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1.  A General Semiparametric Hazards Regression Model: Efficient Estimation and Structure Selection 
Statistics in medicine  2013;32(28):4980-4994.
We consider a general semiparametric hazards regression model that encompasses Cox’s proportional hazards model and the accelerated failure time model for survival analysis. To overcome the nonexistence of the maximum likelihood, we derive a kernel-smoothed profile likelihood function, and prove that the resulting estimates of the regression parameters are consistent and achieve semiparametric efficiency. In addition, we develop penalized structure selection techniques to determine which covariates constitute the accelerate failure time model and which covariates constitute the proportional hazards model. The proposed method is able to estimate the model structure consistently and model parameters efficiently. Furthermore, variance estimation is straightforward. The proposed estimation performs well in simulation studies and is applied to the analysis of a real data set. Copyright
PMCID: PMC3913752  PMID: 23824784
Accelerated failure time model; Cox’s proportional hazards model; Efficiency; Kernel-smoothed profile likelihood function; Model selection; Penalized likelihood
2.  Non-Neuronal Release of Gamma-Aminobutyric Acid by Embryonic Pluripotent Stem Cells 
Stem Cells and Development  2013;22(22):2944-2953.
γ-Aminobutyric acid (GABA), the principle inhibitory transmitter in the mature central nervous system, is also involved in activities outside the nervous system. Recent studies have shown that functional GABA receptors are expressed in embryonic stem (ES) cells and these receptors control ES cell proliferation. However, it is not clear whether ES cells have their own GABAergic transmission output machinery that can fulfill GABA release or whether the cells merely process the GABA receptors by receiving and responding to the diffused GABA released elsewhere. To get further insight into this unresolved problem, we detected the repertoire of components for GABA synthesis, storage, reaction, and termination in ES and embryonal carcinoma stem cells by biological assays, and then directly quantified released GABA in the intercellular milieu from these pluripotent stem (PS) cells by an analytical chemical assay based on high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). We found that embryonic PS cells processed a GABAergic circuit machinery and spontaneously released GABA, which suggests the potential that embryonic PS cells could autonomously establish a GABA niche via release of the transmitter.
PMCID: PMC3822375  PMID: 23799822
3.  Skp2 deletion unmasks a p27 safeguard that blocks tumorigenesis in the absence of pRb and p53 tumor suppressors 
Cancer cell  2013;24(5):10.1016/j.ccr.2013.09.021.
pRb and p53 are two major tumor suppressors. Here, we found that p53 activates expression of Pirh2 and KPC1, two of the three ubiquitin ligases for p27. Loss of p53 in the absence of Skp2, the third ubiquitin ligase for p27, shrinks the cellular pool of p27 ubiquitin ligases to accumulate p27 protein. In the absence of pRb and p53, p27 was unable to inhibit DNA synthesis in spite of its abundance, but could inhibit division of cells that maintain DNA replication with re-replication. This mechanism blocked pRb and p53 doubly deficient pituitary and prostate tumorigenesis lastingly coexistent with BrdU-labeling neoplastic lesions, revealing an unconventional cancer cell vulnerability when pRb and p53 are inactivated.
PMCID: PMC3880806  PMID: 24229711
4.  A chronic obstructive pulmonary disease negatively influences the prognosis of patients with bladder urothelial carcinoma via hypoxia inducible factor-1α 
Objective: In this study, we investigated the relationship between the expression of hypoxia inducible factor-1α (HIF-1α) and tumor hypoxia, which is caused by chronic hypoxemic hypoxia in chronic obstructive pulmonary disease (COPD), and the prognostic value of COPD in patients with bladder urothelial carcinoma (BUC). Methods: The clinicopathological variables of 80 patients with BUC who underwent surgery were analyzed by retrospective methods. Overall survival (OS), disease-specific survival (DSS) and progression-free survival (PFS) were analyzed with clinicopathological variables including concomitant COPD, pulmonary function test (PFT), serum hemoglobin level and smoking history, using Kaplan-Meier survival analysis. The Cox proportional hazards regression model was used for multivariate analysis. The localization of HIF-1α expression was analyzed by immunohistochemistry. Results: Both the median OS and PFS of patients with COPD were shorter than the patients without COPD (P < 0.001). High levels of HIF-1α expression were associated with BUC of higher clinicopathological stage and histological grade (P < 0.001). COPD was an independent prognostic variable for OS, PFS and DSS. The clinicopathological stage was an independent prognostic variable for OS and DSS. The level of HIF-1α expression was an independent prognostic variable for PFS. Conclusions: COPD is an independent prognostic variable for BUC, and contributes to poor prognosis.
PMCID: PMC4238552  PMID: 25419367
Bladder urothelial carcinoma; chronic obstructive pulmonary disease; chronic hypoxia; hypoxia inducible factor-1α; prognosis
5.  Interpolation of Longitudinal Shape and Image Data via Optimal Mass Transport 
Longitudinal analysis of medical imaging data has become central to the study of many disorders. Unfortunately, various constraints (study design, patient availability, technological limitations) restrict the acquisition of data to only a few time points, limiting the study of continuous disease/treatment progression. Having the ability to produce a sensible time interpolation of the data can lead to improved analysis, such as intuitive visualizations of anatomical changes, or the creation of more samples to improve statistical analysis. In this work, we model interpolation of medical image data, in particular shape data, using the theory of optimal mass transport (OMT), which can construct a continuous transition from two time points while preserving “mass” (e.g., image intensity, shape volume) during the transition. The theory even allows a short extrapolation in time and may help predict short-term treatment impact or disease progression on anatomical structure. We apply the proposed method to the hippocampus-amygdala complex in schizophrenia, the heart in atrial fibrillation, and full head MR images in traumatic brain injury.
PMCID: PMC4187117  PMID: 25302008
6.  Osteogenic fate of hypertrophic chondrocytes 
Cell Research  2014;24(10):1266-1269.
PMCID: PMC4185343  PMID: 25145361
7.  Skp2 suppresses apoptosis in Rb1 deficient tumors by limiting E2F1 activity 
Nature communications  2014;5:3463.
One mechanism of tumor suppression by pRb is repressing E2F1. Hence, E2f1 deletion diminishes tumorigenesis following Rb1 loss. However, E2F1 promotes both proliferation and apoptosis. It therefore remains unclear how de-repressed E2F1 promotes tumorigenesis. Another mechanism of pRb function is repressing Skp2 to elevate p27 to arrest proliferation. However, Skp2 deletion induced apoptosis, not proliferation arrest, in Rb1 deficient pituitary tumorigenesis. Here, we show that Rb1 deletion induces higher expression of E2F1 target genes in the absence of Skp2. E2F1 binds less cyclin A but more target promoters when Rb1 is deleted with Skp2 knockout or p27T187A knockin, suggesting that stabilized p27 prevents cyclin A from binding and inhibiting E2F1. In Rb1 deficient pituitary tumorigenesis, Skp2 deletion or p27T187A mutation converts E2F1’s role from proliferative to apoptotic. These findings delineate a pRb-Skp2-p27-cyclin A-E2F1 pathway that determines whether E2F1 is proliferative or apoptotic in Rb1 deficient tumorigenesis.
PMCID: PMC3982150  PMID: 24632684
Skp2 ubiquitin ligase; Rb1 tumor suppressor; E2F1 transcription factor; cyclin A; p27
8.  Circulating tumor cells in the central and peripheral venous compartment – assessing hematogenous dissemination after transarterial chemoembolization of hepatocellular carcinoma 
OncoTargets and therapy  2014;7:1311-1318.
The aims of this study were to assess the effect of transarterial chemoembolization (TACE) on circulating tumor cells (CTCs) in the peripheral blood and right atrium of patients with HCC and to evaluate whether perioperative shedding of CTCs affects time to progression of HCC. Before and after TACE, peripheral and right atrial blood samples (7.5 mL) were collected from 42 patients with HCC. CTCs were enriched using EpCAM antibody-conjugated magnetic beads. The number of CTCs was 0–30 and 0–54 in peripheral blood before and after TACE, respectively (P=0.166), and 0–65 and 0–98 in the right atrium before and after TACE, respectively (P=0.102). The number of CTCs was significantly different between the two samples both before (P=0.007) and after (P=0.021) TACE. There was no difference in time to progression between patients with and without an increase in the number of CTCs after TACE in either sample (P>0.05 for both). There were more CTCs in right atrial blood than in peripheral blood. The numbers of CTCs in both samples remained unchanged after TACE. Shedding of tumor cells did not affect time to progression of disease in patients with HCC.
PMCID: PMC4111660  PMID: 25071374
hepatocellular carcinoma; transcatheter arterial chemoembolization; circulating tumor cells; metastasis; positive screening
9.  Survivor Typologies Predict Medical Surveillance Participation: The Childhood Cancer Survivor Study 
Psycho-oncology  2012;22(7):1534-1542.
Adult survivors of childhood cancer adhere poorly to recommended medical surveillance. We sought to identify modifiable factors that contribute to non-adherence.
Latent class analysis categorized survivors (ages 18–52 years) at risk of cardiac, breast, or bone late sequelae on the basis of their health-related concerns, fears, and motivation. These classifications were compared at two time points for self-reported adherence to recommended echocardiography, mammography, and bone densitometry screening.
Three classes (worried, collaborative, self-controlling) characterized survivors in each of the 3 risk groups: cardiac (N=564; BIC=10,824.66; LRMLRT P=.002), breast (N=584; BIC=11,779.97, LRMLRT P<.001), and bone (N=613; BIC=11,773.56; LMRLRT P=.028). Only 9% of at-risk survivors in the self-controlling class reported undergoing bone density screening in 2005, compared to 17.2% in the collaborative class (P=.034). Thirteen percent of the self-controlling, 24% of the collaborative (P=.025), and 34% of the worried (P=.010) classes reported undergoing bone densitometry in 2009. While 73% of at-risk survivors in the worried class reported having had an echocardiogram in 2009, only 57% of the collaborative (P=.040) and 43% of the self-controlling (P<.001) classes did. In 2005 and 2009, respectively, fewer survivors in the self-controlling class (37% and 53%) than in the collaborative (51%, P=.038 and 70%, P=.01) and worried (58%, P=0.002 and 69%, P=0.025) classes reported undergoing mammograms.
Modifiable intrapersonal characteristics associated with these 3 classes predict self-reported participation in medical surveillance. Continued observation and validation of these survivor profiles may inform tailored interventions to enhance survivors’ screening participation.
PMCID: PMC3548022  PMID: 22968964
childhood cancer; screening; late effects; pediatric oncology
10.  Knockdown of Aurora-B inhibits osteosarcoma cell invasion and migration via modulating PI3K/Akt/NF-κB signaling pathway 
Increasing evidences reveal that Aurora-B may be involved in metastasis of malignant tumor. In this study, we investigated the inhibitory effect of Aurora-B on invasion and migration of OS cells and the activity of PI3K/Akt/NF-κB signaling pathway in vitro. The expression of Aurora-B and p-Akt (Ser473) proteins was detected by immunohistochemistry in OS tissues from 24 patients with pulmonary metastatic disease, and the relationship between Aurora-B and p-Akt was investigated. The results showed that there was a positive correlation between Aurora-B and p-Akt protein expression. Furthermore, we down-regulated the expression of Aurora-B through a recombinant lentivirus (Lv-shAURKB). Migration and invasion of cells were investigated by wound healing and transwell invasion assays. Results showed that silencing Aurora-B inhibited cell migratory and invasive ability of OS cells in vitro. Finally, knockdown of Aurora-B suppresses the activity of PI3K/Akt/NF-κB signaling pathway in OS cells. Our results indicated that knockdown of Aurora-B suppresses OS cells migratory and invasive ability via modulating the “PI3K/Akt/NF-κB” signaling pathway in vitro. The Aurora-B blocker may be a new therapeutic strategy in OS management.
PMCID: PMC4129010  PMID: 25120775
Osteosarcoma; Aurora-B; invasion and migration; PI3K/Akt/NF-κB signaling pathway
11.  Fluconazole Assists Berberine To Kill Fluconazole-Resistant Candida albicans 
Antimicrobial Agents and Chemotherapy  2013;57(12):6016-6027.
It was found in our previous study that berberine (BBR) and fluconazole (FLC) used concomitantly exhibited a synergism against FLC-resistant Candida albicans in vitro. The aim of the present study was to clarify how BBR and FLC worked synergistically and the underlying mechanism. Antifungal time-kill curves indicated that the synergistic effect of the two drugs was BBR dose dependent rather than FLC dose dependent. In addition, we found that BBR accumulated in C. albicans cells, especially in the nucleus, and resulted in cell cycle arrest and significant change in the transcription of cell cycle-related genes. Besides BBR, other DNA intercalators, including methylene blue, sanguinarine, and acridine orange, were all found to synergize with FLC against FLC-resistant C. albicans. Detection of intracellular BBR accumulation by fluorescence measurement showed that FLC played a role in increasing intracellular BBR concentration, probably due to its effect in disrupting the fungal cell membrane. Similar to the case with FLC, other antifungal agents acting on the cell membrane were able to synergize with BBR. Interestingly, we found that the efflux of intracellular BBR was FLC independent but strongly glucose dependent and associated with the drug efflux pump Cdr2p. These results suggest that BBR plays a major antifungal role in the synergism of FLC and BBR, while FLC plays a role in increasing the intracellular BBR concentration.
PMCID: PMC3837902  PMID: 24060867
12.  Statistical analysis of mixed recurrent event data with application to cancer survivor study 
Statistics in medicine  2012;32(11):10.1002/sim.5674.
Event history studies occur in many fields including economics, medical studies and social science. In such studies concerning some recurrent events, two types of data have been extensively discussed in the literature. One is recurrent event data that arise if study subjects are monitored or observed continuously. In this case, the observed information provides the times of all occurrences of the recurrent events of interest. The other is panel count data, which occur if the subjects are monitored or observed only periodically. This can happen if the continuous observation is too expensive or not practical and in this case, only the numbers of occurrences of the events between subsequent observation times are available. In this paper, we discuss a third type of data, which is a mixture of recurrent event and panel count data and for which there exists little literature. For regression analysis of such data, a marginal mean model is presented and we propose an estimating equation-based approach for estimation of regression parameters. A simulation study is conducted to assess the finite sample performance of the proposed methodology and indicates that it works well for practical situations. Finally it is applied to a motivating study on childhood cancer survivors.
PMCID: PMC3884548  PMID: 23139023
Childhood cancer survivor study; Estimating equation-based approach; Regression analysis
13.  Lack of Specificity of Plasma Concentrations of Inhibin B and Follicle-Stimulating Hormone for Identification of Azoospermic Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(10):1324-1328.
Many male survivors of childhood cancer are at risk for azoospermia. Although both the levels of follicle-stimulating hormone (FSH) and inhibin B are correlated with sperm concentration, their ability to predict azoospermia in survivors of childhood cancer remains uncertain.
Patients and Methods
Semen analysis was performed and serum levels of FSH and inhibin B were measured in 275 adult male survivors of childhood cancer who had received gonadotoxic therapy. Receiver operating characteristic (ROC) analysis was performed to determine the optimal inhibin B and FSH values for identifying patients with azoospermia. The patient sample was divided into a learning set and a validation set. Sensitivity, specificity, and positive and negative predictive value were calculated.
Inhibin B was dichotomized as ≤ 31 ng/L or more than 31 ng/L and FSH was dichotomized as ≤ 11.5 mIU/mL or more than 11.5 mIU/mL based on results of the ROC analysis. Using these values, the specificity of the serum level of inhibin B for identifying azoospermic survivors was 45.0%, and the positive predictive value was 52.1%. The specificity for FSH was 74.1%, and the positive predictive value was 65.1%.
Neither serum inhibin B nor FSH is a suitable surrogate for determination of sperm concentration in a semen sample. Young men and their physicians should be aware of the limitations of these measures for assessment of fertility potential.
PMCID: PMC3607671  PMID: 23423746
14.  β-catenin is overexpressed in hepatic fibrosis and blockage of Wnt/β-catenin signaling inhibits hepatic stellate cell activation 
Molecular Medicine Reports  2014;9(6):2145-2151.
β-catenin, a core component of Wnt/β-catenin signaling, has been shown to be an important regulator of cellular proliferation and differentiation. Abnormal activation of Wnt/β-catenin signaling promotes tissue fibrogenesis. In the present study, the role of β-catenin during liver fibrogenesis was analyzed and the functional effects of β-catenin gene silencing in hepatic stellate cells (HSCs) using small interfering (si)RNA were investigated. The expression of β-catenin in human hepatic fibrosis tissues of different grades and normal human hepatic tissues was examined using immunohistochemistry. To inhibit the Wnt/β-catenin signaling pathway, siRNA for β-catenin was developed and transiently transfected into HSC-T6 cells using Lipofectamine 2000. β-catenin expression was evaluated by quantitative polymerase chain reaction (qPCR) and western blot analysis. The expression of collagen types I and III was evaluated by qPCR and immunofluorescent staining. Cellular proliferation and the cell cycle were analyzed using a methyl thiazolyl tetrazolium assay. Apoptosis was assessed by Annexin V staining. A higher expression level of β-catenin was identified in the patients with high-grade hepatic fibrosis in comparison with that of the normal controls. Additionally, β-catenin siRNA molecules were successfully transfected into HSCs and induced inhibition of β-catenin expression in a time-dependent manner. β-catenin siRNA treatment also inhibited synthesis of collagen types I and I in transfected HSCs. Furthermore, compared with those of the control group, siRNA-mediated knockdown of β-catenin in HSC-T6 cells inhibited cell proliferation and resulted in cell apoptosis. This study suggests a significant functional role for β-catenin in the development of liver fibrosis and demonstrates that downregulation of the Wnt/β-catenin signaling pathway inhibits HSC activation. Thus, this study provides a novel strategy for the treatment of hepatic fibrosis.
PMCID: PMC4055486  PMID: 24691643
hepatic fibrosis; β-catenin; hepatic stellate cells; RNA interference
15.  mAChRs activation induces epithelial-mesenchymal transition on lung epithelial cells 
Epithelial-mesenchymal transition (EMT) has been proposed as a mechanism in the progression of airway diseases and cancer. Here, we explored the role of acetylcholine (ACh) and the pathway involved in the process of EMT, as well as the effects of mAChRs antagonist.
Human lung epithelial cells were stimulated with carbachol, an analogue of ACh, and epithelial and mesenchymal marker proteins were evaluated using western blot and immunofluorescence analyses.
Decreased E-cadherin expression and increased vimentin and α-SMA expression induced by TGF-β1 in alveolar epithelial cell (A549) were significantly abrogated by the non-selective mAChR antagonist atropine and enhanced by the acetylcholinesterase inhibitor physostigmine. An EMT event also occurred in response to physostigmine alone. Furthermore, ChAT express and ACh release by A549 cells were enhanced by TGF-β1. Interestingly, ACh analogue carbachol also induced EMT in A549 cells as well as in bronchial epithelial cells (16HBE) in a time- and concentration-dependent manner, the induction of carbachol was abrogated by selective antagonist of M1 (pirenzepine) and M3 (4-DAMP) mAChRs, but not by M2 (methoctramine) antagonist. Moreover, carbachol induced TGF-β1 production from A549 cells concomitantly with the EMT process. Carbachol-induced EMT occurred through phosphorylation of Smad2/3 and ERK, which was inhibited by pirenzepine and 4-DAMP.
Our findings for the first time indicated that mAChR activation, perhaps via M1 and M3 mAChR, induced lung epithelial cells to undergo EMT and provided insights into novel therapeutic strategies for airway diseases in which lung remodeling occurs.
PMCID: PMC3975135  PMID: 24678619
Epithelial-mesenchymal transition (EMT); Lung epithelial cells; Non-neuronal cholinergic system; Signaling pathway
16.  RelB regulates Bcl-xl expression and the irradiation-induced apoptosis of murine prostate cancer cells 
Biomedical Reports  2014;2(3):354-358.
Apoptosis in prostate cancer (PCa) induced by ionizing radiation (IR) is believed to play a critical role in radioresistance. Bcl-xl, an important member of the anti-apoptotic Bcl-2 family, has critical roles in tumor progression and development. The aim of the present study was to investigate the association of Bcl-xl expression and radiosensitivity from murine PCa RM-1 cells. An adenovirus-mediated RNA interference technique was employed to inhibit the expression of the RelB gene. RelB proteins were detected upon irradiation following transfection with small interfering (si)RelB, as shown by western blot analysis. The radiosensitivity of the RM-1 cells was determined by clonogenic assays. The apoptosis of the RM-1 cells were detected by flow cytometry assay, then quantitative polymerase chain reaction assays were performed to determine the expression level of Bcl-xl mRNA in the RM-1 cells. Radiation treatment increased the RelB protein levels from the cytosol and nucleus in the RM-1 cells. The protein expression levels of RelB in the pLentilox-sh-RelB-transfected RM-1 cells were significantly lower than in the negative interference group following radiation treatment. The percentage of cells undergoing apoptosis in the siRelB-RM-1 group was significantly higher than that in the control group following radiation treatment. Finally, a positive link between Bcl-xl expression and RelB activity was established in the RM-1 cells. Inhibition of RelB correlates with a decrease in expression of Bcl-xl. In conclusion, adenovirus-mediated siRNA targeting RelB inhibits Bcl-xl expression, enhances radiosensitivity and regulates the irradiation-induced apoptosis of the murine PCa RM-1 cell line.
PMCID: PMC4022971  PMID: 24839547
RNA interference; RelB; Bcl-xl; radiosensitivity; prostate cancer
17.  Para-Aminobenzoic Acid (PABA) Synthase Enhances Thermotolerance of Mushroom Agaricus bisporus 
PLoS ONE  2014;9(3):e91298.
Most mushrooms are thermo-sensitive to temperatures over 23°C, which greatly restricts their agricultural cultivation. Understanding mushroom’s innate heat-tolerance mechanisms may facilitate genetic improvements of their thermotolerance. Agaricus bisporus strain 02 is a relatively thermotolerant mushroom strain, while strain 8213 is quite thermo-sensitive. Here, we compared their responses at proteomic level to heat treatment at 33°C. We identified 73 proteins that are differentially expressed between 02 and 8213 or induced upon heat stress in strain 02 itself, 48 of which with a known identity. Among them, 4 proteins are constitutively more highly expressed in 02 than 8213; and they can be further upregulated in response to heat stress in 02, but not in 8213. One protein is encoded by the para-aminobenzoic acid (PABA) synthase gene Pabs, which has been shown to scavenge the reactive oxygen species in vitro. Pabs mRNA and its chemical product PABA show similar heat stress induction pattern as PABA synthase protein and are more abundant in 02, indicating transcriptional level upregulation of Pabs upon heat stress. A specific inhibitor of PABA synthesis impaired thermotolerance of 02, while exogenous PABA or transgenic overexpression of 02 derived PABA synthase enhanced thermotolerance of 8213. Furthermore, compared to 8213, 02 accumulated less H2O2 but more defense-related proteins (e.g., HSPs and Chitinase) under heat stress. Together, these results demonstrate a role of PABA in enhancing mushroom thermotolerance by removing H2O2 and elevating defense-related proteins.
PMCID: PMC3948851  PMID: 24614118
18.  The effects of China’s urban basic medical insurance schemes on the equity of health service utilisation: evidence from Shaanxi Province 
In order to alleviate the problem of “Kan Bing Nan, Kan Bing Gui” (medical treatment is difficult to access and expensive) and improve the equity of health service utilisation for urban residents in China, the Urban Employee Basic Medical Insurance scheme (UEBMI) and Urban Resident Basic Medical Insurance scheme (URBMI) were established in 1999 and 2007, respectively. This study aims to analyse the effects of UEBMI and URBMI on the equity of outpatient and inpatient utilisation in Shaanxi Province, China.
Using the data from the fourth National Health Services Survey in Shaanxi Province, the method of Propensity Score Matching was employed to generate comparable samples between the insured and uninsured residents, through a one-to-one match algorithm. Next, based on the matched data, the method of decomposition of the concentration index was employed to compare the horizontal inequity indexes of health service utilisation between the UEBMI/URBMI insured and the matched uninsured residents.
For the UEBMI insured and matched uninsured residents, the horizontal inequity indexes of outpatient visits are 0.1256 and -0.0511 respectively, and the horizontal inequity indexes of inpatient visits are 0.1222 and 0.2746 respectively. Meanwhile, the horizontal inequity indexes of outpatient visits are -0.1593 and 0.0967 for the URBMI insured and matched uninsured residents, and the horizontal inequity indexes of inpatient visits are 0.1931 and 0.3199 respectively.
The implementation of UEBMI increased the pro-rich inequity of outpatient utilisation (rich people utilise outpatient facilities more than the poor people) and the implementation of URBMI increased the pro-poor inequity of outpatient utilisation. Both of these two health insurance schemes reduced the pro-rich inequity of inpatient utilisation.
PMCID: PMC4016277  PMID: 24606592
19.  Significance of peripheral neutrophil-lymphocyte ratio among gastric cancer patients and construction of a treatment-predictive model: a study based on 1131 cases 
Gastric cancer (GC) is one of the most common and deadly malignancies nowadays, and inflammatory cells are closely related to tumor progression. This prospective study aims to uncover clinical significance of peripheral immune cells and build a treatment-predictive model. From July 2006 to July 2011, a total of 1131 GC patients were selected, with their general characteristics, peripheral blood and pathological parameters, and operational information obtained. The relevancies between preoperational neutrophil-lymphocyte ratio (NLR) and postsurgical pathological indexes were analyzed. SPSS 17.0 was applied in data analysis, comparing the differences of NLR between different groups using Mann-Whitney U test, contrasting the pathological differences between NLR elevated and reduced groups using Fisher test, and quantifying the correlation between post-surgical pathology and pre-operational NLR using univariate analysis. Patients were then classified into radical (applied in the training dataset) and non-radical gastrectomy (applied in the test dataset) groups, based on which we further tried to build a predictive model indicating appropriateness for radical resection using support vector machine (SVM). We found that: patients with tumor invading out of the myometrium (pT3-4) had significantly larger NLR than those with lesion limited within the myometrium (pT1-2) (P<0.05); poorly differentiated and undifferentiated malignancies were associated with higher NLR than well and moderately differentiated ones (P<0.05); there was larger NLR among patients with tumor length ≥4 cm than those <4 cm (P<0.01); preoperative NLR was significantly positively correlated with tumor TNM classification, number of metastatic lymph nodes, invasive depth and tumor size (P<0.05); larger proportion of elevated NLR was significantly associated with larger tumor size, later tumor and nodal stages, and higher TNM classification (P<0.01). We finally built a SVM model based on peripheral carcinoembryonic antigen, carbohydrate antigen 19-9, lymphocyte percentage and platelet count, effectively predicting the inappropriateness of patients undergoing curative gastrectomy when all the 4 parameters elevated with high accuracy (74.61% for the training dataset and 75.28% for the test dataset). We concluded that peripheral blood NLR indicated tumor progression, and that an efficient treatment-predictive SVM model was constructed.
PMCID: PMC3960456  PMID: 24660108
Gastric carcinoma; neutrophil-lymphocyte ratio; support vector machine; gastrectomy; tumor progression
20.  Increased Tricuspid Regurgitant Jet Velocity by Doppler Echocardiography in Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(6):774-781.
To determine the prevalence of pulmonary hypertension, a late effect of cancer therapy not previously identified in aging survivors of childhood cancer, and associations with chest-directed radiation therapy (RT) and measures of current cardiac function, lung function, and exercise capacity.
Patients and Methods
Cross-sectional evaluation of 498 survivors at a median age of 38.0 years (range, 20.0 to 59.0 years) and a median of 27.3 years (range, 12.2 to 46.0 years) from primary cancer diagnosis was performed. Abnormal tricuspid regurgitant jet velocity (TRV) was defined as more than 2.8 m/s by Doppler echocardiography.
Increased TRV was identified in 25.2% of survivors who received chest-directed RT and 30.8% of those who received more than 30 Gy. In multivariable models, increased TRV was associated with increasing dose of RT (1 to 19.9 Gy: odds ratio [OR], 2.09; 95% CI, 0.63 to 6.96; 20 to 29.9 Gy: OR, 3.46; 95% CI, 1.59 to 7.54; ≥ 30 Gy: OR, 4.54; 95% CI, 1.77 to 11.64 compared with no RT; P for trend < .001), body mass index more than 40 kg/m2 (OR, 3.89; 95% CI, 1.46 to 10.39), and aortic valve regurgitation (OR, 5.85; 95% CI, 2.05 to 16.74). Survivors with a TRV more than 2.8 m/s had increased odds (OR, 5.20; 95% CI, 2.5 to 11.0) of severe functional limitation on a 6-minute walk compared with survivors with a TRV ≤ 2.8 m/s.
A substantial number of adult survivors of childhood cancer who received chest-directed RT have an increased TRV and may have pulmonary hypertension as a result of both direct lung injury and cardiac dysfunction. Longitudinal follow-up and confirmation by cardiac catheterization are warranted.
PMCID: PMC3574270  PMID: 23295810
21.  Recoverability Analysis for Modified Compressive Sensing with Partially Known Support 
PLoS ONE  2014;9(2):e87985.
The recently proposed modified-compressive sensing (modified-CS), which utilizes the partially known support as prior knowledge, significantly improves the performance of recovering sparse signals. However, modified-CS depends heavily on the reliability of the known support. An important problem, which must be studied further, is the recoverability of modified-CS when the known support contains a number of errors. In this letter, we analyze the recoverability of modified-CS in a stochastic framework. A sufficient and necessary condition is established for exact recovery of a sparse signal. Utilizing this condition, the recovery probability that reflects the recoverability of modified-CS can be computed explicitly for a sparse signal with nonzero entries. Simulation experiments have been carried out to validate our theoretical results.
PMCID: PMC3919832  PMID: 24520341
22.  Upregulation of a spliced variant of human interferon regulatory factor 3 through binding of the transcription factor Sp1 to the promoter 
Biomedical Reports  2013;2(1):142-146.
Interferon regulatory factor 3 (IRF-3) plays an important role in host defense against viral and bacterial infection. IRF-3 includes a variety of spliced variants, which may regulate the transcription of IRF-3. We previously identified two novel IRF-3 spliced variants, Int2V1 and Int2V2, starting from intron 2 of the wild-type of IRF-3. However, the mechanism through which the IRF-3 spliced variants regulate transcription has not been elucidated. In this study, we demonstrated that the transcription factor Sp1 upregulates the basal transcriptional activity of IRF-3 Int2V1. By transient transfection analysis, we demonstrated that the overexpression of Sp1 led to positive regulation, whereas knocking down of the endogenous Sp1 resulted in repression of IRF-3 promoter activity. Electrophoretic gel mobility shift assays and chromatin immunoprecipitation assays demonstrated that Sp1 interacted with the IRF-3 promoter in vitro and in vivo. These results suggested that Sp1 positively regulated the transcription of a spliced variant of IRF-3 through directly binding to the Sp1 consensus binding site.
PMCID: PMC3917023  PMID: 24649086
interferon regulatory factor 3; spliced variant; transcription; Sp1; reporter gene assay
23.  Transcatheter arterial embolization promotes liver tumor metastasis by increasing the population of circulating tumor cells 
OncoTargets and therapy  2013;6:1563-1572.
Transcatheter arterial embolization (TAE) is widely used as an effective palliative treatment for hepatocellular carcinoma (HCC), and can prolong survival time. However, the high incidence of tumor recurrence and metastasis after TAE is still a major problem. Recent studies demonstrated that circulating tumor cells (CTCs) contribute to tumor metastasis. In this study, we tried to clarify whether the residual HCC after TAE can increase metastasis by increasing the number of CTCs. An orthotopic liver tumor model in the Buffalo rat was established using green fluorescent protein (GFP)-transfected HCC cell line, McA-RH7777. Two weeks after orthotopic liver tumor implantation, the rats underwent TAE treatment from the gastroduodenal artery. Iodized oil or saline was injected intra-arterially. Blood samples were taken on day 0, 1, 3, 7, 14, and 21 for detection of CTCs after TAE treatment. We analyzed the number of CTCs and assessed the metastatic potential of surviving tumor cells in rats between TAE and control groups. Our results demonstrated that the metastatic colonies in the lung were significantly increased by TAE treatment. The number of CTCs was also significantly increased by TAE treatment from day 7 to day 21. The expression of hypoxia-inducible factor (HIF)-1α and epithelial–mesenchymal transition (EMT) marker proteins (N-cadherin and vimentin) was upregulated, but E-cadherin was downregulated after TAE treatment. In conclusion, the metastatic potential of residual HCC can be induced by TAE treatment in a rat liver tumor model, which involves the acquisition of EMT features and an increased number of CTCs.
PMCID: PMC3821789  PMID: 24235842
transcatheter arterial embolization; hepatocellular carcinoma; circulating tumor cells; epithelial–mesenchymal transition
24.  All-Trans Retinoic Acid Modulates ORMDL3 Expression via Transcriptional Regulation 
PLoS ONE  2013;8(10):e77304.
All-trans retinoic acid (ATRA) is an active metabolite of Vitamin A, it shows protective effects on asthma, including maintains airway epithelial integrity, inhibits asthma effector cells differentiation, modulates immune response, et al. However, the promoting effect of ATRA on Th2 response has restricted the clinical application of ATRA in asthma treatment. ORMDL3 is a candidate gene of childhood onset asthma, and high-transcript of ORMDL3 is associated with the development of asthma. Here we show that ATRA increases ORMDL3 production in vitro via inducing PKA-dependent CREB phosphorylation which in turn binds to the CRE element in promoter region of ORMDL3 and initiates ORMDL3 transcription. This finding is in consistent with the previous reports that ATRA could regulate target genes without the presence of retinoic acid response element (RARE) in promoter region but through other signals such as PKA/CREB. Nevertheless, in the present study, the traditional signal pathway of ATRA, retinoic acid receptor (RAR) signal transduction pathway, indirectly modulated ORMDL3 expression. RAR-α agonist (Am-80) increased ORMDL3 production even though there was no RARE in ORMDL3 promoter, introns or 3′-downstream region. Besides, the signal of RAR might differ from that of ATRA since Am-80 failed to induce CREB activation. In conclusion, our data indicate that ATRA facilitates ORMDL3 production probable through PKA/CREB, and this may be a starting point for more detailed mechanism researches on ATRA and asthma.
PMCID: PMC3812219  PMID: 24204796
25.  Neurocognitive Function and CNS Integrity in Adult Survivors of Childhood Hodgkin Lymphoma  
Journal of Clinical Oncology  2012;30(29):3618-3624.
Long-term survivors of childhood Hodgkin lymphoma (HL) are at risk for cardiopulmonary complications and CNS stroke, although neurocognitive function has not been previously examined. The aim of this study was to examine neurocognitive and brain imaging outcomes in adult survivors of childhood HL.
Patients and Methods
In all, 62 adult survivors (mean age, 42.2 years; standard deviation [SD], 4.77; mean age at diagnosis, 15.1 years; SD, 3.30) were identified by stratified random selection from a large cohort treated with either high-dose (≥ 30 Gy) thoracic radiation (n = 38) or lower-dose (< 30 Gy) thoracic radiation combined with anthracycline (n = 24). Patients underwent neurocognitive evaluations, brain magnetic resonance imaging (MRI), echocardiograms, pulmonary function tests, and physical examinations.
Compared with national age-adjusted norms, HL survivors demonstrated lower performance on sustained attention (P = .004), short-term memory (P = .001), long-term memory (P = .006), working memory (P < .001), naming speed (P < .001), and cognitive fluency (P = .007). MRI revealed leukoencephalopathy in 53% of survivors, and 37% had evidence of cerebrovascular injury. Higher thoracic radiation dose was associated with impaired cardiac diastolic function (E/E′; ratio of peak mitral flow velocity of early rapid filling [E] to early diastolic velocity of the mitral annulus [E′]; P = .003), impaired pulmonary function (diffusing capacity of lungs for carbon monoxide [DLcocorr; P = .04), and leukoencephalopathy (P = .02). Survivors with leukoencephalopathy demonstrated reduced cognitive fluency (P = .001). Working memory impairment was associated with E/E′, although impaired sustained attention and naming speed were associated with DLcocorr. Neurocognitive performance was associated with academic and vocational functioning.
These results suggest that adult long-term survivors of childhood HL are at risk for neurocognitive impairment, which is associated with radiologic indices suggestive of reduced brain integrity and which occurs in the presence of symptoms of cardiopulmonary dysfunction.
PMCID: PMC3462045  PMID: 22949149

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