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1.  G6PD Deficiency and Hemoglobinopathies: Molecular Epidemiological Characteristics and Healthy Effects on Malaria Endemic Bioko Island, Equatorial Guinea 
PLoS ONE  2015;10(4):e0123991.
Background
Glucose-6-phosphate dehydrogenase (G6PD) deficiency and hemoglobinopathies were the inherited conditions found mostly in African. However, few epidemiological data of these disorders was reported in Equatorial Guinea (EQG). This study aimed to assess the prevalence and healthy effects of G6PD deficiency and hemoglobinopathies among the people on malaria endemic Bioko Island, EQG.
Materials and Methods
Blood samples from 4,144 unrelated subjects were analyzed for G6PD deficieny by fluorescence spot test (FST), high-resolution melting assay and PCR-DNA sequencing. In addition, 1,186 samples were randomly selected from the 4,144 subjects for detection of hemoglobin S (HbS), HbC, and α-thalassemia deletion by complete blood count, PCR-DNA sequencing and reverse dot blot (RDB).
Results
The prevalence of malaria and anemia was 12.6% (522/4,144) and 32.8% (389/1,186), respectively. Overall, 8.7% subjects (359/4,144) were G6PD-deficient by FST, including 9.0% (249/2,758) males and 7.9% (110/1,386) females. Among the 359 G6PD-deficient individuals molecularly studied, the G6PD A- (G202A/A376G) were detected in 356 cases (99.2%), G6PD Betica (T968C/A376G) in 3 cases. Among the 1,186 subjects, 201 cases were HbS heterozygotes, 35 cases were HbC heterozygotes, and 2 cases were HbCS double heterozygotes; 452 cases showed heterozygous α-thalassemia 3.7 kb deletion (-α3.7 kb deletion) and 85 homozygous - α3.7 kb deletion. The overall allele frequencies were HbS 17.1% (203/1186); HbC, 3.1% (37/1186); and –α3.7 kb deletion 52.4% (622/1186), respectively.
Conclusions
High G6PD deficiency in this population indicate that diagnosis and management of G6PD deficiency is necessary on Bioko Island. Obligatory newborn screening, prenatal screening and counseling for these genetic disorders, especially HbS, are needed on the island.
doi:10.1371/journal.pone.0123991
PMCID: PMC4411145  PMID: 25915902
2.  High Resolution Melting Analysis: A Rapid Screening and Typing Tool for Common β-Thalassemia Mutation in Chinese Population 
PLoS ONE  2014;9(8):e102243.
β-thalassemia is a common inherited disorder worldwide including southern China, and at least 45 distinct β-thalassemia mutations have been identified in China. High-resolution melting (HRM) assay was recently introduced as a rapid, inexpensive and effective method for genotyping. However, there was no systemic study on the diagnostic capability of HRM to identify β-thalassemia. Here, we used an improved HRM method to screen and type 12 common β-thalassemia mutations in Chinese, and the rapidity and reliability of this method was investigated. The whole PCR and HRM procedure could be completed in 40 min. The heterozygous mutations and 4 kinds of homozygous mutations could be readily differentiated from the melting curve except c.-78A>G heterozygote and c.-79A>G heterozygote. The diagnostic reliability of this HRM assay was evaluated on 756 pre-typed genomic DNA samples and 50 cases of blood spots on filter paper, which were collected from seven high prevalent provinces in southern China. If c.-78A>G heterozygote and c.-79A>G heterozygote were classified into the same group (c.-78&79 A>G heterozygote), the HRM method was in complete concordance with the reference method (reverse dot blot/DNA-sequencing). In a conclusion, the HRM method appears to be an accurate and sensitive method for the rapid screening and identification of β-thalassemia mutations. In the future, we suggest this technology to be used in neonatal blood spot screening program. It could enlarge the coverage of β-thalassemia screening program in China. At the same time, its value should be confirmed in prospectively clinical and epidemiological studies.
doi:10.1371/journal.pone.0102243
PMCID: PMC4121066  PMID: 25089872
3.  Molecular Epidemiological Characterization and Health Burden of Thalassemia in Jiangxi Province, P. R. China 
PLoS ONE  2014;9(7):e101505.
Background
Thalassemia is the most common inherited disease in southern China. However, this disorder is usually ignored by Jiangxi provincial health system and government due to lack of epidemiological data.
Materials and Methods
A total of 9489 samples from Hakka Han and Gan-speaking Han in three geographical areas of Jiangxi Province were analyzed for both complete blood cell (CBC) count and reverse dot blot (RDB) gene chip for thalassemia.
Results
1182 cases of suspected thalassemia carriers with microcytosis (MCV<82 fL) were found by CBC count, and were tested by RDB gene chip to reveal a total of 594 mutant chromosomes, including 433 α-thalassemia mutant chromosomes and 172 β-thalassemia mutant chromosomes. Our results indicated a higher prevalence of thalassemia with the heterozygote frequency of 9.49% in southern Jiangxi province, whereas the low frequency was found in middle (3.90%) and northern Jiangxi (2.63%).
Conclusions
Based on the epidemiological data, the estimated numbers of pregnancies in Jiangxi province in which the fetus is at risk for β-thalassemia major or intermedia, Bart's hydrops fetalis and Hb H disease are 34 (95% CI, 16 to 58), 79 (95% CI, 50 to 114) and 39 (95% CI, 27 to 58) per year, respectively. We suggested that prevention network of thalassemia should be established, especially in high prevalent southern Jiangxi (Hakka Han), including establishment of thalassemia database collection, hematological analysis laboratories, genetic counselling clinics, prenatal diagnosis centers and neonatal screening centers.
doi:10.1371/journal.pone.0101505
PMCID: PMC4084819  PMID: 25000193
4.  Hemoglobinopathy: Molecular Epidemiological Characteristics and Health Effects on Hakka People in the Meizhou Region, Southern China 
PLoS ONE  2013;8(2):e55024.
Background
Hemoglobinopathies are the most common inherited diseases in southern China. However, there have been only a few epidemiological studies of hemoglobinopathies in Guangdong province.
Materials and Methods
Peripheral blood samples were collected from 15299 “healthy” unrelated subjects of dominantly ethnic Hakka in the Meizhou region, on which hemoglobin electrophoresis and routine blood tests were performed. Suspected cases with hemoglobin variants and hereditary persistence of fetal hemoglobin (HPFH) were further characterized by PCR, DNA sequencing, reverse dot blot (RDB) or multiplex ligation-dependent probe amplification (MLPA). In addition, 1743 samples were randomly selected from the 15299 subjects for thalassemia screening, and suspected thalassemia carriers were identified by PCR and RDB.
Results
The gene frequency of hemoglobin variants was 0.477% (73/15299). The five main subgroups of the ten hemoglobin variants were Hb E, Hb G-Chinese, Hb Q-Tahiland, Hb New York and Hb J-Bangkok. 277 cases (15.89%, 277/1743) of suspected thalassemia carriers with microcytosis (MCV<82 fl) were found by thalassemia screening, and were tested by a RDB gene chip to reveal a total of 196 mutant chromosomes: including 124 α-thalassemia mutant chromosomes and 72 β-thalassemia mutant chromosomes. These results give a heterozygote frequency of 11.24% for common α and β thalassemia in the Hakka population in the Meizhou region. 3 cases of HPFH/δβ-thalassemia were found, including 2 cases of Vietnamese HPFH (FPFH-7) and a rare Belgian Gγ(Aγδβ)0–thalassemia identified in Chinese.
Conclusions
Our results provide a detailed prevalence and molecular characterization of hemoglobinopathies in Hakka people of the Meizhou region. The estimated numbers of pregnancies each year in the Meizhou region, in which the fetus would be at risk for β thalassemia major or intermedia, Bart’s hydrops fetalis, and Hb H disease, are 25 (95% CI, 15 to 38), 40 (95% CI, 26 to 57), and 15 (95% CI, 8 to 23), respectively.
doi:10.1371/journal.pone.0055024
PMCID: PMC3562339  PMID: 23383304
5.  The Calcineurin-NFAT Axis Controls Allograft Immunity in Myeloid-Derived Suppressor Cells through Reprogramming T Cell Differentiation 
Molecular and Cellular Biology  2014;35(3):598-609.
While cyclosporine (CsA) inhibits calcineurin and is highly effective in prolonging rejection for transplantation patients, the immunological mechanisms remain unknown. Herein, the role of calcineurin signaling was investigated in a mouse allogeneic skin transplantation model. The calcineurin inhibitor CsA significantly ameliorated allograft rejection. In CsA-treated allograft recipient mice, CD11b+ Gr1+ myeloid-derived suppressor cells (MDSCs) were functional suppressive immune modulators that resulted in fewer gamma interferon (IFN-γ)-producing CD8+ T cells and CD4+ T cells (TH1 T helper cells) and more interleukin 4 (IL-4)-producing CD4+ T cells (TH2) and prolonged allogeneic skin graft survival. Importantly, the expression of NFATc1 is significantly diminished in the CsA-induced MDSCs. Blocking NFAT (nuclear factor of activated T cells) with VIVIT phenocopied the CsA effects in MDSCs and increased the suppressive activities and recruitment of CD11b+ Gr1+ MDSCs in allograft recipient mice. Mechanistically, CsA treatment enhanced the expression of indoleamine 2,3-dioxygenase (IDO) and the suppressive activities of MDSCs in allograft recipients. Inhibition of IDO nearly completely recovered the increased MDSC suppressive activities and the effects on T cell differentiation. The results of this study indicate that MDSCs are an essential component in controlling allograft survival following CsA or VIVIT treatment, validating the calcineurin-NFAT-IDO signaling axis as a potential therapeutic target in transplantation.
doi:10.1128/MCB.01251-14
PMCID: PMC4285420  PMID: 25452304
7.  Virtual screening and optimization of Type II inhibitors of JAK2 from a natural product library† 
Amentoflavone has been identified as a JAK2 inhibitor by structure-based virtual screening of a natural product library. In silico optimization using the DOLPHIN model yielded analogues with enhanced potency against JAK2 activity and HCV activity in cellulo. Molecular modeling and kinetic experiments suggested that the analogues may function as Type II inhibitors of JAK2.
doi:10.1039/c4cc04498c
PMCID: PMC4521218  PMID: 25225654
8.  Sudden loss of the deep brain stimulation effect with high impedance without macroscopic fracture: a case report and review of the published literature 
The number of deep brain stimulation (DBS) hardware complications has increased during the past decade. In cases of abnormally high lead impedance with no evidence of a macroscopic fracture, optimal treatment options have not yet been established. Here, we present the case of a 49-year-old woman with a 12-year history of Parkinson’s disease who received bilateral subthalamic nucleus DBS in March 2006. The patient showed good control of parkinsonism until December 24, 2010, when she awoke with abrupt worsening of parkinsonian symptoms. At telemetric testing, lead impedances were found at >2,000 Ω in all four leads on the left side. Fracture of a lead or an extension wire was suspected. However, radiological screening and palpation revealed no macroscopic fracture. In June 2011, the implantable pulse generator (IPG) was changed under local anesthesia without any complications. Postoperatively, her parkinsonism immediately improved to the previous level, and the lead impedance readings by telemetry were also normalized. The disconnection of the neurostimulator connector block and the hybrid circuit board of the IPG was confirmed by destructive analysis. The present report illustrates that a staged approach that starts with simple IPG replacement can be an option for some cases of acute DBS effect loss with high impedance, when radiological findings are normal, thereby sparing the intact electrodes and extension wires.
doi:10.2147/NDT.S86120
PMCID: PMC4516336
connector block; hardware complication; implantable neurostimulators; Parkinson’s disease
9.  Multiple Genetic Modifiers of Bilirubin Metabolism Involvement in Significant Neonatal Hyperbilirubinemia in Patients of Chinese Descent 
PLoS ONE  2015;10(7):e0132034.
The potential for genetic variation to modulate neonatal hyperbilirubinemia risk is increasingly being recognized. A case-control study was designed to assess comprehensive contributions of the multiple genetic modifiers of bilirubin metabolism on significant neonatal hyperbilirubinemia in Chinese descendents. Eleven common mutations and polymorphisms across five bilirubin metabolism genes, namely those encoding UGT1A1, HMOX1, BLVRA, SLCO1B1 and SLCO1B3, were determined using the high resolution melt (HRM) assay or PCR-capillary electrophoresis analysis. A total of 129 hyperbilirubinemic infants and 108 control subjects were evaluated. Breastfeeding and the presence of the minor A allele of rs4148323 (UGTA*6) were correlated with an increased risk of hyperbilirubinemia (OR=2.17, P=0.02 for breastfeeding; OR=9.776, P=0.000 for UGTA*6 homozygote; OR=3.151, P=0.000 for UGTA*6 heterozygote); whereas, increasing gestational age and the presence of –TA7 repeat variant of UGT1A1 decreased the risk (OR=0.721, P=0.003 for gestational age; OR=0.313, P=0.002 for heterozygote TA6/TA7). In addition, the SLCO1B1 and SLCO1B3 polymorphisms also contributed to an increased risk of hyperbilirubinemia. This detailed analysis revealed the impact of multiple genetic modifiers on neonatal hyperbilirubinemia. This may support the use of genetic tests for clinical risk assessment. Furthermore, the established HRM assay can serve as an effective method for large-scale investigation.
doi:10.1371/journal.pone.0132034
PMCID: PMC4493094  PMID: 26146841
10.  Genome-Wide Association Analysis for Blood Lipid Traits Measured in Three Pig Populations Reveals a Substantial Level of Genetic Heterogeneity 
PLoS ONE  2015;10(6):e0131667.
Serum lipids are associated with myocardial infarction and cardiovascular disease in humans. Here we dissected the genetic architecture of blood lipid traits by applying genome-wide association studies (GWAS) in 1,256 pigs from Laiwu, Erhualian and Duroc × (Landrace × Yorkshire) populations, and a meta-analysis of GWAS in more than 2,400 pigs from five diverse populations. A total of 22 genomic loci surpassing the suggestive significance level were detected on 11 pig chromosomes (SSC) for six blood lipid traits. Meta-analysis of GWAS identified 5 novel loci associated with blood lipid traits. Comparison of GWAS loci across the tested populations revealed a substantial level of genetic heterogeneity for porcine blood lipid levels. We further evaluated the causality of nine polymorphisms nearby or within the APOB gene on SSC3 for serum LDL-C and TC levels. Of the 9 polymorphisms, an indel showed the most significant association with LDL-C and TC in Laiwu pigs. But the significant association was not identified in the White Duroc × Erhualian F2 resource population, in which the QTL for LDL-C and TC was also detected on SSC3. This indicates that population-specific signals may exist for the SSC3 QTL. Further investigations are warranted to validate this assumption.
doi:10.1371/journal.pone.0131667
PMCID: PMC4488070  PMID: 26121138
11.  LPS-Induced G-CSF Expression in Macrophages Is Mediated by ERK2, but Not ERK1 
PLoS ONE  2015;10(6):e0129685.
Granulocyte colony-stimulating factor (G-CSF) selectively stimulates proliferation and differentiation of neutrophil progenitors which play important roles in host defense against infectious agents. However, persistent G-CSF production often leads to neutrophilia and excessive inflammatory reactions. There is therefore a need to understand the mechanism regulating G-CSF expression. In this study, we showed that U0126, a MEK1/2 inhibitor, decreases lipopolysaccharide (LPS)-stimulated G-CSF promoter activity, mRNA expression and protein secretion. Using short hairpin RNA knockdown, we demonstrated that ERK2, and not ERK1, involves in LPS-induced G-CSF expression, but not LPS-regulated expression of TNF-α. Reporter assays showed that ERK2 and C/EBPβ synergistically activate G-CSF promoter activity. Further chromatin immunoprecipitation (ChIP) assays revealed that U0126 inhibits LPS-induced binding of NF-κB (p50/p65) and C/EBPβ to the G-CSF promoter, but not their nuclear protein levels. Knockdown of ERK2 inhibits LPS-induced accessibility of the G-CSF promoter region to DNase I, suggesting that chromatin remodeling may occur. These findings clarify that ERK2, rather than ERK1, mediates LPS-induced G-CSF expression in macrophages by remodeling chromatin, and stimulates C/EBPβ-dependent activation of the G-CSF promoter. This study provides a potential target for regulating G-CSF expression.
doi:10.1371/journal.pone.0129685
PMCID: PMC4483241  PMID: 26114754
12.  Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells 
Leukemia  2013;27(11):2177-2186.
The molecular bases of myelodysplastic syndromes (MDS) are not fully understood. Trimethylated histone 4 lysine 3 (H3K4me3) is present in promoters of actively transcribed genes and has been shown to be involved in hematopoietic differentiation. We performed a genome-wide H3K4me3 CHIP-Seq analysis of primary MDS bone marrow (BM) CD34+ cells. This resulted in the identification of 36 genes marked by distinct higher levels of promoter H3K4me3 in MDS. A majority of these genes are involved in NF-kB activation and innate immunity signaling. We then analyzed expression of histone demethylases and observed significant overexpression of the JmjC-domain histone demethylase JMJD3 (KDM6b) in MDS CD34+ cells. Furthermore, we demonstrated that JMJD3 has a positive effect on transcription of multiple CHIP-Seq identified genes involved in NF-kB activation. Inhibition of JMJD3 using shRNA in primary BM MDS CD34+ cells resulted in an increased number of erythroid colonies in samples isolated from patients with lower-risk MDS. Taken together, these data indicate the deregulation of H3K4me3 and associated abnormal activation of innate immunity signals play a role in the pathogenesis of MDS and that targeting these signals may have potential therapeutic value in MDS.
doi:10.1038/leu.2013.91
PMCID: PMC4476310  PMID: 23538751
myelodysplastic syndromes; H3K4me3; CHIP-Seq; JMJD3; innate immunity
14.  Lead Induces Apoptosis and Histone Hyperacetylation in Rat Cardiovascular Tissues 
PLoS ONE  2015;10(6):e0129091.
Acute and chronic lead (Pb) exposure might cause hypertension and cardiovascular diseases. The purpose of this study was to evaluate the effects of early acute exposure to Pb on the cellular morphology, apoptosis, and proliferation in rats and to elucidate the early mechanisms involved in the development of Pb-induced hypertension. Very young Sprague-Dawley rats were allowed to drink 1% Pb acetate for 12 and 40 days. Western blot analysis indicated that the expression of proliferating cell nuclear antigen (PCNA) decreased in the tissues of the abdominal and thoracic aortas and increased in the cardiac tissue after 12 and 40 days of Pb exposure, respectively. Bax was upregulated and Bcl-2 was downregulated in vascular and cardiac tissues after 40 days of Pb exposure. In addition, an increase in caspase-3 activity was observed after 40 days of exposure to Pb. In terms of morphology, we found that the internal elastic lamina (IEL) of aorta lost the original curve and the diameter of cardiac cell was enlarged after 40 days. Furthermore, the exposure led to a marked increase in acetylated histone H3 levels in the aortas and cardiac tissue after 12 and 40 days, than that in the control group. These findings indicate that Pb might increase the level of histone acetylation and induce apoptosis in vascular and cardiac tissues. However, the mechanism involved need to be further investigated.
doi:10.1371/journal.pone.0129091
PMCID: PMC4468051  PMID: 26075388
15.  The rs2237892 Polymorphism in KCNQ1 Influences Gestational Diabetes Mellitus and Glucose Levels: A Case-Control Study and Meta-Analysis 
PLoS ONE  2015;10(6):e0128901.
Objective
Recent genetic studies have shown that potassium voltage-gated channel, KQT-like subfamily, member1 (KCNQ1) gene is related to gestational diabetes mellitus (GDM). However, studies for the rs2237892 polymorphism in KCNQ1 and GDM remain conflicting in Asians. Furthermore, associations of this polymorphism with glucose levels during oral glucose tolerance test (OGTT) have not been described in Chinese pregnant women. The present study aimed to provide evidence for the associations of rs2237892 in KCNQ1 with GDM and glucose levels, and to systematically evaluate the effect of rs2237892 on GDM in Asians.
Methods
A case-control study on 562 women with GDM and 453 controls was conducted in Beijing, China. The association of rs2237892 with risk of GDM was analyzed using logistic regression. The associations with quantitative glucose levels were assessed using linear regression models. A meta-analysis including the present case-control study and four previously published reports in Asians was conducted.
Results
The rs2237892 polymorphism in KCNQ1 was associated with GDM (OR (95%CI) =1.99(1.26-3.15)). Additionally, the polymorphism was associated with levels of 1h and 2h glucose during OGTT. The pre-pregnancy BMI, age and genotypes of KCNQ1 polymorphism were independent risk factors of GDM. Subsequently, we performed a meta-analysis in Asians. In total, C-allele carriers of rs2237892 polymorphism had a 50% higher risk for GDM (OR (95%CI) =1.50(1.15-1.78)).
Conclusion
The study demonstrated for the first time that the KCNQ1 rs2237892 polymorphism was associated with GDM and glucose levels in Chinese women. The study provides systematic evidence for the association between this polymorphism and GDM in Asians.
doi:10.1371/journal.pone.0128901
PMCID: PMC4454508  PMID: 26039078
16.  No Effect of Acute Exposure to Coarse Particulate Matter Air Pollution in a Rural Location on High Density Lipoprotein Function 
Inhalation toxicology  2014;26(1):23-29.
Context
High density lipoprotein (HDL) particles perform numerous vascular-protective functions. Animal studies demonstrate that exposure to fine or ultrafine particulate matter (PM) can promote HDL dysfunction. However, the impact of PM on humans remains unknown.
Objective
We aimed to determine the effect of exposure to coarse concentrated ambient particles (CAP) on several metrics of HDL function.
Methods
Thirty-two adults (25.9 ± 6.6 years) were exposed to coarse CAP [76.2 ± 51.5 µg·m−3] in a rural location and filtered air (FA) for 2-hours in a randomized double-blind crossover study. Venous blood collected 2 and 20 hours post-exposures was measured for HDL-mediated efflux of [3H]-cholesterol from cells and 20 hours post-exposures for HDL anti-oxidant capacity by the HDL oxidation index (HOI) and paraoxonase activity. The changes [median (first, third quartiles)] between exposures among 29 subjects with available results were compared by matched Wilcoxon tests.
Results
HDL-mediated cholesterol efflux capacity did not differ between exposures at either time point [16.60% (15.17, 19.19) 2-hours post-CAP versus 17.56% (13.43, 20.98) post-FA, p=0.768 and 14.90% (12.47, 19.15) 20-hours post-CAP versus 17.75% (13.22, 23.95) post-FA, p=0.216]. HOI [0.26 (0.24, 0.35) versus 0.28 (0.25, 0.40), p=0.198] and paraoxonase activity [0.54 (0.39, 0.82) versus 0.60 µmol·min−1·ml plasma−1 (0.40, 0.85), p=0.137] did not differ 20-hours post-CAP versus FA, respectively.
Conclusions
Brief inhalation of coarse PM from a rural location did not acutely impair several facets of HDL functionality. Whether coarse PM derived from urban sites, fine particles, or longer-term PM exposures can promote HDL dysfunction warrant future investigations.
doi:10.3109/08958378.2013.850761
PMCID: PMC4445365  PMID: 24417404
Air pollution; atherosclerosis; high density lipoprotein
17.  Human adenovirus type 8 epidemic keratoconjunctivitis with large corneal epithelial full-layer detachment: an endemic outbreak with uncommon manifestations 
Epidemic viral conjunctivitis is a highly contagious disease that is encountered year-round. The causative agents are mainly adenoviruses and enteroviruses. It occurs most commonly upon infection with subgroup D adenoviruses of types 8, 19, or 37. For common corneal involvement of human adenovirus type 8 epidemic keratoconjunctivitis, full-layer epithelial detachment is rarely seen. Herein, we report three cases of epidemic keratoconjunctivitis during an outbreak which manifested as large corneal epithelial full-layer detachment within a few days. The lesions healed without severe sequelae under proper treatment. The unique manifestation of this outbreak may indicate the evolution of human adenovirus type 8.
doi:10.2147/OPTH.S79697
PMCID: PMC4454193  PMID: 26060391
EKC; HAdV-8; cornea; virology; epidemic viral conjunctivitis
18.  Silencing of Receptor Tyrosine Kinase ROR1 Inhibits Tumor-Cell Proliferation via PI3K/AKT/mTOR Signaling Pathway in Lung Adenocarcinoma 
PLoS ONE  2015;10(5):e0127092.
Receptor tyrosine kinase ROR1, an embryonic protein involved in organogenesis, is expressed in certain hematological malignancies and solid tumors, but is generally absent in adult tissues. This makes the protein an ideal drug target for cancer therapy. In order to assess the suitability of ROR1 as a cell surface antigen for targeted therapy of lung adenocarcinoma, we carried out a comprehensive analysis of ROR1 protein expression in human lung adenocarcinoma tissues and cell lines. Our data show that ROR1 protein is selectively expressed on lung adenocarcinoma cells, but do not support the hypothesis that expression levels of ROR1 are associated with aggressive disease. However silencing of ROR1 via siRNA treatment significantly down-regulates the activity of the PI3K/AKT/mTOR signaling pathway. This is associated with significant apoptosis and anti-proliferation of tumor cells. We found ROR1 protein expressed in lung adenocarcinoma but almost absent in tumor-adjacent tissues of the patients. The finding of ROR1-mediated proliferation signals in both tyrosine kinase inhibitor (TKI)-sensitive and -resistant tumor cells provides encouragement to develop ROR1-directed targeted therapy in lung adenocarcinoma, especially those with TKI resistance.
doi:10.1371/journal.pone.0127092
PMCID: PMC4433279  PMID: 25978653
19.  The Correlation between Aquaporin-4 Antibody and the Visual Function of Patients with Demyelinating Optic Neuritis at Onset 
Journal of Ophthalmology  2015;2015:672931.
ON patients with AQP4-Ab seropositivity tend to be predominantly female and young and have worse visual acuity and more severe damage to their visual fields compared with AQP4-Ab seronegativity.
doi:10.1155/2015/672931
PMCID: PMC4442297  PMID: 26078876
20.  Maternal Consumption of Non-Staple Food in the First Trimester and Risk of Neural Tube Defects in Offspring 
Nutrients  2015;7(5):3067-3077.
To study the associations between maternal consumption of non-staple food in the first trimester and risk of neural tube defects (NTDs) in offspring. Data collected from a hospital-based case-control study conducted between 2006 and 2008 in Shandong/Shanxi provinces including 459 mothers with NTDs-affected births and 459 mothers without NTDs-affected births. Logistic regression models were used to examine the associations between maternal consumption of non-staple food in the first trimester and risk of NTDs in offspring. The effects were evaluated by odds ratio (OR) and 95% confidence intervals (95% CIs) with SAS9.1.3.software. Maternal consumption of milk, fresh fruits and nuts in the first trimester were protective factors for total NTDs. Compared with consumption frequency of ˂1 meal/week, the ORs for milk consumption frequency of 1–2, 3–6, ≥7 meals/week were 0.50 (95% CI: 0.28–0.88), 0.56 (0.32–0.99), and 0.59 (0.38–0.90), respectively; the ORs for fresh fruits consumption frequency of 1–2, 3–6, ≥7 meals/week were 0.29 (95% CI: 0.12–0.72), 0.22 (0.09–0.53), and 0.32 (0.14–0.71), respectively; the ORs for nuts consumption frequency of 1–2, 3–6, ≥7 meals/week were 0.60 (95% CI: 0.38–0.94), 0.49 (0.31–0.79), and 0.63 (0.36–1.08), respectively. Different effects of above factors on NTDs were found for subtypes of anencephaly and spina bifida. Maternal non-staple food consumption of milk, fresh fruits and nuts in the first trimester was associated with reducing NTDs risk in offspring.
doi:10.3390/nu7053067
PMCID: PMC4446739  PMID: 25919306
case-control study; nutrition; neural tube defects
21.  Implementing a Chronic Disease Self-Management Program into China: The Happy Life Club™ 
China is experiencing population aging, increased prevalence of chronic diseases, and reductions in the frequency of healthy lifestyle behaviors. In response to these significant transitions, China is implementing major reforms in health care services with a focus on strengthening primary health care. In this paper, we describe a 12-month diabetes management program, the Happy Life Club™ (HLC™), implemented in a primary health care setting in Beijing, that uses doctor and nurse health coaches trained in behavior change techniques and motivational interviewing (MI). This paper reports the results of this pilot study and discusses issues involved in the implementation of Chronic Diseases Self-Management Programs in China. The intervention group showed improvements in HbA1c levels at 6 months and both the control and intervention groups showed reductions in waist circumference over time. Systolic blood pressure improved over time in the intervention group. The intervention group showed improvement in quality of life across the intervention period and both groups showed decreases in psychological distress across the intervention. Doctor visits increased between baseline and 6 months, but there was no change in doctor visits between 6 and 12 months for both groups. The effects were modest, and further investigations are required to evaluate the long-term impact of health coach approaches in China.
doi:10.3389/fpubh.2014.00181
PMCID: PMC4410613  PMID: 25964910
chronic disease self-management; motivational interviewing; diabetes; older people; China
22.  Influence of Preoperative Peripheral Parenteral Nutrition with Micronutrients after Colorectal Cancer Patients 
BioMed Research International  2015;2015:535431.
Background. The inflammatory reactions are stronger after surgery of malnourished preoperative patients. Many studies have shown vitamin and trace element deficiencies appear to affect the functioning of immune cells. Enteral nutrition is often inadequate for malnourished patients. Therefore, total parenteral nutrition (TPN) is considered an effective method for providing preoperative nutritional support. TPN needs a central vein catheter, and there are more risks associated with TPN. However, peripheral parenteral nutrition (PPN) often does not provide enough energy or nutrients. Purpose. This study investigated the inflammatory response and prognosis for patients receiving a modified form of PPN with added fat emulsion infusion, multiple vitamins (MTV), and trace elements (TE) to assess the feasibility of preoperative nutritional support. Methods. A cross-sectional design was used to compare the influence of PPN with or without adding MTV and TE on malnourished abdominal surgery patients. Results. Both preoperative groups received equal calories and protein, but due to the lack of micronutrients, patients in preoperative Group B exhibited higher inflammation, lower serum albumin levels, and higher anastomotic leak rates and also required prolonged hospital stays. Conclusion. Malnourished patients who receive micronutrient supplementation preoperatively have lower postoperative inflammatory responses and better prognoses. PPN with added fat emulsion, MTV, and TE provides valid and effective preoperative nutritional support.
doi:10.1155/2015/535431
PMCID: PMC4426776  PMID: 26000296
23.  D-2-hydroxyglutarate is essential for maintaining oncogenic property of mutant IDH-containing cancer cells but dispensable for cell growth 
Oncotarget  2015;6(11):8606-8620.
Cancer-associated isocitrate dehydrogenase (IDH) 1 and 2 mutations gain a new activity of reducing α-KG to produce D-2-hydroxyglutarate (D-2-HG), which is proposed to function as an oncometabolite by inhibiting α-KG dependent dioxygenases. We investigated the function of D-2-HG in tumorigenesis using IDH1 and IDH2 mutant cancer cell lines. Inhibition of D-2-HG production either by specific deletion of the mutant IDH1-R132C allele or overexpression of D-2-hydroxyglutarate dehydrogenase (D2HGDH) increases α-KG and related metabolites, restores the activity of some α-KG-dependent dioxygenases, and selectively alters gene expression. Ablation of D-2-HG production has no significant effect on cell proliferation and migration, but strongly inhibits anchorage independent growth in vitro and tumor growth in xenografted mouse models. Our study identifies a new activity of oncometabolite D-2-HG in promoting tumorigenesis.
PMCID: PMC4496170  PMID: 25825982
D-2-HG; IDH mutation; D2HGDH; tumorigenesis
24.  Ophthalmic findings in two cases of methanol optic neuropathy with relapsed vision disturbance 
doi:10.3980/j.issn.2222-3959.2015.02.37
PMCID: PMC4413572  PMID: 25938067
25.  RNA-Seq Analysis and Gene Discovery of Andrias davidianus Using Illumina Short Read Sequencing 
PLoS ONE  2015;10(4):e0123730.
The Chinese giant salamander, Andrias davidianus, is an important species in the course of evolution; however, there is insufficient genomic data in public databases for understanding its immunologic mechanisms. High-throughput transcriptome sequencing is necessary to generate an enormous number of transcript sequences from A. davidianus for gene discovery. In this study, we generated more than 40 million reads from samples of spleen and skin tissue using the Illumina paired-end sequencing technology. De novo assembly yielded 87,297 transcripts with a mean length of 734 base pairs (bp). Based on the sequence similarities, searching with known proteins, 38,916 genes were identified. Gene enrichment analysis determined that 981 transcripts were assigned to the immune system. Tissue-specific expression analysis indicated that 443 of transcripts were specifically expressed in the spleen and skin. Among these transcripts, 147 transcripts were found to be involved in immune responses and inflammatory reactions, such as fucolectin, β-defensins and lymphotoxin beta. Eight tissue-specific genes were selected for validation using real time reverse transcription quantitative PCR (qRT-PCR). The results showed that these genes were significantly more expressed in spleen and skin than in other tissues, suggesting that these genes have vital roles in the immune response. This work provides a comprehensive genomic sequence resource for A. davidianus and lays the foundation for future research on the immunologic and disease resistance mechanisms of A. davidianus and other amphibians.
doi:10.1371/journal.pone.0123730
PMCID: PMC4395309  PMID: 25874626

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