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1.  Trends in incidence and mortality of nasopharyngeal carcinoma over a 20–25 year period (1978/1983–2002) in Sihui and Cangwu counties in southern China 
BMC Cancer  2006;6:178.
Nasopharyngeal carcinoma (NPC) is a rare malignancy in most parts of the world but is common in southern China. A recent report from the Hong Kong Cancer Registry, a high-risk area for NPC in southern China, showed that incidence rate decreased by 29% for males and by 30% for females from 1980–1999, while mortality rate decreased by 43% for males and 50% for females. Changing environmental risk factors and improvements in diagnosis and treatment were speculated to be the major factors contributing to the downward trend of the incidence and mortality rates of NPC. To investigate the secular trends in different Cantonese populations with different socio-economic backgrounds and lifestyles, we report the incidences and mortality rates from two population-based cancer registries in Sihui and Cangwu counties from 1978–2002.
Incidence and mortality rates were aggregated by 5-year age groups and 5 calendar years. To adjust for the effect of difference in age composition for different periods, the total and age-specific rates of NPC incidence and mortality rate were adjusted by direct standardization according to the World Standard Population (1960). The Estimated Annual Percentage Change (EAPC) was used as an estimate of the trend.
The incidence rate of NPC has remained stable during the recent two decades in Sihui and in females in Cangwu, with a slight increase observed in males in Cangwu from 17.81 to 19.76 per 100,000. The incidence rate in Sihui is 1.4–2.0 times higher during the corresponding years than in Cangwu, even though the residents of both areas are of Cantonese ethnicity. A progressive decline in mortality rate was observed in females only in Sihui, with an average reduction of 6.3% (p = 0.016) per five-year period.
To summarize, there is great potential to work in the area of NPC prevention and treatment in southern China to decrease NPC risk and improve survival risk rates in order to reduce M:I ratios. Future efforts on effective prevention, early detection and treatment strategies were also discussed in this paper. Furthermore, the data quality and completeness also need to be improved.
PMCID: PMC1557527  PMID: 16822324
2.  Epstein-Barr Virus (EBV) Infection in Chinese Children: A Retrospective Study of Age-Specific Prevalence 
PLoS ONE  2014;9(6):e99857.
Epstein-Barr Virus (EBV) is a globally prevalent herpesvirus associated with infectious mononucleosis and many malignancies. The survey on EBV prevalence appears to be important to study EBV-related diseases and determine when to administer prophylactic vaccine. The purpose of this retrospective study was to collect baseline information about the prevalence of EBV infection in Chinese children.
Methodology/Principal Finding
We collected 1778 serum samples from healthy children aged 0 to 10, who were enrolled in conventional health and nutrition examinations without any EBV-related symptom in 2012 and 2013 in North China (n = 973) and South China (n = 805). We detected four EBV-specific antibodies, i.e., anti-VCA-IgG and IgM, anti-EBNA-IgG and anti-EA-IgG, by ELISA, representing all of the phases of EBV infection. The overall EBV seroprevalence in samples from North and South China were 80.78% and 79.38% respectively. The EBV seropositivity rates dropped slightly at age 2, and then increased gradually with age. The seroprevalence became stabilized at over 90% after age 8. In this study, the seroprevalence trends between North and South China showed no difference (P>0.05), and the trends of average antibody concentrations were similar as well (P>0.05).
EBV seroprevalence became more than 50% before age 3 in Chinese children, and exceed 90% after age 8. This study can be helpful to study the relationship between EBV and EBV-associated diseases, and supportive to EBV vaccine development and implementation.
PMCID: PMC4051769  PMID: 24914816
3.  c-Ski Inhibits Autophagy of Vascular Smooth Muscle Cells Induced by oxLDL and PDGF 
PLoS ONE  2014;9(6):e98902.
Autophagy is increasingly being recognized as a critical determinant of vascular smooth muscle cell (VSMC) biology. Previously, we have demonstrated that c-Ski inhibits VSMC proliferation stimulated by transforming growth factor β (TGF-β), but it is not clear whether c-Ski has the similar protective role against other vascular injury factors and whether regulation of autophagy is involved in its protective effects on VSMC. Accordingly, in this study, rat aortic A10 VSMCs were treated with 40 µg/ml oxidized low-density lipoprotein (oxLDL) or 20 ng/ml platelet-derived growth factor (PDGF), both of which were autophagy inducers and closely related to the abnormal proliferation of VSMCs. Overexpression of c-Ski in A10 cells significantly suppressed the oxLDL- and PDGF- induced autophagy. This action of c-Ski resulted in inhibiting the cell proliferation, the decrease of contractile phenotype marker α-SMA expression while the increase of synthetic phenotype marker osteopontin expression stimulated by oxLDL or PDGF. Inversely, knockdown of c-Ski by RNAi enhanced the stimulatory effects of oxLDL or PDGF on A10 cell growth and phenotype transition. And further investigation found that inhibition of AKT phosphorylation to downregulate proliferating cell nuclear antigen (PCNA) expression, was involved in the regulation of autophagy and associated functions by c-Ski in the oxLDL- and PDGF-stimulated VSMCs. Collectively, c-Ski may play an important role in inhibiting autophagy to protect VSMCs against some harsh stress including oxLDL and PDGF.
PMCID: PMC4041777  PMID: 24887307
4.  Household and Living Arrangement Projections at the Subnational Level: An Extended Cohort-Component Approach 
Demography  2013;50(3):10.1007/s13524-012-0171-3.
This article presents the core methodological ideas, empirical assessments, and applications of an extended cohort-component approach (known as the “ProFamy model”) to simultaneously project household composition, living arrangements, and population sizes at the subnational level in the United States. Comparisons of projections from 1990 to 2000 using this approach with census counts in 2000 for each of the 50 states and Washington, DC show that 68.0 %, 17.0 %, 11.2 %, and 3.8 % of the absolute percentage errors are <3.0 %, 3.0 % to 4.99 %, 5.0 % to 9.99 %, and ≥10.0 %, respectively. Another analysis compares average forecast errors between the extended cohort-component approach and the still widely used classic headship-rate method, by projecting number-of-bedrooms–specific housing demands from 1990 to 2000 and then comparing those projections with census counts in 2000 for each of the 50 states and Washington, DC. The results demonstrate that, compared with the extended cohort-component approach, the headship-rate method produces substantially more serious forecast errors because it cannot project households by size while the extended cohort-component approach projects detailed household sizes. We also present illustrative household and living arrangement projections for the five decades from 2000 to 2050, with medium-, small-, and large-family scenarios for each of the 50 states; Washington, DC; six counties of southern California, and the Minneapolis–St. Paul metropolitan area. Among many interesting numerical outcomes of household and living arrangement projections with medium, low, and high bounds, the aging of American households over the next few decades across all states/areas is particularly striking. Finally, the limitations of the present study and potential future lines of research are discussed.
PMCID: PMC3622161  PMID: 23208782
Household and living arrangement projections; Cohort-component approach; Subnational projections; Aging of households; Forecast errors
5.  Weighted Risk Score-Based Multifactor Dimensionality Reduction to Detect Gene-Gene Interactions in Nasopharyngeal Carcinoma 
Determining the complex relationships between diseases, polymorphisms in human genes and environmental factors is challenging. Multifactor dimensionality reduction (MDR) has been proven to be capable of effectively detecting the statistical patterns of epistasis, although classification accuracy is required for this approach. The imbalanced dataset can cause seriously negative effects on classification accuracy. Moreover, MDR methods cannot quantitatively assess the disease risk of genotype combinations. Hence, we introduce a novel weighted risk score-based multifactor dimensionality reduction (WRSMDR) method that uses the Bayesian posterior probability of polymorphism combinations as a new quantitative measure of disease risk. First, we compared the WRSMDR to the MDR method in simulated datasets. Our results showed that the WRSMDR method had reasonable power to identify high-order gene-gene interactions, and it was more effective than MDR at detecting four-locus models. Moreover, WRSMDR reveals more information regarding the effect of genotype combination on the disease risk, and the result was easier to determine and apply than with MDR. Finally, we applied WRSMDR to a nasopharyngeal carcinoma (NPC) case-control study and identified a statistically significant high-order interaction among three polymorphisms: rs2860580, rs11865086 and rs2305806.
PMCID: PMC4100176  PMID: 24933637
gene-gene interaction; weighted risk score; multifactor dimensionality reduction; nasopharyngeal carcinoma
6.  Hemodynamic effects of various support modes of continuous flow LVADs on the cardiovascular system: A numerical study 
The aim of this study was to determine the hemodynamic effects of various support modes of continuous flow left ventricular assist devices (CF-LVADs) on the cardiovascular system using a numerical cardiovascular system model.
Three support modes were selected for controlling the CF-LVAD: constant flow mode, constant speed mode, and constant pressure head mode of CF-LVAD. The CF-LVAD is established between the left ventricular apex and the ascending aorta, and was incorporated into the numerical model. Various parameters were evaluated, including the blood assist index (BAI), the left ventricular external work (LVEW), the energy of blood flow (EBF), pulsatility index (PI), and surplus hemodynamic energy (SHE).
The results show that the constant flow mode, when compared to the constant speed mode and the constant pressure head mode, increases LVEW by 31% and 14%, and EBF by 21% and 15%, respectively, indicating that this mode achieved the best ventricular unloading among the 3 support modes. As BAI is increased, PI and SHE are gradually decreased, whereas PI of the constant pressure head reaches the maximum value.
The study demonstrates that the continuous flow control mode of the CF-LVAD may achieve the highest ventricular unloading. In contrast, the constant rotational speed mode permits the optimal blood perfusion. Finally, the constant pressure head strategy, permitting optimal pulsatility, should optimize the vascular function.
PMCID: PMC4020910  PMID: 24793178
Blood Flow Velocity; Heart Failure; Ventricular Function; Left
7.  Health Consequences of Familial Longevity Influence Among the Chinese Elderly 
A comparative analysis between centenarians’ children and neighborhood controls is an efficient approach to learn how familial longevity influence and its interaction with environmental factors affect healthy aging. Yet, there are few extant studies that inform this topic; this study expands this literature.
We analyze data from 417 children of centenarians and 560 neighborhood controls without family history of longevity in China (all participants aged 60–80) using ordered logit regression models.
We found that, compared to the neighborhood controls and adjusted for various potentially confounding factors, centenarians’ children had significantly better instrumental activities of daily living function(p < .001), smaller number of chronic conditions or health problems(p < .01), less anxiety and loneliness(p < .01), better cognitive function (p < .01), more resilience (p < .01), better self-rated health (p < .001), and better self-rated life satisfaction (p < .001). The results also reveal that interactions between familial longevity influence and one of three environmental factors (whether, as children, they received adequate medical care when ill, number of living children, and household economic conditions) may possibly affect health outcomes at old ages (p < .05). We discovered that effects of the environmental factors on health outcome are substantially stronger among elders who have no family history of longevity compared to centenarians’ children who probably carry positive genes and/or lifestyle behaviors from their long-lived parent(s), which may promote longevity.
Familial longevity influence, through genetics and family lifestyle, is significantly associated with various aspects of health at older ages. Interactions between familial longevity influence and some environmental factors may affect health in old age.
PMCID: PMC3593617  PMID: 23064818
Centenarians’ children; Familial longevity influence; Genetics and family environment; Healthy aging; China.
8.  Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-wide Meta-analysis 
Peters, Ulrike | Jiao, Shuo | Schumacher, Fredrick R. | Hutter, Carolyn M. | Aragaki, Aaron K. | Baron, John A. | Berndt, Sonja I. | Bézieau, Stéphane | Brenner, Hermann | Butterbach, Katja | Caan, Bette J. | Campbell, Peter T. | Carlson, Christopher S. | Casey, Graham | Chan, Andrew T. | Chang-Claude, Jenny | Chanock, Stephen J. | Chen, Lin S. | Coetzee, Gerhard A. | Coetzee, Simon G. | Conti, David V. | Curtis, Keith R. | Duggan, David | Edwards, Todd | Fuchs, Charles S. | Gallinger, Steven | Giovannucci, Edward L. | Gogarten, Stephanie M. | Gruber, Stephen B. | Haile, Robert W. | Harrison, Tabitha A. | Hayes, Richard B. | Henderson, Brian E. | Hoffmeister, Michael | Hopper, John L. | Hudson, Thomas J. | Hunter, David J. | Jackson, Rebecca D. | Jee, Sun Ha | Jenkins, Mark A. | Jia, Wei-Hua | Kolonel, Laurence N. | Kooperberg, Charles | Küry, Sébastien | Lacroix, Andrea Z. | Laurie, Cathy C. | Laurie, Cecelia A. | Le Marchand, Loic | Lemire, Mathieu | Levine, David | Lindor, Noralane M. | Liu, Yan | Ma, Jing | Makar, Karen W. | Matsuo, Keitaro | Newcomb, Polly A. | Potter, John D. | Prentice, Ross L. | Qu, Conghui | Rohan, Thomas | Rosse, Stephanie A. | Schoen, Robert E. | Seminara, Daniela | Shrubsole, Martha | Shu, Xiao-Ou | Slattery, Martha L. | Taverna, Darin | Thibodeau, Stephen N. | Ulrich, Cornelia M. | White, Emily | Xiang, Yongbing | Zanke, Brent W. | Zeng, Yi-Xin | Zhang, Ben | Zheng, Wei | Hsu, Li
Gastroenterology  2012;144(4):799-807.e24.
Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.
We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.
Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10−8: an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10−8). We also found evidence for 3 additional loci with P values less than 5.0 × 10−7: a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10−8), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10−8), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10−7).
In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
PMCID: PMC3636812  PMID: 23266556
Colon Cancer; Genetics; Risk Factors; SNP
9.  Air pollution: a smoking gun for cancer 
Chinese Journal of Cancer  2014;33(4):173-175.
Once considered a taboo topic or stigma, cancer is the number one public health enemy in the world. Once a product of an almost untouchable industry, tobacco is indisputably recognized as a major cause of cancer and a target for anticancer efforts. With the emergence of new economic powers in the world, especially in highly populated countries such as China, air pollution has rapidly emerged as a smoking gun for cancer and has become a hot topic for public health debate because of the complex political, economic, scientific, and technologic issues surrounding the air pollution problem. This editorial and the referred articles published in this special issue of the Chinese Journal of Cancer discuss these fundamental questions. Does air pollution cause a wide spectrum of cancers? Should air pollution be considered a necessary evil accompanying economic transformation in developing countries? Is an explosion of cancer incidence coming to China and how soon will it arrive? What must be done to prevent this possible human catastrophe? Finally, the approaches for air pollution control are also discussed.
PMCID: PMC3975182  PMID: 24636233
Air pollution; cancer; public health
10.  Oncogene mutational profile in nasopharyngeal carcinoma 
OncoTargets and therapy  2014;7:457-467.
Nasopharyngeal carcinoma (NPC) is a common tumor in Southern China, but the oncogene mutational status of NPC patients has not been clarified. Using time-of-flight mass spectrometry, 238 mutation hotspots in 19 oncogenes were examined in 123 NPC patients. The relationships between mutational status and clinical data were assessed with a χ2 or Fisher’s exact test. Survival analysis was performed using the Kaplan–Meier method with the log-rank test. In 123 patients, 21 (17.1%) NPC tumors were positive for mutations in eight oncogenes: six patients had PIK3CA mutations (4.9%), five NRAS mutations (4.1%), four KIT mutations (3.3%), two PDGFRA mutations (1.6%), two ABL mutations (1.6%), and one with simultaneous mutations in HRAS, EGFR, and BRAF (1%). Patients with mutations were more likely to relapse or develop metastasis than those with wild-type alleles (P=0.019). No differences or correlations were found in other clinical characteristics or in patient survival. No mutations were detected in oncogenes AKT1, AKT2, CDK, ERBB2, FGFR1, FGFR3, FLT3, JAK2, KRAS, MET, and RET. These results demonstrate an association between NPC and mutations in NRAS, KIT, PIK3CA, PDGFRA, and ABL, which are associated with patient relapse and metastasis.
PMCID: PMC3964172  PMID: 24672248
NPC; oncogene; mutation
11.  PhenX RISING: real world implementation and sharing of PhenX measures 
BMC Medical Genomics  2014;7:16.
The purpose of this manuscript is to describe the PhenX RISING network and the site experiences in the implementation of PhenX measures into ongoing population-based genomic studies.
Eighty PhenX measures were implemented across the seven PhenX RISING groups, thirty-three of which were used at more than two sites, allowing for cross-site collaboration. Each site used between four and 37 individual measures and five of the sites are validating the PhenX measures through comparison with other study measures. Self-administered and computer-based administration modes are being evaluated at several sites which required changes to the original PhenX Toolkit protocols. A network-wide data use agreement was developed to facilitate data sharing and collaboration.
PhenX Toolkit measures have been collected for more than 17,000 participants across the PhenX RISING network. The process of implementation provided information that was used to improve the PhenX Toolkit. The Toolkit was revised to allow researchers to select self- or interviewer administration when creating the data collection worksheets and ranges of specimens necessary to run biological assays has been added to the Toolkit.
The PhenX RISING network has demonstrated that the PhenX Toolkit measures can be implemented successfully in ongoing genomic studies. The next step will be to conduct gene/environment studies.
PMCID: PMC3994539  PMID: 24650325
PhenX; Phenotype; Epidemiology; Risk factors; Harmonization
12.  ABCC5, a Gene That Influences the Anterior Chamber Depth, Is Associated with Primary Angle Closure Glaucoma 
PLoS Genetics  2014;10(3):e1004089.
Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size = −0.045 mm, P = 8.17×10−9). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06–1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45×10−9; 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.
Author Summary
The anterior chamber is the space within the eye which is bound by the cornea, and the anterior surfaces of the iris and lens. Anterior chamber depth (ACD) is the distance measured along the eye's optical axis, from the cornea to the lens surface. ACD is an important risk factor for primary angle closure glaucoma (PACG), a major cause of irreversible blindness worldwide, and in particular, individuals of Asian ethnicity. In order to identify the genes that underlie PACG susceptibility, we conducted a two-staged study. We first conducted a large scale genetic study on a total of 5,308 population-based individuals of Asian descent to identify the genetic variants that influence ACD. This was followed by testing for associations between the identified genetic variant and PACG in another independent collection of 4,276 PACG cases and 18,801 controls. We found that a genetic variant within ABCC5 was associated with an increased risk of having PACG. Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants that influence the anterior chamber dimensions of the eye.
PMCID: PMC3945113  PMID: 24603532
13.  Vascularised greater trochanter bone graft, combined free iliac flap and impaction bone grafting for osteonecrosis of the femoral head 
International Orthopaedics  2013;37(3):391-398.
To investigate the curative efficacy of osteonecrosis of the femoral head (ONFH) in a hip-preserving operative approach, by grafting a vascularized greater trochanter flap combined with a free iliac flap, in an attempt to seek an innovative approach for patients who suffered middle to late stage ONFH without total hip arthroplasty (THA) surgery.
Our research included a total of 60 patients (66 hips) who accepted hip-preserving surgery by grafting a vascularized greater trochanter flap combined with a free iliac flap which was tightly filled by hammering because of ONFH (most were Association Research Circulation Osseous (ARCO) stage III patients) from January, 2006 to December, 2010. A Harris Hip Score was obtained during follow-ups, evaluating the clinical efficacy, X-rays were taken regularly for image assessing, and the SF-36 scale was used for estimating quality of life. Terminal observation time was considered when patients had symptom-dependant indications for performing another hip-preserving surgery or THA surgery.
Fifty-eight patients (64 hips) were eventually contacted by telephone for an out-patient clinic return visit, with a mean follow-up time of 35.8 months (varied from 12 months to 60 months), but two patients lost contact for various reasons. The demographic data were as follows: there were 16 ARCO IIIA cases, 22 ARCO IIIB cases, and 26 ARCO IIIC cases, respectively. Postoperative X-rays revealed a well-repaired necrotic area of the femoral head and improvement of femoral-acetabulum coverage. The last follow-up mean Harris Hip Score was 86.56 ± 7.38 (excellent results reached 87.50 %), which were greatly improved compared to 50.95 ± 6.86 pre-operatively. Also the postoperative mean scores of all dimensions of the SF-36 scale were improved to some extent. Additionally the physical component summary (PSC) scores were enhanced from 42 ± 13 pre-operatively to 78 ± 11, while the postoperative mental component summary (MCS) scores (76 ± 11) largely increased in contrast to pre-operative scores (51 ± 10), with both target indices having statistical significance (p = 0.005, p = 0.01), signifying hugely improvement of the quality of life of the patients. A correlation was found between Harris Hip Score and all dimensions of SF-36 scale (r = 0.32–0.72), especially closely correlated with physical functioning (PF), role-physical (RP) and bodily pain (BP) in PCS aspect (r = 0.72, p < 0.01; r = 0.58, p < 0.01; r = 0.65, p < 0.01, respectively).
There is definite curative efficacy for the treatment of ONFH with an hip-preserving operative approach by grafting a vascularized greater trochanter flap combined with a free iliac flap which was tightly filled by hammering. This kind of operative approach reconstructs the biological stability of femoral head, which promotes repair of necrotic areas and indirectly preserves the femoral head of patients and a majority of hip function. It possesses vast clinical as well as practical significance, because the long-term efficacy can satisfy fundamental life requirements, especially for those young and middle-aged patients who suffer ONFH to avoid or put off the time of total hip arthroplasty(THA) surgery.
PMCID: PMC3580089  PMID: 23340673
14.  hSSB1 regulates both the stability and the transcriptional activity of p53 
Cell Research  2012;23(3):423-435.
The tumor suppressor p53 is essential for several cellular processes that are involved in the response to diverse genotoxic stress, including cell cycle arrest, DNA repair, apoptosis and senescence. Studies of the regulation of p53 have mostly focused on its stability and transactivation; however, new regulatory molecules for p53 have also been frequently identified. Here, we report that human ssDNA binding protein SSB1 (hSSB1), a novel DNA damage-associated protein, can interact with p53 and protect p53 from ubiquitin-mediated degradation. Furthermore, hSSB1 also associates with the acetyltransferase p300 and is required for efficient transcriptional activation of the p53 target gene p21 by affecting the acetylation of p53 at lysine382. Functionally, the hSSB1 knockdown-induced abrogation of the G2/M checkpoint is partially dependent on p53 or p300. Collectively, our results indicate that hSSB1 may regulate DNA damage checkpoints by positively modulating p53 and its downstream target p21.
PMCID: PMC3587703  PMID: 23184057
hSSB1; p53; stability; transcriptional activity; acetylation
15.  Knockdown of miR-214 Promotes Apoptosis and Inhibits Cell Proliferation in Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(1):e86149.
MicroRNA-214 (MiR-214) is aberrantly expressed in several human tumors such as ovarian cancer and breast cancer. However, the role of miR-214 in nasopharyngeal carcinoma (NPC) is still unknown. In this study, we report that miR-214 was overexpressed in NPC cell lines and tissues. Silencing of miR-214 by LNA-antimiR-214 in NPC cells resulted in promoting apoptosis and suppressing cell proliferation in vitro, and suppressed tumor growth in nude mice in vivo. Luciferase reporter assay was performed to identify Bim as a direct target of miR-214. Furthermore, this study showed that low Bim expression in NPC tissues correlated with poor survival of NPC patients. Taken together, our findings suggest that miR-214 plays an important role in NPC carcinogenesis.
PMCID: PMC3897649  PMID: 24465927
16.  Towards Deeper Research and Better Policy for Healthy Aging --Using the Unique Data of Chinese Longitudinal Healthy Longevity Survey1 
China economic journal  2013;5(2-3):131-149.
The objectives of this review article are to facilitate deeper research and better policy analysis for healthy aging, which not only means surviving to old ages in good health, but also mean the economics and society of our country would be aging healthily, with sound policy and intervention programs. Toward these objectives, we introduce the Chinese Longitudinal Healthy Longevity Survey (CLHLS), which has been conducted by Center for Healthy Aging and Development Studies, National School of Development of Peking University since 1998. We present a comprehensive and summarized introduction of the CLHLS study design, sample distributions, contents, general quality assessment and availability of the CLHLS data collected. Such an introduction would be helpful for our colleagues who may be interested in using this unique and more-than-fourteen-year longitudinal survey data resource for deeper interdisciplinary research and better policy analysis on healthy aging. To illustrate how the unique data resources of CLHLS may be useful, we also summarize and discuss ten selected healthy aging policy related research based on data from the CLHLS. Finally, we discussed the future perspectives using the unique and rich CLHLS datasets.
PMCID: PMC3893304  PMID: 24443653
17.  Foxo3a transcription factor is a negative regulator of Skp2 and Skp2 SCF complex 
Oncogene  2012;32(1):78-85.
Skp2 SCF complex displays E3 ligase activity and oncogenic activity by regulating protein ubiquitination and degradation, in turn regulating cell cycle entry, senescence and tumorigenesis. The maintenance of the integrity of Skp2 SCF complex is critical for its E3 ligase activity. The Skp2 F-box protein is a rate-limiting step and key factor in this complex, which binds to its protein substrates and triggers ubiquitination and degradation of its substrates. Skp2 is found to be overexpressed in numerous human cancers, which plays an important role in tumorigenesis. The molecular mechanism by which the function of Skp2 and Skp2 SCF complex is regulated remains largely unknown. Here we show that Foxo3a transcription factor is a novel and negative regulator of Skp2 SCF complex. Foxo3a is found to be a transcriptional repressor of Skp2 gene expression by directly binding to the Skp2 promoter, thereby inhibiting Skp2 protein expression. Surprisingly, we found for the first time that Foxo3a also displays a transcription-independent activity by directly interacting with Skp2 and disrupting Skp2 SCF complex formation, in turn inhibiting Skp2 SCF E3 ligase activity and promoting p27 stability. Finally, we show that the oncogenic activity of Skp2 is repressed by Foxo3a overexpression. Our results not only reveal novel insights into how Skp2 SCF complex is regulated, but also establish a new role for Foxo3a in tumor suppression through a transcription-dependent and independent manner.
PMCID: PMC3536937  PMID: 22310285
18.  A Large Cohort Study Reveals the Association of Elevated Peripheral Blood Lymphocyte-to-Monocyte Ratio with Favorable Prognosis in Nasopharyngeal Carcinoma 
PLoS ONE  2013;8(12):e83069.
Nasopharyngeal carcinoma (NPC) is an endemic neoplasm in southern China. Although NPC sufferers are sensitive to radiotherapy, 20–30% of patients finally progress with recurrence and metastases. Elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with favorable prognosis in some hematology malignancies, but has not been studied in NPC. The aim of this study was to evaluate whether LMR could predict the prognosis of NPC patients.
A retrospective cohort of 1,547 non-metastatic NPC patients was recruited between January 2005 and June 2008. The counts for peripheral lymphocyte and monocyte were retrieved, and the LMR was calculated. Receiver operating characteristic curve analysis, univariate and multivariate COX proportional hazards analyses were applied to evaluate the associations of LMR with overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and loco-regional recurrence-free survival (LRRFS), respectively.
Univariate analysis revealed that higher LMR level (≥5.220) was significantly associated with superior OS, DFS and DMFS (P values <0.001). The higher lymphocyte count (≥2.145×109/L) was significantly associated with better OS (P = 0.002) and DMFS (P = 0.031), respectively, while the lower monocyte count (<0.475×109/L) was associated with better OS (P = 0.012), DFS (P = 0.011) and DMFS (P = 0.003), respectively. Multivariate Cox proportional hazard analysis showed that higher LMR level was a significantly independent predictor for superior OS (hazard ratio or HR  = 0.558, 95% confidence interval or 95% CI  = 0.417–0.748; P<0.001), DFS (HR  = 0.669, 95% CI  = 0.535–0.838; P<0.001) and DMFS (HR = 0.543, 95% CI  = 0.403–0.732; P<0.001), respectively. The advanced T and N stages were also independent indicators for worse OS, DFS, and DMFS, except that T stage showed borderline statistical significance for DFS (P = 0.053) and DMFS (P = 0.080).
The elevated pretreatment peripheral LMR level was a significant favorable factor for NPC prognosis and this easily accessed variable may serve as a potent marker to predict the outcomes of NPC patients.
PMCID: PMC3873908  PMID: 24386144
19.  Immunization of N terminus of enterovirus 71 VP4 elicits cross-protective antibody responses 
BMC Microbiology  2013;13:287.
Enterovirus 71 (EV71) is major cause of hand, foot and mouth disease. Large epidemics of EV71 infection have been recently reported in the Asian-Pacific region. Currently, no vaccine is available to prevent EV71 infection.
The peptide (VP4N20) consisting of the first 20 amino acids at the N-terminal of VP4 of EV71 genotype C4 were fused to hepatitis B core (HBcAg) protein. Expression of fusion proteins in E. coli resulted in the formation of chimeric virus-like particles (VLPs). Mice immunized with the chimeric VLPs elicited anti-VP4N20 antibody response. In vitro microneutralization experiments showed that anti-chimeric VLPs sera were able to neutralize not only EV71 of genotype C4 but also EV71 of genotype A. Neonatal mice model confirmed the neutralizing ability of anti-chimeric VLPs sera. Eiptope mapping led to the identification of a “core sequence” responsible for antibody recognition within the peptide.
Immunization of chimeric VLPs is able to elicit antibodies displaying a broad neutralizing activity against different genotypes of EV71 in vitro. The “core sequence” of EV71-VP4 is highly conserved across EV71 genotypes. The chimeric VLPs have a great potential to be a novel vaccine candidate with a broad cross-protection against different EV71 genotypes.
PMCID: PMC4029445  PMID: 24320792
Enterovirus 71; Vaccine; VP4; Peptide; Chimeric virus-like particle
20.  Common genetic variants of the β2-adrenergic receptor affect its translational efficiency and are associated with human longevity 
Aging cell  2012;11(6):1094-1101.
β-adrenoceptors are the common pharmacological targets for the treatment of cardiovascular diseases and asthma. Genetic modifications of β-adrenergic system in engineered mice affect their lifespans. Here we tested whether genes encoding for key components of the β-adrenergic signaling pathway are associated with human longevity. We performed a 10-year follow-up study of the Chinese longitudinal healthy longevity survey. The Han Chinese population in this study consisted of 963 long-lived and 1028 geography matched young individuals. Sixteen SNPs from ADRB1, ADRB2, ADCY5, ADCY6, and MAPK1 were selected and genotyped. Two SNPs, rs1042718 (C/A) and rs1042719 (G/C), of ADRB2 in linkage disequilibrium (D′ = 1.0; r2 = 0.67) were found to be associated with enhanced longevity in males in two geographically isolated populations. Bonferroni corrected p values in a combined analysis were 0.00053–0.010. Men with haplotype A-C showed an increased probability to become centenarians (the frequency of A-C in long-lived and young individuals are 0.332 and 0.250, respectively, OR = 1.49, CI95% = 1.17–1.88, p = 0.0007), in contrast to those with haplotype C-G (the frequency of C-G in long-lived and young individuals are 0.523 and 0.635, respectively, OR = 0.63, CI95% = 0.51–0.78, p = 0.000018). The permuted p values were 0.00005 and 0.0009, respectively. ADRB2 encodes the β2-adrenergic receptor; the haplotype A-C markedly reduced its translational efficiency compared to C-G (p = 0.002) in transfected HEK293 cells. Thus, our data indicate that enhanced production of β2-adrenergic receptors caused by genetic variants is inversely associated with human lifespan.
PMCID: PMC3633790  PMID: 23020224
β2-adrenergic receptor; single nucleotide polymorphism; haplotype; longevity; translational efficiency
21.  Centrifugation: an important pre-analytic procedure that influences plasma microRNA quantification during blood processing 
Chinese Journal of Cancer  2013;32(12):667-672.
Circulating microRNAs are robustly present in plasma or serum and have become a research focus as biomarkers for tumor diagnosis and prognosis. Centrifugation is a necessary procedure for obtaining high-quality blood supernatant. Herein, we investigated one-step and two-step centrifugations, two centrifugal methods routinely used in microRNA study, to explore their effects on plasma microRNA quantification. The microRNAs obtained from one-step and two-step centrifugations were quantified by microarray and TaqMan-based real-time quantitative polymerase chain reaction (Q-PCR). Dynamic light scattering was performed to explore the difference underlying the two centrifugal methods. The results from the microarray containing 1,347 microRNAs showed that the signal detection rate was greatly decreased in the plasma sample prepared by two-step centrifugation. More importantly, the microRNAs missing in this plasma sample could be recovered and detected in the precipitate generated from the second centrifugation. Consistent with the results from microarray, a marked decrease of three representative microRNAs in two-step centrifugal plasma was validated by Q-PCR. According to the size distribution of all nanoparticles in plasma, there were fewer nanoparticles with size >1,000 nm in two-step centrifugal plasma. Our experiments directly demonstrated that different centrifugation methods produced distinct quantities of plasma microRNAs. Thus, exosomes or protein complexes containing microRNAs may be involved in large nanoparticle formation and may be precipitated after two-step centrifugation. Our results remind us that sample processing methods should be first considered in conducting research.
PMCID: PMC3870851  PMID: 23601242
Centrifugation; microRNA quantification; one-step centrifugation; two-step centrifugation
22.  A Multistate Life Table Analysis of Union Regimes in the United States: Trends and Racial Differentials, 1970–2002 
Population research and policy review  2011;31(2):10.1007/s11113-011-9217-2.
We estimate trends and racial differentials in marriage, cohabitation, union formation and dissolution (union regimes) for the period 1970–2002 in the United States. These estimates are based on an innovative application of multistate life table analysis to pooled survey data. Our analysis demonstrates (1) a dramatic increase in the lifetime proportions of transitions from never-married, divorced or widowed to cohabiting; (2) a substantial decrease in the stability of cohabiting unions; (3) a dramatic increase in mean ages at cohabiting after divorce and widowhood; (4) a substantial decrease in direct transition from never-married to married; (5) a significant decrease in the overall lifetime proportion of ever marrying and re-marrying in the 1970s to 1980s but a relatively stable pattern in the 1990s to 2000–2002; and (6) a substantial decrease in the lifetime proportion of transition from cohabiting to marriage. We also present, for the first time, comparable evidence on differentials in union regimes between four racial groups.
PMCID: PMC3810991  PMID: 24179311
Multistate life table; Cohabitation; Union dissolution; Marriage; Divorce; Racial differentials
23.  Relationship between birth size and coronary heart disease in China 
Annals of medicine  2010;42(8):596-602.
Clinical epidemiological studies suggested a link between fetal growth conditions and later coronary heart disease (CHD) in adult life. However, no such studies have been conducted in a Chinese population.
We investigated the association between various birth characteristics and CHD occurrence in a Chinese cohort.
Retrospective cohort study.
Peking Union Medical College Hospital, Beijing, China.
A total of 2,033 subjects who were born at Peking Union Medical College Hospital between 1921 and 1954.
Neonatal birth-weight, placental weight, length from crown to heel, head circumference, and biparietal and occipitofrontal diameters were routinely recorded at the time of birth. All participants were followed up between May 2002 and April 2004 for the occurrence of CHD.
CHD was identified in 135 patients. The occurrence of CHD was inversely related to birth sizes, such as birth-weight, head circumference, placental weight (P < 0.05), but was not significantly related to birth length or ponderal index (birth-weight/birth length3). After multivariable logistic regression, the ratio of birth-weight to birth length was an independent predictor of CHD along with two other variables: obesity and age.
This was a single-center retrospective study.
In China low birth size or birth disproportion, which is suggestive of fetal growth retardation, has an effect on CHD occurrence during adulthood. This suggests that environmental factors operate in both the prenatal and postnatal periods with regard to the development of CHD.
PMCID: PMC3787846  PMID: 20828358
Birth size; coronary artery disease; fetal growth retardation; risk factors
24.  Detection of persistent organic pollutants binding modes with androgen receptor ligand binding domain by docking and molecular dynamics 
Persistent organic pollutants (POPs) are persistent in the environment after release from industrial compounds, combustion productions or pesticides. The exposure of POPs has been related to various reproductive disturbances, such as reduced semen quality, testicular cancer, and imbalanced sex ratio. Among POPs, dichlorodiphenyldichloroethylene (4,4’-DDE) and polychlorinated biphenyls (PCBs) are the most widespread and well-studied compounds. Recent studies have revealed that 4,4’-DDE is an antagonist of androgen receptor (AR). However, the mechanism of the inhibition remains elusive. CB-153 is the most common congener of PCBs, while the action of CB-153 on AR is still under debate.
Molecular docking and molecular dynamics (MD) approaches have been employed to study binding modes and inhibition mechanism of 4,4’-DDE and CB-153 against AR ligand binding domain (LBD). Several potential binding sites have been detected and analyzed. One possible binding site is the same binding site of AR natural ligand androgen 5α-dihydrotestosterone (DHT). Another one is on the ligand-dependent transcriptional activation function (AF2) region, which is crucial for the co-activators recruitment. Besides, a novel possible binding site was observed for POPs with low binding free energy with the receptor. Detailed interactions between ligands and the receptor have been represented. The disrupting mechanism of POPs against AR has also been discussed.
POPs disrupt the function of AR through binding to three possible biding sites on AR/LBD. One of them shares the same binding site of natural ligand of AR. Another one is on AF2 region. The third one is in a cleft near N-terminal of the receptor. Significantly, values of binding free energy of POPs with AR/LBD are comparable to that of natural ligand androgen DHT.
PMCID: PMC3848780  PMID: 24053684
Persistent organic pollutants; Androgen receptor; Molecular docking; Molecular dynamics; MM/PBSA
25.  Interactions between Social/ behavioral factors and ADRB2 genotypes may be associated with health at advanced ages in China 
BMC Geriatrics  2013;13:91.
Existing literature indicates that ADRB2 gene is associated with health and longevity, but none of previous studies investigated associations of carrying the ADRB2 minor alleles and interactions between ADRB2 genotypes and social/behavioral factors(GxE) with health outcomes at advanced ages. This study intends to fill in this research gap.
We conducted an exploratory analysis, using longitudinal survey phenotype/genotype data from 877 oldest-old aged 90+. To estimate association of GxE interactions with health outcome, adjusted for the potential correlation between genotypes and social/behavioral factors and various other potentially confounding factors, we develop and test an innovative three-step procedure which combines logistic regression and structural equation methods.
Interaction between regular exercise and carrying rs1042718 minor allele is significantly and positively associated with good cognitive function; interaction between regular exercise and carrying rs1042718 or rs1042719 minor allele is significantly and positively associated with self-reported good health; and interaction between social-leisure activities and carrying rs1042719 minor allele is significantly and positively associated with self-reported good health. Carrying rs1042718 or rs1042719 minor alleles is significantly and negatively associated with negative emotion, but the ADRB2 SNPs are not significantly associated with cognitive function and self-reported health. Our structural equation analysis found that, adjusted for the confounding effects of correlation of the ADRB2 SNPs with negative emotion, interaction between negative emotion and carrying rs1042718 or rs1042719 minor allele is significantly and negatively associated with cognitive function. The positive association of regular exercise and social-leisure activities with cognitive function and self-reported health, and negative association of negative emotion with cognitive function, were much stronger among carriers of rs1042718 or rs1042719 alleles, compared to the non-carriers.
The results indicate significant positive associations of interactions between social/behavioral factors and the ADRB2 genotypes with health outcomes of cognitive function and self-reported health, and negative associations of carrying rs1042718 or rs1042719 minor alleles with negative emotion, at advanced ages in China. Our findings are exploratory rather than causal conclusions. This study implies that near-future health promotion programs considering individuals’ genetic profiles, with appropriate protection of privacy/confidentiality, would yield increased benefits and reduced costs to the programs and their participants.
PMCID: PMC3846634  PMID: 24016068
Health aging; Oldest-old; Social/behavioral factors; ADRB2 genotypes; GxE Interactions; Cognitive function; Self-reported health; Regular exercise; Social-leisure activities; Negative emotion

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