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1.  Frequent copy number variations of PI3K/AKT pathway and aberrant protein expressions of PI3K subunits are associated with inferior survival in diffuse large B cell lymphoma 
Background
It has been reported that the PI3K/AKT signaling pathway is activated in diffuse large B-cell lymphoma (DLBCL), PI3K constitutive activation plays a crucial role in PI3K/AKT pathway. However, the copy number variations (CNVs) of PI3K subunits on gene level remain unknown in DLBCL. Therefore, the aim of the study is to investigate the CNV of PI3K subunits and their relationship with clinicopathological features exploring the possible mechanism underlying of PI3K activation in DLBCL.
Methods
CNV of 12 genes in the PI3K/AKT pathway was detected by NanoString nCounter in 60 de novo DLBCLs and 10 reactive hyperplasia specimens as controls. Meanwhile, immunohistochemistry (IHC) was performed to examine the expression of p110α, p110β, p110γ, p110δ, and pAKT on DLBCL tissue microarrays.
Results
All PI3K and AKT subunits, except for PIK3R1, had various CNVs in the form of copy number amplifications and copy number losses. Their rates were in the range of 8.3–20.0%. Of them PIK3CA and PIK3CB gene CNVs were significantly associated with decreased overall survival (P = 0.029 and P = 0.019, respectively). IHC showed that the frequency of strong positive expression of p110α, p110β, p110γ, and p110δ were 26.7%, 25.0%, 18.3%, and 25.0% respectively, and they were found to be associated with decreased survival (P = 0.022, P = 0.015, P = 0.015, and P = 0.008, respectively). Expression of p110α was not only significantly associated with CNVs of PIK3CA (P = 0.002) but also positively correlated with strong positive expression of pAKT (P = 0.026).
Conclusions
CNV of PIK3CA is highly associated with aberrant p110α protein expression and subsequent activation of PI3K/AKT pathway. CNVs of PIK3CA and PIK3CB, and aberrant protein expression of p110 isoforms are of great important value for predicting inferior prognosis in DLBCL. Frequent CNVs of PI3K/AKT subunits may play an important role in the tumorigenesis of DLBCL.
doi:10.1186/1479-5876-12-10
PMCID: PMC3896773  PMID: 24418330
DLBCL; CNV; PI3K/AKT; Subunits; Survival
2.  Abnormal expression of CDK11p58 in prostate cancer 
Background
CDK11p58 is one of the large families of p34cdc2-related kinases whose functions are linked with cell cycle progression, tumorigenesis and apoptotic signaling. Our previous investigation demonstrated that CDK11p58 repressed androgen receptor (AR) transcriptional activity and was involved in the negative regulation of AR function.
Methods
CDK11p58 expression was examined in the prostate cancer tissues and adjacent tissues by IHC and qRT-PCR. Cell apoptosis was detected by flow cytometry. The metastasis of cancer cells was evaluated by the Transwell Assay. Finally we further investigated the underlying molecular mechanisms by examining expression levels of relevant proteins using western blot analysis.
Results
We found that both RNA and protein expression of CDK11p58 were low in prostate cancer tissues compared with its adjacent noncancerous tissues. CDK11p58 promoted the prostate cancer cell apoptosis and inhibited its metastasis in a kinase dependent way. And finally CDK11p58 could inhibit the metastasis of AR positive prostate cancer cells through inhibition of integrin β3 and MMP2.
Conclusions
These data indicate that CDK11p58 is an anti-metastasis gene product in prostate cancer.
doi:10.1186/1475-2867-14-2
PMCID: PMC3893504  PMID: 24397471
CDK11p58; Metastasis; Prostate cancer; Androgen receptor
3.  Changes of predominant species/biovars and sequence types of Brucella isolates, Inner Mongolia, China 
BMC Infectious Diseases  2013;13:514.
Background
Human brucellosis incidence in China was divided into 3 stages, high incidence (1950-1960s), decline (1970-1980s) and re-emergence (1990-2000s). Human brucellosis has been reported in all the 32 provinces, of which Inner Mongolia has the highest prevalence, accounting for over 40% of the cases in China. To investigate the etiology alteration of human brucellosis in Inner Mongolia, the species, biovars and genotypes of 60 Brucella isolates from this province were analyzed.
Methods
Species and biovars of the Brucella strains isolated from outbreaks were determined based on classical identification procedures. Strains were genotyped by multi locus sequence typing (MLST). Sequences of 9 housekeeping genes were obtained and sequence types were defined. The distribution of species, biovars and sequence types (STs) among the three incidence stages were analyzed and compared.
Results
The three stages of high incidence, decline and re-emergence were predominated by B. melitensis biovar 2 and 3, B. abortus biovar 3, and B. melitensis biovar 1, respectively, implying changes in the predominant biovars. Genotyping by MLST revealed a total of 14 STs. Nine STs (from ST28 to ST36), accounting for 64.3% of all the STs, were newly defined and different from those observed in other countries. Different STs were distributed among the three stages. ST8 was the most common ST in 1950-1960s and 1990-2000s, while ST2 was the most common in 1970-1980s.
Conclusions
The prevalence of biovars and sequence types of Brucella strains from Inner Mongolia has changed over time in the three stages. Compared with those from other countries, new sequence types of Brucella strains exist in China.
doi:10.1186/1471-2334-13-514
PMCID: PMC3819263  PMID: 24176041
Brucella; Genotype; Biovar; Multi locus sequence typing
4.  Over Time, Do Anthropometric Measures Still Predict Diabetes Incidence in Chinese Han Nationality Population from Chengdu Community? 
Objective. To examine whether anthropometric measures could predict diabetes incidence in a Chinese population during a 15-year follow-up. Design and Methods. The data were collected in 1992 and then again in 2007 from the same group of 687 individuals. Waist circumference, body mass index, waist to hip ratio, and waist to height ratio were collected based on a standard protocol. To assess the effects of baseline anthropometric measures on the new onset of diabetes, Cox's proportional hazards regression models were used to estimate the hazard ratios of them, and the discriminatory power of anthropometric measures for diabetes was assessed by the area under the receiver operating curve (AROC). Results. Seventy-four individuals were diagnosed with diabetes during a 15-year follow-up period (incidence: 10.8%). These anthropometric measures also predicted future diabetes during a long follow-up (P < 0.001). At 7-8 years, the AROC of central obesity measures (WC, WHpR, WHtR) were higher than that of general obesity measures (BMI) (P < 0.05). But, there were no significant differences among the four anthropometric measurements at 15 years. Conclusions. These anthropometric measures could still predict diabetes with a long time follow-up. However, the validity of anthropometric measures to predict incident diabetes may change with time.
doi:10.1155/2013/239376
PMCID: PMC3810432  PMID: 24222764
5.  Central nervous system involvement in adult patients with diffuse large B-cell lymphoma: Influence of rituximab 
Oncology Letters  2012;4(3):541-545.
CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like chemotherapy, in combination with rituximab (R-CHOP-like), improves outcome in patients with diffuse large B-cell lymphoma (DLBCL). We aimed to investigate the impact of rituximab on central nervous system (CNS) disease in adult patients. We studied 315 patients (aged 18–60 years old) from six hospitals between July 2003 and May 2008. All patients received CHOP-like (n=165) or R-CHOP-like (n=150) regimen every 3 weeks. With a median follow-up of 3.69 years, 10 patients (3.17%) developed CNS disease. The cumulative risk of CNS occurrence was not significantly different between the two treatment groups (P=0.871). We conclude that the addition of rituximab did not reduce the risk of CNS disease in adult patients with DLBCL.
doi:10.3892/ol.2012.755
PMCID: PMC3439009  PMID: 22970053
central nervous system; diffuse large B-cell lymphoma; rituximab
6.  Geographical Analysis of the Distribution and Spread of Human Rabies in China from 2005 to 2011 
PLoS ONE  2013;8(8):e72352.
Background
Rabies is a significant public health problem in China in that it records the second highest case incidence globally. Surveillance data on canine rabies in China is lacking and human rabies notifications can be a useful indicator of areas where animal and human rabies control could be integrated. Previous spatial epidemiological studies lacked adequate spatial resolution to inform targeted rabies control decisions. We aimed to describe the spatiotemporal distribution of human rabies and model its geographical spread to provide an evidence base to inform future integrated rabies control strategies in China.
Methods
We geo-referenced a total of 17,760 human rabies cases of China from 2005 to 2011. In our spatial analyses we used Gaussian kernel density analysis, average nearest neighbor distance, Spatial Temporal Density-Based Spatial Clustering of Applications with Noise and developed a model of rabies spatiotemporal spread.
Findings
Human rabies cases increased from 2005 to 2007 and decreased during 2008 to 2011 companying change of the spatial distribution. The ANN distance among human rabies cases increased between 2005 and 2011, and the degree of clustering of human rabies cases decreased during that period. A total 480 clusters were detected by ST-DBSCAN, 89.4% clusters initiated before 2007. Most of clusters were mainly found in South of China. The number and duration of cluster decreased significantly after 2008. Areas with the highest density of human rabies cases varied spatially each year and in some areas remained with high outbreak density for several years. Though few places have recovered from human rabies, most of affected places are still suffering from the disease.
Conclusion
Human rabies in mainland China is geographically clustered and its spatial extent changed during 2005 to 2011. The results provide a scientific basis for public health authorities in China to improve human rabies control and prevention program.
doi:10.1371/journal.pone.0072352
PMCID: PMC3753237  PMID: 23991098
7.  Polymorphisms in the mTOR Gene and Risk of Sporadic Prostate Cancer in an Eastern Chinese Population 
PLoS ONE  2013;8(8):e71968.
Background
The mTOR gene regulates cell growth by controlling mRNA translation, ribosome biogenesis, autophagy, and metabolism. Abnormally increased expression of mTOR was associated with carcinogenesis, and its functional single nucleotide polymorphisms (SNPs) may regulate the expression of mTOR and thus contribute to cancer risk.
Methodology/Principal Findings
In a hospital-based case-control study of 1004 prostate cancer (PCa) cases and 1051 cancer-free controls, we genotyped six potentially functional SNPs of mTOR (rs2536 T>C, rs1883965 G>A, rs1034528 G>C, rs17036508 T>C, rs3806317 A>G, and rs2295080 T>G) and assessed their associations with risk of PCa by using logistic regression analysis.
Conclusions/Significances
In the single-locus analysis, we found a significantly increased risk of PCa associated with mTOR rs2536 CT/CC and rs1034528 CG/CC genotypes [adjusted OR = 1.42 (1.13–1.78), P = 0.003 and 1.29 (1.07–1.55), P = 0.007), respectively], compared with their common homozygous genotypes, whereas mTOR rs2295080 GT/GG genotypes were associated with a decreased risk of PCa [adjusted OR = 0.76 (0.64–0.92), P = 0.003], compared with wild-type TT genotypes. In the combined analysis of the six SNPs, we found that individuals carrying two or more adverse genotypes had an increased risk of PCa [adjusted OR = 1.24 (1.04–1.47), P = 0.016], compared with individuals carrying less than two adverse genotypes. In the multiple dimension reduction analysis, body mass index (BMI) was the best one-factor model with the highest CVC (100%) and the lowest prediction error (42.7%) among all seven factors. The model including an interaction among BMI, rs17036508, and rs2536 was the best three-factor model with the highest CVC (100%) and the lowest prediction error of 41.9%. These findings suggested that mTOR SNPs may contribute to the risk of PCa in Eastern Chinese men, but the effect was weak and needs further validation by larger population-based studies.
doi:10.1371/journal.pone.0071968
PMCID: PMC3734314  PMID: 23940798
8.  Role of MUC20 overexpression as a predictor of recurrence and poor outcome in colorectal cancer 
Background
Colorectal cancer (CRC) remains one of the most common cancers worldwide. We observed that MUC20 was significantly up-regulated in CRC patients with poor prognosis based on the microarray analysis. However, little is known about the role of MUC20 in CRC.
Methods
Microarray experiments were performed on the Affymetrix U133 plus 2.0 GeneChip Array. The protein and mRNA levels of MUC20 were examined by immunohistochemistry (IHC) and Real-Time quantitative PCR (RT-qPCR) in CRC tissues and adjacent noncancerous tissues (ANCT). ShRNA and overexpression plasmids were used to regulate MUC20 expression in CRC cell lines in vitro; wound healing, Transwell migration assays, and Western blotting were used to detect migration and invasion changes.
Results
MUC20 was one of the up-regulated genes in CRC patients with poor prognosis by microarray. Using IHC and RT-qPCR, we showed that MUC20 expression was significantly higher in CRC tissues than in ANCT (P < 0.05). We further showed that MUC20 overexpression was correlated with recurrence and poor outcome (P < 0.05). The Kaplan-Meier survival curves indicated that disease-free survival (DFS) and overall survival (OS) were significantly worse in CRC patients with MUC20 overexpression. The Cox multivariate analysis revealed that MUC20 overexpression and TNM stage were independent prognostic factors. Elevated expression of MUC20 in cells promoted migration and invasion, whereas ShRNA-mediated knockdown inhibited these processes. In addition, Western blotting demonstrated that MUC20-induced invasion was associated with MMP-2, MMP-3, and E-cadherin.
Conclusions
Cumulatively, MUC20 may serve as an important predictor of recurrence and poor outcome for CRC patients. MUC20 overexpression could enhance migration and invasion abilities of CRC cells. Translation of its roles into clinical practice will need further investigation and additional test validation.
doi:10.1186/1479-5876-11-151
PMCID: PMC3702436  PMID: 23787019
MUC20; Colorectal Cancer; Invasion; Recurrence
9.  The effects of a histone deacetylase inhibitor on biological behavior of diffuse large B-cell lymphoma cell lines and insights into the underlying mechanisms 
Background
Epigenetic control using histone deacetylase (HDAC) inhibitors is a promising therapy for lymphomas. Insights into the anti-proliferative effects of HDAC inhibitors on diffuse large B-cell lymphoma (DLBCL) and further understanding of the underlying mechanisms, which remain unclear to date, are of great importance.
Methods
Three DLBCL cell lines (DoHH2, LY1 and LY8) were used to define the potential epigenetic targets for Trichostatin A (TSA)-mediated anti-proliferative effects via CCK-8 assay. Cell cycle distribution and apoptosis were detected by flow cytometry. We further investigated the underlying molecular mechanisms by examining expression levels of relevant proteins using western blot analysis.
Results
TSA treatment inhibited the growth of all three DLBCL cell lines and enhanced cell cycle arrest and apoptosis. Molecular analysis revealed upregulated acetylation of histone H3, α-tubulin and p53, and dephosphorylation of pAkt with altered expression of its main downstream effectors (p21, p27, cyclin D1 and Bcl-2). HDAC profiling revealed that all three cell lines had varying HDAC1–6 expression levels, with the highest expression of all six isoforms, in DoHH2 cells, which displayed the highest sensitivity to TSA.
Conclusion
Our results demonstrated that the HDAC inhibitor TSA inhibited DLBCL cell growth, and that cell lines with higher expression of HDACs tended to be more sensitive to TSA. Our data also suggested that inhibition of pAkt and activation of p53 pathway are the main molecular events involved in inhibitory effects of TSA.
doi:10.1186/1475-2867-13-57
PMCID: PMC3681717  PMID: 23758695
Diffuse large B-cell lymphoma; HDAC; Trichostatin A; Akt pathway; p53
10.  Live Poultry Trade in Southern China Provinces and HPAIV H5N1 Infection in Humans and Poultry: The Role of Chinese New Year Festivities 
PLoS ONE  2012;7(11):e49712.
Background
The number of outbreaks of highly pathogenic avian influenza virus of the H5N1 subtype (HPAIV H5N1) over the past 5 years has been drastically reduced in China but sporadic infections in poultry and humans are still occurring. In this study, we aimed to investigate seasonal patterns in the association between the movement of live poultry originating from southern China and HPAIV H5N1 infection history in humans and poultry in China.
Methodology/Principal Findings
During January to April 2010, longitudinal questionnaire surveys were carried out monthly in four wholesale live bird markets (LBMs) in Hunan and Guangxi provinces of South China. Using social network analysis, we found an increase in the number of observed links and degree centrality between LBMs and poultry sources in February and March compared to the months of January and April. The association of some live poultry traders (LPT’s) with a limited set of counties (within the catchment area of LBMs) in the months of February and March may support HPAIV H5N1 transmission and contribute to perpetuating HPAIV H5N1 virus circulation among certain groups of counties. The connectivity among counties experiencing human infection was significantly higher compared to counties without human infection for the months of January, March and April. Conversely, counties with poultry infections were found to be significantly less connected than counties without poultry infection for the month of February.
Conclusions/Significance
Our results show that temporal variation in live poultry trade in Southern China around the Chinese New Year festivities is associated with higher HPAIV H5N1 infection risk in humans and poultry. This study has shown that capturing the dynamic nature of poultry trade networks in Southern China improves our ability to explain the spatiotemporal dissemination in avian influenza viruses in China.
doi:10.1371/journal.pone.0049712
PMCID: PMC3500328  PMID: 23166751
11.  Abnormal expression of GADD45B in human colorectal carcinoma 
Background
GADD45B is a member of the growth arrest DNA damage-inducible gene family associated with cell growth control, apoptosis, and DNA damage repair response. The aim of this study is to detect the role of GADD45B in colorectal carcinoma (CRC); the area not studied in depth to date.
Methods
The mRNA and protein levels of GADD45B were examined by Real-Time quantitative PCR (RT-qPCR) and immunohistochemistry (IHC) in CRC tissues and adjacent noncancerous tissues (ANCT). Over-expression plasmids and SiRNA were used to regulate GADD45B expression in CRC cell lines in vitro and flow cytometry and Western blotting were used to detect apoptotic changes.
Results
The mRNA and protein levels of GADD45B were significantly higher in CRC tissues than those in ANCT (P<0.05). Up-regulation of GADD45B was also correlated with relapse and death of CRC patients (P<0.05). The Kaplan-Meier survival curves indicated that disease-free survival (DFS) was significantly worse in CRC patients who showed GADD45B overexpression. A Cox multivariate analysis revealed that GADD45B overexpression and TNM stage were significant factors affecting patients’ survival. On the other hand, as a tumor suppressor gene, GADD45B amplified from normal colorectal tissues could induce apoptosis in CRC cell lines and may be associated with the p53-mediated apoptotic pathways.
Conclusion
GADD45B, a tumor suppressor gene potentially through the p53-mediated apoptotic pathways, is paradoxically overexpressed in CRC and as such may play an unappreciated role in tumorigenesis. The exact mechanism of GADD45B inactivation and overexpression requires further investigation. GADD45B could be a potential therapeutic target for CRC treatment in future.
doi:10.1186/1479-5876-10-215
PMCID: PMC3495754  PMID: 23110778
Colorectal carcinoma; GADD45B; Carcinogenesis; Relapse
12.  Overexpression of 14-3-3ζ in cancer cells activates PI3K via binding the p85 regulatory subunit 
Oncogene  2011;31(7):897-906.
The ubiquitously expressed 14-3-3 proteins regulate many pathways involved in transformation. Previously, we found that 14-3-3ζ overexpression increased Akt phosphorylation in human mammary epithelial cells. Here, we investigated the clinical relevance and molecular mechanism of 14-3-3ζ overexpression-mediated Akt phosphorylation and the potential impact on breast cancer progression. We found that 14-3-3ζ overexpression was significantly (P = 0.005) associated with increased Akt phosphorylation in human breast tumors. Additionally, 14-3-3ζ overexpression combined with strong Akt phosphorylation was significantly (P=0.01) associated with increased cancer recurrence in patients. In contrast, knockdown of 14-3-3ζ expression by siRNA in cancer cell lines and tumor xenografts reduced Akt phosphorylation. Furthermore, 14-3-3ζ enhanced Akt phosphorylation through activation of PI3K. Mechanistically, 14-3-3ζ bound to the p85 regulatory subunit of PI3K and increased PI3K translocation to the cell membrane. A single 14-3-3 binding motif encompassing serine 83 on p85 is largely responsible for 14-3-3ζ-mediated p85 binding and PI3K/Akt activation. Mutation of serine 83 to alanine on p85 inhibited 14-3-3ζ binding to the p85 subunit of PI3K, reduced PI3K membrane localization and activation, impeded anchorage independent growth and enhanced stress induced apoptosis. These findings revealed a novel mechanism by which 14-3-3ζ overexpression activates PI3K, a key node in the mitogenic signaling network known to promote malignancies in many cell types.
doi:10.1038/onc.2011.284
PMCID: PMC3193867  PMID: 21743495
14-3-3ζ; breast cancer; PI3K; Akt
13.  Potentially Functional Variants of PLCE1 Identified by GWASs Contribute to Gastric Adenocarcinoma Susceptibility in an Eastern Chinese Population 
PLoS ONE  2012;7(3):e31932.
Background
Recent genome-wide association studies (GWAS) have found a single nucleotide polymorphism (SNP, rs2274223 A>G) in PLCE1 to be associated with risk of gastric adenocarcinoma. In the present study, we validated this finding and also explored the risk associated with another unreported potentially functional SNP (rs11187870 G>C) of PLCE1 in a hospital-based case-control study of 1059 patients with pathologically confirmed gastric adenocarcinoma and 1240 frequency-matched healthy controls.
Methodology/Principal Findings
We determined genotypes of these two SNPs by the Taqman assay and used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). We found that a significant higher gastric adenocarcinoma risk was associated with rs2274223 variant G allele (adjusted OR = 1.35, 95% CI = 1.14–1.60 for AG+GG vs. AA) and rs11187870 variant C allele (adjusted OR = 1.26, 95% CI = 1.05–1.50 for CG+CC vs. GG). We also found that the number of combined risk alleles (i.e., rs2274223G and rs11187870C) was associated with risk of gastric adenocarcinoma in an allele-dose effect manner (Ptrend = 0.0002). Stratification analysis indicated that the combined effect of rs2274223G and rs11187870C variant alleles was more evident in subgroups of males, non-smokers, non-drinkers and patients with gastric cardia adenocarcinoma. Further real-time PCR results showed that expression levels of PLCE1 mRNA were significantly lower in tumors than in adjacent noncancerous tissues (0.019±0.002 vs. 0.008±0.001, P<0.05).
Conclusions/Significances
Our results further confirmed that genetic variations in PLCE1 may contribute to gastric adenocarcinoma risk in an eastern Chinese population.
doi:10.1371/journal.pone.0031932
PMCID: PMC3295761  PMID: 22412849
14.  Chronic Antagonism of the Mineralocorticoid Receptor Ameliorates Hypertension and End Organ Damage in a Rodent Model of Salt-Sensitive Hypertension 
We investigated the effects of chronic mineralocorticoid receptor blockade with eplerenone on the development and progression of hypertension and end organ damage in Dahl salt-sensitive rats. Eplerenone significantly attenuated the progressive rise in systolic blood pressure (SBP) (204 ± 3 vs. 179±3 mmHg, p < 0.05), reduced proteinuria (605.5 ± 29.6 vs. 479.7 ± 26.1 mg/24h, p < 0.05), improved injury scores of glomeruli, tubules, renal interstitium, and vasculature in Dahl salt-sensitive rats fed a high-salt diet. These results demonstrate that mineralocorticoid receptor antagonism provides target organ protection and attenuates the development of elevated blood pressure (BP) in a model of salt-sensitive hypertension.
doi:10.3109/10641963.2011.566956
PMCID: PMC3231850  PMID: 21950654
mineralocorticoid receptor antagonist; hypertension; end organ protection; eplerenone; Dahl salt-sensitive rats
15.  Spatial Distribution and Risk Factors of Highly Pathogenic Avian Influenza (HPAI) H5N1 in China 
PLoS Pathogens  2011;7(3):e1001308.
Highly pathogenic avian influenza (HPAI) H5N1 was first encountered in 1996 in Guangdong province (China) and started spreading throughout Asia and the western Palearctic in 2004–2006. Compared to several other countries where the HPAI H5N1 distribution has been studied in some detail, little is known about the environmental correlates of the HPAI H5N1 distribution in China. HPAI H5N1 clinical disease outbreaks, and HPAI virus (HPAIV) H5N1 isolated from active risk-based surveillance sampling of domestic poultry (referred to as HPAIV H5N1 surveillance positives in this manuscript) were modeled separately using seven risk variables: chicken, domestic waterfowl population density, proportion of land covered by rice or surface water, cropping intensity, elevation, and human population density. We used bootstrapped logistic regression and boosted regression trees (BRT) with cross-validation to identify the weight of each variable, to assess the predictive power of the models, and to map the distribution of HPAI H5N1 risk. HPAI H5N1 clinical disease outbreak occurrence in domestic poultry was mainly associated with chicken density, human population density, and elevation. In contrast, HPAIV H5N1 infection identified by risk-based surveillance was associated with domestic waterfowl density, human population density, and the proportion of land covered by surface water. Both models had a high explanatory power (mean AUC ranging from 0.864 to 0.967). The map of HPAIV H5N1 risk distribution based on active surveillance data emphasized areas south of the Yangtze River, while the distribution of reported outbreak risk extended further North, where the density of poultry and humans is higher. We quantified the statistical association between HPAI H5N1 outbreak, HPAIV distribution and post-vaccination levels of seropositivity (percentage of effective post-vaccination seroconversion in vaccinated birds) and found that provinces with either outbreaks or HPAIV H5N1 surveillance positives in 2007–2009 appeared to have had lower antibody response to vaccination. The distribution of HPAI H5N1 risk in China appears more limited geographically than previously assessed, offering prospects for better targeted surveillance and control interventions.
Author Summary
The geographical distribution of highly pathogenic avian influenza (HPAI) H5N1 and agro-ecological risk factors have been studied in a number of countries in Southeast Asia. However, little is know of its distribution in China where HPAI H5N1 first emerged in 1996, evolved, and spread throughout Asia and the western Palearctic in 2004–2006. This study analyzes separately the distribution, in domestic poultry, of HPAI virus (HPAIV) H5N1 isolated from active risk-based surveillance sampling and HPAI H5N1 clinical disease outbreaks. These data are analyzed in relation to the distribution of chicken and domestic waterfowl population density, proportion of land covered by rice or surface water, cropping intensity, elevation, and human population density. HPAI H5N1 viruses identified by risk-based surveillance are found to be associated with domestic waterfowl density, human population density, and the proportion of land covered by surface water. In contrast, HPAI H5N1 clinical disease outbreak occurrences were mainly associated with chicken density, human population density, and low elevation. These results show that the distribution of HPAI H5N1 risk in China appears more limited geographically than previously assessed, offering prospects for better targeted surveillance and control interventions.
doi:10.1371/journal.ppat.1001308
PMCID: PMC3048366  PMID: 21408202
16.  14-3-3ζ Cooperates with ErbB2 to Promote Progression of Ductal Carcinoma in Situ to Invasive Breast Cancer by Inducing Epithelial-Mesenchymal Transition 
Cancer cell  2009;16(3):195-207.
Summary
ErbB2, a metastasis-promoting oncoprotein, is overexpressed in ~25% of invasive/metastatic breast cancers, but in 50–60% of non-invasive ductal carcinomas in situ (DCIS). It has been puzzling how a subset of ErbB2-overexpressing DCIS develops into invasive breast cancer (IBC). We found that co-overexpression of 14-3-3ζ in ErbB2-overexpressing DCIS conferred a higher risk of progression to IBC. ErbB2 and 14-3-3ζ overexpression, respectively, increased cell migration and decreased cell adhesion, two prerequisites of tumor cell invasion. 14-3-3ζ overexpression reduced cell adhesion by activating the TGFβ/Smads pathway that led to ZFHX1B/SIP-1 upregulation, E-cadherin loss, and epithelial-mesenchymal transition (EMT). Importantly, patients whose breast tumors overexpressed both ErbB2 and 14-3-3ζ had higher rates of metastatic recurrence and death than those whose tumors overexpressed only one.
doi:10.1016/j.ccr.2009.08.010
PMCID: PMC2754239  PMID: 19732720
17.  14-3-3ζ Overexpression Defines High Risk for Breast Cancer Recurrence and Promotes Cancer Cell Survival 
Cancer research  2009;69(8):3425-3432.
The ubiquitously expressed 14-3-3 proteins are involved in numerous important cellular functions. The loss of 14-3-3σ is a common event in breast cancer; however, the role of other 14-3-3s in breast cancer is unclear. Recently, we found that 14-3-3ζ overexpression occurs in early stage breast diseases and contributes to transformation of human mammary epithelial cells. Here, we show that 14-3-3ζ overexpression also persisted in invasive ductal carcinoma and contributed to the further progression of breast cancer. To examine the clinical impact of 14-3-3ζ overexpression in advanced stage breast cancer, we performed immunohistochemical analysis of 14-3-3ζ expression in primary breast carcinomas. 14-3-3ζ overexpression occurred in 42% of breast tumors and was determined to be an independent prognostic factor for reduced disease-free survival. 14-3-3ζ overexpression combined with ErbB2 overexpression and positive lymph node status identified a subgroup of patients at high risk for developing distant metastasis. To investigate whether 14-3-3ζ overexpression causally promotes breast cancer progression, we overexpressed 14-3-3ζ by stable transfection or reduced 14-3-3ζ expression by siRNA in cancer cell lines. Increased 14-3-3ζ expression enhanced anchorage independent growth and inhibited stress-induced apoptosis, whereas downregulation of 14-3-3ζ reduced anchorage independent growth and sensitized cells to stress-induced apoptosis via the mitochondrial apoptotic pathway. Transient blockade of 14-3-3ζ expression by siRNA in cancer cells effectively reduced the onset and growth of tumor xenografts in vivo. Therefore, 14-3-3ζ overexpression is a novel molecular marker for disease recurrence in breast cancer patients and may serve as an effective therapeutic target in patients whose tumors overexpress 14-3-3ζ.
doi:10.1158/0008-5472.CAN-08-2765
PMCID: PMC2671640  PMID: 19318578
14-3-3ζ; breast cancer; apoptosis resistance; disease recurrence; prognostic marker
18.  Validity of self-reported weight, height and resultant body mass index in Chinese adolescents and factors associated with errors in self-reports 
BMC Public Health  2010;10:190.
Background
Validity of self-reported height and weight has not been adequately evaluated in diverse adolescent populations. In fact there are no reported validity studies conducted in Asian children and adolescents. This study aims to examine the accuracy of self-reported weight, height, and resultant BMI values in Chinese adolescents, and of the adolescents' subsequent classification into overweight categories.
Methods
Weight and height were self-reported and measured in 1761 adolescents aged 12-16 years in a cross-sectional survey in Xi'an city, China. BMI was calculated from both reported values and measured values. Bland-Altman plots with 95% limits of agreement, Pearson's correlation and Kappa statistics were calculated to assess the agreement.
Results
The 95% limits of agreement were -11.16 and 6.46 kg for weight, -4.73 and 7.45 cm for height, and -4.93 and 2.47 kg/m2 for BMI. Pearson correlation between measured and self-reported values was 0.912 for weight, 0.935 for height and 0.809 for BMI. Weighted Kappa was 0.859 for weight, 0.906 for height and 0.754 for BMI. Sensitivity for detecting overweight (includes obese) in adolescents was 56.1%, and specificity was 98.6%. Subjects' area of residence, age and BMI were significant factors associated with the errors in self-reporting weight, height and relative BMI.
Conclusions
Reported weight and height does not have an acceptable agreement with measured data. Therefore, we do not recommend the application of self-reported weight and height to screen for overweight adolescents in China. Alternatively, self-reported data could be considered for use, with caution, in surveillance systems and epidemiology studies.
doi:10.1186/1471-2458-10-190
PMCID: PMC2864211  PMID: 20384994
19.  Hemoglobin levels and anemia evaluation during pregnancy in the highlands of Tibet: a hospital-based study 
BMC Public Health  2009;9:336.
Background
Anemia is regarded as a major risk factor for unfavorable pregnancy outcomes, but there have been no previous studies describing the pattern of hemoglobin concentration during pregnancy in Tibet and the relationship between altitude and Hb concentration in the pregnant women living in Tibet still has not been clearly established. The main objectives of this study were to study the hemoglobin levels and prevalence of anemia among pregnant women living in the highlands of Tibet and to evaluate potential associations of hemoglobin and anemia with women's characteristics.
Methods
The hospital-based study was conducted in 380 pregnant women. Their blood samples were tested and related sociodemographic information was collected. Multiple linear regression model and multiple logistic regression model were used to assess the association of pregnant women's characteristics with hemoglobin level and the occurrence of anemia. Centers for Disease Control (CDC), Dirren et al. and Dallman et al. methods were used to adjust the hemoglobin measurements based on altitude for estimating the prevalence of anemia.
Results
The mean hemoglobin concentration was 127.6 g/L (range: 55.0-190.0 g/L). Prevalence rate of anemia in this study was 70.0%, 77.9% and 41.3%, respectively for three altitude-correction methods for hemoglobin (CDC method, Dirren et al. method, and Dallman et al. method). Gestational age, ethnicity, residence and income were significantly associated with the hemoglobin concentration and prevalence of anemia in the study population. Specially, the hemoglobin concentration of pregnant women decreased with increase in gestational age.
Conclusion
The hemoglobin level was low and prevalence rate of anemia was high among pregnant women in Lhasa, Tibet. Gestational age, ethnicity, residence and income were found to be significantly associated with the hemoglobin level and the occurrence of anemia in the study population.
doi:10.1186/1471-2458-9-336
PMCID: PMC2753353  PMID: 19754927
20.  Evaluation of a portable hemoglobin photometer in pregnant women in a high altitude area: a pilot study 
BMC Public Health  2009;9:228.
Background
Anemia is a widespread public health problem associated with an increased risk of morbidity and mortality, especially in pregnant women. This study examined the agreement between a portable hemoglobin photometer and a laboratory analyzer in determining hemoglobin level in pregnant women.
Methods
This study recruited 69 pregnant women in Tibet, China. Capillary blood samples were taken to measure hemoglobin concentration using the hemoglobin photometer and the laboratory analyzer. Limit of agreement, concordance and intraclass correlation coefficient were used to evaluate the agreement. Laboratory measurement was considered as the standard reference method. Sensitivity and specificity were calculated to assess the error in screening for anemia.
Results
Mean difference between the two methods was -2.1 g/l. wide 95% limits of agreement were found (-22.6 g/l to 18.4 g/l). The intraclass correlation coefficient was 0.795, and concordance correlation coefficient was 0.793. Sensitivity and specificity were 94.9% and 76.7% respectively. Positive predictive value was 84.1%, and negative predictive value was 92.0%.
Conclusion
This hemoglobin photometer is not recommended for determining hemoglobin concentration in pregnancy in a high altitude area.
doi:10.1186/1471-2458-9-228
PMCID: PMC2717084  PMID: 19591672

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