets, telomere sister chromatid exchanges and t-circles that presumably are involved in telomere lengthening by recombination also are found in porcine iPS cells. These data suggest that both telomerase-dependent and telomerase-independent mechanisms are involved in telomere reprogramming during induction and passages of porcine iPS cells, but these are insufficient, resulting in increased telomere damage and shortening, and chromosomal instability. Active exogenes might compensate for insufficient activation of endogenous genes and incomplete telomere reprogramming and maintenance of porcine iPS cells. Further understanding of telomere reprogramming and maintenance may help improve the quality of porcine iPS cells.
doi:10.1371/journal.pone.0074202
PMCID: PMC3787036  PMID: 24098638
11.  Zinc-finger-nucleases mediate specific and efficient excision of HIV-1 proviral DNA from infected and latently infected human T cells 
Nucleic Acids Research  2013;41(16):7771-7782.
HIV-infected individuals currently cannot be completely cured because existing antiviral therapy regimens do not address HIV provirus DNA, flanked by long terminal repeats (LTRs), already integrated into host genome. Here, we present a possible alternative therapeutic approach to specifically and directly mediate deletion of the integrated full-length HIV provirus from infected and latently infected human T cell genomes by using specially designed zinc-finger nucleases (ZFNs) to target a sequence within the LTR that is well conserved across all clades. We designed and screened one pair of ZFN to target the highly conserved HIV-1 5′-LTR and 3′-LTR DNA sequences, named ZFN-LTR. We found that ZFN-LTR can specifically target and cleave the full-length HIV-1 proviral DNA in several infected and latently infected cell types and also HIV-1 infected human primary cells in vitro. We observed that the frequency of excision was 45.9% in infected human cell lines after treatment with ZFN-LTR, without significant host-cell genotoxicity. Taken together, our data demonstrate that a single ZFN-LTR pair can specifically and effectively cleave integrated full-length HIV-1 proviral DNA and mediate antiretroviral activity in infected and latently infected cells, suggesting that this strategy could offer a novel approach to eradicate the HIV-1 virus from the infected host in the future.
doi:10.1093/nar/gkt571
PMCID: PMC3763554  PMID: 23804764
12.  Identification of the Causative Gene for Simmental Arachnomelia Syndrome Using a Network-Based Disease Gene Prioritization Approach 
PLoS ONE  2013;8(5):e64468.
Arachnomelia syndrome (AS), mainly found in Brown Swiss and Simmental cattle, is a congenital lethal genetic malformation of the skeletal system. In this study, a network-based disease gene prioritization approach was implemented to rank genes in the previously reported ∼7 Mb region on chromosome 23 associated with AS in Simmental cattle. The top 6 ranked candidate genes were sequenced in four German Simmental bulls, one known AS-carrier ROMEL and a pooled sample of three known non-carriers (BOSSAG, RIFURT and HIRMER). Two suspicious mutations located in coding regions, a mis-sense mutation c.1303G>A in the bystin-like (BYSL) gene and a 2-bp deletion mutation c.1224_1225delCA in the molybdenum cofactor synthesis step 1 (MOCS1) gene were detected. Bioinformatic analysis revealed that the mutation in MOCS1 was more likely to be the causative mutation. Screening the c.1224_1225delCA site in 383 individuals from 12 cattle breeds/lines, we found that only the bull ROMEL and his 12 confirmed progeny carried the mutation. Thus, our results confirm the conclusion of Buitkamp et al. that the 2-bp deletion mutation c.1224_1225delCA in exon 11 of the MOCS1 gene is causative for AS in Simmental cattle. Furthermore, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was developed to detect the causative mutation.
doi:10.1371/journal.pone.0064468
PMCID: PMC3655968  PMID: 23696895
13.  Molecular insights into the heterogeneity of telomere reprogramming in induced pluripotent stem cells 
Cell Research  2011;22(4):757-768.
Rejuvenation of telomeres with various lengths has been found in induced pluripotent stem cells (iPSCs). Mechanisms of telomere length regulation during induction and proliferation of iPSCs remain elusive. We show that telomere dynamics are variable in mouse iPSCs during reprogramming and passage, and suggest that these differences likely result from multiple potential factors, including the telomerase machinery, telomerase-independent mechanisms and clonal influences including reexpression of exogenous reprogramming factors. Using a genetic model of telomerase-deficient (Terc−/− and Terc+/−) cells for derivation and passages of iPSCs, we found that telomerase plays a critical role in reprogramming and self-renewal of iPSCs. Further, telomerase maintenance of telomeres is necessary for induction of true pluripotency while the alternative pathway of elongation and maintenance by recombination is also required, but not sufficient. Together, several aspects of telomere biology may account for the variable telomere dynamics in iPSCs. Notably, the mechanisms employed to maintain telomeres during iPSC reprogramming are very similar to those of embryonic stem cells. These findings may also relate to the cloning field where these mechanisms could be responsible for telomere heterogeneity after nuclear reprogramming by somatic cell nuclear transfer.
doi:10.1038/cr.2011.201
PMCID: PMC3317559  PMID: 22184006
telomere; telomerase; recombination; iPSCs; reprogramming
14.  Revised Genome Sequence of Burkholderia thailandensis MSMB43 with Improved Annotation 
Journal of Bacteriology  2012;194(17):4749-4750.
There is growing interest in discovery of novel bioactive natural products from Burkholderia thailandensis. Here we report a significantly improved genome sequence and reannotation of Burkholderia thailandensis MSMB43, which will facilitate the discovery of new natural products through genome mining and studies of the metabolic versatility of this bacterium.
doi:10.1128/JB.00931-12
PMCID: PMC3415525  PMID: 22887659
15.  Association of telomere instability with senescence of porcine cells 
BMC Cell Biology  2012;13:36.
Background
Telomeres are essential for the maintenance of genomic stability, and telomere dysfunction leads to cellular senescence, carcinogenesis, aging, and age-related diseases in humans. Pigs have become increasingly important large animal models for preclinical tests and study of human diseases, and also may provide xeno-transplantation sources. Thus far, Southern blot analysis has been used to estimate average telomere lengths in pigs. Telomere quantitative fluorescence in situ hybridization (Q-FISH), however, can reveal status of individual telomeres in fewer cells, in addition to quantifying relative telomere lengths, and has been commonly used for study of telomere function of mouse and human cells. We attempted to investigate telomere characteristics of porcine cells using telomere Q-FISH method.
Results
The average telomere lengths in porcine cells measured by Q-FISH correlated with those of quantitative real-time PCR method (qPCR) or telomere restriction fragments (TRFs) by Southern blot analysis. Unexpectedly, we found that porcine cells exhibited high incidence of telomere doublets revealed by Q-FISH method, coincided with increased frequency of cellular senescence. Also, telomeres shortened during subculture of various porcine primary cell types. Interestingly, the high frequency of porcine telomere doublets and telomere loss was associated with telomere dysfunction-induced foci (TIFs). The incidence of TIFs, telomere doublets and telomere loss increased with telomere shortening and cellular senescence during subculture.
Conclusion
Q-FISH method using telomere PNA probe is particularly useful for characterization of porcine telomeres. Porcine cells exhibit high frequency of telomere instability and are susceptible to telomere damage and replicative senescence.
doi:10.1186/1471-2121-13-36
PMCID: PMC3563453  PMID: 23241441
Telomere; Q-FISH; qPCR; Telomere doublets; Telomere dysfunction; Senescence
16.  Germline competency of parthenogenetic embryonic stem cells from immature oocytes of adult mouse ovary 
Human Molecular Genetics  2011;20(7):1339-1352.
Parthenogenetic embryonic stem cells (pESCs) have been generated in several mammalian species from parthenogenetic embryos that would otherwise die around mid-gestation. However, previous reports suggest that pESCs derived from in vivo ovulated (IVO) mature oocytes show limited pluripotency, as evidenced by low chimera production, high tissue preference and especially deficiency in germline competence, a critical test for genetic integrity and pluripotency of ESCs. Here, we report efficient generation of germline-competent pESC lines (named as IVM pESCs) from parthenogenetic embryos developed from immature oocytes of adult mouse ovaries following in vitro maturation (IVM) and artificial activation. In contrast, pESCs derived from IVO oocytes show defective germline competence, consistent with previous reports. Further, IVM pESCs resemble more ESCs from fertilized embryos (fESCs) than do IVO pESCs on genome-wide DNA methylation and global protein profiles. In addition, IVM pESCs express higher levels of Blimp1, Lin28 and Stella, relative to fESCs, and in their embryoid bodies following differentiation. This may indicate differences in differentiation potentially to the germline. The mechanisms for acquisition of pluripotency and germline competency of IVM pESCs from immature oocytes remain to be determined.
doi:10.1093/hmg/ddr016
PMCID: PMC3049357  PMID: 21239471
17.  Clinical application of CT-guided 125I seed interstitial implantation for local recurrent rectal carcinoma 
Purpose
The present study aimed to explore the safety profile and clinical efficacy of CT-guided radioactive seed implantation in treating local recurrent rectal carcinoma.
Materials and methods
CT-guided 125I seed implantation was carried out in 20 patients with locally recurrent rectal carcinoma. 14 of the 20 patient had prior adjuvant external-beam radiation therapy (EBRT). The treatment planning system (TPS) was used preoperatively to reconstruct three dimensional images of the tumor and to calculate the estimated seed number and distribution. The median matched peripheral dose (MPD) was 120 Gy (range, 100-160 Gy).
Results
Of the 20 patients, 12 were male, 8 were female, and ages ranged from 38 to 78, with a median age of 62. Duration of follow-up was 3-34 months. The response rate of pain relief was 85% (17/20). Repeat CT scan 2 months following the procedure revealed complete response (CR) of the tumor in 2 patients, partial response (PR) in 13 patients, stable disease (SD) in 3 patients, and progressive disease (PD) in 2 patients. 75% of patients had either CR or PR. Median survival time was 18.8 months (95% CI: 3.5-22.4 months). 1 and 2 year survival rates were 75% and 25%, respectively. 4 patients died of recurrent tumor; 4 patients died of distant metastases; 9 patients died of recurrent tumor and distant metastases. 3 patients survived after 2 year follow up. Two patients were found to have mild hematochezia, which was reversible with symptomatic management.
Conclusion
CT-guided 125I seed implantation appeared to be a safe, useful and less complicated interventional treatment option for local recurrent rectal carcinoma.
doi:10.1186/1748-717X-6-138
PMCID: PMC3214185  PMID: 22004599
20.  KSR-Based Medium Improves the Generation of High-Quality Mouse iPS Cells 
PLoS ONE  2014;9(8):e105309.
Induced pluripotent stem (iPS) cells from somatic cells have great potential for regenerative medicine. The efficiency in generation of iPS cells has been significantly improved in recent years. However, the generation of high-quality iPS cells remains of high interest. Consistently, we demonstrate that knockout serum replacement (KSR)-based medium accelerates iPS cell induction and improves the quality of iPS cells, as confirmed by generation of chimeras and all iPS cell-derived offspring with germline transmission competency. Both alkaline phosphatase (AP) activity assay and expression of Nanog have been used to evaluate the efficiency of iPS cell induction and formation of ES/iPS cell colonies; however, appropriate expression of Nanog frequently indicates the quality of ES/iPS cells. Interestingly, whereas foetal bovine serum (FBS)-based media increase iPS cell colony formation, as revealed by AP activity, KSR-based media increase the frequency of iPS cell colony formation with Nanog expression. Furthermore, inhibition of MAPK/ERK by a specific inhibitor, PD0325901, in KSR- but not in FBS-based media significantly increases Nanog-GFP+ iPS cells. In contrast, addition of bFGF in KSR-based media decreases proportion of Nanog-GFP+ iPS cells. Remarkably, PD can rescue Nanog-GFP+ deficiency caused by bFGF. These data suggest that MAPK/ERK pathway influences high quality mouse iPS cells and that KSR- and PD-based media could enrich homogeneous authentic pluripotent stem cells.
doi:10.1371/journal.pone.0105309
PMCID: PMC4149410  PMID: 25171101
21.  SPF Rabbits Infected with Rabbit Hepatitis E Virus Isolate Experimentally Showing the Chronicity of Hepatitis 
PLoS ONE  2014;9(6):e99861.
This study focused on investigating the pathogenesis seen in specific-pathogen-free (SPF) rabbits following infection with a homologous rabbit HEV isolate (CHN-BJ-rb14) and comparing it to that seen following infection with a heterologous swine genotype 4 HEV isolate (CHN-XJ-SW13). Three of the four animals inoculated with the homologous rabbit HEV became infected, exhibiting an intermittent viremia, obvious fluctuations of liver function biomarkers alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and persistent fecal virus shedding throughout the nine month study. In addition, liver histopathology showed both chronic inflammation and some degree of fibrosis. Both positive and negative-stranded HEV RNA and HEV antigen expression were detected in liver, brain, stomach, duodenum and kidney from the necropsied rabbits. Inflammation of extrahepatic tissue (duodenum and kidney) was also observed. Three of the four rabbits inoculated with the heterologous genotype 4 swine HEV also became infected, showing similar levels of anti-HEV antibody to that generated following infection with the homologous virus isolate. The duration of both viremia and fecal shedding of virus was however shorter following infection with the heterologous virus and there was no significant elevation of liver function biomarkers. These results suggest that rabbit HEV infection may cause more severe hepatitis and prolong the course of the disease, with a possible chronic trend of hepatitis in SPF rabbits.
doi:10.1371/journal.pone.0099861
PMCID: PMC4061063  PMID: 24937350
22.  Oomycete pathogens encode RNA silencing suppressors 
Nature genetics  2013;45(3):330-333.
Effectors are essential virulence proteins produced by a broad range of parasites, including viruses, bacteria, fungi, oomycetes, protozoa, insects and nematodes. Upon entry into host cells, pathogen effectors manipulate specific physiological processes or signaling pathways to subvert host immunity. Most effectors, especially those of eukaryotic pathogens, remain functionally uncharacterized. Here, we show that two effectors from the oomycete plant pathogen Phytophthora sojae suppress RNA silencing in plants by inhibiting the biogenesis of small RNAs. Ectopic expression of these Phytophthora suppressors of RNA silencing enhances plant susceptibility to both a virus and Phytophthora, showing that some eukaryotic pathogens have evolved virulence proteins that target host RNA silencing processes to promote infection. These findings identify RNA silencing suppression as a common strategy used by pathogens across kingdoms to cause disease and are consistent with RNA silencing having key roles in host defense.
doi:10.1038/ng.2525
PMCID: PMC4049077  PMID: 23377181
23.  MicroRNA-410 Reduces the Expression of Vascular Endothelial Growth Factor and Inhibits Oxygen-Induced Retinal Neovascularization 
PLoS ONE  2014;9(4):e95665.
Retinal neovascularization (RNV) is an eye disease that can cause retinal detachment and even lead to blindness. RNV mainly occurs in the elderly population. The pathogenesis of RNV has been previously reported to be highly related to the expression of vascular endothelial growth factor A (VEGFA), basic fibroblast growth factor (bFGF) and other angiogenic factors. It has also been reported that VEGFA and other factors associated with RNV could be regulated by certain microRNAs (miRNA), a group of small non-coding RNAs which are able to regulate the expression of many genes in vivo. Here, we demonstrate that the miRNA miR-410 is highly expressed in mice within two weeks after birth. miR-410 could suppress VEGFA expression through interaction with the 3′UTR of the VEGFA messenger RNA. Overexpressing a miR-410 mimic effectively suppresses VEGFA expression in various cell lines. Further experiments on oxygen-induced retinopathy (OIR) in mice revealed that eye drops containing large amounts of miR-410 efficiently downregulate VEGFA expression, prevent retinal angiogenesis and effectively treat RNV. These results not only show the underlying mechanism of how miR-410 targets VEGFA but also provide a potential treatment strategy for RNV that might be used in the near future.
doi:10.1371/journal.pone.0095665
PMCID: PMC4002426  PMID: 24777200
24.  In situ preparation of fluorescent CdTe quantum dots with small thiols and hyperbranched polymers as co-stabilizers 
Nanoscale Research Letters  2014;9(1):121.
A new strategy for in situ preparation of highly fluorescent CdTe quantum dots (QDs) with 3-mercaptopropionic acid (MPA) and hyperbranched poly(amidoamine)s (HPAMAM) as co-stabilizers was proposed in this paper. MPA and HPAMAM were added in turn to coordinate Cd2+. After adding NaHTe and further microwave irradiation, fluorescent CdTe QDs stabilized by MPA and HPAMAM were obtained. Such a strategy avoids the aftertreatment of thiol-stabilized QDs in their bioapplication and provides an opportunity for direct biomedical use of QDs due to the existence of biocompatible HPAMAM. The resulting CdTe QDs combine the mechanical, biocompatibility properties of HPAMAM and the optical, electrical properties of CdTe QDs together.
doi:10.1186/1556-276X-9-121
PMCID: PMC3974601  PMID: 24636234
Hyperbranched poly (amidoamine) s; Quantum dots; Nanocomposites; Photoluminescence
25.  Interleukin-6 disrupts blood-testis barrier through inhibiting protein degradation or activating phosphorylated ERK in Sertoli cells 
Scientific Reports  2014;4:4260.
It has been recently ascribed to several inflammatory cytokines (i.e. TGF-β3, TNF-α, and IL-1) a functional role in regulating Sertoli cell blood-testis barrier (BTB) dynamics. In the testis, IL-6 inhibits meiotic DNA synthesis during the seminiferous epithelium cycle, reduces sperm motility and influences the secretion of transferrin and inhibin B by Sertoli cells. Also, it has been shown that IL-6 affects tight junction permeability in Sertoli cells, but, little is known about its role in regulating the BTB. The aim of this study was to investigate the molecular mechanisms by which IL-6 affects BTB dynamics. We show that IL-6 perturbs the integrity of the BTB, and alters the normal localization and steady-state levels of BTB integral membrane proteins. We demonstrated that IL-6 regulates the BTB by inhibiting the degradation of BTB constitutive proteins and activating ERK-MAPK pathways. Our results provide mechanistic insight into the roles of IL-6 in regulating BTB dynamics.
doi:10.1038/srep04260
PMCID: PMC3939460  PMID: 24584780

Results 1-25 (201)