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1.  Validation of gene expression biomarker analysis for biopsy-based clinical trials in Crohn’s disease 
Inflammatory bowel diseases  2015;21(2):323-330.
Background
The ability to measure the expression of pro-inflammatory cytokines from intestinal biopsies in patients with Crohn’s disease in an accurate and reproducible way is critical for proof-of-concept and mechanism-of-action trials; however, the number of biopsies from a segment of the ileum or colon required to yield reproducible results has not been rigorously evaluated. We examined intestinal biopsies from patients with Crohn’s disease to validate methods for detecting changes in inflammatory gene expression.
Methods
To evaluate the reproducibility of gene expression measurements, intestinal biopsies were obtained from designated segmentsfrom6 healthy controls, 6 patients with active Crohn’s disease, and 6 patients with inactive Crohn’s disease. Disease activity was based on the simple endoscopic score for Crohn’s disease (SES-CD). Expression of 7 pro-inflammatory genes was measured from each biopsy using quantitative PCR. Using a linear mixed effects model, the power to detect transcriptional changes corresponding to active and inactive Crohn’s disease was calculated.
Results
Total SES-CD score corresponds with expression of most inflammatory biomarkers. For most genes, 2 – 5biopsies are needed to reduce sampling error to <25% for most genes. To measure changes in mRNA expression corresponding to active versus inactive Crohn’s disease, one to two intestinal biopsies from 3 patients before and after treatment are needed to yield power of at least 80%.
Conclusion
Measuring pro-inflammatory gene expression from mucosal biopsies from patients with Crohn’s disease is practicable and provides objective biomarkers that can be utilized in proof-of-concept and mechanism-of-action trials to assess response to therapy.
doi:10.1097/MIB.0000000000000264
PMCID: PMC4404151  PMID: 25545378
Crohn’s disease; gene expression; biomarker; coefficient of variation; sampling error; proof-of-concept; power
2.  An Open-Source Analytical Platform for Analysis of C. elegans Swimming Induced Paralysis 
Background
The nematode Caenhorhabditis elegans offers great power for the identification and characterization of genes that regulate behavior. In support of this effort, analytical methods are required that provide dimensional analyses of subcomponents of behavior. Previously, we demonstrated that loss of the presynaptic dopamine (DA) transporter, dat-1, evokes DA-dependent Swimming Induced Paralysis (Swip) (Mcdonald et al. 2007), a behavior compatible with forward genetic screens (Hardaway et al. 2012).
New Method
Here, we detail the development and implementation of SwimR, a set of tools that provide for an automated, kinetic analysis of C. elegans Swip. SwimR relies on open source programs that can be freely implemented and modified.
Results
We show that SwimR can display time-dependent alterations of swimming behavior induced by drug-treatment, illustrating this capacity with the dat-1 blocker and tricyclic antidepressant imipramine (IMI). We demonstrate the capacity of SwimR to extract multiple kinetic parameters that are impractical to obtain in manual assays.
Comparison with Existing Methods
Standard measurements of C. elegans swimming utilizes manual assessments of the number of animals exhibiting swimming versus paralysis. Our approach deconstructs the time course and rates of movement in an automated fashion, offering a significant increase in the information that can be obtained from swimming behavior.
Conclusions
The SwimR platform is a powerful tool for the deconstruction of worm thrashing behavior in the context of both genetic and pharmacological manipulations that can be used to segregate pathways that underlie nematode swimming mechanics.
doi:10.1016/j.jneumeth.2014.04.024
PMCID: PMC4179448  PMID: 24792527
C. elegans; swimming; dopamine; paralysis; imipramine; transporter
4.  Does introducing an immunization package of services for migrant children improve the coverage, service quality and understanding? An evidence from an intervention study among 1548 migrant children in eastern China 
BMC Public Health  2015;15:664.
Background
An EPI (Expanded Program on Immunization) intervention package was implemented from October 2011 to May 2014 among migrant children in Yiwu, east China. This study aimed to evaluate its impacts on vaccination coverage, maternal understanding of EPI and the local immunization service performance.
Methods
A pre- and post-test design was used. The EPI intervention package included: (1) extending the EPI service time and increasing the frequency of vaccination service; (2) training program for vaccinators; (3) developing a screening tool to identify vaccination demands among migrant clinic attendants; (4) Social mobilization for immunization. Data were obtained from random sampling investigations, vaccination service statistics and qualitative interviews with vaccinators and mothers of migrant children. The analysis of quantitative data was based on a “before and after” evaluation and qualitative data were analyzed using content analysis.
Results
The immunization registration (records kept by immunization clinics) rate increased from 87.4 to 91.9 % (P = 0.016) after implementation of the EPI intervention package and the EPI card holding (EPI card kept by caregivers) rate increased from 90.9 to 95.6 % (P = 0.003). The coverage of fully immunized increased from 71.5 to 88.6 % for migrant children aged 1–4 years (P < 0.001) and increased from 42.2 to 80.5 % for migrant children aged 2–4 years (P < 0.001). The correct response rates on valid doses and management of adverse events among vaccinators were over 90 % after training. The correct response rates on immunization among mothers of migrant children were 86.8–99.3 % after interventions.
Conclusion
Our study showed a substantial improvement in vaccination coverage among migrant children in Yiwu after implementation of the EPI intervention package. Further studies are needed to evaluate the cost-effectiveness of the interventions, to identify individual interventions that make the biggest contribution to coverage, and to examine the sustainability of the interventions within the existing vaccination service delivery system in a larger scale settings or in a longer term.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-015-1998-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12889-015-1998-5
PMCID: PMC4501193  PMID: 26173803
Migrant children; Vaccination coverage; Interventions; EPI; Evaluation
5.  Revealing Missing Human Protein Isoforms Based on Ab Initio Prediction, RNA-seq and Proteomics 
Scientific Reports  2015;5:10940.
Biological and biomedical research relies on comprehensive understanding of protein-coding transcripts. However, the total number of human proteins is still unknown due to the prevalence of alternative splicing. In this paper, we detected 31,566 novel transcripts with coding potential by filtering our ab initio predictions with 50 RNA-seq datasets from diverse tissues/cell lines. PCR followed by MiSeq sequencing showed that at least 84.1% of these predicted novel splice sites could be validated. In contrast to known transcripts, the expression of these novel transcripts were highly tissue-specific. Based on these novel transcripts, at least 36 novel proteins were detected from shotgun proteomics data of 41 breast samples. We also showed L1 retrotransposons have a more significant impact on the origin of new transcripts/genes than previously thought. Furthermore, we found that alternative splicing is extraordinarily widespread for genes involved in specific biological functions like protein binding, nucleoside binding, neuron projection, membrane organization and cell adhesion. In the end, the total number of human transcripts with protein-coding potential was estimated to be at least 204,950.
doi:10.1038/srep10940
PMCID: PMC4496727  PMID: 26156868
6.  KRAS-dependent sorting of miRNA to exosomes 
eLife  null;4:e07197.
Mutant KRAS colorectal cancer (CRC) cells release protein-laden exosomes that can alter the tumor microenvironment. To test whether exosomal RNAs also contribute to changes in gene expression in recipient cells, and whether mutant KRAS might regulate the composition of secreted microRNAs (miRNAs), we compared small RNAs of cells and matched exosomes from isogenic CRC cell lines differing only in KRAS status. We show that exosomal profiles are distinct from cellular profiles, and mutant exosomes cluster separately from wild-type KRAS exosomes. miR-10b was selectively increased in wild-type exosomes, while miR-100 was increased in mutant exosomes. Neutral sphingomyelinase inhibition caused accumulation of miR-100 only in mutant cells, suggesting KRAS-dependent miRNA export. In Transwell co-culture experiments, mutant donor cells conferred miR-100-mediated target repression in wild-type-recipient cells. These findings suggest that extracellular miRNAs can function in target cells and uncover a potential new mode of action for mutant KRAS in CRC.
DOI: http://dx.doi.org/10.7554/eLife.07197.001
eLife digest
Cells use several different methods to control which genes are expressed to produce the proteins and RNA molecules that they need to work efficiently. The first step of gene expression is to transcribe a gene to form an RNA molecule. Protein-coding mRNA molecules can then be translated to make proteins. However, many RNA transcripts do not encode proteins. One example of these non-coding RNAs is a class of small RNAs called microRNAs (miRNAs), which are predicted to target more than 60% of protein-coding genes and can control which proteins are made.
It was once thought that miRNAs exist only within the cell where they are synthesized. Recently, however, miRNAs have been found outside the cell bound to lipids and proteins, or encased in extracellular vesicles, such as exosomes. Exosomes are small bubble-like structures used by cells to export material into the space outside of cells. Exosomes containing miRNAs can circulate throughout the body, potentially transferring information between cells to alter gene expression in recipient cells.
Many colorectal cancer cells have mutations in a gene that encodes a protein called KRAS. In 2011 and 2013, researchers found that the contents of the exosomes released from these mutant KRAS colorectal cancer cells can influence normal cells in ways that would help a cancer to spread. Furthermore, the exosomes released from the KRAS mutant cells contain different proteins than non-mutant cells.
Now, Cha, Franklin et al.—including several researchers who worked on the 2011 and 2013 studies—show that exosomes released by mutant KRAS cells also contain miRNAs, and that these miRNAs are different from the ones exported in exosomes by cells with a normal copy of the KRAS gene. In particular, several miRNAs that suppress cancer growth in a healthy cell are found at lower levels in mutant KRAS cells. Instead, these miRNAs are highly represented in the exosomes that are released by the KRAS mutant cells.
When cells with a normal copy of the KRAS gene were exposed to the contents of the exosomes released from KRAS mutant cells, an important gene involved in cell growth was suppressed. This indicates that the miRNAs exported from cancerous cells can influence gene expression in neighboring cells. Getting rid of such cancer-suppressing miRNAs could give cancer cells a growth advantage over normal cells to promote tumor growth. Cha, Franklin et al. also suggest that it might be possible to create a non-invasive test to detect colorectal cancer by monitoring the levels of circulating miRNAs in patients. Potential treatments for the disease could also target these miRNAs.
DOI: http://dx.doi.org/10.7554/eLife.07197.002
doi:10.7554/eLife.07197
PMCID: PMC4510696  PMID: 26132860
cancer; miRNA; KRAS; colorectal cancer; extracellular RNA; human
7.  Notching up vascular regeneration 
Cell Research  2014;24(7):777-778.
Regenerative medicine for cardiovascular disease requires effective approaches for therapeutic revascularization. In a recent paper in Cell Research, Sahara et al. establish a new role for Notch signaling to promote endothelial progenitor differentiation, and develop a protocol based on Notch inhibition in endothelial progenitors to markedly enhance the yield and purity of functional endothelial cells differentiated from embryonic stem cells.
doi:10.1038/cr.2014.68
PMCID: PMC4085764  PMID: 24853955
8.  The association of APOC4 polymorphisms with premature coronary artery disease in a Chinese Han population 
Background
Hypercholesterolemia arising from abnormal lipid metabolism is one of the critical risk factors for coronary artery disease (CAD), however the roles of genetic variants in lipid metabolism-related genes on premature CAD (≤60 years old) development still require further investigation. We herein genotyped four single nucleotide polymorphisms (SNPs) in lipid metabolism-related genes (rs1132899 and rs5167 in APOC4, rs1801693 and rs7765781 in LPA), aimed to shed light on the influence of these SNPs on individual susceptibility to early-onset CAD.
Methods
Genotyping of the four SNPs (rs1132899, rs5167, rs1801693 and rs7765781) was performed in 224 premature CAD cases and 297 control subjects (≤60 years old) using polymerase chain reaction-ligation detection reaction (PCR–LDR) method. The association of these SNPs with premature CAD was performed with SPSS software.
Results
Multivariate logistic regression analysis showed that C allele (OR = 1.50, P = 0.027) and CC genotype (OR = 2.84, P = 0.022) of APOC4 rs1132899 were associated with increased premature CAD risk, while the other three SNPs had no significant effect. Further stratified analysis uncovered a more evident association with the risk of premature CAD among male subjects (C allele, OR = 1.65, and CC genotype, OR = 3.33).
Conclusions
Our data provides the first evidence that APOC4 rs1132899 polymorphism was associated with an increased risk of premature CAD in Chinese subjects, and the association was more significant among male subjects.
Electronic supplementary material
The online version of this article (doi:10.1186/s12944-015-0065-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12944-015-0065-7
PMCID: PMC4511022  PMID: 26129832
APOC4; Single nucleotide polymorphism; Premature coronary artery disease; Risk
9.  Proteomic analysis of colon and rectal carcinoma using standard and customized databases 
Scientific Data  2015;2:150022.
Understanding proteomic differences underlying the different phenotypic classes of colon and rectal carcinoma is important and may eventually lead to a better assessment of clinical behavior of these cancers. We here present a comprehensive description of the proteomic data obtained from 90 colon and rectal carcinomas previously subjected to genomic analysis by The Cancer Genome Atlas (TCGA). Here, the primary instrument files and derived secondary data files are compiled and presented in forms that will allow further analyses of the biology of colon and rectal carcinoma. We also discuss new challenges in processing these large proteomic datasets for relevant proteins and protein variants.
doi:10.1038/sdata.2015.22
PMCID: PMC4477697  PMID: 26110064
10.  Atrophic Patterns of the Frontal-Subcortical Circuits in Patients with Mild Cognitive Impairment and Alzheimer’s Disease 
PLoS ONE  2015;10(6):e0130017.
Atrophy of the cortical thickness and gray matter volume are regarded as sensitive markers for the early clinical diagnosis of Alzheimer’s disease (AD). This study aimed to investigate differences in atrophy patterns in the frontal-subcortical circuits between MCI and AD, assess whether these differences were essential for the pathologic basis of cognitive impairment. A total of 131 individuals were recruited, including 45 with cognitively normal controls (CN), 46 with MCI, and 40 with AD. FreeSurfer software was used to perform volumetric measurements of the frontal-subcortical circuits from 3.0T magnetic resonance (MR) scans. Data revealed that both MCI and AD subjects had a thinner cortex in the left caudal middle frontal gyrus and the left lateral orbitofrontal gyrus compared with CN individuals. The left lateral orbitofrontal gyrus was also thinner in AD compared with MCI patients. There were no statistically significant differences in the cortical mean curvature among the three groups. Both MCI and AD subjects exhibited smaller bilateral hippocampus volumes compared with CN individuals. The volumes of the bilateral hippocampus and the right putamen were also smaller in AD compared with MCI patients. Logistic regression analyses revealed that the left lateral orbitofrontal gyrus and bilateral hippocampus were risk factors for cognitive impairment. These current results suggest that atrophy was heterogeneous in subregions of the frontal-subcortical circuits in MCI and AD patients. Among these subregions, the reduced thickness of the left lateral orbitofrontal and the smaller volume of the bilateral hippocampus seemed to be markers for predicting cognitive impairment.
doi:10.1371/journal.pone.0130017
PMCID: PMC4466229  PMID: 26066658
11.  Early Alzheimer's Disease Neuropathology Detected by Proton MR Spectroscopy 
The Journal of Neuroscience  2014;34(49):16247-16255.
Proton magnetic resonance spectroscopy (1H-MRS) is sensitive to early neurodegenerative processes associated with Alzheimer's disease (AD). Although 1H-MRS metabolite ratios of N-acetyl aspartate (NAA)/creatine (Cr), NAA/myoinositol (mI), and mI/Cr measured in the posterior cingulate gyrus reveal evidence of disease progression in AD, pathologic underpinnings of the 1H-MRS metabolite changes in AD are unknown. Pathologically diagnosed human cases ranging from no likelihood to high likelihood AD (n = 41, 16 females and 25 males) who underwent antemortem 1H-MRS of the posterior cingulate gyrus at 3 tesla were included in this study. Immunohistochemical evaluation was performed on the posterior cingulate gyrus using antibodies to synaptic vesicles, hyperphosphorylated tau (pTau), neurofibrillary tangle conformational-epitope (cNFT), amyloid-β, astrocytes, and microglia. The slides were digitally analyzed using Aperio software, which allows neuropathologic quantification in the posterior cingulate gray matter. MRS and pathology associations were adjusted for time from scan to death. Significant associations across AD and control subjects were found between reduced synaptic immunoreactivity and both NAA/Cr and NAA/mI in the posterior cingulate gyrus. Higher pTau burden was associated with lower NAA/Cr and NAA/mI. Higher amyloid-β burden was associated with elevated mI/Cr and lower NAA/mI ratios, but not with NAA/Cr. 1H-MRS metabolite levels reveal early neurodegenerative changes associated with AD pathology. Our findings support the hypothesis that a decrease in NAA/Cr is associated with loss of synapses and early pTau pathology, but not with amyloid-β or later accumulation of cNFT pathology in the posterior cingulate gyrus. In addition, elevation of mI/Cr is associated with the occurrence of amyloid-β plaques in AD.
doi:10.1523/JNEUROSCI.2027-14.2014
PMCID: PMC4252542  PMID: 25471565
Alzheimer's disease; digital microscopy; magnetic resonance spectroscopy; neuropathology; posterior cingulate; tau
12.  Trends in dietary cholesterol intake among Chinese adults: a longitudinal study from the China Health and Nutrition Survey, 1991–2011 
BMJ Open  2015;5(6):e007532.
Objectives
Dietary cholesterol is the leading risk factor for cardiovascular disease and other chronic diseases. Changes in dietary patterns in China recently might have an impact on the trends of diet-related risk factors of chronic diseases. This study aims to monitor the changes in daily cholesterol intake and its food sources in Chinese adults.
Design
A longitudinal study using demographic and dietary data of adults younger than 60 years from eight waves (1991–2011) of the China Health and Nutrition Surveys was conducted. Mixed-effect models were used in this study.
Setting
The data were derived from urban and rural communities in nine provinces (autonomous regions) in China.
Participants
There were 21 273 participants (10 091 males and 11 182 females) in this study.
Outcomes
The major outcome is daily cholesterol intake amount, which was calculated by using the Chinese Food Composition Table, based on dietary data.
Results
The mean daily cholesterol intake in Chinese adults increased from 165.8 mg/day in 1991 to 266.3 mg/day in 2011. Cholesterol consumed by participants in different age (18–39 and 40–59 years), sex and urbanisation groups steadily elevated over time (p<0.0001), as did the proportions of participants with greater than 300 mg/day cholesterol consumption. In each subgroup, cholesterol originating from most of the food groups showed increasing trends over time (p<0.0001), except for animal fat and organ meats. Eggs, pork, fish and shellfish in that order remained the top three sources in 1991, 2000 and 2011, whereas milks were a negligible contributor. Cholesterol from animal fat declined and was insignificant in 2011 in most of the subgroups, while cholesterol being of poultry origin increased and became considerable in 2011.
Conclusions
Adults in China consumed increasingly high cholesterol and deviated from the recommended intake level over the past two decades. Adults need to pay more attention to intakes of eggs, pork, fish and shellfish.
doi:10.1136/bmjopen-2014-007532
PMCID: PMC4458604  PMID: 26038359
13.  Changes in waist circumference relative to body mass index in Chinese adults, 1993–2009 
Background
Although BMI and waist circumference (WC) are correlated, the relationship between WC and BMI may have changed over time.
Objectives
Describe temporal trends in BMI and WC distributions and quantify the increase in WC at a given BMI over time.
Subjects/Methods
Data on adults aged 20–59 years from two waves (1993 and 2009) of the China Health and Nutrition Survey (CHNS) were used in a pooled cross-sectional analysis. Quantile regression examined age-adjusted temporal trends in the distributions of BMI and WC. Linear regression examined changes in mean WC over time, adjusting for BMI, age at survey and survey year. All models were stratified by gender.
Results
There was a significant increase in BMI and WC over time, particularly at the 95th quantile: on average, men had 2.8 kg/m2 (95% CI: 2.4, 3.3) and women 1.5 kg/m2 (95% CI: 1.1, 2.0) higher BMI in 2009 compared to their counterparts in 1993. WC increased by 9.0 cm (95% CI: 7.5, 10.1) and 5.0 cm (95% CI: 3.4, 6.6) for and women had a 3.2 cm (95% CI: 2.8, 3.7) and 2.1 cm (95% CI: 1.7, 2.5) higher WC in 2009 compared to their counterparts in 1993, holding BMI and age constant. WC adjusted for BMI increased to a larger extent amongst obese versus lean individuals and amongst younger versus older women.
Conclusions
For both genders, BMI and WC increased significantly over time, with particularly greatest increase in magnitude in the upper tail of the BMI and WC distributions. Furthermore, WC at equivalent BMI was higher in 2009, compared to their counterparts in 1993. Our findings suggest that even if BMI remained constant from 1993 to 2009, adults in 2009 might be at increased cardiometabolic risk as a result of their higher WC.
doi:10.1038/ijo.2014.74
PMCID: PMC4229489  PMID: 24813367
Waist circumference; body mass index; quantile regression; China; epidemiology
14.  URG4/URGCP enhances the angiogenic capacity of human hepatocellular carcinoma cells in vitro via activation of the NF-κB signaling pathway 
BMC Cancer  2015;15:368.
Background
Angiogenesis is essential for tumor growth. Hepatocellular carcinoma (HCC) is characterized by hypervascularity; high levels of angiogenesis are associated with poor prognosis and a highly invasive phenotype in HCC. Up-regulated gene-4 (URG4), also known as upregulator of cell proliferation (URGCP), is overexpressed in multiple tumor types and has been suggested to act as an oncogene. This study aimed to elucidate the effect of URG4/URGCP on the angiogenic capacity of HCC cells in vitro.
Methods
Expression of URG4/URGCP in HCC cell lines and normal liver epithelial cell lines was examined by Western blotting and quantitative real-time PCR. URG4/URGCP was stably overexpressed or transiently knocked down using a shRNA in two HCC cell lines. The human umbilical vein endothelial cell (HUVEC) tubule formation and Transwell migration assays and chicken chorioallantoic membrane (CAM) assay were used to examine the angiogenic capacity of conditioned media from URG4/URGCP-overexpressing and knockdown cells. A luciferase reporter assay was used to examine the transcriptional activity of nuclear factor kappa – light – chain - enhancer of activated B cells (NF-κB). NF-κB was inhibited by overexpressing degradation-resistant mutant inhibitor of κB (IκB)-α. Expression of vascular endothelial growth factor C (VEGFC), tumor necrosis factor-α (TNFα), interleukin (IL)-6, IL-8 and v-myc avian myelocytomatosis viral oncogene homolog (MYC) were examined by quantitative real-time PCR; VEGFC protein expression was analyzed using an ELISA.
Results
URG4/URGCP protein and mRNA expression were significantly upregulated in HCC cell lines. Overexpressing URG4/URGCP enhanced - while silencing URG4/URGCP decreased - the capacity of HCC cell conditioned media to induce HUVEC tubule formation and migration and neovascularization in the CAM assay. Furthermore, overexpressing URG4/URGCP increased - whereas knockdown of URG4/URGCP decreased - VEGFC expression, NF-κB transcriptional activity, the levels of phosphorylated (but not total) IκB kinase (IKK) and IκB-α, and expression of TNFα, IL-6, IL-8 and MYC in HCC cells. Additionally, inhibition of NF-κB activity in HCC cells abrogated URG4/URGCP-induced NF-κB activation and angiogenic capacity.
Conclusions
This study suggests that URG4/URGCP plays an important pro-angiogenic role in HCC via a mechanism linked to activation of the NF-κB pathway; URG4/URGCP may represent a potential target for anti-angiogenic therapy in HCC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1378-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1378-7
PMCID: PMC4437676  PMID: 25947641
URG4/URGCP; Hepatocellular carcinoma; Angiogenesis
15.  Integrating Genomic, Transcriptomic, and Interactome Data to Improve Peptide and Protein Identification in Shotgun Proteomics 
Journal of Proteome Research  2014;13(6):2715-2723.
Mass spectrometry (MS)-based shotgun proteomics is an effective technology for global proteome profiling. The ultimate goal is to assign tandem MS spectra to peptides and subsequently infer proteins and their abundance. In addition to database searching and protein assembly algorithms, computational approaches have been developed to integrate genomic, transcriptomic, and interactome information to improve peptide and protein identification. Earlier efforts focus primarily on making databases more comprehensive using publicly available genomic and transcriptomic data. More recently, with the increasing affordability of the Next Generation Sequencing (NGS) technologies, personalized protein databases derived from sample-specific genomic and transcriptomic data have emerged as an attractive strategy. In addition, incorporating interactome data not only improves protein identification but also puts identified proteins into their functional context and thus facilitates data interpretation. In this paper, we survey the major integrative bioinformatics approaches that have been developed during the past decade and discuss their merits and demerits.
doi:10.1021/pr500194t
PMCID: PMC4059263  PMID: 24792918
shotgun proteomics; proteogenomics; personalized proteomics; data integration; peptide identification; protein identification; Next Generation Sequencing; RNA-Seq
16.  PSCA s2294008 C>T and rs2976392 G>A polymorphisms contribute to cancer susceptibility: evidence from published studies 
Genes & Cancer  2015;6(5-6):254-264.
PSCA gene plays an important role in cell adhesion, proliferation and survival. Increasing studies have focused on the association of PSCA gene rs2294008 C>T and rs2976392 G>A with cancer risk. However, the conclusions were inconsistent. Therefore, we performed a meta-analysis to elucidate whether there is a true association, or artifact. We systematically searched eligible studies from MEDLINE, EMBASE and CBM database. Odds ratios and 95% confidence intervals were used to evaluate the strength of the association. The final analysis included 32 studies consisting of 30028 cases and 38765 controls for the rs2294008 C>T polymorphism, and 14 studies with 8190 cases and 7176 controls for the rs2976392 G>A polymorphism. Consequently, the PSCA rs2294008 C>T polymorphism was significantly associated with increased overall cancer risk. Further stratifications indicated the increased risk was more pronounced for gastric (diffused type and non-gastric cardia adenocarcinoma) and bladder cancer. A similar association was observed for the rs2976392 G>A polymorphism. This meta-analysis demonstrated that both of the PSCA rs2294008 C>T and rs2976392 G>A polymorphisms are associated with increased cancer risk, especially for gastric cancer and bladder cancer. Further large-scale studies with different ethnicities and subtypes of gastric cancer are required to confirm the results from this meta-analysis.
PMCID: PMC4482246  PMID: 26124924
PSCA; GWAS; polymorphism; susceptibility; meta-analysis
17.  Bats Respond to Very Weak Magnetic Fields 
PLoS ONE  2015;10(4):e0123205.
How animals, including mammals, can respond to and utilize the direction and intensity of the Earth’s magnetic field for orientation and navigation is contentious. In this study, we experimentally tested whether the Chinese Noctule, Nyctalus plancyi (Vespertilionidae) can sense magnetic field strengths that were even lower than those of the present-day geomagnetic field. Such field strengths occurred during geomagnetic excursions or polarity reversals and thus may have played an important role in the evolution of a magnetic sense. We found that in a present-day local geomagnetic field, the bats showed a clear preference for positioning themselves at the magnetic north. As the field intensity decreased to only 1/5th of the natural intensity (i.e., 10 μT; the lowest field strength tested here), the bats still responded by positioning themselves at the magnetic north. When the field polarity was artificially reversed, the bats still preferred the new magnetic north, even at the lowest field strength tested (10 μT), despite the fact that the artificial field orientation was opposite to the natural geomagnetic field (P<0.05). Hence, N. plancyi is able to detect the direction of a magnetic field even at 1/5th of the present-day field strength. This high sensitivity to magnetic fields may explain how magnetic orientation could have evolved in bats even as the Earth’s magnetic field strength varied and the polarity reversed tens of times over the past fifty million years.
doi:10.1371/journal.pone.0123205
PMCID: PMC4414586  PMID: 25922944
18.  Linking patient outcome to high throughput protein expression data identifies novel regulators of colorectal adenocarcinoma aggressiveness 
F1000Research  2015;4:99.
A key question in cancer systems biology is how to use molecular data to predict the biological behavior of tumors from individual patients. While genomics data have been heavily used, protein signaling data are more directly connected to biological phenotype and might predict cancer phenotypes
such as invasion, metastasis, and patient survival. In this study, we mined publicly available data for colorectal adenocarcinoma from the Cancer Genome Atlas and identified protein expression and signaling changes that are statistically associated with patient outcome. Our analysis identified a number of known and potentially new regulators of colorectal cancer. High levels of insulin growth factor binding protein 2 (IGFBP2) were associated with both recurrence and death, and this was validated by immunohistochemical staining of a tissue microarray for a secondary patient dataset. Interestingly, GATA binding protein 3 (GATA3) was the protein most frequently associated with death in our analysis, and GATA3 expression was significantly decreased in tumor samples from stage I-II deceased patients. Experimental studies using engineered colon cancer cell lines show that exogenous expression of GATA3 decreases three-dimensional colony growth and invasiveness of colon cancer cells but does not affect two-dimensional proliferation. These findings suggest that protein data are useful for biomarker discovery and identify GATA3 as a regulator of colorectal cancer  aggressiveness.
doi:10.12688/f1000research.6388.1
PMCID: PMC4457132  PMID: 26097693
Proteomics; Reverse Phase Protein Array; TCGA; Colorectal Cancer; Bioinformatics; Prognosis; Cancer Biology
19.  A novel role for microRNA-129-5p in inhibiting ovarian cancer cell proliferation and survival via direct suppression of transcriptional co-activators YAP and TAZ 
Oncotarget  2015;6(11):8676-8686.
Transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are key oncogenes in mammalian cells. Activities of YAP and TAZ are largely restricted by the Hippo tumor suppressor pathway through phosphorylation-ubiquitination mechanisms. The involvement of microRNA in cancer progression has recently been reported, though whether they have a role in activating YAP and TAZ in human cancer cells remains unclear. Here, we report a microRNA, miR-129-5p, directly represses YAP and TAZ expression, leading to the inactivation of TEA domain (TEAD) transcription, and the downregulation of Hippo downstream genes, connective tissue growth factor (CTGF) and Cyclin A. Furthermore, we reveal miR-129-5p inhibits ovarian cancer cell proliferation, survival and tumorigenicity, and that downregulation of miR-129-5p in ovarian cancer cells highly correlates with malignant progression and poor survival. Hence, we demonstrate a novel mechanism for YAP and TAZ activation in cancers, indicating not only a potentially pivotal role for miR-129-5p in the progression of ovarian cancer, but also offering new therapeutic strategies to circumvent the disease.
PMCID: PMC4496175  PMID: 25895125
miR-129-5p; YAP; TAZ; cell proliferation; survival
20.  Decellularized liver scaffolds effectively support the proliferation and differentiation of mouse fetal hepatic progenitors 
Decellularized whole organs represent ideal scaffolds for engineering new organs and/or cell transplantation. Here, we investigate whether decellularized liver scaffolds provide cell-friendly biocompatible three-dimensional environment to support the proliferation and differentiation of hepatic progenitor cells. Mouse liver tissues are efficiently decellularized through portal vein perfusion. Using the reversibly immortalized mouse fetal hepatic progenitor cells (iHPCs), we are able to effectively recellularize the decellularized liver scaffolds. The perfused iHPCs survive and proliferate in the three-dimensional scaffolds in vitro for 2 weeks. When the recellularized scaffolds are implanted into the kidney capsule of athymic nude mice, cell survival and proliferation of the implanted scaffolds are readily detected by whole body imaging for 10 days. Furthermore, EGF is shown to significantly promote the proliferation and differentiation of the implanted iHPCs. Histologic and immunochemical analyses indicate that iHPCs are able to proliferate and differentiate to mature hepatocytes upon EGF stimulation in the scaffolds. The recellularization of the biomaterial scaffolds is accompanied with vascularization. Taken together, these results indicate that decullarized liver scaffolds effectively support the proliferation and differentiation of iHPCs, suggesting that decellularized liver matrix may be used as ideal biocompatible scaffolds for hepatocyte transplantation.
doi:10.1002/jbm.a.34764
PMCID: PMC4056447  PMID: 23625886
Cell Transplantation; Liver Progenitor Cells; Immortalized Progenitors; Decellularized Scaffolds; Tissue Engineering; Regenerative Medicine
21.  Use of quantile regression to investigate changes in the body mass index distribution of Chinese adults aged 18–60 years: a longitudinal study 
BMC Public Health  2015;15:278.
Background
Traditional linear regression analyses have detected increasing trends in the incidence of overweight/obesity among both genders in China. However, these previous regression analyses were limited in their ability to capture cross-distribution variations among effects. The objective of our study was to analyze the change in the body mass index (BMI) distribution of adults and investigated the relationships between the key covariates and the BMI distribution.
Methods
We used longitudinal data from the China Health and Nutrition Surveys (CHNS) in 1991, 1993, 1997, 2000, 2004, 2006, 2009, and 2011, with at least two waves of data collection. In total, 17,819 participants aged 18–60 years (N = 8587 men and 9232 women) were included in the final analysis with 48,900 observations. The lambda-mu-sigma (LMS) method was used to describe changes in the BMI distribution. Separate sex-stratified longitudinal quantile regression (QR) analyses were used to investigate changes in the BMI distribution over time.
Results
The main characteristics of the BMI changes in both genders were that the curves shifted to the right and the distributions became wider. All of the BMI percentile curves tended to increase from 1991 to 2011, where the levels increased more in the higher percentiles. The QR analyses showed that these patterns remain consistent after adjusting for individual and community level factors. Physical activity (PA) had a negative association with BMI for both genders in all percentiles. Income and energy intake were associated with positive changes in male BMI in the upper percentile. Sedentary time had a positive association with female BMI in the middle percentile. Compared with less educated women, women with senior school education at 75th percentile had 0.951 kg/m2 lower BMIs.
Conclusions
This longitudinal quantile regression suggests that effects of different covariates worked differently across the BMI distribution. Since social and economic characteristics in China have underlined the significant disparities in many aspects, national strategies to tackle overweight/obesity should be tailored as appropriate for various segments.
doi:10.1186/s12889-015-1606-8
PMCID: PMC4374289  PMID: 25885045
China; Body mass index; Quantile regression; Trend
22.  Meta-analysis of plate fixation versus intramedullary fixation for the treatment of mid-shaft clavicle fractures 
Background
This systematic review and meta-analysis aims to critically compare the outcomes of plate fixation (PF) versus intramedullary fixation (IF) for the treatment of mid-shaft clavicle fractures.
Methods
Relevant original studies were searched in electronic databases of Medline, Embase, Cochrane central database and CNKI (all through October 2014). The study was performed according to the PRISMA statement. Studies that investigated the comparing effectiveness or complications between both groups and provided sufficient data of interest were included in this meta-analysis.
Results
Thirteen studies fulfilling inclusion and exclusion criteria were included in this meta-analysis, which included 479 participants in PF group and 457 in IF group. Compared to PFs, IFs outperformed PFs associated with a reduced surgery time, a shorter incision, rapid union time, better shoulder function recovery at 6 months and fewer complications of symptomatic hardware, refracture after hardware removal and hypertrophic scar. In other aspects such as functional recovery at 12 months and 24 months follow-up, shoulder motion range, complications of superficial infection,temporary brachial plexus lesion, nonunion, malunion, delayed union, implant failure, major revision needed, both techniques were comparable.
Conclusions
The present evidence from this meta-analysis suggested that IF was a more advantaged method for the treatment of midshaft clavicle fractures. This present study might aid surgeons in making evidence-based decision about optimal surgical treatment of mid-shaft clavicular fracture.
Electronic supplementary material
The online version of this article (doi:10.1186/s13049-015-0108-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13049-015-0108-0
PMCID: PMC4372272  PMID: 25886940
Mid-shaft clavicle fractures; Intramedullary fixation; Plate fixation; Meta-analysis
23.  Proteogenomic characterization of human colon and rectal cancer 
Nature  2014;513(7518):382-387.
Summary
We analyzed proteomes of colon and rectal tumors previously characterized by the Cancer Genome Atlas (TCGA) and performed integrated proteogenomic analyses. Somatic variants displayed reduced protein abundance compared to germline variants. mRNA transcript abundance did not reliably predict protein abundance differences between tumors. Proteomics identified five proteomic subtypes in the TCGA cohort, two of which overlapped with the TCGA “MSI/CIMP” transcriptomic subtype, but had distinct mutation, methylation, and protein expression patterns associated with different clinical outcomes. Although copy number alterations showed strong cis- and trans-effects on mRNA abundance, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. The chromosome 20q amplicon was associated with the largest global changes at both mRNA and protein levels; proteomics data highlighted potential 20q candidates including HNF4A, TOMM34 and SRC. Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords a new paradigm for understanding cancer biology.
doi:10.1038/nature13438
PMCID: PMC4249766  PMID: 25043054
24.  Novel inhibitor discovery and the conformational analysis of inhibitors of listeriolysin O via protein-ligand modeling 
Scientific Reports  2015;5:8864.
Increasing bacterial resistance to available antibiotics makes the discovery of novel efficacious antibacterial agents a priority. A previous report showed that listeriolysin O (LLO) is a critical virulence factor and suggested that it is a target for developing anti-virulence drugs against Listeria monocytogenes infections. In this study, we report the discovery of LLO natural compound inhibitors with differential activity by using hemolysis assay. The mechanism of action of the inhibitors was consistent with that of fisetin, a natural flavonoid without antimicrobial activity, which we showed in our previous report via molecular simulation. Furthermore, a substantial increase in anti-hemolytic activity was observed when the single bond (C1-C2) was replaced by a double bond (C1-C2) in the inhibitor molecule. This change was based on the decomposition of the ligand-residue interaction, which indicated that the double bond (C1-C2) in the inhibitors was required for their inhibition of LLO. The current MD simulation work provides insights into the mechanism by which the compounds inhibit LLO at the atomic level and will be useful for the development of new, selective LLO inhibitors.
doi:10.1038/srep08864
PMCID: PMC4352855  PMID: 25749652
25.  Mirror neuron therapy for hemispatial neglect patients 
Scientific Reports  2015;5:8664.
Mirror neuron system(MNS) based therapy has been employed to treat stroke induced movement disorders. However, its potential effects on patients with hemispatial neglect were uninvestigated. The present study set out to test the therapeutic efficiency of video watching of series of hand actions/movements (protocol A) in two patients with left hemispatial neglect, due to the right hemisphere stroke. The video containing dynamic landscape of natural scene or cities but not human/animals was used as the protocol B. The “ABA” training procedure for 3 weeks therefore allows us to internally control the individual differences. Before and after each week of training, the Chinese behavioral inattention test- Hongkong version (CBIT-HK) was implemented to evaluate the hemispatial neglect severity. Functional magnetic resonance imaging (fMRI) experiment was implemented in two health subjects to reveal the difference of brain activation between protocol A and B. The results showed that protocol A rather than protocol B significantly improved the CBIT-HK scores at first and third weeks, respectively. Protocol A induced more bilateral activations including right inferior parietal lobe (supramarginal gyrus), which belongs to MNS and is also critical region resulting to hemineglect. Conclusion: MNS activation can provide a novel therapy for hemispatial neglect patients.
doi:10.1038/srep08664
PMCID: PMC4345335  PMID: 25727354

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