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1.  5-(4-Chloro­phen­oxy)-1-methyl-3-tri­fluoro­methyl-1H-pyrazole-4-carbaldehyde O-[(2-chloro­pyridin-5-yl)meth­yl]oxime 
In the title mol­ecule, C18H13Cl2F3N4O2, the intra­molecular distance between the centroids of the benzene and pyridine rings is 3.953 (3) Å, and the trifluoro­methyl group is rotationally disordered over two orientations in a 0.678 (19):0.322 (19) ratio. The crystal packing exhibits weak inter­molecular C—H⋯F inter­actions.
PMCID: PMC3238903  PMID: 22199756
2.  Case-case comparison of smoking and alcohol risk associations with Epstein-Barr virus-positive gastric cancer 
Helicobacter pylori is the primary cause of gastric cancer. However, monoclonal Epstein-Barr virus (EBV) nucleic acid is also present in up to 10% of these tumors worldwide. EBV prevalence is increased with male sex, non-antral localization and surgically disrupted anatomy. To further examine associations between EBV and gastric cancer, we organized an international consortium of 11 studies with tumor EBV status assessed by in situ hybridization. We pooled individual-level data on 2,648 gastric cancer patients, including 184 (7%) with EBV-positive cancers; all studies had information on cigarette use (64% smokers) and 9 had data on alcohol (57% drinkers). We compared patients with EBV-positive and EBV-negative tumors to evaluate smoking and alcohol interactions with EBV status. To account for within-population clustering, multi-level logistic regression models were used to estimate interaction odds ratios (OR) adjusted for distributions of sex (72% male), age (mean 59 years), tumor histology (56% Lauren intestinal-type), anatomic subsite (61% noncardia) and year of diagnosis (1983–2012). In unadjusted analyses, the OR of EBV positivity with smoking was 2.2 (95% confidence interval [CI], 1.6–3.2). The OR was attenuated to 1.5 (95% CI, 1.01–2.3) by adjustment for the possible confounders. There was no significant interaction of EBV status with alcohol drinking (crude OR, 1.4; adjusted OR, 1.0). Our data indicate the smoking association with gastric cancer is stronger for EBV-positive than EBV-negative tumors. Conversely, the null association with alcohol does not vary by EBV status. Distinct epidemiologic characteristics of EBV-positive cancer further implicate the virus as a co-factor in gastric carcinogenesis.
PMCID: PMC3961829  PMID: 23904115
Alcohol; EBV; gastric cancer; smoking; pooled-analysis
4.  Conditions Causing Disability and Current Pregnancy Among U.S. Women with Chronic Physical Disabilities 
Medical care  2014;52(1):20-25.
Growing numbers of reproductive-age U.S. women with chronic physical disabilities (CPD) are becoming pregnant. Little is known about the health conditions causing their CPD.
To identify health conditions causing CPD among reproductive-age women and specifically among currently pregnant women.
Research Design
Cross-sectional, nationally-representative National Health Interview Survey data from 2006–2011.
6,043 civilian, noninstitutionalized women ages 18–49 with CPD
NHIS asks about various movement difficulties and their underlying causes and about current pregnancy. We used responses from 8 movement difficulty and other questions to identify women with mobility difficulties caused by chronic physical health conditions.
Among women with CPD, 2.0% report current pregnancy, with pregnancy rates falling monotonically as CPD severity rises. Regardless of pregnancy, 20.8% report 2 causes for their CPD, and 12.7% report 3+ causes; the most common causes are arthritis, back or neck problems, and other musculoskeletal conditions. Compared with nonpregnant women, currently pregnant women report fewer causal conditions: 15.8% report 2 causes and 8.0% 3+ causes; back or neck problems are reported most frequently, followed by musculoskeletal problems and arthritis. Multivariable logistic regression analyses predicting current pregnancy controlling for age category and individual common causes of CPD found that no cause was significantly associated with higher or lower adjusted odds of pregnancy.
Almost one-quarter of currently pregnant women with CPD report more than one cause for their disability. Further research will need to examine how obstetrical needs vary for depending on the cause of a pregnant woman’s disability.
PMCID: PMC3893693  PMID: 24220686
disability; pregnancy; mobility; comorbidities; National Health Interview Survey
5.  Transcriptome-Wide Analysis of SAMe Superfamily to Novelty Phosphoethanolamine N-Methyltransferase Copy in Lonicera japonica 
The S-adenosyl-l-methionine-dependent methyltransferase superfamily plays important roles in plant development. The buds of Lonicera japonica are used as Chinese medical material and foods; chinese people began domesticating L. japonica thousands of years ago. Compared to the wild species, L. japonica var. chinensis, L. japonica gives a higher yield of buds, a fact closely related to positive selection over the long cultivation period of the species. Genome duplications, which are always detected in the domestic species, are the source of the multifaceted roles of the functional gene. In this paper, we investigated the evolution of the SAMe genes in L. japonica and L. japonica var. chinensis and further analyzed the roles of the duplicated genes among special groups. The SAMe protein sequences were subdivided into three clusters and several subgroups. The difference in transcriptional levels of the duplicated genes showed that seven SAMe genes could be related to the differences between the wild and the domesticated varieties. The sequence diversity of seven SAMe genes was also analyzed, and the results showed that different gene expression levels between the varieties could not be related to amino acid variation. The transcriptional level of duplicated PEAMT could be regulated through the SAM–SAH cycle.
PMCID: PMC4307260  PMID: 25551601
phosphoethanolamine N-methyltransferase; duplicated gene; Lonicera japonica; domestication; bud yield
6.  MicroRNA-185 regulates expression of lipid metabolism genes and improves insulin sensitivity in mice with non-alcoholic fatty liver disease 
World Journal of Gastroenterology : WJG  2014;20(47):17914-17923.
AIM: To assess the regulatory effect of microRNA-185 (miR-185) on lipid metabolism and the insulin signalling pathway in human HepG2 hepatocytes and a high-fat diet mouse model.
METHODS: Quantitative reverse transcription-polymerase chain reaction was used to assess the mRNA levels of lipogenic genes after loss or gain of miR-185. In addition, the amounts of insulin signalling intermediates were determined after transfection of HepG2 cells with pre-miR-185.
RESULTS: MiR-185 levels decreased in a time- and dose-dependent manner in response to palmitic acid in human HepG2 hepatocytes. Transfection of HepG2 cells with miR-185 significantly decreased the mRNA levels of fatty acid synthase, 3-hydroxy-3-methylglutaryl-CoA reductase, sterol-regulatory element binding protein-2, and sterol-regulatory element binding protein-1c, whereas inhibition of miR-185 using an anti-miR-185 oligonucleotide produced the opposite effect in HepG2 cells. In a high-fat diet mouse model, the accumulation of lipids was significantly improved after treatment with miR-185, compared with control animals. Induction of miR-185 enhanced the insulin signalling pathway by up-regulating the insulin-receptor substrate-2.
CONCLUSION: These findings suggest that miR-185 plays an important role in regulating fatty-acid metabolism and cholesterol homeostasis in hepatocytes, as well as in improving insulin sensitivity, both in vitro and in vivo.
PMCID: PMC4273141  PMID: 25548489
MiR-185; Insulin signalling pathway; Lipid metabolism; Non-alcoholic fatty liver disease
7.  Efficacy of prophylactic intravenous ondansetron on the prevention of hypotension during cesarean delivery: a dose-dependent study 
Objective: This study was to determine the optimal dosage of ondansetron for preventing maternal hypotension during cesarean delivery. Methods: One hundred and fifty parturient women scheduled for elective cesarean section were randomly assigned to five groups (n=30). Five minutes prior to spinal anesthesia, women were injected with 5 ml of physiological saline (S), 2 mg (O2), 4 mg (O4), 6 mg (O6), or 8 mg (O8) of ondansetron in saline, respectively. Maternal blood pressure and heart rate were measured at 2-min intervals for 30 min. The serum parameters in umbilical cord blood were analyzed after delivery. Results: Compared with group S, the incidence of maternal hypotension was significantly lower in groups O4 and O6 (P < 0.05). The umbilical venous pH was significantly higher in group O4 (P < 0.05); while the partial pressure of carbon dioxide (Pco2) was significantly lower in groups O4, O6, and O8 (P < 0.05); and the bicarbonate (Hco3 -) and base excess in extracellular fluid (BEecf) were significantly lower in groups O6 and O8 (P < 0.05). Moreover, minimal changes of systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure were observed in group O4 (P < 0.05). Conclusion: The optimal dose of ondansetron preloading was 4 mg during cesarean delivery.
PMCID: PMC4307470  PMID: 25664023
Ondansetron; hypotension; spinal anesthesia; optimal dose
8.  Reduced mir-29b-3p expression up-regulate CDK6 and contributes to IgA nephropathy 
IgA nephropathy (IgAN) is the most common glomerulonephritis and the etiology of which is complex and multiple, and the pathological damage of IgAN is diversified. MicroRNA is a kind of gene expression suppressor and recently, researchers have found that microRNAs may play an important role in the pathogenesis of IgAN. Herein, we found that miR-29b-3p not miR-29a or miR-29c was significantly down regulated in IgAN patients’ renal tissues. Predicted by bioinformatics tools and confirmed by dual luciferase assay and western blot, we found that the expression of CDK6 was repressed by miR-29b-3p directly. Subsequently, we found that miR-29b-3p down-regulation caused CDK6 overexpression can promote NF-κB signal by phosphorylating p65 which may enhance inflammation during IgAN pathogenesis.
PMCID: PMC4307478  PMID: 25664031
MicroRNA; IgA nephropathy; CDK6; p65; phosphorylation
9.  Flexibility and Symmetry of Prokaryotic Genome Rearrangement Reveal Lineage-Associated Core-Gene-Defined Genome Organizational Frameworks 
mBio  2014;5(6):e01867-14.
The prokaryotic pangenome partitions genes into core and dispensable genes. The order of core genes, albeit assumed to be stable under selection in general, is frequently interrupted by horizontal gene transfer and rearrangement, but how a core-gene-defined genome maintains its stability or flexibility remains to be investigated. Based on data from 30 species, including 425 genomes from six phyla, we grouped core genes into syntenic blocks in the context of a pangenome according to their stability across multiple isolates. A subset of the core genes, often species specific and lineage associated, formed a core-gene-defined genome organizational framework (cGOF). Such cGOFs are either single segmental (one-third of the species analyzed) or multisegmental (the rest). Multisegment cGOFs were further classified into symmetric or asymmetric according to segment orientations toward the origin-terminus axis. The cGOFs in Gram-positive species are exclusively symmetric and often reversible in orientation, as opposed to those of the Gram-negative bacteria, which are all asymmetric and irreversible. Meanwhile, all species showing strong strand-biased gene distribution contain symmetric cGOFs and often specific DnaE (α subunit of DNA polymerase III) isoforms. Furthermore, functional evaluations revealed that cGOF genes are hub associated with regard to cellular activities, and the stability of cGOF provides efficient indexes for scaffold orientation as demonstrated by assembling virtual and empirical genome drafts. cGOFs show species specificity, and the symmetry of multisegmental cGOFs is conserved among taxa and constrained by DNA polymerase-centric strand-biased gene distribution. The definition of species-specific cGOFs provides powerful guidance for genome assembly and other structure-based analysis.
Prokaryotic genomes are frequently interrupted by horizontal gene transfer (HGT) and rearrangement. To know whether there is a set of genes not only conserved in position among isolates but also functionally essential for a given species and to further evaluate the stability or flexibility of such genome structures across lineages are of importance. Based on a large number of multi-isolate pangenomic data, our analysis reveals that a subset of core genes is organized into a core-gene-defined genome organizational framework, or cGOF. Furthermore, the lineage-associated cGOFs among Gram-positive and Gram-negative bacteria behave differently: the former, composed of 2 to 4 segments, have their fragments symmetrically rearranged around the origin-terminus axis, whereas the latter show more complex segmentation and are partitioned asymmetrically into chromosomal structures. The definition of cGOFs provides new insights into prokaryotic genome organization and efficient guidance for genome assembly and analysis.
PMCID: PMC4251990  PMID: 25425232
10.  Methylation of ras association domain protein 10 (RASSF10) promoter negative association with the survival of gastric cancer 
Objective: The present study was conducted to elucidate the prognostic prediction value of the methylation of the RASSF10 promoter in gastric cancer (GC). Methods: A total of 300 patients with GC revealed the methylation degrees of the DNA of the RASSF10 promoter. Methylation-specific PCR (MSP) analysis was performed to qualitatively detect the methylated degrees of the DNA of the RASSF10 promoter of 300 patients with GC. Associations between molecular, clinicopathological and survival data were analyzed. Results: The protein and mRNA expressions of RASSF10 in GC tissues were lower than those in normal gastric mucosal tissues. In the MSP analysis cohort, patients with methylated RASSF10 promoter exhibited significantly shorter median OS than those with unmethylated RASSF10 promoter (P < 0.001). Multivariate survival analysis results showed that methylated RASSF10 promoter was an independent predictor of the survival of patients with GC. Conclusions: The methylation of the RASSF10 promoter could be applied for the clinical prediction of the prognosis of GC.
PMCID: PMC4266723  PMID: 25520879
Stomach; neoplasm; ras association domain protein; survival; methylation
11.  Comparison of Surface Markers between Human and Rabbit Mesenchymal Stem Cells 
PLoS ONE  2014;9(11):e111390.
This study investigated whether there are marked differences in surface markers between rabbit and human mesenchymal stem cells (MSCs). Murine and rabbit MSCs have been reported to be CD90-negative. Rat MSCs have been reported to be CD71-negative. Our previous study also shows that rabbit MSCs are CD29-negative. However, human MSCs are generally considered to be CD29-, CD71-, and CD90-positive. Therefore, the surface markers of human MSCs might differ from those of other species. Rabbit bone marrow MSCs were obtained that had a multi-differentiation potential. The phenotype of these cells was studied using flow cytometry antibodies for 25 rabbit surface markers, namely, CD13, CD14, CD29, CD31, CD34, CD44, CD45, CD49d, CD49f, CD51, CD54, CD59, CD71, CD73, CD90, CD105, CD106, CD133, CD166, MHC I, MHC II, α-smooth muscle actin (α-SMA), cytokeratin, desmin, and vimentin. The phenotype of commercially available human MSCs was similarly studied using antibodies for human surface markers. CD14, CD31, CD34, CD45, CD49d, CD49f, CD51, CD54, CD71, CD106, CD133, MHC II, and cytokeratin were absent from both rabbit and human MSCs, while CD44, α-SMA, and vimentin were present on both cell lines. CD13, CD29, CD59, CD73, CD90, CD105, CD166, and MHC I were present on human MSCs, but not on rabbit MSCs. However, desmin was present on rabbit MSCs, but not on human MSCs. In total, the surface expression of nine markers differed between human and rabbit MSCs, whereas the surface expression of 16 markers was the same in the two cell lines.
PMCID: PMC4224397  PMID: 25380245
12.  Investigation of the caspase-dependent mitochondrial apoptotic pathway in mononuclear cells of patients with systemic lupus erythematosus 
This study aimed to explore the role of apoptosis initiators, caspase-9, caspase-10, mitochondrial anti-viral signaling protein (MAVS), and interferon regulatory factor 7 (pIRF7), in patients with systemic lupus erythematosus (SLE).
Leukocyte apoptosis was determined by flow cytometry, including annexin V, APO2.7, and 7-amino-actinomycin D (7-AAD) on each subtype of leukocyte in 35 patients with SLE, 15 disease controls, and 17 volunteer normal controls. Levels of caspase-9, caspase-10, MAVS, and pIRF7 in mononuclear cells and the disease activity index (SLEDAI) in the SLE patients were determined. Correlation among intracellular adaptor proteins and caspase levels were calculated.
The SLE patients had higher APO2.7 in total leukocyte, lymphocyte, and monocytes, and higher late apoptosis markers in total leukocytes and neutrophils than normal controls (all p < 0.05). Disease activity was positively associated with the APO2.7 of CD19+ cells in SLE, but negatively associated with MAVS and caspase-9 levels (all p < 0.05). Markers of viral infection and anti-virus transcription factors like MDA5, MAVS, and pIRF7 were significantly higher in SLE patients than in disease controls (p < 0.05). Caspase-9 and caspase-10 levels positively correlated with MAVS and pIRF7 in SLE patients (p < 0.05).
The disease activity of SLE is positively associated with APO2.7 level of CD19+ cells but negatively associated with MAVS and caspase-9 levels, which all point to a mitochondrial pathway.
PMCID: PMC4226892  PMID: 25370148
Caspase; Leukocyte apoptosis; Systemic lupus erythematosus; Interferon
13.  Chronic vagus nerve stimulation improves left ventricular function in a canine model of chronic mitral regurgitation 
Autonomic dysfunction, characterized by sympathetic activation and vagal withdrawal, contributes to the progression of heart failure (HF). We hypothesized that chronic vagus nerve stimulation (VNS) could prevent left ventricular (LV) remodeling and dysfunction in a canine HF model induced by chronic mitral regurgitation (MR).
Methods and results
After the MR inducing procedure, 12 survived canines were randomly divided into the control (n = 6) and the VNS (n = 6) groups. At month 2, a VNS stimulator system was implanted in all canines. From month 3 to month 6, VNS therapy was applied in the VNS group but not in the control group. At month 6, compared with the control group, the canines in VNS group had significantly higher cardiac output (2.3 ± 0.3 versus 2.9 ± 0.4 L/min, P < 0.05, LV forward stroke volume (20.1 ± 3.7 versus 24.8 ± 3.9 ml, P < 0.05), and end-systolic stiffness constant (2.2 ± 0.3 versus 2.7 ± 0.3, P < 0.05). NT-proBNP and C-reactive protein were decreased significantly in the VNS group. However, no statistical difference was found in LV ejection fraction, LV end-diastolic dimension, LV end-diastolic volume, myocyte cross-sectional area, or collagen volume fraction between two groups.
Chronic VNS therapy may ameliorate MR-induced LV contractile dysfunction and improve the expression of biomarkers, but has less effect in improving LV chamber remodeling.
PMCID: PMC4228179  PMID: 25366939
Autonomic nervous system; Vagus nerve stimulation; Mitral valve insufficiency; Heart failure
14.  Mortality and complications of hip fracture in young adults: a nationwide population-based cohort study 
This study assessed the mortality and complications of hip fractures using in-patients aged 20–40 years from a nationwide population database in Taiwan.
Subjects were selected from Taiwan’s National Health Insurance Research Database for the period 2000–2008, and these subjects were followed up until the end of 2010. A total of 5,079 (3,879 male and 1,200 female) subjects were admitted for the first time with primary diagnosis of hip fracture and treated with operation. We calculated the long-term overall survival rate and complication-free rate. We also assessed the risk factors for mortality and complications.
The 1-month, 3-month, 6-month, 1-year, 2-year, 5-year, and 10-year complication-free rates were 98.3%, 96.2%, 94.5%, 86.8%, 80.4%, 75.3%, and 73.5% for the entire cohort, respectively. The 10-year survival rates were 93.3%, 91.8%, and 94.5% for total cases, trochanteric fracture, and cervical fracture, respectively. The 10-year complication-free rates were 73.5%, 80.5%, and 67.3% for total cases, trochanteric fracture, and cervical fracture, respectively. The risk factors for overall death were male, older age, and greater number of Charlson comorbidity index (CCI) comorbidities. The risk factors for complication were cervical fracture, and greater number of CCI comorbidities. Complications resulted in 42.83% of patients receiving internal fixation implants or prothesis removal and 2.01% underwent conversion to revision arthroplasty during follow-up.
The overall 10-year survival rate in hip fracture patients aged 20–40 years in Taiwan was over 90%. The 10-year complication-free rates were around 70%. Preventing the occurrence of severe complications after hip fracture among young adults is an important public health issue that warrants greater attention.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2474-15-362) contains supplementary material, which is available to authorized users.
PMCID: PMC4289162  PMID: 25361701
Hip fracture; Complication; Mortality
15.  TET2 is a Master Regulator of Smooth Muscle Cell Plasticity 
Circulation  2013;128(18):2047-2057.
Smooth muscle cells (SMC) are remarkably plastic. Their reversible differentiation is required for growth and wound healing, but also contributes to pathologies including atherosclerosis and restenosis. While key regulators of the SMC phenotype including myocardin (MYOCD) and KLF4 have been identified, a unifying epigenetic mechanism that confers reversible SMC differentiation has not been reported.
Methods and Results
Using human SMC, human arterial tissue, and mouse models, we report that SMC plasticity is governed by the DNA modifying enzyme ten-eleven translocation-2 (TET2). TET2 and its 5-hydroxymethylcytosine (5-hmC) product are enriched in contractile SMC but reduced in dedifferentiated SMC. TET2 knockdown inhibits expression of key pro-contractile genes including MYOCD and SRF with concomitant transcriptional upregulation of KLF4. TET2 knockdown prevents rapamycin-induced SMC differentiation, while TET2 overexpression is sufficient to induce a contractile phenotype. TET2 overexpression also induces SMC gene expression in fibroblasts. Chromatin immunoprecipitation demonstrates that TET2 coordinately regulates phenotypic modulation through opposing effects on chromatin accessibility at the promoters of pro-contractile versus dedifferentiation-associated genes. Notably, we find that TET2 binds, and 5-hmC is enriched, in CArG-rich regions of active SMC contractile promoters (MYOCD, SRF, and MYH11). Loss of TET2 and 5-hmC positively correlates with the degree of injury in murine models of vascular injury and human atherosclerotic disease. Importantly, localized TET2 knockdown exacerbates injury response while local TET2 overexpression restores the 5-hmC epigenetic landscape, contractile gene expression, and greatly attenuates intimal hyperplasia in vivo.
We identify TET2 as a novel and necessary master epigenetic regulator of SMC differentiation.
PMCID: PMC3899790  PMID: 24077167
smooth muscle; differentiation; gene expression/regulation; epigenetics; hyperplasia
16.  Order-disorder phase transitions in the two-dimensional semiconducting transition metal dichalcogenide alloys Mo1−xWxX2 (X = S, Se, and Te) 
Scientific Reports  2014;4:6691.
A combination of density functional theory, an empirical model, and Monte Carlo simulations is used to shed light on the evolution of the atomic distribution in the two-dimensional semiconducting transition metal dichalcogenide alloys Mo1−xWxX2 (X = S, Se, and Te) as a function of the W concentration and temperature. Both random and ordered phases are discovered and the origin of the phase transitions is clarified. While the empirical model predicts at x = 1/3 and 2/3 ordered alloys, Monte Carlo simulations suggest that they only exist at low temperature due to a small energetic preference of Mo-X-W over Mo-X-Mo and W-X-W interactions, explaining the experimental observation of random alloy Mo1−xWxS2. Negative formation energies point to a high miscibility. Tunability of the band edges and band gaps by alteration of the W concentration gives rise to a broad range of applications.
PMCID: PMC4204064  PMID: 25331363
17.  Phylogeny of C4-Photosynthesis Enzymes Based on Algal Transcriptomic and Genomic Data Supports an Archaeal/Proteobacterial Origin and Multiple Duplication for Most C4-Related Genes 
PLoS ONE  2014;9(10):e110154.
Both Calvin-Benson-Bassham (C3) and Hatch-Slack (C4) cycles are most important autotrophic CO2 fixation pathways on today’s Earth. C3 cycle is believed to be originated from cyanobacterial endosymbiosis. However, studies on evolution of different biochemical variants of C4 photosynthesis are limited to tracheophytes and origins of C4-cycle genes are not clear till now. Our comprehensive analyses on bioinformatics and phylogenetics of novel transcriptomic sequencing data of 21 rhodophytes and 19 Phaeophyceae marine species and public genomic data of more algae, tracheophytes, cyanobacteria, proteobacteria and archaea revealed the origin and evolution of C4 cycle-related genes. Almost all of C4-related genes were annotated in extensive algal lineages with proteobacterial or archaeal origins, except for phosphoenolpyruvate carboxykinase (PCK) and aspartate aminotransferase (AST) with both cyanobacterial and archaeal/proteobacterial origin. Notably, cyanobacteria may not possess complete C4 pathway because of the flawed annotation of pyruvate orthophosphate dikinase (PPDK) genes in public data. Most C4 cycle-related genes endured duplication and gave rise to functional differentiation and adaptation in different algal lineages. C4-related genes of NAD-ME (NAD-malic enzyme) and PCK subtypes exist in most algae and may be primitive ones, while NADP-ME (NADP-malic enzyme) subtype genes might evolve from NAD-ME subtype by gene duplication in chlorophytes and tracheophytes.
PMCID: PMC4196954  PMID: 25313828
18.  MicroRNA dysregulation as a prognostic biomarker in colorectal cancer 
Colorectal cancer (CRC) is one of the most potentially curable cancers, yet it remains the fourth most common overall cause of cancer death worldwide. The identification of robust molecular prognostic biomarkers can refine the conventional tumor–node–metastasis staging system, avoid understaging of tumor, and help pinpoint patients with early-stage CRC who may benefit from aggressive treatments. Recently, epigenetic studies have provided new molecular evidence to better categorize the CRC subtypes and predict clinical outcomes. In this review, we summarize recent findings concerning the prognostic potential of microRNAs (miRNAs) in CRC. We first discuss the prognostic value of three tissue miRNAs (miR-21-5p, miR-29-3p, miR-148-3p) that have been examined in multiple studies. We also summarize the dysregulation of miRNA processing machinery DICER in CRC and its association with risk for mortality. We also reviewe the potential application of miRNA-associated single-nucleotide polymorphisms as prognostic biomarkers for CRC, especially the miRNA-associated polymorphism in the KRAS gene. Last but not least, we discuss the microsatellite instability-related miRNA candidates. Among all these candidates, miR-21-5p is the most promising prognostic marker, yet further prospective validation studies are required before it can go into clinical usage.
PMCID: PMC4206254  PMID: 25342918
microRNA; colorectal cancer; prognostic biomarker; single-nucleotide polymorphism; microsatellite instability
19.  Fabrication of uniform 4H-SiC mesopores by pulsed electrochemical etching 
Nanoscale Research Letters  2014;9(1):570.
In this letter, the uniform 4H silicon carbide (SiC) mesopores was fabricated by pulsed electrochemical etching method. The length of the mesopores is about 19 μm with a diameter of about 19 nm. The introduction of pause time (Toff) is crucial to form the uniform 4H-SiC mesopores. The pore diameter will not change if etching goes with Toff. The hole concentration decreasing at the pore tips during the Toff is the main reason for uniformity.
PMCID: PMC4198072  PMID: 25324708
Constant pulsed current; Uniform mesopores; Cycle time; Pause time
20.  Predictors and long-term outcome of seizures in human immuno-deficiency virus (HIV)-negative cryptococcal meningitis 
BMC Neurology  2014;14(1):208.
Seizures are one of the most important neurologic complications of human immuno-deficiency virus (HIV)-negative cryptococcal meningitis. A better understanding of the risk associated factors can help predict those who will require treatment.
This 22-year retrospective study enrolled 180 patients. Prognostic variables independently associated with seizures or fatality were analyzed using stepwise logistic regression.
Twenty-eight patients with HIV-negative cryptococcal meningitis had seizures, including 13 with early seizures and 15 with late seizures. The mean time interval from HIV-negative cryptococcal meningitis to first seizure in the early and late seizure groups were 1.5 and 51.4 days, respectively. Nine out of the 28 cases (32%) occurred within 24 hours of presentation. The overall mortality rate was 54% (15/28) and two patients progressed to epilepsy.
Patients with seizure have worse outcomes and longer hospitalization. Most first seizures occur within one year after the diagnosis of HIV-negative cryptococcal meningitis.
PMCID: PMC4203868  PMID: 25307800
Outcome; Risk factors; Seizures; HIV-negative cryptococcal meningitis
21.  Leptin Downregulates Aggrecan through the p38-ADAMST Pathway in Human Nucleus Pulposus Cells 
PLoS ONE  2014;9(10):e109595.
The mechanistic basis of obesity-associated intervertebral disc degeneration (IDD) is unclear. Aberrant expression of aggrecan and its degrading enzymes ADAMTS-4 and ADAMTS-5 is implicated in the development of IDD. Here, we investigated the effect of leptin, a hormone with increased circulating levels in obesity, on the expression of aggrecan and ADAMTSs in primary human nucleus pulposus (NP) cells. Real-time PCR and Western blots showed that leptin increased the mRNA and protein expression of ADAMTS-4 and ADAMTS-5 and reduced the level of aggrecan in NP cells, accompanied by a prominent induction of p38 phosphorylation. Treatment of NP cells with SB203580 (a p38 inhibitor) abolished the regulation of aggrecan and ADAMTSs by leptin. Knockdown of ADAMTS-4 and ADAMTS-5 by siRNAs also attenuated the degradation of aggrecan in leptin-stimulated NP cells. To conclude, we demonstrated that leptin induces p38 to upregulate ADAMTSs and thereby promoting aggrecan degradation in human NP cells. These results provide a novel mechanistic insight into the molecular pathogenesis of obesity-associated IDD.
PMCID: PMC4192299  PMID: 25299465
22.  let-7b/g silencing activates AKT signaling to promote gastric carcinogenesis 
Aberrant AKT activation contributes to gastric cancer cell survival and chemotherapy resistance, however its regulation is poorly understood. microRNAs have been established to be important regulators in gastric carcinogenesis. Here, we showed the functional role and putative target of let-7b and let-7g (let-7b/g) in gastric carcinogenesis.
The expression of let-7b/g in gastric cancer cell lines and primary tumors were evaluated by miRNA qRT-PCR. The putative target gene of let-7b/g was explored by TargetScan followed by further validation. Functional analyses including MTT proliferation, monolayer colony formation, cell invasion assays and in vivo study were performed in both ectopic expression and knockdown approaches.
let-7b/g was found down-regulated in gastric cancer and its downregulation was associated with poor survival and correlated with lymph node metastasis. let-7b/g inhibited AKT2 expression by directly binding to its 3’UTR, reduced p-AKT (S473) activation and suppressed expression of the downstream effector pS6. AKT2 mRNA expression showed negative correlation with the expression of let-7b/g in primary tumors. Short interfering RNA (siRNA) mediated knockdown of AKT2 phenocopied the tumor-suppressive effects of let-7b/g. Moreover, AKT2 re-expression partly abrogated the growth-inhibitory effect of let-7b/g.
In conclusion, our findings reveal decreased let-7b/g contributes to aberrant AKT activation in gastric tumorigenesis and provide a potential therapeutic strategy for gastric cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0281-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4196013  PMID: 25288334
let-7b; let-7g; AKT2; Gastric cancer; Tumor suppressor
23.  Population pharmacokinetics modeling of oxcarbazepine to characterize drug interactions in Chinese children with epilepsy 
Acta Pharmacologica Sinica  2014;35(10):1342-1350.
To develop a population pharmacokinetics model of oxcarbazepine in Chinese pediatric patients with epilepsy, and to study the interactions between oxcarbazepine and other antiepileptic drugs (AEDs).
A total of 688 patients with epilepsy aged 2 months to 18 years were divided into model (n=573) and valid (n=115) groups. Serum concentrations of the main active metabolite of oxcarbazepine, 10-hydroxycarbazepine (MHD), were determined 0.5–48 h after the last dosage. A population pharmacokinetics (PPK) model was constructed using NLME software. This model was internally evaluated using Bootstrapping and goodness-of-fit plots inspection. The data of the valid group were used to calculate the mean prediction error (MPE), mean absolute prediction error (MAE), mean squared prediction error (MSE) and the 95% confidence intervals (95% CI) to externally evaluate the model.
The population values of pharmacokinetic parameters estimated in the final model were as follows: Ka=0.83 h-1, Vd=0.67 L/kg, and CL=0.035 L·kg−1·h−1. The enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital) and newer generation AEDs (levetiracetam, lamotrigine, topiramate) increased the weight-normalized CL value of MHD by 17.4% and 10.5%, respectively, whereas the enzyme-inhibiting AED valproic acid decreased it by 3%. No significant association was found between the CL value of MHD and the other covariates. For the final model, the evaluation results (95% CI) were MPE=0.01 (−0.07–0.10) mg/L, MAE=0.46 (0.40–0.51) mg/L, MSE=0.39 (0.27–0.51) (mg/L)2.
A PPK model of OXC in Chinese pediatric patients with epilepsy is established. The enzyme-inducing AEDs and some newer generation AEDs (lamotrigine, topiramate) could slightly increase the metabolism of MHD.
PMCID: PMC4186992  PMID: 25220641
epilepsy; oxcarbazepine; 10-hydroxycarbazepine; population pharmacokinetics; drug interaction; CYP450; pediatric patients; Chinese children
24.  Water chemistry in 179 randomly selected Swedish headwater streams related to forest production, clear-felling and climate 
Environmental Monitoring and Assessment  2014;186(12):8907-8928.
From a policy perspective, it is important to understand forestry effects on surface waters from a landscape perspective. The EU Water Framework Directive demands remedial actions if not achieving good ecological status. In Sweden, 44 % of the surface water bodies have moderate ecological status or worse. Many of these drain catchments with a mosaic of managed forests. It is important for the forestry sector and water authorities to be able to identify where, in the forested landscape, special precautions are necessary. The aim of this study was to quantify the relations between forestry parameters and headwater stream concentrations of nutrients, organic matter and acid-base chemistry. The results are put into the context of regional climate, sulphur and nitrogen deposition, as well as marine influences. Water chemistry was measured in 179 randomly selected headwater streams from two regions in southwest and central Sweden, corresponding to 10 % of the Swedish land area. Forest status was determined from satellite images and Swedish National Forest Inventory data using the probabilistic classifier method, which was used to model stream water chemistry with Bayesian model averaging. The results indicate that concentrations of e.g. nitrogen, phosphorus and organic matter are related to factors associated with forest production but that it is not forestry per se that causes the excess losses. Instead, factors simultaneously affecting forest production and stream water chemistry, such as climate, extensive soil pools and nitrogen deposition, are the most likely candidates The relationships with clear-felled and wetland areas are likely to be direct effects.
PMCID: PMC4210647  PMID: 25260924
Water chemistry; Headwater streams; Boreal landscape; Forestry; Representative sampling; Probabilistic classifying
25.  Developing conversed microsatellite markers and their implications in evolutionary analysis of the Bemisia tabaci complex 
Scientific Reports  2014;4:6351.
The study of population genetics among the Bemisia tabaci complex is limited due to the lack of conserved molecular markers. In this study, 358, 433 and 322 new polynucleotide microsatellites are separately identified from the transcriptome sequences of three cryptic species of the B. tabaci complex. The cross species transferability of 57 microsatellites was then experimentally validated. The results indicate that these markers are conserved and have high inter-taxon transferability. Thirteen markers were employed to assess the genetic relationships among six cryptic species of the B. tabaci complex. To our surprise, the inferred phylogeny was consistent with that of mitochondrial COI sequences, indicating that microsatellites have the potential to distinguish species of the B. tabaci complex. Our results demonstrate that development of microsatellites from transcriptome data is a fast and cost-effective approach. These markers can be used to analyze the population genetics and evolutionary patterns of the B. tabaci complex.
PMCID: PMC4163675  PMID: 25220501

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