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1.  Selection occurs within linear fruit and during the early stages of reproduction in Robinia pseudoacacia 
Pollen donor compositions differ during the early stages of reproduction due to various selection mechanisms. In addition, ovules linearly ordered within a fruit have different probabilities of reaching maturity. Few attempts, however, have been made to directly examine the magnitude and timing of selection, as well as the mechanisms during early life stages and within fruit. Robinia pseudoacacia, which contains linear fruit and non-random ovule maturation and abortion patterns, has been used to study the viability of selection within fruit and during the early stages of reproduction. To examine changes in the pollen donor composition during the early stages of reproduction and of progeny originating from different positions within fruit, paternity analyses were performed for three early life stages (aborted seeds, mature seeds and seedlings) in the insect-pollinated tree R. pseudoacacia.
Selection resulted in an overall decrease in the level of surviving selfed progeny at each life stage. The greatest change was observed between the aborted seed stage and mature seed stage, indicative of inbreeding depression (the reduced fitness of a given population that occurs when related individual breeding was responsible for early selection). A selective advantage was detected among paternal trees. Within fruits, the distal ends showed higher outcrossing rates than the basal ends, indicative of selection based on the order of seeds within the fruit.
Our results suggest that selection exists both within linear fruit and during the early stages of reproduction, and that this selection can affect male reproductive success during the early life stages. This indicates that tree species with mixed-mating systems may have evolved pollen selection mechanisms to increase the fitness of progeny and adjust the population genetic composition. The early selection that we detected suggests that inbreeding depression caused the high abortion rate and low seed set in R. pseudoacacia.
PMCID: PMC3998051  PMID: 24655746
Pollen donor composition; Inbreeding depression; Paternity analysis; Robinia pseudoacacia; Viability selection
2.  Removing reference mapping biases using limited or no genotype data identifies allelic differences in protein binding at disease-associated loci 
BMC Medical Genomics  2015;8:43.
Genetic variation can alter transcriptional regulatory activity contributing to variation in complex traits and risk of disease, but identifying individual variants that affect regulatory activity has been challenging. Quantitative sequence-based experiments such as ChIP-seq and DNase-seq can detect sites of allelic imbalance where alleles contribute disproportionately to the overall signal suggesting allelic differences in regulatory activity.
We created an allelic imbalance detection pipeline, AA-ALIGNER, to remove reference mapping biases influencing allelic imbalance detection and evaluate accuracy of allelic imbalance predictions in the absence of complete genotype data. Using the sequence aligner, GSNAP, and varying amounts of genotype information to remove mapping biases we investigated the accuracy of allelic imbalance detection (binomial test) in CREB1 ChIP-seq reads from the GM12878 cell line. Additionally we thoroughly evaluated the influence of experimental and analytical parameters on imbalance detection.
Compared to imbalances identified using complete genotypes, using imputed partial sample genotypes, AA-ALIGNER detected >95 % of imbalances with >90 % accuracy. AA-ALIGNER performed nearly as well using common variants when genotypes were unknown. In contrast, predicting additional heterozygous sites and imbalances using the sequence data led to >50 % false positive rates. We evaluated effects of experimental data characteristics and key analytical parameter settings on imbalance detection. Overall, total base coverage and signal dispersion across the genome most affected our ability to detect imbalances, while parameters such as imbalance significance, imputation quality thresholds, and alignment mismatches had little effect. To assess the biological relevance of imbalance predictions, we used electrophoretic mobility shift assays to functionally test for predicted allelic differences in CREB1 binding in the GM12878 lymphoblast cell line. Six of nine tested variants exhibited allelic differences in binding. Two of these variants, rs2382818 and rs713875, are located within inflammatory bowel disease-associated loci.
AA-ALIGNER accurately detects allelic imbalance in quantitative sequence data using partial genotypes or common variants filling a critical methodological gap in these analyses, as full genotypes are rarely available. Importantly, we demonstrate how experimental and analytical features impact imbalance detection providing guidance for similar future studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s12920-015-0117-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4515314  PMID: 26210163
Allelic imbalance; Genome mapping bias; Transcription factor binding; CREB1; Inflammatory bowel disease; Alleles; GWAS; ChIP-seq
3.  Phosphodiesterase-4D Knock-down in the Prefrontal Cortex Alleviates Chronic Unpredictable Stress-Induced Depressive-Like Behaviors and Memory Deficits in Mice 
Scientific Reports  2015;5:11332.
Phosphodiesterase 4 (PDE4) has four isoforms (PDE4A-D) with at least 25 splice variants. PDE4 subtype nonselective inhibitors produce potent antidepressant-like and cognition-enhancing effects via increased intracellular cyclic AMP (cAMP) signaling in the brain. Our previous data have demonstrated that long-form PDE4Ds appear to be involved in these pharmacological properties of PDE4 inhibitors in the normal animals. However, it is not clear whether long-form PDE4Ds are critical for the behaviors and related cellular signaling/neuronal plasticity/neuroendocrine alterations in the depressed animals. In the present study, animals exposed to the chronic unpredictable stress (CUS), a rodent model of depression, exhibited elevated corticosterone, depressive-like behavior, memory deficits, accompanied with decreased cAMP-PKA-CREB and cAMP-ERK1/2-CREB signaling and neuroplasticity. These alterations induced by CUS were reversed by RNA interference (RNAi)-mediated prefrontal cortex long-form PDE4Ds (especially PDE4D4 and PDE4D5) knock-down, similar to the effects of the PDE4 subtype nonselective inhibitor rolipram. Furthermore, these effects of RNAi were not enhanced by rolipram. These data indicate a predominant role of long-form PDE4Ds in the pharmacotherapies of PDE4 inhibitors for depression and concomitant memory deficits. Long-form PDE4Ds, especially PDE4D4 and PDE4D5, appear to be the promising targets for the development of antidepressants with high therapeutic indices.
PMCID: PMC4498385  PMID: 26161529
4.  Hydrogen sulfide protects spinal cord and induces autophagy via miR-30c in a rat model of spinal cord ischemia-reperfusion injury 
Hydrogen sulfide (H2S), a novel gaseous mediator, has been recognized as an important neuromodulator and neuroprotective agent in the nervous system. The present study was undertaken to study the effects of exogenous H2S on ischemia/reperfusion (I/R) injury of spinal cord and the underlying mechanisms.
The effects of exogenous H2S on I/R injury were examined by using assessment of hind motor function, spinal cord infarct zone by Triphenyltetrazolium chloride (TTC) staining. Autophagy was evaluated by expressions of Microtubule associated protein 1 light chain 3 (LC3) and Beclin-1 which were determined by using Quantitative Real-Time PCR and Western blotting, respectively.
Compared to I/R injury groups, H2S pretreatment had reduced spinal cord infarct zone, improved hind motor function in rats. Quantitative Real-Time PCR or Western blotting results showed that H2S pretreatment also downregulated miR-30c expression and upregulated Beclin-1 and LC3II expression in spinal cord. In vitro, miR-30c was showed to exert negative effect on Beclin-1 expression by targeting its 3’UTR in SY-SH-5Y cells treated with Oxygen, Glucose Deprivation (OGD). In rat model of I/R injury, pretreatment of pre-miR-30c or 3-MA (an inhibitor for autophagy) can abrogated spinal cord protective effect of H2S.
H2S protects spinal cord and induces autophagy via miR-30c in a rat model of spinal cord hemia-reperfusion injury.
PMCID: PMC4491897  PMID: 26149869
Autophagy; Beclin-1; miR-30c; Microtubule associated protein 1 light chain 3 (LC3); Oxygen glucose deprivation (OGD)
5.  Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome 
Neuropsychopharmacology  2014;39(8):1955-1967.
Fragile X syndrome, caused by the mutation of the Fmr1 gene, is characterized by deficits of attention and learning ability. In the hippocampus of Fmr1 knockout mice (KO), long-term depression is enhanced whereas long-term potentiation (LTP) including late-phase LTP (L-LTP) is reduced or unaffected. Here we examined L-LTP in the anterior cingulate cortex (ACC) in Fmr1 KO mice by using a 64-electrode array recording system. In wild-type mice, theta-burst stimulation induced L-LTP that does not occur in all active electrodes/channels within the cingulate circuit and is typically detected in ∼75% of active channels. Furthermore, L-LTP recruited new responses from previous inactive channels. Both L-LTP and the recruitment of inactive responses were blocked in the ACC slices of Fmr1 KO mice. Bath application of metabotropic glutamate receptor 5 (mGluR5) antagonist or glycogen synthase kinase-3 (GSK3) inhibitors rescued the L-LTP and network recruitment. Our results demonstrate that loss of FMRP will greatly impair L-LTP and recruitment of cortical network in the ACC that can be rescued by pharmacological inhibition of mGluR5 or GSK3. This study is the first report of the network properties of L-LTP in the ACC, and provides basic mechanisms for future treatment of cortex-related cognitive defects in fragile X patients.
PMCID: PMC4059905  PMID: 24553731
6.  What weather variables are important in predicting heat-related mortality? A new application of statistical learning methods 
Environmental research  2014;132:350-359.
Hot weather increases risk of mortality. Previous studies used different sets of weather variables to characterize heat stress, resulting in variation in heat-mortality- associations depending on the metric used. We employed a statistical learning method – random forests – to examine which of various weather variables had the greatest impact on heat-related mortality. We compiled a summertime daily weather and mortality counts dataset from four U.S. cities (Chicago, IL; Detroit, MI; Philadelphia, PA; and Phoenix, AZ) from 1998 to 2006. A variety of weather variables were ranked in predicting deviation from typical daily all-cause and cause-specific death counts. Ranks of weather variables varied with city and health outcome. Apparent temperature appeared to be the most important predictor of heat-related mortality for all-cause mortality. Absolute humidity was, on average, most frequently selected one of the top variables for all-cause mortality and seven cause-specific mortality categories. Our analysis affirms that apparent temperature is a reasonable variable for activating heat alerts and warnings, which are commonly based on predictions of total mortality in next few days. Additionally, absolute humidity should be included in future heat-health studies. Finally, random forests can be used to guide choice of weather variables in heat epidemiology studies.
PMCID: PMC4091921  PMID: 24834832
Absolute humidity; Climate; Heat; Mortality; Random forests; Temperature; Weather
7.  Impact of Adjuvant Chemotherapy on Long-Term Employment of Early-Stage Breast Cancer Survivors 
Cancer  2014;120(12):1854-1862.
Many women with early-stage breast cancer are working at the time of diagnosis and survive without recurrence. The short-term impact of chemotherapy receipt on employment has been demonstrated, but the long-term impact merits further research.
We conducted a longitudinal multicenter cohort study of women diagnosed with non-metastatic breast cancer in 2005–2007, as reported to the population-based Los Angeles and Detroit SEER registries. Of 3133 individuals sent surveys, 2290 (73%) completed a baseline survey soon after diagnosis and 1536 (68%) completed a four-year follow-up questionnaire.
Of the 1026 patients aged <65 at diagnosis whose breast cancer did not recur and who responded to both surveys, 746 (76%) worked for pay before diagnosis. Of these, 236 (30%) were no longer working at follow-up. Women who received chemotherapy as part of initial treatment were less likely to work at follow-up (38% vs. 27%, p=0.003). Chemotherapy receipt at the time of diagnosis (OR 1.4, p=0.04) was independently associated with unemployment during survivorship in a multivariable model. Many women who were not employed in the survivorship period wanted to work: 50% reported that it was important for them to work and 31% were actively seeking work.
Unemployment among breast cancer survivors four years after diagnosis is often undesired and appears related to the receipt of chemotherapy during initial treatment. These findings should be considered when patients decide whether to receive adjuvant chemotherapy, particularly when expected benefit is low.
PMCID: PMC4047155  PMID: 24777606
employment; breast cancer; chemotherapy; survivorship; work; survey; SEER
8.  Efficacy of poly-unsaturated fatty acid therapy on patients with nonalcoholic steatohepatitis 
AIM: To examine whether poly-unsaturated fatty acid (PUFA) therapy is beneficial for improving nonalcoholic steatohepatitis (NASH).
METHODS: In total, 78 patients pathologically diagnosed with NASH were enrolled and were randomly assigned into the control group and the PUFA therapy group (added 50 mL PUFA with 1:1 ratio of EHA and DHA into daily diet). At the initial analysis and after 6 mo of PUFA therapy, parameters of interest including liver enzymes, lipid profiles, markers of inflammation and oxidation, and histological changes were evaluated and compared between these two groups.
RESULTS: At the initial analysis, in patients with NASH, serum levels of alanine aminotransferase (ALT) and aspartase aminotransferase (AST) were slightly elevated. Triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol levels, markers of systemic inflammation [C-reactive protein (CRP)] and oxidation [malondialdehyde (MDA)], as well as fibrosis parameters of type IV collagen and pro-collagen type III pro-peptide were also increased beyond the normal range. Six months later, ALT and AST levels were significantly reduced in the PUFA group compared with the control group. In addition, serum levels of TG and TC, CRP and MDA, and type IV collagen and pro-collagen type III pro-peptide were also simultaneously and significantly reduced. Of note, histological evaluation showed that steatosis grade, necro-inflammatory grade, fibrosis stage, and ballooning score were all profoundly improved in comparison to the control group, strongly suggesting that increased PUFA consumption was a potential way to offset NASH progression.
CONCLUSION: Increased PUFA consumption is a potential promising approach for NASH prevention and reversal.
PMCID: PMC4462743  PMID: 26078579
Poly-unsaturated fatty acid; Nonalcoholic steatohepatitis; Management
9.  Quality of Life Is Related to Social Support in Elderly Osteoporosis Patients in a Chinese Population 
PLoS ONE  2015;10(6):e0127849.
To explore the association between quality of life and social support in elderly osteoporosis patients in a Chinese population.
A total of 214 elderly patients who underwent bone mineral density screening were divided into two groups: elderly patients with primary osteoporosis (case group, n = 112) and normal elderly patients (control group, n = 102). Quality of life and social support were compared between the two groups.
Quality of life and social support were significantly different between the case and control groups. The physical function, role-physical, bodily pain, general health, vitality, social-functioning, role-emotional and mental health scores in case group were significantly lower than those in the control group (P < 0.01). The objective support, subjective support, utilization of support, and total scores in case group were significantly lower than those in the control group (P < 0.01). Quality of life and social support were positively correlated in the case group (r = 0.672, P < 0.01).
Quality of life and social support in elderly patients with osteoporosis in China were poorer than in elderly patients without osteoporosis and were positively correlated. Our findings indicate that increased efforts to improve the social support and quality of life in elderly osteoporosis patients are urgently needed in China. Further longitudinal studies should be conducted to provide more clinical evidence to determine causative factors for the observed association between risk factors and outcomes.
PMCID: PMC4465171  PMID: 26061550
10.  The Clinical Features and Bacteriological Characterizations of Bone and Joint Tuberculosis in China 
Scientific Reports  2015;5:11084.
Bone and Joint tuberculosis (BJTB) constitutes about 10% of total extra-pulmonary TB cases. Since the BJTB is a paucibacillary condition, there has been no systematic study on the bacterial characterization, especially the epidemiological feature. Here we collected the mycobacterial clinical isolates, analyzed the clinical features and the bacteriological characteristics from 113 BJTB cases reported in China. The mean age of the cases was 40.33 years while most of the patients fell into the 20–29 year age group; local pain was the most common onset symptom of BJTB cases; mean time from symptom onset to BJTB diagnosis was 13.16 months. 31 isolates were defined as drug resistant, including 15 multidrug resistant (MDR) and 2 extensively drug resistant (XDR) isolates according to the drug susceptibility test outcomes; after spoligotyping, 87.6% (99/113) isolates were categorized as Beijing family. In contrast to the isolates from pulmonary tuberculosis patients, here the MIRU-VNTR assay did not find anything significant. A prolonged time span for BJTB diagnosis highlights the requirement of paying further attention to BJTB infection in China. This study provides essential insights into the demographic and microbial characteristics of BJTB cases in China.
PMCID: PMC4459174  PMID: 26053666
11.  Acetylation of Beclin 1 inhibits autophagosome maturation and promotes tumour growth 
Nature Communications  2015;6:7215.
Beclin 1, a protein essential for autophagy, regulates autophagy by interacting with Vps34 and other cofactors to form the Beclin 1 complex. Modifications of Beclin 1 may lead to the induction, inhibition or fine-tuning of the autophagic response under a variety of conditions. Here we show that Beclin 1 is acetylated by p300 and deacetylated by SIRT1 at lysine residues 430 and 437. In addition, the phosphorylation of Beclin 1 at S409 by CK1 is required for the subsequent p300 binding and Beclin 1 acetylation. Beclin 1 acetylation inhibits autophagosome maturation and endocytic trafficking by promoting the recruitment of Rubicon. In tumour xenografts, the expression of 2KR mutant Beclin 1 (substitution of K430 and K437 to arginines) leads to enhanced autophagosome maturation and tumour growth suppression. Therefore, our study identifies an acetylation-dependent regulatory mechanism governing Beclin 1 function in autophagosome maturation and tumour growth.
Beclin 1 is an essential autophagy effector, necessary to form the autophagosome. Here Sun et al. show that Beclin 1 acetylation regulated by p300 and SIRT1 inhibits autophagosome maturation, and mutation of the acetylation sites leads to tumour growth suppression in vivo.
PMCID: PMC4455096  PMID: 26008601
12.  Anesthetic Propofol Overdose Causes Vascular Hyperpermeability by Reducing Endothelial Glycocalyx and ATP Production 
Prolonged treatment with a large dose of propofol may cause diffuse cellular cytotoxicity; however, the detailed underlying mechanism remains unclear, particularly in vascular endothelial cells. Previous studies showed that a propofol overdose induces endothelial injury and vascular barrier dysfunction. Regarding the important role of endothelial glycocalyx on the maintenance of vascular barrier integrity, we therefore hypothesized that a propofol overdose-induced endothelial barrier dysfunction is caused by impaired endothelial glycocalyx. In vivo, we intraperitoneally injected ICR mice with overdosed propofol, and the results showed that a propofol overdose significantly induced systemic vascular hyperpermeability and reduced the expression of endothelial glycocalyx, syndecan-1, syndecan-4, perlecan mRNA and heparan sulfate (HS) in the vessels of multiple organs. In vitro, a propofol overdose reduced the expression of syndecan-1, syndecan-4, perlecan, glypican-1 mRNA and HS and induced significant decreases in the nicotinamide adenine dinucleotide (NAD+)/NADH ratio and ATP concentrations in human microvascular endothelial cells (HMEC-1). Oligomycin treatment also induced significant decreases in the NAD+/NADH ratio, in ATP concentrations and in syndecan-4, perlecan and glypican-1 mRNA expression in HMEC-1 cells. These results demonstrate that a propofol overdose induces a partially ATP-dependent reduction of endothelial glycocalyx expression and consequently leads to vascular hyperpermeability due to the loss of endothelial barrier functions.
PMCID: PMC4490431  PMID: 26023717
propofol; mice; endothelial cells; glycocalyx; vascular permeability; ATP
13.  Hemipteran Mitochondrial Genomes: Features, Structures and Implications for Phylogeny 
The study of Hemipteran mitochondrial genomes (mitogenomes) began with the Chagas disease vector, Triatoma dimidiata, in 2001. At present, 90 complete Hemipteran mitogenomes have been sequenced and annotated. This review examines the history of Hemipteran mitogenomes research and summarizes the main features of them including genome organization, nucleotide composition, protein-coding genes, tRNAs and rRNAs, and non-coding regions. Special attention is given to the comparative analysis of repeat regions. Gene rearrangements are an additional data type for a few families, and most mitogenomes are arranged in the same order to the proposed ancestral insect. We also discuss and provide insights on the phylogenetic analyses of a variety of taxonomic levels. This review is expected to further expand our understanding of research in this field and serve as a valuable reference resource.
PMCID: PMC4490450  PMID: 26039239
Hemiptera; mitogenomes; rearrangement; phylogenetic relationships
14.  Making the genomic leap in HCT: application of second-generation sequencing to clinical advances in hematopoietic cell transplantation 
Recent developments in second-generation sequencing (SGS) technologies provide an avenue for achieving rapid and accurate high-throughput analysis of human and microbial genomic diversity. SGS technologies have the potential to transform existing medical management of complex and life-threatening medical conditions by enabling clinicians to develop disease-targeted clinical care plans for each patient. In this review, we outline how innovative SGS-based approaches can improve the care of recipients of allogeneic hematopoietic cell transplantation (HCT), a life-saving procedure that carries a 1-year mortality risk of over 30%. We specifically evaluate foreseeable applications of SGS-based technology in facilitating rapid, phase-sensitive human leukocyte antigen (HLA) typing, assessment of non-HLA genomic compatibility, identifying patients at high risk for adverse drug reactions, and post-HCT monitoring for engraftment, minimal residual disease and infection. We conclude that innovative SGS approaches have the capacity to revolutionize the HCT recipient risk assessment process, support non-invasive clinical monitoring and improve patient outcomes, thereby setting the stage for a new era of genomically informed patient-centered medicine.
PMCID: PMC4023221  PMID: 24253860
HLA; genomics; sequencing; GWAS; leukemia; SGS
15.  Interleukin-8 -251A/T gene polymorphism and lung cancer susceptibility: a meta-analysis 
Many studies have examined the association between the interleukin-8 -251T/A (rs4073) gene polymorphism and lung cancer risk in various populations, but the results have been inconsistent. In this meta-analysis, PubMed was searched for case–control studies published through 01 December 2013. The data were extracted, and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. We assessed six published studies on the association between the interleukin-8 -251T/A polymorphism and lung cancer risk. The included studies yielded a total of 3265 lung cancer cases and 3607 controls. For the homozygous A/A and A allele carriers (T/A + A/A), the pooled ORs for all studies combining 3265 cases and 3607 controls were 1.03 (95% CI = 0.92–1.14; P = 0.235 for heterogeneity) and 1.07 (95% CI = 0.96–1.19; P = 0.245 for heterogeneity) when compared with the homozygous wild-type genotype (T/T). When the analysis was stratified by ethnicity, significant risks were found among Asians for both the A allele carriers and the homozygous A/A individuals. However, no significant associations were found in non-Asian populations using any of the genetic models. This meta-analysis suggests that the interleukin-8 -251A allele confer an increased risk for the development of lung cancer among Asians.
PMCID: PMC4459837  PMID: 25817779
Interleukin-8; polymorphism; lung cancer; susceptibility; meta-analysis
16.  Monitoring serum HER2 levels in breast cancer patients 
SpringerPlus  2015;4:237.
We have developed a new approach to reduce the serum interference for ELISA. The purpose of this study is to investigate if we can use the optimized ELISA (MBB-ELISA) to detect serum soluble HER2/neu (sHER2) in early stage primary breast cancer and monitor its change during treatments.
We collected sera preoperatively from 118 primary breast cancer patients. Serum samples were also collected sequentially from a subset of patients during and after adjuvant treatment. sHER2 in these samples was measured by the MBB-ELISA. Only 16.7 % of tissue HER2 (tHER2) positive patients had significantly elevated sHER2 levels in serum. Interestingly, sera of some patients with tHER2 negative tumors, including those that were 2+ by IHC but negative by FISH, demonstrated slightly elevated sHER2 levels. Multivariate analysis demonstrated that patients with elevated sHER2 (> = 7 ng/ml) had significantly worse disease free survival. During treatments, sHER2 levels consistently fell in response to adjuvant therapies. Nevertheless, in all 4 patients who developed metastases, a steady rise in sHER2 levels was noted before metastatic disease became clinically evident.
For early stage breast cancers, sHER2 is a poor biomarker to predict tHER2 status, but may have value to supplement tissue tests to identify patients with HER2 tumors. Our results also suggest that sHER2 is worth further study as a biomarker to monitor breast cancer patients during treatments.
PMCID: PMC4456592  PMID: 26069876
HER2/neu; SHER2; Biomarker; MBB buffer; Breast cancer
17.  GSTT1 polymorphism and breast cancer risk in the Chinese population: an updated meta-analysis and review 
Background: Although a number of studies have been conducted on the association between GSTT1 polymorphism and breast cancer in China, this association remains elusive and controversial. To clarify the effects of GSTT1 polymorphism on the risk of breast cancer, an updated meta-analysis was performed in the Chinese population. Material/methods: Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) to up 28th January 2015. Pooled ORs and 95% CIs were used to assess the strength of the associations. Results: A total of 13 studies including 3387 breast cancer cases and 5085 controls were involved in this meta-analysis. Overall, a significant association (OR = 1.31, 95% CI: 1.02-1.67) was found between the null GSTT1 and breast cancer risk when all studies in Chinese population pooled into the meta-analysis. In subgroup analyses stratified by geographic areas and source of controls, it revealed the significant results in population-based studies (OR = 1.42, 95% CI: 1.23-1.65) and South China (OR = 1.47, 95% CI: 1.27-1.70). Conclusions: This meta-analysis showed that the null GSTT1 may be potential biomarkers for breast cancer risk in Chinese, and further studies with gene-gene and gene-environment interactions are required for definite conclusions.
PMCID: PMC4509147  PMID: 26221202
Meta-analysis; GSTT1; polymorphism; breast cancer
18.  Positive emotion and cardiovascular disease in elderly people 
Cardiovascular disease in elderly people is a psychosomatic disease, but the research on the relationship between positive emotion and cardiovascular diseases is few. Most previous studies have focused on a range of health status changes caused by negative emotion but have ignored the role of positive emotion in elderly people. Positive emotion has been considered a protective factor against health problems in elderly people. Research shows that a significant relationship between positive emotion and blood pressure remains after adjusting for depression in elderly people. In this paper, we summarize the relationship between positive emotion and cardiovascular diseases in elderly people.
PMCID: PMC4509151  PMID: 26221206
Positive emotion; cardiovascular disease; elderly
19.  Timing and Spatial Distribution of Loess in Xinjiang, NW China 
PLoS ONE  2015;10(5):e0125492.
Central Asia is one of the most significant loess regions on Earth, with an important role in understanding Quaternary climate and environmental change. However, in contrast to the widely investigated loess deposits in the Chinese Loess Plateau, the Central Asian loess–paleosol sequences are still insufficiently known and poorly understood. Through field investigation and review of the previous literature, the authors have investigated the distribution, thickness and age of the Xinjiang loess, and analyzed factors that control these parameters in the Xinjiang in northwest China, Central Asia. The loess sediments cover river terraces, low uplands, the margins of deserts and the slopes of the Tianshan Mountains and Kunlun Mountains and are also present in the Ili Basin. The thickness of the Xinjiang loess deposits varies from several meters to 670 m. The variation trend of the sand fraction (>63 μm) grain-size contour can indicate the local major wind directions, so we conclude that the NW and NE winds are the main wind directions in the North and South Xinjiang, and the westerly wind mainly transport dust into the Ili basin. We consider persistent drying, adequate regional wind energy and well-developed river terraces to be the main factors controlling the distribution, thickness and formation age of the Xinjiang loess. The well-outcropped loess sections have mainly developed since the middle Pleistocene in Xinjiang, reflecting the appearance of the persistent drying and the present air circulation system. However, the oldest loess deposits are as old as the beginning of the Pliocene in the Tarim Basin, which suggests that earlier aridification occurred in the Tarim Basin rather than in the Ili Basin and the Junggar Basin.
PMCID: PMC4430276  PMID: 25970617
20.  Relatively Small Contribution of Methylation and Genomic Copy Number Aberration to the Aberrant Expression of Inflammation-Related Genes in HBV-Related Hepatocellular Carcinoma 
PLoS ONE  2015;10(5):e0126836.
It is well known that chronic inflammation plays a pivotal role in the development of hepatitis B virus (HBV) related hepatocellular carcinoma (HCC). However, the causes behind aberrant expression of inflammation-related genes occurred in HCC remain unclear.
We performed array-based analyses to comprehensively investigate the contributions of DNA methylation and somatic copy number aberration (SCNA) to the aberrant expression of 1,027 inflammation-related genes in 30 HCCs and paired non-tumor tissues. The results were validated in public datasets and an additional sample set of 47 paired HCCs and non-tumor tissues.
We identified 252 differentially expressed, 125 aberrantly methylated and 287 copy number changed inflammation-related genes. Despite reasonable statistical power, among them, only 11 genes and 56 genes whose aberrant expression was associated with DNA methylation or SCNA, respectively. DNA methylation and SCNA together contributed to less than 30% aberrant expression of inflammation-related genes.
These results suggest that molecular mechanisms other than DNA methylation and SCNA might play major role in the regulation of aberrant expression of inflammation-related gene in HBV-related HCCs.
PMCID: PMC4429029  PMID: 25965583
21.  LncRNA-ATB promotes trastuzumab resistance and invasion-metastasis cascade in breast cancer 
Oncotarget  2015;6(13):11652-11663.
Trastuzumab resistance is leading cause of mortality in HER2-positive breast cancers, and the role of TGF-β-induced epithelial-mesenchymal transition (EMT) in trastuzumab resistance is well established, but the involvement of lncRNAs in trastuzumab resistance is still unknown. Here, we generated trastuzumab-resistant breast cancer cells with increased invasiveness compared with parental cells, and observed robust epithelial–mesenchymal transition (EMT) and consistently elevated TGF-β signaling in these cells. We identified long noncoding RNA activated by TGF-β (lnc-ATB) was the most remarkably upregulated lncRNA in TR SKBR-3 cells and the tissues of TR breast cancer patients. We found that lnc-ATB could promote trastuzumab resistance and invasion-metastasis cascade in breast cancer by competitively biding miR-200c, up-regulating ZEB1 and ZNF-217, and then inducing EMT. In addition, we also found that the high level of lnc-ATB was correlated with trastuzumab resistance of breast cancer patients. Thus, these findings suggest that lncRNA-ATB, a mediator of TGF-β signaling, could predispose breast cancer patients to EMT and trastuzumab resistance.
PMCID: PMC4484483  PMID: 25871474
lnc-ATB; trastuzumab resistance; EMT; TGF-β; Breast cancer
22.  Effect of hepatitis B vaccination in hepatitis B surface antibody-negative pregnant mothers on the vertical transmission of hepatitis B virus from father to infant 
The aim of the present study was to investigate the effects of vaccination with the hepatitis B vaccine (HBVac) in HB surface antibody (HBsAb)-negative pregnant mothers on the vertical transmission of HB virus (HBV) from father to infant. All the fathers tested positive for the serum HBV DNA and HB surface antigen (HBsAg) markers. The pregnant females were divided into an observation group or a control group depending on whether their serum was HBsAb-negative or positive. A total of 93 healthy individuals without HBV infection were included in a blank group, while 96 females who were serum HBV marker-negative or HB core antibody (HBcAb)-positive/(HBsAb)-negative were included in the observation group. The control group comprised 89 females who all tested positive for serum HBsAb, HB envelope antibodies and HBcAb. In the observation group, the positive rate of HBV DNA in the newborns was 7.29% (7/96), the positive rate of HBsAg was 3.13% (3/96) and the positive rate of HBsAb was 81.3% (78/96). In the control group, the positive rates of HBV DNA, HBsAg and HBsAb in the newborns were 4.49% (4/89), 2.25% (2/89) and 89.9% (80/89), respectively. No statistically significant differences were observed between the two groups. Therefore, the results of the present study indicate that HBVac treatment for HBsAb-negative pregnant females may have a positive role in blocking the vertical transmission of HBV from father to infant, as long as the vaccination is able to induce the production of a sufficient quantity of HBsAb. The HBVac exhibited no difference compared with pre-pregnancy HBsAb in blocking the vertical transmission of HBV from father to infant.
PMCID: PMC4486883  PMID: 26170949
hepatitis B surface antibody-negative pregnant mothers; vertical transmission from father to infant; blocking; remedial measures; effects
23.  Does academic achievement during childhood and adolescence benefit later health? 
Annals of epidemiology  2014;24(5):344-355.
Educational disparities in health persist after adjustment for income and occupation, suggesting that other purely cognitive and psychosocial mechanisms may be involved. Unlike occupation- or income-mediated effects, effects of cognitive and psychosocial gains—as reflected in academic achievement—may be apparent even before schooling is completed.
We used data spanning 10 years on a national U.S. cohort of 2,546 children aged 3–14 at baseline to estimate effects of academic achievement, measured by standardized tests of cognitive achievement, on future health. We used marginal structural models to address potential mutual influence of achievement and health on each other over time.
One standard deviation higher academic achievement 1997– 2002 was associated with a lower prevalence of poorer health status in 2007 in girls (prevalence ratio [PR] = 0.87 [(95% confidence interval) 0.78–0.97]) but not in boys (PR = 0.96 [0.86–1.08]). Higher achievement was also weakly associated with lower BMI and less psychological distress among girls only.
Academic achievement may benefit future health but a number of questions remain unanswered, including reasons for the gender differences and how academic-achievement-related health disparities may progress over the life course and interact with other social determinants of health.
PMCID: PMC4037140  PMID: 24792585
academic achievement; body mass index; children and adolescents; education; gender; health status; marginal structural models; mental health
24.  Matching methods for obtaining survival functions to estimate the effect of a time-dependent treatment 
Statistics in biosciences  2014;6(1):105-126.
In observational studies of survival time featuring a binary time-dependent treatment, the hazard ratio (an instantaneous measure) is often used to represent the treatment effect. However, investigators are often more interested in the difference in survival functions. We propose semiparametric methods to estimate the causal effect of treatment among the treated with respect to survival probability. The objective is to compare post-treatment survival with the survival function that would have been observed in the absence of treatment. For each patient, we compute a prognostic score (based on the pre-treatment death hazard) and a propensity score (based on the treatment hazard). Each treated patient is then matched with an alive, uncensored and not-yet-treated patient with similar prognostic and/or propensity scores. The experience of each treated and matched patient is weighted using a variant of Inverse Probability of Censoring Weighting to account for the impact of censoring. We propose estimators of the treatment-specific survival functions (and their difference), computed through weighted Nelson-Aalen estimators. Closed-form variance estimators are proposed which take into consideration the potential replication of subjects across matched sets. The proposed methods are evaluated through simulation, then applied to estimate the effect of kidney transplantation on survival among end-stage renal disease patients using data from a national organ failure registry.
PMCID: PMC4188446  PMID: 25309633
Causal inference; Matching; Observational study; Propensity score; Survival function; Time-dependent treatment
25.  Population-Based in Vitro Hazard and Concentration–Response Assessment of Chemicals: The 1000 Genomes High-Throughput Screening Study 
Environmental Health Perspectives  2015;123(5):458-466.
Background: Understanding of human variation in toxicity to environmental chemicals remains limited, so human health risk assessments still largely rely on a generic 10-fold factor (10½ each for toxicokinetics and toxicodynamics) to account for sensitive individuals or subpopulations.
Objectives: We tested a hypothesis that population-wide in vitro cytotoxicity screening can rapidly inform both the magnitude of and molecular causes for interindividual toxicodynamic variability.
Methods: We used 1,086 lymphoblastoid cell lines from the 1000 Genomes Project, representing nine populations from five continents, to assess variation in cytotoxic response to 179 chemicals. Analysis included assessments of population variation and heritability, and genome-wide association mapping, with attention to phenotypic relevance to human exposures.
Results: For about half the tested compounds, cytotoxic response in the 1% most “sensitive” individual occurred at concentrations within a factor of 10½ (i.e., approximately 3) of that in the median individual; however, for some compounds, this factor was > 10. Genetic mapping suggested important roles for variation in membrane and transmembrane genes, with a number of chemicals showing association with SNP rs13120371 in the solute carrier SLC7A11, previously implicated in chemoresistance.
Conclusions: This experimental approach fills critical gaps unaddressed by recent large-scale toxicity testing programs, providing quantitative, experimentally based estimates of human toxicodynamic variability, and also testable hypotheses about mechanisms contributing to interindividual variation.
Citation: Abdo N, Xia M, Brown CC, Kosyk O, Huang R, Sakamuru S, Zhou YH, Jack JR, Gallins P, Xia K, Li Y, Chiu WA, Motsinger-Reif AA, Austin CP, Tice RR, Rusyn I, Wright FA. 2015. Population-based in vitro hazard and concentration–response assessment of chemicals: the 1000 Genomes high-throughput screening study. Environ Health Perspect 123:458–466;
PMCID: PMC4421772  PMID: 25622337

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