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1.  Evaluating Effects of Hypomorphic Thoc1 Alleles on Embryonic Development in Rb1 Null Mice 
Molecular and Cellular Biology  2016;36(11):1621-1627.
The Rb1 tumor suppressor protein is a molecular adaptor that physically links transcription factors like E2f with various proteins acting on DNA or RNA to repress gene expression. Loss of Rb1 liberates E2f to activate the expression of genes mediating resulting phenotypes. Most Rb1 binding proteins, including E2f, interact through carboxyl-terminal protein interaction domains, but genetic evidence suggests that an amino-terminal protein interaction domain is also important. One protein that binds Rb1 through the amino-terminal domain is encoded by Thoc1, a required component of the THO ribonucleoprotein complex important for RNA processing and transport. The physiological relevance of this interaction is unknown. Here we tested whether Thoc1 mediates effects of Rb1 loss on mouse embryonic development. We found that Thoc1 deficiency delays embryo death, and this delay correlates with reduced apoptosis in the brain. E2f protein levels are reduced in Rb1:Thoc1-deficient brain tissue. Expression of apoptotic regulatory genes regulated by E2f, like Apaf1 and Bak1, is also reduced. These observations suggest that Thoc1 is required to support increased expression of E2f and apoptotic regulatory genes that trigger apoptosis upon Rb1 loss. These findings implicate Rb1 in the regulation of the THO ribonucleoprotein complex.
doi:10.1128/MCB.01003-15
PMCID: PMC4959316  PMID: 27001308
2.  Effects of resveratrol on P-glycoprotein and cytochrome P450 3A in vitro and on pharmacokinetics of oral saquinavir in rats 
Background
The intestinal cytochrome P450 3A (CYP 3A) and P-glycoprotein (P-gp) present a barrier to the oral absorption of saquinavir (SQV). Resveratrol (RESV) has been indicated to have modulatory effects on P-gp and CYP 3A. Therefore, this study was to investigate the effects of RESV on P-gp and CYP 3A activities in vitro and in vivo on oral SQV pharmacokinetics in rats.
Methods
In vitro, intestinal microsomes were used to evaluate RESV effect on CYP 3A-mediated metabolism of SQV; MDR1-expressing Madin–Darby canine kidney (MDCKII-MDR1) cells were employed to assess the impact of RESV on P-gp-mediated efflux of SQV. In vivo effects were studied using 10 rats randomly assigned to receive oral SQV (30 mg/kg) with or without RESV (20 mg/kg). Serial blood samples were obtained over the following 24 h. Concentrations of SQV in samples were ascertained using high-performance liquid chromatography-tandem mass spectrometry analysis.
Results
RESV (1–100 μM) enhanced residual SQV (% of control) in a dose-dependent manner after incubation with intestinal microsomes. RESV (1–100 μM) reduced the accumulation of SQV in MDCKII-MDR1 cells in a concentration-dependent manner. A double peaking phenomenon was observed in the plasma SQV profiles in rats. The first peak of plasma SQV concentration was increased, but the second peak was reduced by coadministration with RESV. The mean AUC0–∞ of SQV was slightly decreased, with no statistical significance probably due to the high individual variation.
Conclusion
RESV can alter the plasma SQV concentration profiles, shorten the Tmax of SQV. RESV might also cause a slight decrease tendency in the SQV bioavailability in rats.
doi:10.2147/DDDT.S118723
PMCID: PMC5117956  PMID: 27895462
resveratrol; saquinavir; P-glycoprotein; CYP 3A; pharmacokinetic
3.  Accuracy of contrast-enhanced ultrasound compared with conventional ultrasound in acute pancreatitis: Diagnosis and complication monitoring 
Contrast-enhanced ultrasound (CEUS) has been used for diagnosing acute pancreatitis (AP), particularly severe acute pancreatitis (SAP). However, the diagnostic difference between CEUS and conventional ultrasonography (CUS) for AP and SAP has not been reported. The aim of the present study was to investigate the diagnostic accuracy of CUS and CEUS for AP. A total of 196 patients clinically diagnosed with AP were selected. All patients underwent CUS, CEUS and contrast-enhanced computed tomography (CECT) within 72 h. CECT was considered the gold standard. Pancreatic size, peripancreatic fluid collection (PPFC) and splenic vessel complications were the variables observed by CUS and CEUS. The differences in the variables among the three methods were analyzed using the χ2 test and statistical analysis software. Significant differences in pancreatic size, PPFC and splenic vessel complications in AP were observed between CEUS and CUS (P<0.05). χ2 test results indicated that CEUS significantly differed from CUS in terms of having a higher diagnostic accuracy for AP and SAP (P<0.05). The results indicate that CEUS is a reliable method for the diagnosis and monitoring of AP and SAP, and may be substituted for CECT.
doi:10.3892/etm.2016.3760
PMCID: PMC5103763  PMID: 27882136
acute pancreatitis; severe acute pancreatitis; conventional ultrasound; contrast-enhanced ultrasound; peripancreatic fluid collection; splenic vessel complications; diagnosis
4.  Two novel AGXT mutations identified in primary hyperoxaluria type-1 and distinct morphological and structural difference in kidney stones 
Scientific Reports  2016;6:33652.
Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive oxalate accumulation in plasma and urine, resulting in various phenotypes because of allelic and clinical heterogeneity. This study aimed to detect disease-associated genetic mutations in three PH1 patients in a Chinese family. All AGXT exons and 3 common polymorphisms which might synergistically interact with mutations, including P11L, I340 M and IVSI+74 bp were analyzed by direct sequencing in all family members. It demonstrated that in each of three patients, a previously reported nonsense mutation p.R333* was in cis with a novel missense mutation p.M49L in the minor allele characterized by the polymorphism of 74-bp duplication in intron 1, while the other novel missense mutation p.N72I was in trans with both p.R333* and P.M49L in the major allele. Kidney stones from two sibling patients were also observed though stereomicroscopic examination and scanning electron microscopy. Distinct morphological and inner-structure differences in calculi were noticed, suggesting clinical heterozygosity of PH1 to a certain extent. In brief, two novel missense mutations were identified probably in association with PH1, a finding which should provide an accurate tool for prenatal diagnosis, genetic counseling and screening for potential presymptomatic individuals.
doi:10.1038/srep33652
PMCID: PMC5028881  PMID: 27644547
5.  Appraisal of clinical practice guidelines on community-acquired pneumonia in children with AGREE II instrument 
BMC Pediatrics  2016;16:119.
Background
Community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality worldwide among children. The growing number of guidelines have been accompanied with a growing concern about variance and conflicts among guideline recommendations. There is a need to critically appraise clinical practice guidelines (CPGs) in order to ensure safe and effective practices.
Methods
A literature search was systematically conducted in English and Chinese major academic databases (from January 2000 to March 2015). CPGs related to CAP in children were evaluated by four independent assessors, according to AGREE II instruments. Standardized domain scores were calculated for each guideline. Inter-rater reliability was assessed by intraclass correlation coefficient. The software used for analysis was SPSS 17.0.
Results
A total of 10 guidelines met the inclusion criteria and were appraised. Scope and purpose (69.03 %) and clarity of presentation (83.33 %) achieved relative high scores, while the scores of the other four domains were low: stakeholder involvement (42.78 %), rigour of development (44.95 %), applicability (37.60 %), and editorial independence (23.74 %). 3 guidelines were strongly recommended as a result of the overall scores were greater than 60 %.
Conclusion
The qualities of CPGs for CAP in children were generally acceptable with several flaws. Stakeholder involvement, rigour of development, applicability and editorial independence should be considered and well described in the future development of CPGs.
doi:10.1186/s12887-016-0651-5
PMCID: PMC4971619  PMID: 27484087
Clinical practice guidelines; Community-acquired pneumonia; Children; Quality assessment; AGREE II
6.  Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming 
Oncotarget  2016;7(26):40558-40570.
Immunosuppression is a prevalent clinical feature in chronic lymphocytic leukemia (CLL) patients, with many patients demonstrating increased susceptibility to infections as well as increased failure of an antitumor immune response. However, much is currently not understood regarding the precise mechanisms that attribute to this immunosuppressive phenotype in CLL. To provide further clarity to this particular phenomenon, we analyzed the T-cell profile of CLL patient samples within a large cohort and observed that patients with an inverted CD4/CD8 ratio had a shorter time to first treatment as well as overall survival. These observations coincided with higher expression of the immune checkpoint receptor PD-1 in CLL patient CD8+ T cells when compared to age-matched healthy donors. Interestingly, we discovered that increased PD-1 expression in CD8+ T cells corresponds with decreased DNA methylation levels in a distal upstream locus of the PD-1 gene PDCD1. Further analysis using luciferase reporter assays suggests that the identified PDCD1 distal upstream region acts as an enhancer for PDCD1 transcription and this region becomes demethylated during activation of naïve CD8+ T cells by anti-CD3/anti-CD28 antibodies and IL2. Finally, we conducted a genome-wide DNA methylation analysis comparing CD8+ T cells from CLL patients against healthy donors and identified additional differentially methylated genes with known immune regulatory functions including CCR6 and KLRG1. Taken together, our findings reveal the occurrence of epigenetic reprogramming taking place within CLL patient CD8+ T cells and highlight the potential mechanism of how immunosuppression is accomplished in CLL.
doi:10.18632/oncotarget.9941
PMCID: PMC5130028  PMID: 27302925
chronic lymphocytic leukemia; DNA methylation; CD8+ T-cells; PD-1
7.  58-F, a flavanone from Ophiopogon japonicus, prevents hepatocyte death by decreasing lysosomal membrane permeability 
Scientific Reports  2016;6:27875.
Lysosome membrane permeabilization (LMP) has been implicated in cell death. In the present study, we investigated the relationship between cell death and H2O2-/CCl4-induced LMP in hepatocytes in vitro and following acute liver injury in vivo. The key finding was that H2O2 triggered LMP by oxidative stress, as evidenced by a suppression of LAMP1 expression, a reduction in LysoTracker Green and AO staining, and the leakage of proton and cathepsin B/D from the lysosome to the cytoplasm, resulting in cell death. CCl4 also triggered hepatocyte death by decreasing lysosome LAMP1 expression and by inducing the accumulation of products of peroxidative lipids and oxidized proteins. Furthermore, a novel compound 5,8-dimethoxy-6-methyl-7-hydroxy-3-3(2-hydroxy-4-methoxybenzyl) chroman-4-one (58-F) was extracted from Ophiopogon japonicus and served as a potential therapeutic drug. In vivo and in vitro results showed that 58-F effectively rescued hepatocytes by decreasing LMP and by inducing lysosomal enzyme translocation to the cytosol.
doi:10.1038/srep27875
PMCID: PMC4910050  PMID: 27306715
8.  Life-table studies revealed significant effects of deforestation on the development and survivorship of Anopheles minimus larvae 
Parasites & Vectors  2016;9:323.
Background
Many developing countries are experiencing rapid ecological changes such as deforestation and shifting agricultural practices. These environmental changes may have an important consequence on malaria due to their impact on vector survival and reproduction. Despite intensive deforestation and malaria transmission in the China-Myanmar border area, the impact of deforestation on malaria vectors in the border area is unknown.
Methods
We conducted life table studies on Anopheles minimus larvae to determine the pupation rate and development time in microcosms under deforested, banana plantation, and forested environments.
Results
The pupation rate of An. minimus was 3.8 % in the forested environment. It was significantly increased to 12.5 % in banana plantations and to 52.5 % in the deforested area. Deforestation reduced larval-to-pupal development time by 1.9–3.3 days. Food supplementation to aquatic habitats in forested environments and banana plantations significantly increased larval survival rate to a similar level as in the deforested environment.
Conclusion
Deforestation enhanced the survival and development of An. minimus larvae, a major malaria vector in the China-Myanmar border area. Experimental determination of the life table parameters on mosquito larvae under a variety of environmental conditions is valuable to model malaria transmission dynamics and impact by climate and environmental changes.
Electronic supplementary material
The online version of this article (doi:10.1186/s13071-016-1611-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13071-016-1611-5
PMCID: PMC4895827  PMID: 27267223
Anopheles minimus; Larvae; Deforestation; Life table; Mosquito; Malaria
9.  The Mechanical Analysis of the Biofilm Streamer Nucleation and Geometry Characterization in Microfluidic Channels 
Bacteria can form biofilm streamers in microfluidic channels with various geometries. Experiments show that the streamer geometry, such as its shape or thickness, depends on the fluid velocity and the geometry and curvature of the microfluidic channel. In the paper, a mechanical analysis of the flow field is made in different channels, which shows that the secondary flow in the channel is the reason for streamer nucleation and that the shear stress distribution decides the streamer geometry including shape and thickness. Through a finite elements simulation, we obtain the secondary flow forming positions in both static and rotating channels: positions that are the location of nucleation of the streamer. Thick or wide biofilm streamers occur at the points of minimum shear stress in static channels. Furthermore, in rotating channels, spiral-like streamers form, due to the helical shape of the minimum shear stress distribution. The findings may allow the prevention of biofilm formation and also the removal of bacteria adhered onto certain surfaces in channels with small cross sections. The analysis also indicates how one can obtain desirable biofilm streamers by control of the channel geometry and the loading conditions.
doi:10.1155/2016/7819403
PMCID: PMC4904103  PMID: 27313658
10.  Adverse Childhood Experiences and Blood Pressure Trajectories from Childhood to Young Adulthood: The Georgia Stress and Heart Study 
Circulation  2015;131(19):1674-1681.
Background
The purpose of this study was to assess the long-term effect of adverse childhood experiences (ACEs) on blood pressure (BP) trajectories from childhood to young adulthood and to examine whether this relation is explained by childhood socioeconomic status (SES) and/or risk behaviors that are associated with ACEs.
Methods and Results
Systolic and diastolic blood pressure (SBP and DBP) were measured up to 16 times (13 times on average) over a 23-year period in 213 African Americans (AAs) and 181 European Americans (EAs) aged 5 to 38 years. Retrospective data on traumatic experiences prior to age 18 were collected, including abuse, neglect and household dysfunction. Individual growth curve modeling within a multilevel framework was used to examine the relation between exposure to ACEs and BP development. No main effect of ACEs on average BP levels was found. However, a significant interaction of ACE score with age3 was observed (SBP: p=0.033; DBP: p=0.017). Subjects who experienced multiple traumatic events during childhood showed a faster rise of BP levels after age of 30 years than those without ACEs. As expected, a graded association of ACEs with childhood SES and negative health behaviors was observed (p<0.001). The ACE-SBP relation was not explained by these factors, while the ACE-DBP relation was partially mediated by illicit drug use.
Conclusions
In this novel longitudinal study, we observed that participants who were exposed to multiple ACEs displayed a greater increase of BP levels in young adulthood compared to their counterparts without ACEs.
doi:10.1161/CIRCULATIONAHA.114.013104
PMCID: PMC4430378  PMID: 25858196
adverse childhood experiences; blood pressure trajectories; risk behaviors; childhood socioeconomic status; longitudinal study
11.  PU.1 controls the expression of long noncoding RNA HOTAIRM1 during granulocytic differentiation 
Background
Long noncoding RNA HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) has been characterized as a critical factor in all-trans retinoic acid (ATRA)-induced differentiation of acute promyelocytic leukemia (APL) cells. However, the essential transcription factor for gene expression of HOTAIRM1 is still unknown.
Findings
Chromatin immunoprecipitation (ChIP) assays revealed that PU.1 constitutively bound to the regulatory region of HOTAIRM1. Co-expression of PU.1 led to the transactivation of the regulatory region of HOTAIRM1 in a reporter assay. Detailed analysis showed that two PU.1 motifs, which were located around +1100 bp downstream of the transcriptional start site of the HOTAIRM1 promoter, were responsible for the PU.1-dependent transactivation. The induction of HOTAIRM1 by ATRA was dependent on PU.1, and ectopic expression of PU.1 significantly up-regulated HOTAIRM1. Furthermore, low HOTAIRM1 expression was observed in APL cells, which was attributed to the reduced PU.1 expression rather than the repression by PML-RARα via the direct binding.
Conclusion
PU.1 directly activates the expression of HOTAIRM1 through binding to the regulatory region of HOTAIRM1 during granulocytic differentiation. The reduced PU.1 expression, rather than PML-RARα itself, results in the low expression of HOTAIRM1 in APL cells. Our findings enrich the knowledge on the regulation of lncRNAs and the underlying mechanisms of the abnormal expression of lncRNAs involved in APL.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-016-0274-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13045-016-0274-1
PMCID: PMC4857283  PMID: 27146823
HOTAIRM1; PU.1; APL; PML-RARα; Transcriptional regulation
12.  Specific Genetic Influences on Nighttime Blood Pressure 
American Journal of Hypertension  2014;28(4):440-443.
OBJECTIVES
Nighttime blood pressure (BP) has been shown to be superior to daytime BP in predicting hypertension related target organ damage and cardiac mortality. In our Georgia Cardiovascular Twin Study, we showed that apart from the genes that also influence daytime BP, specific genetic determinants explained 44% and 67% of the nighttime systolic BP (SBP) and diastolic BP (DBP) heritabilities, respectively. Here, we determined whether these results could be confirmed in a much larger twin cohort of young adults with 24-hour ambulatory BP measurements.
METHODS
Ambulatory BP was available in 703 white twins (308 pairs and 87 singletons, aged 18–34 years, 50% males) from the Prenatal Programming Twin Study. A bivariate quantitative genetic twin model was used to analyze daytime and nighttime BP. We conducted a meta-analysis to compare and integrate results from the 2 twin cohorts.
RESULTS
Model fitting showed no sex differences for any of the measures. Heritabilities were 0.60 and 0.51 for SBP and 0.54 and 0.46 for DBP at daytime and nighttime. The specific heritability due to novel genetic effects emerging during the nighttime was 0.21 for SBP and 0.26 for DBP, which comprised 41% and 57% of the total nighttime heritability for SBP and DBP, respectively. Meta-analysis confirmed absence of cohort differences with very similar combined results.
CONCLUSIONS
In addition to genes that influence both daytime and nighttime BP, a large part of the heritability is explained by genes that specifically influence BP at night.
doi:10.1093/ajh/hpu162
PMCID: PMC4366586  PMID: 25205800
nighttime blood pressure; heritability; meta-analysis; twin study.
13.  A genome-wide screen for copy number alterations in an adolescent pilot cohort with Müllerian anomalies 
Fertility and sterility  2014;103(2):487-493.
Objective
To examine whether pathogenic CNCs can be identified in DNA from females with different classes of Müllerian anomalies.
Design
We conducted array-based CNV analysis using an oligonucleotide array from DNA in 12 adolescent females with different types of Müllerian anomalies.
Setting
University-affiliated tertiary care institution
Patients
20 adolescent females with clinically confirmed Müllerian anomalies
Interventions
array-based CNV analysis
Main Outcome Measure(s)
Copy number changes and/or regions with absence of heterozygosity
Results
192 copy-number variants that we identified in these samples were previously annotated as polymorphic. Three copy number changes that were identified in regions with minimal to no overlap with annotated polymorphisms failed significance criteria with detailed inspection. One subject harbored a 5.1 Mb region of absence of heterozygosity at Xq23 that is of unknown significance.
Conclusions
In conclusion, we did not identify pathogenic CNCs in this small pilot cohort of patients with various Müllerian anomalies, but larger studies will be needed to further investigate more comprehensively whether CNCs are associated with all classes of Müllerian anomalies.
doi:10.1016/j.fertnstert.2014.10.044
PMCID: PMC4476902  PMID: 25492685
Müllerian anomalies; copy-number change; array-based copy number analysis; absence of heterozygosity
14.  Disruption of microRNA-21 by TALEN leads to diminished cell transformation and increased expression of cell-environment interaction genes 
Cancer letters  2014;356(2 0 0):506-516.
MicroRNA-21 is dysregulated in many cancers and fibrotic diseases. Since miR-21 suppresses several tumor suppressor and anti-apoptotic genes, it is considered a cancer therapeutic target. Antisense oligonucleotides are commonly used to inhibit a miRNA; however, blocking miRNA function via an antagomir is temporary, often only achieves a partial knock-down, and may be complicated by off-target effects. Here, we used transcription activator-like effector nucleases (TALENs) to disrupt miR-21 in cancerous cells. Individual deletion clones were screened and isolated without drug selection. Sequencing and quantitative RT-PCR identified clones with no miR-21 expression. The loss of miR-21 led to subtle but global increases of mRNAs containing miR-21 target sequences. Cells without miR-21 became more sensitive to cisplatin and less transformed in culture and in mouse xenografts. In addition to the increase of PDCD4 and PTEN protein, mRNAs for COL4A1, JAG1, SERPINB5/Maspin, SMAD7, and TGFBI – all are miR-21 targets and involved in TGFβ and fibrosis regulation – were significantly upregulated in miR-21 knockout cells. Gene ontology and pathway analysis suggested that cell-environment interactions involving extracellular matrix can be an important miR-21 pathogenic mechanism. The study also demonstrates the value of using TALEN-mediated microRNA gene disruption in human pathobiological studies.
doi:10.1016/j.canlet.2014.09.034
PMCID: PMC4615566  PMID: 25304376
microRNA; miR-21; TALEN; gene editing; cancer; extracellular matrix; fibrosis
15.  Invariant community structure of soil bacteria in subtropical coniferous and broadleaved forests 
Scientific Reports  2016;6:19071.
Soil bacteria may be influenced by vegetation and play important roles in global carbon efflux and nutrient cycling under global changes. Coniferous and broadleaved forests are two phyletically distinct vegetation types. Soil microbial communities in these forests have been extensively investigated but few studies have presented comparable data regarding the characteristics of bacterial communities in subtropical forests. We investigated soil bacterial biomass and community composition in three pairs of coniferous and broadleaved forests across a subtropical climatic gradient. We found that bacterial biomass differed between the coniferous and broadleaved forests across the subtropical climate gradient; however, this difference disappeared at some individual sites. In contrast, the same 90 bacterial genera were found in both forest types, and their relative abundances didn’t differ between the forest types, with the exception of one genus that was more abundant in broadleaved forests. Soil nitrogen or moisture was associated with bacterial groups in the coniferous and broadleaved forests, respectively. Thus, we inferred that these forests can respond differently to future changes in nitrogen deposition or precipitation. This study highlights soil bacterial invariant community composition in contrasting subtropical forests and provides a new perspective on the potential response and feedback of forests to global changes.
doi:10.1038/srep19071
PMCID: PMC4709558  PMID: 26754326
16.  Ethnic Differences in Resting Heart Rate Variability: A Systematic Review and Meta-Analysis 
Psychosomatic medicine  2015;77(1):16-25.
Background
Ethnic disparities in cardiovascular morbidity and mortality are widely documented in the literature. Recently, research has shown that decreased parasympathetic (PNS) cardiac modulation is associated with the established and emerging risk factors for cardiovascular disease (CVD) and stroke. In consideration of the disproportionate CVD risk and disease profile of African Americans (AAs), it is plausible that decreased cardiac PNS functioning may partially explain these disparities. In the present systematic review and meta-analysis, we assess the available evidence for a reliable ethnic difference in tonic vagally-mediated heart rate variability (HRV), an indicator of PNS cardiac modulation.
Methods
A systematic literature search was conducted yielding studies comparing tonic HRV in AAs and European Americans (EAs). Adjusted standardized effect sizes, (Hedges g), were calculated using a mixed effects model with restricted maximum likelihood estimation for 17 studies containing appropriate measures of vagally-mediated HRV.
Results
Meta-analysis results suggest that AAs have greater HRV than EAs (Hedges g = .93, 95% C.I. [.25, 1.62]) even after consideration of several covariates including health status, medication use, and subgroup stratification by gender and age.
Conclusions
These findings suggest that decreased vagally-mediated HRV is not likely to account for the persistent health disparities experienced by AAs with respect to cardiovascular disease risk and burden. These disparities underscore the need for continued research addressing socio-ethnic cardiovascular differences and the biobehavioral mechanisms involved
doi:10.1097/PSY.0000000000000133
PMCID: PMC4293235  PMID: 25551201
ethnic differences; health disparities; heart rate variability; meta-analysis
17.  Environmental Polychlorinated Biphenyl Exposure and Breast Cancer Risk: A Meta-Analysis of Observational Studies 
PLoS ONE  2015;10(11):e0142513.
Background
Association between polychlorinated biphenyl (PCB) exposure and breast cancer risk has been widely studied, but the results remain controversial. We performed a meta-analysis to evaluate the evidences from observational studies on PCB exposure and breast cancer risk.
Methods
Relevant studies with data on internal PCB dose were identified from PubMed, EMBASE, CBM and CNKI databases through November 2014. Multivariable-adjusted odds ratio (OR) with 95% confidence intervals (CIs) were applied to assess the association between PCB exposure and breast cancer risk. Heterogeneity test, sensitivity analysis, subgroup analysis and publication bias test were also performed. To further explore the association between specific groups of PCB congeners and breast cancer, we examined the PCB congeners classified, according to their structural, biological and pharmacokinetics properties, as group I (potentially estrogenic), group II (potentially anti-estrogenic and immunotoxic, dioxin-like), and group III (phenobarbital, CYP1A and CYP2B inducers, biologically persistent).
Results
Of 660 studies screened, 25 studies which met criteria were selected, involving a total of 12866 participants (6088 cases and 6778 controls) from eight countries. The results showed that the risk of breast cancer was associated with group II (OR = 1.23, 95% CI: 1.08–1.40) and group III (OR = 1.25, 95% CI: 1.09–1.43) PCBs, but not with group I (OR = 1.10, 95%CI: 0.97–1.24) PCBs or total PCB exposure (OR = 1.09, 95%CI: 0.97–1.22).
Conclusions
Our meta-analysis based on the selected studies found group II and group III PCB exposure might contribute to the risk of breast cancer. More studies in developing countries with higher PCB levels are needed, as well as studies to explore the relationships between mixtures of organochlorine compounds and breast cancer risk.
doi:10.1371/journal.pone.0142513
PMCID: PMC4640539  PMID: 26555153
18.  Modeling of the Bacillus subtilis Bacterial Biofilm Growing on an Agar Substrate 
Bacterial biofilms are organized communities composed of millions of microorganisms that accumulate on almost any kinds of surfaces. In this paper, a biofilm growth model on an agar substrate is developed based on mass conservation principles, Fick's first law, and Monod's kinetic reaction, by considering nutrient diffusion between biofilm and agar substrate. Our results show biofilm growth evolution characteristics such as biofilm thickness, active biomass, and nutrient concentration in the agar substrate. We quantitatively obtain biofilm growth dependence on different parameters. We provide an alternative mathematical method to describe other kinds of biofilm growth such as multiple bacterial species biofilm and also biofilm growth on various complex substrates.
doi:10.1155/2015/581829
PMCID: PMC4556878  PMID: 26355542
20.  Adverse Childhood Experiences are Associated with Detrimental Hemodynamics and Elevated Circulating Endothelin-1 in Adolescents and Young Adults RR 
Hypertension  2014;64(1):201-207.
Growing evidence suggests that adverse childhood experiences (ACEs) increase the risks for coronary heart disease and hypertension in mid and late adulthood. We previously reported that early life stress induces a hyper-reactive endothelin (ET)-dependent cardiovascular phenotype in a rat model. In the present study, we evaluated whether exposure to ACEs is associated with greater peripheral resistance, arterial stiffness, blood pressure, or elevated circulating ET-1 levels in humans. In 221 healthy adolescents and young adults (mean age: 21; age range: 13–29), we found a graded association of ACE exposure with plasma ET-1 levels, of which on average 18% and 24% were higher in subjects with 1 ACE, and ≥2 ACEs compared to those with no ACEs (P=0.001). The subjects with moderate/severe exposure to ACEs (≥2 ACEs) had significantly higher total peripheral resistance index (+12%), diastolic blood pressure (+5%) and pulse wave velocity (+9%) compared with those who were not exposed. These associations were independent of age, race, gender, body mass index and childhood socioeconomic status. Our results indicate that early life stress promotes cardiovascular disease risk, specifically detrimental vascular and cardiac function, detectable in very young adulthood.
doi:10.1161/HYPERTENSIONAHA.113.02755
PMCID: PMC4057352  PMID: 24777980
early life stress; endothelin-1; peripheral resistance; pulse wave velocity; blood pressure; adverse childhood experiences
21.  Obesity is Associated with More Activated Neutrophils in African American Male Youth 
Background
There is emerging evidence suggesting the role of peripheral blood leukocytes in the pathogenesis of obesity and related diseases. However, few studies have taken a genome wide approach to investigating gene expression profiles in peripheral leukocytes between obese and lean individuals with the consideration of obesity related shifts in leukocyte types.
Method
We conducted this study in 95 African Americans of both genders (age 14-20, 46 lean and 49 obese). Complete blood count with differential test (CBC) was performed in whole blood. Genome wide gene expression analysis was obtained using Illumina HumanHT-12 V4 Beadchip with RNA extracted from peripheral leukocytes. Out of the 95 participants, 64 had neutrophils stored. The validation study was based on Real-time polymerase chain reaction with RNA extracted from purified neutrophils.
Results
CBC test suggested that in males, obesity was associated with increased neutrophil percentage (p=0.03). Genome wide gene expression analysis showed that in males, the majority of the most differentially expressed genes were related to neutrophil activation. Validation of the gene expression levels of ELANE (neutrophil elastase) and MPO (myeloperoxidase) in purified neutrophils demonstrated that the expression of these two genes – important biomarkers of neutrophils activation – were significantly elevated in obese males (p=0.01 and p=0.02, respectively).
Conclusion
The identification of increased neutrophil percentage and activation in obese African American males suggests that neutrophils play an essential role in the pathogenesis of obesity related disease. Further functional and mechanistic studies on neutrophils may contribute to the development of novel intervention strategies reducing the burden associated with obesity-related health problems.
doi:10.1038/ijo.2014.194
PMCID: PMC4286492  PMID: 25388404
Obesity; gene expression; African American; neutrophil; leukocyte
22.  Association between hormone receptors and HER-2/neu is age-related 
Purpose: To investigate the association between hormone receptors and HER-2/neu in different age groups of women with breast cancers. Methods: A total of 1036 women with breast cancers were recruited. All the patients were divided into nine groups. The expression of hormone receptors and HER-2/neu was studied by IHC, while FISH test was used to determine HER-2/neu status in cases scored IHC 2+. The association between hormone receptors and HER-2/neu in different age groups was evaluated using the χ2 test. Multivariate analysis was used to find out the independent factors predicting HER-2/neu amplification. Significant findings: The expression of ER and PR was inversely correlated with HER-2/neu status in women aged >40 years. By multivariate analysis, as far as the overall groups were concerned, PR, lymph node status and tumor grade were independently associated with HER-2/neu; Considering the younger age group (≤40), the only predictor for HER-2/neu was the tumor grade; Considering the older age group (>40), tumor grade, PR status, tumor size and lymph node status were associated with HER-2/neu overexpression. Conclusions: Our data suggest that the association between ER, PR and HER-2/neu is age-related. The negative relationship is only applied for women aged >40 years.
PMCID: PMC4555748  PMID: 26339420
ER; PR; HER-2/neu; breast cancer
23.  Phosphorylation of Beet black scorch virus coat protein by PKA is required for assembly and stability of virus particles 
Scientific Reports  2015;5:11585.
Plant virus coat proteins (CPs) play a fundamental role in protection of genomic RNAs, virion assembly, and viral movement. Although phosphorylation of several CPs during virus infection have been reported, little information is available about CP phosphorylation of the spherical RNA plant viruses. Here, we demonstrate that the CP of Beet black scorch virus (BBSV), a member of the genus Necrovirus, can be phosphorylated at threonine-41 (T41) by cAMP-dependent protein kinase (PKA)-like kinase in vivo and in vitro. Mutant viruses containing a T41A non-phosphorylatable alanine substitution, and a T41E glutamic acid substitution to mimic threonine phosphorylation were able to replicate but were unable to move systemically in Nicotiana benthamiana. Interestingly, the T41A and T41E mutants generated unstable 17 nm virus-like particles that failed to package viral genomic (g) RNA, compared with wild-type BBSV with 30 nm virions during viral infection in N. benthamiana. Further analyses showed that the T41 mutations had little effect on the gRNA-binding activity of the CP. Therefore, we propose a model whereby CP phosphorylation plays an essential role in long-distance movement of BBSV that involves formation of stable virions.
doi:10.1038/srep11585
PMCID: PMC4479801  PMID: 26108567
24.  Familial Aggregation and Childhood Blood Pressure 
There is growing concern about elevated blood pressure (BP) in children. The evidence for familial aggregation of childhood BP is substantial. Twin studies have shown that a large part of the familial aggregation of childhood BP is due to genes. The first part of this review provides the latest progress in gene finding for childhood BP, focusing on the combined effects of multiple loci identified from the genome-wide association studies on adult BP. We further review the evidence on the contribution of the genetic components of other family risk factors to the familial aggregation of childhood BP including obesity, birth weight, sleep quality, sodium intake, parental smoking, and socioeconomic status. At the end, we emphasize the promise of using genomic-relatedness-matrix restricted maximum likelihood (GREML) analysis, a method that uses genome-wide data from unrelated individuals, in answering a number of unsolved questions in the familial aggregation of childhood BP.
doi:10.1007/s11906-014-0509-x
PMCID: PMC4476022  PMID: 25432901
Blood pressure; Childhood; Children; Familial aggregation; Genetic risk scores; Genome-wide association studies; Family risk factors
25.  Expression levels of seprase/FAPα and DPPIV/CD26 in epithelial ovarian carcinoma 
Oncology Letters  2015;10(1):34-42.
Dipeptidyl peptidase IV (DPPIV; also known as cluster of differentiation 26) and the surface-expressed protease, seprase [also known as fibroblast activation protein alpha (FAPα)], are able to degrade the extracellular matrix; therefore, they are involved in malignant cell invasion and metastasis. However, the prognostic implications of their overexpression in carcinomas remain controversial. The aim of the present study was to investigate the expression and potential prognostic effects of DPPIV and seprase in cases of ovarian carcinoma. Immunohistochemical analysis (IHC) was performed to assess the protein expression of DPPIV and seprase/FAPα in 199 patients (malignant epithelial ovarian cancer, 128; borderline ovarian tumors, 41; and benign ovarian tumors, 30). In addition, in situ hybridization was used to detect the mRNA expression levels of DPPIV and seprase in 86 malignant epithelial ovarian cancer samples. IHC revealed positive staining for seprase and DPPIV proteins in 110/128 (85.94%) and 106/128 (82.81%) patients with ovarian cancer, respectively. Seprase and DPPIV protein expression was associated with lymph node metastasis and the International Federation of Gynecology and Obstetrics stage. By contrast, no significant correlation was detected between the proteins and the patient age or histological grade and type of tumor. Immunostaining was stronger in the cancerous tissues compared with the borderline and benign tissues. Increased levels of seprase, but not DPPIV, were significantly associated with a shorter disease-free survival (P=0.033). Further analysis revealed that 96.5 (83/86) and 97.67% (84/86) of the malignant epithelial ovarian cancer samples stained positively for seprase and DPPIV mRNA, respectively. Therefore, DPPIV and seprase may be involved in the development of ovarian cancer, and that they are potential predictive markers of epithelial ovarian carcinoma.
doi:10.3892/ol.2015.3151
PMCID: PMC4487033  PMID: 26170973
seprase; dipeptidyl peptidase IV; ovarian carcinoma

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