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1.  A Variant of IL6R Is Associated with the Recurrence of Atrial Fibrillation after Catheter Ablation in a Chinese Han Population 
PLoS ONE  2014;9(6):e99623.
Background
Recent studies have identified a variant, rs4845625, in the interleukin-6 receptor (IL6R) gene associated with Atrial Fibrillation (AF). Levels of circulating interleukin-6 and other proinflammatory molecules have consistently been associated with a risk for AF and its recurrence after catheter ablation. This study tested the hypothesis that variant rs4845625 is associated with AF recurrence after catheter ablation in a Chinese Han population.
Methods
A total of 278 consecutive patients (mean age 59.4±11.5 years, 43% female) with paroxysmal (36.0%), persistent (59.7%), and permanent (4.3%) AF who underwent catheterablation from 2007–2011, were included in this study. Patients were monitored for 12 months for a recurrence of AF. The SNP rs4845625 was genotyped using high resolution melting analysis.
Results
In our study cohort, an early recurrence of AF (ERAF), defined as a recurrence within the first 4 weeks, was observed in 42.8% of the patients, whereas late recurrence of AF (LRAF) (between 3 and 12 months) occurred in 25.9% of the patients. No significant differences in baseline clinical or echocardiographic characteristics were observed between patients with ERAF and LRAF. In contrast, the presence of the T allele of rs4845625 was associated with an increase in the risk for both ERAF (odds ratio [OR]: 1.84, 95% confidence interval [CI]: 1.31–2.59, p = 4.10×10−4) and LRAF (OR: 1.92, 95% CI: 1.30–2.81, p = 0.001). Furthermore, this association was significant after adjustments for age, sex, hypertension, diabetes and other risk factors. No significant relationship between rs4845625 and serum levels of IL6 was observed.
Conclusions
In this study, a variant of the IL6R gene, rs4845625, was found confer risk to AF recurrence after catheter ablation in a Chinese Han population. Our findings indicated that the IL6R pathway or inflammation may play important rols in the recurrence of AF after catheter ablation.
doi:10.1371/journal.pone.0099623
PMCID: PMC4062460  PMID: 24940886
2.  The Routine Utilization of Dental Care during Pregnancy in Eastern China and the Key Underlying Factors: A Hangzhou City Study 
PLoS ONE  2014;9(6):e98780.
Objectives
Oral diseases are associated with adverse pregnancy outcomes. The routine utilization of dental care (RUDC) during pregnancy is an effective way to improve pregnant women’s oral health, and thus safeguard the health of their babies. As China has one fifth of the world’s population, it is especially meaningful to encourage RUDC there. However, the status of RUDC in China and the key underlying factors are largely unknown.
Methods
This cross-sectional survey investigated the current status of RUDC during pregnancy and the key underlying factors in Hangzhou City, Zhejiang Province, eastern China. We collected participants’ demographics, individual oral-hygiene behaviors, individual lifestyle, oral-health conditions and attitudes, and also their RUDC during pregnancy. Binary Logistic Regression Analysis was used to analyze the key underlying factors.
Results
Only 16.70% of the participants reported RUDC during pregnancy. The percentage of RUDC was significantly lower among pregnant women with the following characteristics: aged 30 or less, an annual household income under $8,000, brushing once a day or less, never flossing or rinsing the mouth, paying no attention to pregnancy-related oral-health knowledge, and being dissatisfied with one’s individual dental hygiene behavior.
Conclusions
RUDC during pregnancy is very low in eastern China and is greatly influenced not only by a woman’s age, annual income, individual hygiene behavior, but also by her attention and attitudes to oral health. To improve this population’s access to and use of dental care during pregnancy, appropriate programs and policies are urgently needed.
doi:10.1371/journal.pone.0098780
PMCID: PMC4046992  PMID: 24901520
3.  Comparative Ecophysiological Study of Salt Stress for Wild and Cultivated Soybean Species from the Yellow River Delta, China 
The Scientific World Journal  2014;2014:651745.
Osmotic and ionic stresses were the primary and instant damage produced by salt stress. They can also bring about other secondary stresses. Soybean is an important economic crop and the wild soybean aroused increasing attention for its excellent performance in salt resistance. For this reason, we compared the different performances of Glycine max L. (ZH13) and Glycine soja L. (BB52) in both young and mature seedlings, hoping to clarify the specific reasons. Our research revealed that, compared to the cultivated soybean, the wild soybean was able to maintain higher water potential and relative water content (RWC), accumulate more amount of proline and glycine betaine, reduce the contents of Na+ and Cl− by faster efflux, and cut down the efflux of the K+ as well as keep higher K+/Na+ ratio. And what is more is that, almost all the excel behaviors became particularly obvious under higher NaCl concentration (300 mM). Therefore, according to all the detections and comparisons, we concluded that the wild soybean had different tolerance mechanisms and better salt resistance. It should be used as eminent germplasm resource to enhance the resistant ability of cultivated soybean or even other crops.
doi:10.1155/2014/651745
PMCID: PMC4066866  PMID: 24999494
4.  Bi-Functionalization of a Calcium Phosphate-Coated Titanium Surface with Slow-Release Simvastatin and Metronidazole to Provide Antibacterial Activities and Pro-Osteodifferentiation Capabilities 
PLoS ONE  2014;9(5):e97741.
Coating the surface of titanium implants or other bone graft substitute materials with calcium phosphate (Ca-P) crystals is an effective way to enhance the osteoconduction of the implants. Ca-P coating alone cannot confer pro-osteodifferentiation and antibacterial capabilities on implants; however, it can serve as a carrier for biological agents which could improve the performance of implants and bone substitutes. Here, we constructed a novel, bi-functional Ca-P coating with combined pro-osteodifferentiation and antibacterial capabilities. Different concentrations of metronidazole (MNZ) and simvastatin (SIM) were integrated into biomimetic Ca-P coatings on the surface of titanium disks. The biological effects of this bi-functional biomimetic coating on human bone marrow mesenchymal stem cells (hBMMSCs), human adipose derived stromal cells (hASCs), and Porphyromonas gingivalis were assessed in vitro. We observed that Ca-P coatings loaded with both SIM and MNZ display favorable release kinetics without affecting cell proliferation or attachment. In the inhibition zone test, we found that the bi-functional coating showed lasting antibacterial effects when incubated with Porphyromonas gingivalis for 2 and 4 days. Moreover, the osteodifferentiation of hBMMSCs and hASCs were increased when cultured on this bi-functional coating for 7 and 14 days. Both drugs were loaded onto the Ca-P coating at specific concentrations (10−5 M SIM; 10−2 M MNZ) to achieve optimal release kinetics. Considering the safety, stability and low cost of SIM and MNZ, this novel bi-functional Ca-P coating technique represents a promising method to improve the performance of metal implants or other bone substitute materials, and can theoretically be easily translated to clinical applications.
doi:10.1371/journal.pone.0097741
PMCID: PMC4028224  PMID: 24844416
5.  Gr-1+CD11b+ cells facilitate Lewis lung cancer recurrence by enhancing neovasculature after local irradiation 
Scientific Reports  2014;4:4833.
Studies have shown that bone marrow-derived cells play an important role in tumor recurrence after chemotherapy and radiotherapy. In this study, we examined the relationship between the accumulation of Gr-1+CD11b+ cells and tumor recurrence after irradiation in tumor-bearing mice. By transplanting bone marrow cells into whole body-irradiated mice depleted of bone marrow, we assessed the role of Gr-1+CD11b+ cells in lung carcinoma models after local irradiation (LI). 20 Gy local irradiation could recruit CD11b+CXCR4+ cells into the irradiated tissues, and the recruited CD11b+CXCR4+ cells could promote tumor recurrence. Further 6 Gy whole body irradiation (WBI6Gy) could decrease tumor recurrence by inhibiting the accumulation of Gr-1+CD11b+ cells and then suppressing tumor vasculogenesis and angiogenesis. Our results suggest that the accumulation of CD11b+Gr-1+ cells promote tumor re-growth after local irradiation by enhancing tumor neovascularization, and low dose of whole body irradiation or irradiation of enlarged spleen may provide a new alternative for anti-angiogenesis therapies.
doi:10.1038/srep04833
PMCID: PMC4003474  PMID: 24776637
6.  Peripheral T-cell lymphoma complicated by immunoglobulin A pemphigus: A case report and literature review 
Oncology Letters  2014;8(1):62-66.
Peripheral T-cell lymphomas (PTCLs) account for 12% of non-Hodgkin’s lymphomas (NHLs). Immunoglobulin (Ig) A pemphigus is an autoimmune blistering disease characterized by tissue-bound and circulating IgA antibodies that target epidermal cell surface components. Malignant lymphomas are often linked with autoimmune disease and the autoimmune blistering disease, paraneoplastic pemphigus, has been associated with NHL. However, cases of PTCLs that are complicated by IgA pemphigus are particularly rare. The current study presents the first known case of PTCL complicated by IgA pemphigus. A 43-year-old male was admitted to the Union Hospital (Wuhan, China) in March 2012 with multiple swollen lymph nodes. Pathology examinations revealed PTCL. Immunohistochemical staining was positive for cluster of differentiation (CD)2, CD3, CD5, CD7 and CD47, and negative for CD20. Ki-67 was ~40% positive. The patient was treated with four cycles of cyclophosphamide, Adriamycin, vincristine and prednisone, and two cycles of gemcitabine, cisplatin and dexamethasone; in addition, the patient received radiation of the retroperitoneal region (total dose, 36 Gy). The patient underwent thalidomide maintenance therapy for 20 days before flaccid blisters appeared on the trunk and limbs. Histopathology and immunofluorescence indicated IgA pemphigus, and intravenous methylprednisolone was administered, followed by treatment with prednisone. Subsequently, no evidence of recurrent lymphoma or pemphigus has been observed.
doi:10.3892/ol.2014.2088
PMCID: PMC4063644  PMID: 24959219
T-cell lymphoma; autoimmune disease; pemphigus; thalidomide
7.  Identification of a recurrent germline PAX5 mutation and susceptibility to pre-B cell acute lymphoblastic leukemia 
Nature genetics  2013;45(10):1226-1231.
doi:10.1038/ng.2754
PMCID: PMC3919799  PMID: 24013638
8.  AKT/ERK activation is associated with gastric cancer cell resistance to paclitaxel 
Paclitaxel (PTX) has shown encouraging activity in the treatment of advanced gastric cancer (GC). However, the fact that more than half of GC patients respond poorly to PTX-based chemotherapies demonstrates the urgent need for biomarkers of PTX sensitivity in GC patients. In the present work, three GC cell lines (BGC-823, HGC-27 and NCI-N87) with different sensitivities to PTX were subjected to DNA microarray analysis. The significantly differentially expressed genes and microRNAs (miRs) were identified and pathway signatures for PTX sensitivity were proposed. Ingenuity Pathway Analysis results showed that the differentially expressed genes were mainly enriched in the ErbB signaling pathway and other pathways. Additionally, the AKT/ERK signaling pathway, which is the pathway downstream of ErbB, was predicted to be active in PTX-resistant GC cell lines. ErbB3 overexpression and AKT/ERK activation in PTX-resistant cell lines were validated, respectively, by quantitative PCR and immunoblotting. Furthermore, 10 miRs were dramatically differently expressed in the three GC cell lines, and a miR-gene network was constructed from these data. Our work uncovered a reliable signature for PTX sensitivity in GC and potential therapeutic targets for GC treatments.
PMCID: PMC4014224  PMID: 24817940
Gastric cancer; paclitaxel; DNA microarray; ErbB signaling; AKT signaling; ERK signaling; microRNA
9.  Comparing Microspheres with Different Internal Phase of Polyelectrolyte as Local Drug Delivery System for Bone Tuberculosis Therapy 
BioMed Research International  2014;2014:297808.
We use hydrophobic poly(lactic-co-glycolic) acid (PLGA) to encapsulate hydrophilic ofloxacin to form drug loading microspheres. Hyaluronic acid (HA) and polylysine (Pls) were used as internal phase additives to see their influences on the drug loading and releasing. Double emulsion (water-in-oil-in-water) solvent extraction/evaporation method was used for the purpose. Particle size analysis display that the polyelectrolytes have low impact on the microsphere average size and distribution. Scanning electron microscope (SEM) pictures show the wrinkled surface resulted by the internal microcavity of the microspheres. Microspheres with HA inside have higher drug loading amounts than microspheres with Pls inside. The loading drug amounts of the microspheres increase with the HA amounts inside, while decreasing with the Pls amounts inside. All the polyelectrolytes adding groups have burst release observed in experiments. The microspheres with Pls internal phase have faster release rate than the HA groups. Among the same polyelectrolyte internal phase groups, the release rate increases with the amounts increasing when Pls is inside, while it decreases with the amounts increasing when HA is inside.
doi:10.1155/2014/297808
PMCID: PMC3950922  PMID: 24707480
10.  miR-372 down-regulates the oncogene ATAD2 to influence hepatocellular carcinoma proliferation and metastasis 
BMC Cancer  2014;14:107.
Background
ATAD2 is associated with many cellular processes, such as cell growth, migration and invasion. However, no studies have been conducted on the molecular biological function of the ATAD2 gene in hepatocellular carcinoma (HCC).
Methods
The protein and mRNA level expression of ATAD2 was examined in tissues and cell lines. Prognostic significance was analyzed by the Kaplan-Meier survival method and Cox regression. ATAD2 knockdown was used to analyze cell proliferation and invasion. The upstream and downstream of ATAD2 was analyzed by RT2 Profiler™ PCR array and luciferasex fluorescence system.
Results
ATAD2 was highly expressed in liver cancer samples and correlated with poor survival. High ATAD2 expression was positively correlated with metastasis (P = 0.005) and was an independent prognostic factor in HCC (P = 0.001). ATAD2 depletion by RNA interference reduced their capacity for invasion and proliferation and led to a G1 phase arrest in vitro. Further study revealed that miR-372 was an upstream target of ATAD2 as miR-372 was bound directly to its 3′ untranslated region (3′ UTR). In addition, ATAD2 knockdown was found to extremely up-regulate APC expression and down-regulate CTNNA1 at the mRNA level.
Conclusions
The findings demonstrated that miR-372 suppressed the expression of ATAD2, which was highly expressed in HCC and exerted a proto-oncogene effect in hepatic carcinogenesis. In conclusion, ATAD2 may promote HCC progression.
doi:10.1186/1471-2407-14-107
PMCID: PMC4016509  PMID: 24552534
11.  THE GENOMIC LANDSCAPE OF HYPODIPLOID ACUTE LYMPHOBLASTIC LEUKEMIA 
Nature genetics  2013;45(3):242-252.
The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole genome and exome sequencing of 40 cases, identified two subtypes that differ in severity of aneuploidy, transcriptional profile and submicroscopic genetic alterations. Near haploid cases with 24–31 chromosomes harbor alterations targeting receptor tyrosine kinase- and Ras signaling (71%) and the lymphoid transcription factor IKZF3 (AIOLOS; 13%). In contrast, low hypodiploid ALL with 32–39 chromosomes are characterized by TP53 alterations (91.2%) which are commonly present in non-tumor cells, and alterations of IKZF2 (HELIOS; 53%) and RB1 (41%). Both near haploid and low hypodiploid tumors exhibit activation of Ras- and PI3K signaling pathways, and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.
doi:10.1038/ng.2532
PMCID: PMC3919793  PMID: 23334668
12.  The Role of Factor Inhibiting HIF (FIH-1) in Inhibiting HIF-1 Transcriptional Activity in Glioblastoma Multiforme 
PLoS ONE  2014;9(1):e86102.
Glioblastoma multiforme (GBM) accounts for about 38% of primary brain tumors in the United States. GBM is characterized by extensive angiogenesis induced by vascular growth factors and cytokines. The transcription of these growth factors and cytokines is regulated by the Hypoxia-Inducible-Factor-1(HIF-1), which is a key regulator mediating the cellular response to hypoxia. It is known that Factor Inhibiting HIF-1, or FIH-1, is also involved in the cellular response to hypoxia and has the capability to physically interact with HIF-1 and block its transcriptional activity under normoxic conditions. Delineation of the regulatory role of FIH-1 will help us to better understand the molecular mechanism responsible for tumor growth and progression and may lead to the design of new therapies targeting cellular pathways in response to hypoxia. Previous studies have shown that the chromosomal region of 10q24 containing the FIH-1 gene is often deleted in GBM, suggesting a role for the FIH-1 in GBM tumorigenesis and progression. In the current study, we found that FIH-1 is able to inhibit HIF-mediated transcription of GLUT1 and VEGF-A, even under hypoxic conditions in human glioblastoma cells. FIH-1 has been found to be more potent in inhibiting HIF function than PTEN. This observation points to the possibility that deletion of 10q23-24 and loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF-1 activity, an alteration of HIF-1 targets such as GLUT-1 and VEGF-A, and may contribute to the survival of cancer cells in hypoxia and the development of hypervascularization observed in GBM. Therefore FIH-1 can be potential therapeutic target for the treatment of GBM patients with poor prognosis.
doi:10.1371/journal.pone.0086102
PMCID: PMC3900478  PMID: 24465898
13.  PHBV/PAM Scaffolds with Local Oriented Structure through UV Polymerization for Tissue Engineering 
BioMed Research International  2014;2014:157987.
Locally oriented tissue engineering scaffolds can provoke cellular orientation and direct cell spread and migration, offering an exciting potential way for the regeneration of the complex tissue. Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) scaffolds with locally oriented hydrophilic polyacrylamide (PAM) inside the macropores of the scaffolds were achieved through UV graft polymerization. The interpenetrating PAM chains enabled good interconnectivity of PHBV/PAM scaffolds that presented a lower porosity and minor diameter of pores than PHBV scaffolds. The pores with diameter below 100 μm increased to 82.15% of PHBV/PAM scaffolds compared with 31.5% of PHBV scaffolds. PHBV/PAM scaffold showed a much higher compressive elastic modulus than PHBV scaffold due to PAM stuffing. At 5 days of culturing, sheep chondrocytes spread along the similar direction in the macropores of PHBV/PAM scaffolds. The locally oriented PAM chains might guide the attachment and spreading of chondrocytes and direct the formation of microfilaments via contact guidance.
doi:10.1155/2014/157987
PMCID: PMC3919120  PMID: 24579074
14.  Initial Imaging Analysis of Budd-Chiari Syndrome in Henan Province of China: Most Cases Have Combined Inferior Vena Cava and Hepatic Veins Involvement 
PLoS ONE  2014;9(1):e85135.
Aim
To evaluate the type of venous involvement in Chinese Budd-Chiari syndrome (BCS) patients and the relative diagnostic accuracy of the different imaging modalities.
Methods
Using digital subtraction angiography (DSA) as a reference standard, color Doppler ultrasound (CDUS), computed tomography angiography (CTA), and magnetic resonance angiography (MRA) were performed on 338 patients with BCS. We analyzed the course of the main and any accessory hepatic veins (HVs) and the inferior vena cava (IVC) to assess the etiology of obstructed segments and diagnostic accuracy of CDUS, CTA and MRA.
Results
Among the 338 cases, there were 8 cases (2.4%) of isolated IVC membranous obstruction, 45 cases (13.3%) of isolated HV occlusion, and 285 cases (84.3%) with both IVC membranous obstruction and HV occlusion. Comparing with DSA, CDUS, CTA had a diagnostic accuracy of 89.3% and 80.2% in detecting BCS, and 83.4% of cases correctly correlated by MRA.
Conclusion
In Henan Province, most patients with BCS have complex lesions combining IVC and HV involvement. The combination of CDUS and CTA or MRI is useful for diagnosis of BCS and guiding therapy.
doi:10.1371/journal.pone.0085135
PMCID: PMC3885682  PMID: 24416352
15.  Changes of Plasma B-Type Natriuretic Peptide Levels after High-Pressure Post-Dilation following Coronary Stent Deployment 
PLoS ONE  2013;8(12):e82357.
Objective
To evaluate the changes of plasma B-type natriuretic peptide(BNP) levels after high-pressure post-dilation following coronary stent deployment.
Methods
A total of 173 patients undergoing percutaneous coronary intervention for the left anterior descending artery were enrolled into the study. All patients were divided into two groups: the conventional group and the post-dilation group. The plasma BNP, troponin I(TnI), myocardial band isoenzyme of creatine kinase(CK-MB) levels and the serum high sensitive C-reactive protein(hs-CRP) levels immediately before and 24 hours after the interventional procedures were compared between the two groups.
Results
There were no significant differences between the two groups in terms of clinical features, clinical and biochemical parameters, stent parameters, pre-procedural plasma BNP and TnI levels, pre-procedural serum hs-CRP levels, as well as pre- and post-procedural CK-MB levels (all P>0.05). In the conventional group, post-procedural plasma BNP levels were significantly reduced when compared with the pre-procedural levels, median(25th,75th) were 32.5 ng/L(15.0,52.4) vs. 37.7 ng/L(18.2,67.3), P = 0.001. In the post-dilation group, post-procedural plasma BNP levels were significantly increased when compared with the pre-procedural levels, median(25th,75th) were 53.5 ng/L(29.6,82.8) vs. 44.2 ng/L(17.15,70.7), P<0.0001. Post-procedural plasma TnI levels were also significantly increased when compared with the pre-procedural levels in both groups, median(25th,75th) were 0.02 ng/L(0.01,0.08) vs. 0.01 ng/L(0.01,0.01), 0.05 ng/L(0.01,0.35) vs. 0.01 ng/L(0.01,0.01), respectively, P<0.0001, so were the serum hs-CRP levels, median(25th,75th) were 3.3 mg/L(2.4,4.7) vs. 2.2 mg/L(1.4,3.3), 4.2 mg/L(3.175,5.825) vs. 2.3 mg/L(1.45,3.6), respectively, P<0.0001. Post-procedural plasma BNP, TnI and serum hs-CRP levels in the post-dilation group were significantly higher than those in the conventional group(all P<0.0001).
Conclusion
High-pressure post-dilation following coronary stent deployment resulted in a significant increase of plasma BNP levels, as well as plasma TnI levels and serum hs-CRP levels, which may be related to myocardial perfusion, more myocardial injury and more inflammation.
doi:10.1371/journal.pone.0082357
PMCID: PMC3855705  PMID: 24324775
16.  Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas 
Nature genetics  2013;45(6):602-612.
The commonest pediatric brain tumors are low-grade gliomas (LGGs). We utilized whole genome sequencing to discover multiple novel genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24/39 (62%) tumors. Intragenic duplications of the FGFR1 tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes containing TKD-duplicated FGFR1 into brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. TKD-duplicated FGFR1 induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs/LGGNTs.
doi:10.1038/ng.2611
PMCID: PMC3727232  PMID: 23583981
17.  An inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia 
Cancer cell  2012;22(5):683-697.
SUMMARY
To define the mutation spectrum in non-Down syndrome acute megkaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL leukemia samples. Our analysis identified a cryptic chromosome 16 inversion [inv(16)(p13.3q24.3)] in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling, and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.
doi:10.1016/j.ccr.2012.10.007
PMCID: PMC3547667  PMID: 23153540
18.  Transcriptome Analysis of Leaf Tissue of Raphanus sativus by RNA Sequencing 
PLoS ONE  2013;8(11):e80350.
Raphanus sativus is not only a popular edible vegetable but also an important source of medicinal compounds. However, the paucity of knowledge about the transcriptome of R. sativus greatly impedes better understanding of the functional genomics and medicinal potential of R. sativus. In this study, the transcriptome sequencing of leaf tissues in R. sativus was performed for the first time. Approximately 22 million clean reads were generated and used for transcriptome assembly. The generated unigenes were subsequently annotated against gene ontology (GO) database. KEGG analysis further revealed two important pathways in the bolting stage of R.sativus including spliceosome assembly and alkaloid synthesis. In addition, a total of 6,295 simple sequence repeats (SSRs) with various motifs were identified in the unigene library of R. sativus. Finally, four unigenes of R. sativus were selected for alignment with their homologs from other plants, and phylogenetic trees for each of the genes were constructed. Taken together, this study will provide a platform to facilitate gene discovery and advance functional genomic research of R. sativus.
doi:10.1371/journal.pone.0080350
PMCID: PMC3827192  PMID: 24265813
19.  Nimotuzumab combined with radiotherapy for esophageal cancer: preliminary study of a Phase II clinical trial 
OncoTargets and therapy  2013;6:1589-1596.
Objective
To determine the safety and therapeutic effects of nimotuzumab (h-R3) combined with radiotherapy in esophageal cancer.
Methods
This Phase II clinical trial involved 42 patients with stage II (inoperable or refused surgery) to stage IV (supraclavicular lymph node metastasis only) esophageal cancers treated between November 2008 and July 2010. All patients had squamous cell carcinomas, and all received three-dimensional conformal radiotherapy and 200 mg nimotuzumab per week during radiotherapy.
Results
There were 9, 25, and 8 patients with stage II, III and IV disease, respectively. All except two patients received 50–70 Gy radiation; 37 patients (88.1%) received more than five nimotuzumab doses. Grade III toxicities (21.4% of all adverse events) included esophagitis and gastrointestinal, dermatological and hematological toxicities. Complete response, partial response, stable disease, and progressive disease were observed in 0, 22 (52.4%), 17 (40.5%) and 3 (7.1%) patients at 1 month after the treatment. The epidermal growth factor receptor (EGFR) overexpression rate was 95.2%. After a median follow-up of 37 months, the median survival time (MST) was 14 months. The 2 year and 3 year overall survival (OS) rates were 33.3% and 26.2%, respectively. The median progression-free survival (PFS) time was 10 months. The 2 year and 3 year PFS rates were 24.5% and 22.1%, respectively. The MST in the 13 patients with (+++) EGFR expression (group A) and 7 patients with (++) EGFR expression (group B) was 15 and 11 months, respectively. The 2 year and 3 year OS rates were 46.2% and 38.5% in group A and 28.6% and 28.6% in group B, respectively (P = 0.405).
Conclusion
Although concurrent chemoradiotherapy was the standard care for locally advanced esophageal cancer, radiotherapy was the choice for those who were refused or could not tolerate chemoradiotherapy. Our study shows that nimotuzumab combined with radiotherapy was well tolerated in patients with esophageal cancer. EGFR overexpression was more common than previously reported. OS was higher after combined therapy than after historical control radiotherapy alone. Further studies are required to confirm the therapeutic efficacy of nimotuzumab in esophageal cancer.
doi:10.2147/OTT.S50945
PMCID: PMC3825695  PMID: 24235844
esophageal neoplasms; nimotuzumab; radiotherapy; targeted therapy; treatment outcomes
20.  Heterodimeric BMP-2/7 Antagonizes the Inhibition of All-Trans Retinoic Acid and Promotes the Osteoblastogenesis 
PLoS ONE  2013;8(10):e78198.
Objectives
Hypervitaminosis A and alcoholism can result in a low mineral density and compromised regenerative capacity of bone, thus delaying implant osteointegration. The inhibitory effect of all-trans retinoic acid on osteoblastogenesis is considered to be one of the mechanisms. We hypothesized that heterodimeric bone morphogenetic protein-2/7 could antagonize all-trans retinoic acid and enhance osteoblastogenesis, with an aim to accelerate and enhance bone regeneration and implant osteointegration.
Materials and Methods
We applied 5 ng/ml or 50 ng/ml bone morphogenetic protein-2/7 to restore the osteoblastogenesis of pre-osteoblasts (MC3T3-E1 cell line) that was inhibited by 1 µM all-trans retinoic acid. We evaluated the efficacy by assessing cell numbers (proliferation), alkaline phosphatase activity (a marker for early differentiation), osteocalcin (a marker for late differentiation), calcium deposition (a marker for final mineralization) and the expression of osteoblastogenic genes (such as Runx2, Collagen Ia, alkaline phosphatase and osteocalcin) at different time points.
Results
All-trans retinoic acid significantly inhibited the expression of all the tested osteoblastogenic genes and proteins except alkaline phosphatase activity. In the presence of ATRA, 50 ng/ml bone morphogenetic protein-2/7 not only completely restored but also significantly enhanced all the osteoblastogenic genes and proteins. On the 28th day, mineralization was completely inhibited by all-trans retinoic acid. In contrast, 50 ng/ml BMP-2/7 could antagonize ATRA and significantly enhance the mineralization about 2.5 folds in comparison with the control treatment (no ATRA, no BMP2/7).
Conclusions
Heterodimeric bone morphogenetic protein-2/7 bears a promising application potential to significantly promote bone regeneration and implant osteointegration for the patients with hypervitaminosis A and alcoholism.
doi:10.1371/journal.pone.0078198
PMCID: PMC3813516  PMID: 24205156
21.  MiR-200c Increases the Radiosensitivity of Non-Small-Cell Lung Cancer Cell Line A549 by Targeting VEGF-VEGFR2 Pathway 
PLoS ONE  2013;8(10):e78344.
MicroRNAs (miRNAs) have been demonstrated to participate in many important cellular processes including radiosensitization. VEGF family, an important regulator of angiogenesis, also plays a crucial role in the regulation of cancer cell radiosensitivity. VEGFR2 mediates the major growth and permeability actions of VEGF in a paracrine/autocrine manner. MiR-200c, at the nexus of epithelial-mesenchymal transition (EMT), is predicted to target VEGFR2. The purpose of this study is to test the hypothesis that regulation of VEGFR2 pathway by miR-200c could modulate the radiosensitivity of cancer cells. Bioinformatic analysis, luciferase reporter assays and biochemical assays were carried out to validate VEGFR2 as a direct target of miR-200c. The radiosensitizing effects of miR-200c on A549 cells were determined by clonogenic assays. The downstream regulating mechanism of miR-200c was explored with western blotting assays, FCM, tube formation assays and migration assays. We identified VEGFR2 as a novel target of miR-200c. The ectopic miR-200c increased the radiosensitivity of A549 while miR-200c down-regulation decreased it. Besides, we proved that miR-200c radiosensitized A549 cells by targeting VEGF-VEGFR2 pathway specifically, thus leading to inhibition of its downstream pro-survival signaling transduction and angiogenesis, and serves as a potential target for radiosensitizition research.
doi:10.1371/journal.pone.0078344
PMCID: PMC3813610  PMID: 24205206
22.  Subgroup and outlier detection analysis 
BMC Bioinformatics  2013;14(Suppl 17):A2.
doi:10.1186/1471-2105-14-S17-A2
PMCID: PMC3853229
23.  RiceWiki: a wiki-based database for community curation of rice genes 
Nucleic Acids Research  2013;42(D1):D1222-D1228.
Rice is the most important staple food for a large part of the world’s human population and also a key model organism for biological studies of crops as well as other related plants. Here we present RiceWiki (http://ricewiki.big.ac.cn), a wiki-based, publicly editable and open-content platform for community curation of rice genes. Most existing related biological databases are based on expert curation; with the exponentially exploding volume of rice knowledge and other relevant data, however, expert curation becomes increasingly laborious and time-consuming to keep knowledge up-to-date, accurate and comprehensive, struggling with the flood of data and requiring a large number of people getting involved in rice knowledge curation. Unlike extant relevant databases, RiceWiki features harnessing collective intelligence in community curation of rice genes, quantifying users' contributions in each curated gene and providing explicit authorship for each contributor in any given gene, with the aim to exploit the full potential of the scientific community for rice knowledge curation. Based on community curation, RiceWiki bears the potential to make it possible to build a rice encyclopedia by and for the scientific community that harnesses community intelligence for collaborative knowledge curation, covers all aspects of biological knowledge and keeps evolving with novel knowledge.
doi:10.1093/nar/gkt926
PMCID: PMC3964990  PMID: 24136999
24.  The effects of different doses of estradiol (E2) on cerebral ischemia in an in vitro model of oxygen and glucose deprivation and reperfusion and in a rat model of middle carotid artery occlusion 
BMC Neuroscience  2013;14:118.
Background
Because neuroprotective effects of estrogen remain controversial, we aimed to investigate the effect of different doses of estradiol (E2) on cerebral ischemia using both in vivo and in vitro experiments.
Results
PC12 cells were cultured at physiological (10 nM and 20 nM) or pharmacological (10 μM and 20 μM) dosages of E2 for 24 hours (h). The results of 5-bromodeoxyuridine (Brdu) incorporation and flow cytometric analysis showed that physiological doses of E2 enhanced cell proliferation and pharmacological doses of E2 inhibited cell proliferation. After the cells were exposed to oxygen and glucose deprivation (OGD) for 4 h and reperfusion for 20 h, the results of 3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphenyl tetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release assay, flow cytometric analysis and Western blot analysis showed that physiological doses of E2 enhanced cell viability, reduced cell apoptosis and decreased the expression of pro-apoptotic protein caspase-3. In contrast, pharmacological doses of E2 decreased cell viability and induced cell apoptosis. In vivo, adult ovariectomized (OVX) female rats received continuous subcutaneous injection of different doses of E2 for 4 weeks. Transient cerebral ischemia was induced for 2 h using the middle cerebral artery occlusion (MCAO) technique, followed by 22 h of reperfusion. The results of Garcia test, 2, 3, 5-triphenyltetrazolium chloride (TTC) staining showed that 6 μg/kg and 20 μg/kg E2 replacement induced an increase in neurological deficit scores, a decrease in the infarct volume and a reduction in the expression of caspase-3 when compared to animals in the OVX group without E2 treatment. However, 50 μg/kg E2 replacement treatment decreased neurological deficit scores, increased the infarct volume and the expression of caspase-3 when compared to animals in the control group and 6 up/kg or 20 μg/kg E2 replacement group.
Conclusion
We conclude that physiological levels of E2 exhibit neuroprotective effects on cerebral ischemia; whereas, pharmacological or supraphysiological doses of E2 have damaging effects on neurons after cerebral ischemia.
doi:10.1186/1471-2202-14-118
PMCID: PMC3851874  PMID: 24106772
Estrogen; Neuroprotection; Ischemia; Middle carotid artery occlusion (MCAO); Oxygen and glucose deprivation (OGD)
25.  Identification of Molecular Pathway Aberrations in Uterine Serous Carcinoma by Genome-wide Analyses 
Background
Uterine cancer is the fourth most common malignancy in women, and uterine serous carcinoma is the most aggressive subtype. However, the molecular pathogenesis of uterine serous carcinoma is largely unknown. We analyzed the genomes of uterine serous carcinoma samples to better understand the molecular genetic characteristics of this cancer.
Methods
Whole-exome sequencing was performed on 10 uterine serous carcinomas and the matched normal blood or tissue samples. Somatically acquired sequence mutations were further verified by Sanger sequencing. The most frequent molecular genetic changes were further validated by Sanger sequencing in 66 additional uterine serous carcinomas and in nine serous endometrial intraepithelial carcinomas (the preinvasive precursor of uterine serous carcinoma) that were isolated by laser capture microdissection. In addition, gene copy number was characterized by single-nucleotide polymorphism (SNP) arrays in 23 uterine serous carcinomas, including 10 that were subjected to whole-exome sequencing.
Results
We found frequent somatic mutations in TP53 (81.6%), PIK3CA (23.7%), FBXW7 (19.7%), and PPP2R1A (18.4%) among the 76 uterine serous carcinomas examined. All nine serous carcinomas that had an associated serous endometrial intraepithelial carcinoma had concordant PIK3CA, PPP2R1A, and TP53 mutation status between uterine serous carcinoma and the concurrent serous endometrial intraepithelial carcinoma component. DNA copy number analysis revealed frequent genomic amplification of the CCNE1 locus (which encodes cyclin E, a known substrate of FBXW7) and deletion of the FBXW7 locus. Among 23 uterine serous carcinomas that were subjected to SNP array analysis, seven tumors with FBXW7 mutations (four tumors with point mutations, three tumors with hemizygous deletions) did not have CCNE1 amplification, and 13 (57%) tumors had either a molecular genetic alteration in FBXW7 or CCNE1 amplification. Nearly half of these uterine serous carcinomas (48%) harbored PIK3CA mutation and/or PIK3CA amplification.
Conclusion
Molecular genetic aberrations involving the p53, cyclin E–FBXW7, and PI3K pathways represent major mechanisms in the development of uterine serous carcinoma.
doi:10.1093/jnci/djs345
PMCID: PMC3692380  PMID: 22923510

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