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1.  Expression of Cystatin SN significantly correlates with recurrence, metastasis, and survival duration in surgically resected non-small cell lung cancer patients 
Scientific Reports  2015;5:8230.
Cystatin SN has been considered to be involved in human cancer, but its clinical significance in non-small cell lung cancer (NSCLC) has not been elucidated. The aim of this study was to evaluate the clinical value of Cystatin SN expression in patients with surgically resected NSCLCs. A retrospective analysis of 174 patients with surgically resected NSCLCs from April 2002 to March 2005 was performed with immunohistochemistry and fluorescence in situ hybridization to analyze the protein expression and amplification of Cystatin SN. The associations between Cystatin SN expression and recurrence, metastasis, and survival were investigated. In recurrence and metastasis analysis, compared with low-Cystatin SN expression NSCLCs, high expression tumors were more likely to recur and metastasize (P < 0.001). Disease-free survival (DFS) and overall survival (OS) were significantly prolonged in the low-Cystatin SN expression subgroup compared with the high-Cystatin SN expression subgroup (DFS, P < 0.001; OS, P = 0.001). A multivariate analysis confirmed that high expression of Cystatin SN was associated with poor survival (DFS, P = 0.001; OS, P = 0.006) and was an independent prognostic indicator. The present study indicates that high expression of Cystatin SN is a significant prognostic indicator of a higher rate of recurrence, metastatic risk, and poor survival in patients with surgically resected NSCLCs.
PMCID: PMC4316172  PMID: 25648368
2.  A GEE Approach to Determine Sample Size for Pre- and Post-Intervention Experiments with Dropout 
Computational statistics & data analysis  2014;69:10.1016/j.csda.2013.07.037.
Pre- and post-intervention experiments are widely used in medical and social behavioral studies, where each subject is supposed to contribute a pair of observations. In this paper we investigate sample size requirement for a scenario frequently encountered by practitioners: All enrolled subjects participate in the pre-intervention phase of study, but some of them will drop out due to various reasons, thus resulting in missing values in the post-intervention measurements. Traditional sample size calculation based on the McNemar’s test could not accommodate missing data. Through the GEE approach, we derive a closed-form sample size formula that properly accounts for the impact of partial observations. We demonstrate that when there is no missing data, the proposed sample size estimate under the GEE approach is very close to that under the McNemar’s test. When there is missing data, the proposed method can lead to substantial saving in sample size. Simulation studies and an example are presented.
PMCID: PMC3842849  PMID: 24293779
3.  Placental Adaptations in Growth Restriction 
Nutrients  2015;7(1):360-389.
The placenta is the primary interface between the fetus and mother and plays an important role in maintaining fetal development and growth by facilitating the transfer of substrates and participating in modulating the maternal immune response to prevent immunological rejection of the conceptus. The major substrates required for fetal growth include oxygen, glucose, amino acids and fatty acids, and their transport processes depend on morphological characteristics of the placenta, such as placental size, morphology, blood flow and vascularity. Other factors including insulin-like growth factors, apoptosis, autophagy and glucocorticoid exposure also affect placental growth and substrate transport capacity. Intrauterine growth restriction (IUGR) is often a consequence of insufficiency, and is associated with a high incidence of perinatal morbidity and mortality, as well as increased risk of cardiovascular and metabolic diseases in later life. Several different experimental methods have been used to induce placental insufficiency and IUGR in animal models and a range of factors that regulate placental growth and substrate transport capacity have been demonstrated. While no model system completely recapitulates human IUGR, these animal models allow us to carefully dissect cellular and molecular mechanisms to improve our understanding and facilitate development of therapeutic interventions.
PMCID: PMC4303845  PMID: 25580812
placental morphology; vascularity; substrate transport; IUGR
4.  Hospitalization for Invasive Pneumococcal Disease in a National Sample of Children with Sickle Cell Disease Before and After PCV7 Licensure 
Pediatric blood & cancer  2011;58(6):945-949.
To estimate national hospitalization rates for invasive pneumococcal disease (IPD) in children with sickle cell disease (SCD) before and after the 2000 licensure of the heptavalent pneumococcal conjugate vaccine (PCV7).
We performed a retrospective trend analysis of the 1994-2007 Nationwide Inpatient Sample databases. Hospitalizations involving children with SCD and IPD were identified by ICD-9CM code. The primary outcomes, the annual hospitalization rate for IPD in children with SCD and the proportion of hospitalizations for IPD per 100 total SCD hospitalizations, were analyzed using multivariable linear regression and contingency analysis, respectively.
A total of 1,242 hospitalizations for IPD in SCD patients were identified from 1994-2007, with a mortality rate of 2.4%. The national mean annual rate of IPD hospitalization decreased by 65%, from 131.8 cases/year from 1994-2000 to 45.5 cases/year from 2001-2007 (p=0.001). The national proportion of hospitalizations for IPD per 100 total SCD hospitalizations decreased from 0.4 to 0.15 (p<0.0001) over the same interval. Following PCV7 licensure, the mean annual cumulative hospital days and cumulative hospital charges decreased nationally by 53% and 36%, respectively.
In a national sample, PCV7 licensure is temporally associated with a nearly three fold reduction in IPD hospitalizations in children with SCD.
PMCID: PMC4248562  PMID: 21793185
sickle cell disease; PCV7; Streptococcus pneumoniae; infection; hospitalization
5.  Hospital volume, hospital teaching status, patient socioeconomic status, and outcomes in patients hospitalized with sickle cell disease 
American journal of hematology  2011;86(4):377-380.
Sickle cell disease (SCD) accounts for ~100,000 hospitalizations in the US annually. Quality of care for hospitalized SCD patients has been insufficiently studied. Therefore, we aimed to examine whether four potential determinants of quality care, [1] hospital volume, [2] hospital teaching status, [3] patient socioeconomic status (SES), and [4] patient insurance status are associated with three quality indicators for patients with SCD: [1] mortality, [2] length of stay (LOS), and [3] hospitalization costs. We conducted an analysis of the 2003–2005 Nationwide Inpatient Sample (NIS) datasets. We identified cases using all ICD-9CM codes for SCD. Both overall and SCD-specific hospital volumes were examined. Multivariable analyses included mixed linear models to examine LOS and costs, and logistic regression to examine mortality. About 71,481 SCD discharges occurred from 2003 to 2005. Four hundred and twenty five patients died, yielding a mortality rate of 0.6%. Multivariable analyses revealed that SCD patients admitted to lower SCD-specific volume hospitals had [1] increased adjusted odds of mortality (quintiles 1–4 vs. quintile 5: OR, 1.36; 95% CI, 1.05, 1.76) and [2] decreased LOS (quintiles 1–4 vs. quintile 5, effect estimate −0.08; 95% CI, −0.12, −0.04). These are the first data describing associations between lower SCD-specific hospital volumes and poorer outcomes.
PMCID: PMC4250088  PMID: 21442644
6.  National Trends in Incidence Rates of Hospitalization for Stroke in Children With Sickle Cell Disease 
Pediatric blood & cancer  2012;60(5):823-827.
The success of primary stroke prevention for children with sickle cell disease (SCD) throughout the United States is unknown. Therefore, we aimed to generate national incidence rates of hospitalization for stroke in children with sickle cell disease (SCD) before and after publication of the Stroke Prevention Trial in Sickle Cell Anemia (STOP trial) in 1998.
We performed a retrospective trend analysis of the 1993–2009 Nationwide Inpatient Sample and Kids’ Inpatient Databases. Hospitalizations for SCD patients 0–18 years old with stroke were identified by ICD-9CM code. The primary outcome, the trend in annual incidence rate of hospitalization for stroke in children with SCD, was analyzed by linear regression. Incidence rates of hospitalization for stroke before and after 1998 were compared by the Wilcoxon rank-sum test.
From 1993 to 2009, 2,024 hospitalizations were identified for stroke. Using the mean annual incidence rate of hospitalization for stroke from 1993 to 1998 as the baseline, the rate decreased from 1993 to 2009 (point estimate = −0.022/100 patient years [95% CI, −0.039, −0.005], P = 0.027). The mean annual incidence rate of hospitalization stroke decreased by 45% from 0.51 per 100 patient years in 1993–1998 to 0.28 per 100 patient years in 1999–2009 (P = 0.008). Total hospital days and charges attributed to stroke also decreased by 45% and 24%, respectively.
After publication of the STOP trial and hydroxyurea licensure in 1998, the incidence of hospitalization for stroke in children with SCD decreased across the United States, suggesting that primary stroke prevention has been effective nationwide, but opportunity for improvement remains.
PMCID: PMC4250091  PMID: 23151905
hospitalization; sickle cell disease; stroke
7.  A comparative study of short- and long-TE 1H-MRS at 3T for in-vivo detection of 2-hydroxyglutarate in brain tumors 
NMR in biomedicine  2013;26(10):1242-1250.
2-hydroxyglutarate (2HG) is produced in gliomas with mutations of isocitrate dehydrogenases (IDH) 1 and 2. The 1H resonances of the J-coupled spins of 2HG are extensively overlapped with signals from other metabolites. Here we report a comparative study at 3T of the utility of the PRESS (point-resolved spectroscopy) sequence with a standard short TE (35 ms) and a long TE (97 ms) which had been theoretically designed for detecting the 2HG 2.25 ppm resonance. The performance of the methods is evaluated using data from phantoms, 7 healthy volunteers, and 22 subjects with IDH-mutated gliomas. The results indicate that TE = 97 ms provides higher detectability of 2HG than TE = 35 ms, and that this improved capability is gained when data are analyzed with basis spectra that include the effects of the volume localizing radio-frequency and gradient pulses.
PMCID: PMC3733061  PMID: 23592268
2-Hydroxyglutarate (2HG); 1H MRS; 3T; Point-resolved spectroscopy (PRESS); Short/Long TE; Volume-localized simulations; Human brain; IDH-mutated gliomas
8.  Spontaneous Brain Activity in Type 2 Diabetics Revealed by Amplitude of Low-Frequency Fluctuations and Its Association with Diabetic Vascular Disease: A Resting-State fMRI Study 
PLoS ONE  2014;9(10):e108883.
To investigate correlations between altered spontaneous brain activity, diabetic vascular disease, and cognitive function for patients with type 2 diabetes mellitus (T2DM) using resting-state functional magnetic resonance imaging (rs-fMRI).
Rs-fMRI was performed for T2DM patients (n = 26) and age-, gender-, and education-matched non-diabetic control subjects (n = 26). Amplitude of low frequency fluctuations (ALFF) were computed from fMRI signals to measure spontaneous neuronal activity. Differences in the ALFF patterns between patients and controls, as well as their correlations with clinical variables, were evaluated.
Compared with healthy controls, T2DM patients exhibited significantly decreased ALFF values mainly in the frontal and parietal lobes, the bilateral thalumi, the posterior lobe of the cerebellum, and increased ALFF values mainly in the visual cortices. Furthermore, lower ALFF values in the left subcallosal gyrus correlated with lower ankle-brachial index values (r = 0.481, p = 0.020), while lower ALFF values in the bilateral medial prefrontal gyri correlated with higher urinary albumin-creatinine ratio (r = −0.418, p = 0.047). In addition, most of the regions with increased ALFF values in the visual cortices were found to negatively correlate with MoCA scores.
These results confirm that ALFF are altered in many brain regions in T2DM patients, and this is associated with the presence of diabetic vascular disease and poor cognitive performance. These findings may provide additional insight into the neurophysiological mechanisms that mediate T2DM-related cognitive dysfunction, and may also serve as a reference for future research.
PMCID: PMC4182760  PMID: 25272033
9.  The RADAR Study: Week 48 Safety and Efficacy of RAltegravir Combined with Boosted DARunavir Compared to Tenofovir/Emtricitabine Combined with Boosted Darunavir in Antiretroviral-Naive Patients. Impact on Bone Health 
PLoS ONE  2014;9(8):e106221.
NRTI-sparing regimens may avoid long-term mitochondrial, bone and renal toxicities and maintain viral suppression.
In the RADAR study, 85 antiretroviral-naïve HIV-infected patients were randomized to receive either raltegravir (RAL) (n = 42) or tenofovir/emtricitabine (TDF/FTC) (n = 43), each with ritonavir-boosted darunavir (DRV/r). Virologic efficacy was assessed at weeks 24 and 48. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry (DXA) scan at baseline and week 48, and bone turnover markers (BTM) assessed at weeks 0, 16 and 48.
Using an intention-to-treat analysis, 62.5% of RAL subjects and 83.7% of TDF/FTC subjects were responders (VL<48 copies/mL) at week 48 (p = 0.045; chi-square test). The proportions of patients achieving VL<200 copies/mL were similar: 72.5% and 86.0% (p = 0.175). Premature treatment discontinuation was the main cause for failure. No treatment-emergent resistance was observed. Changes from baseline in RAL vs. TDF/FTC for CD4+ (+199 vs. +216 cells/µL, p = 0.63), total cholesterol/HDL (−0.25 vs. −0.71 mg/dL (p = 0.270), and eGFR (−4.4 vs. −7.9 ml/min, p = 0.44) were comparable between groups. Changes in subtotal BMD to week 48 were: +9.2 with RAL vs. −7 g/cm2 with TDF/FTC (p = 0.002). Mean CTX changes were +0.04 vs. +0.24 ng/mL (p = 0.001), and mean P1NP changes were +3.59 vs. +30.09 ng/mL (p = 0.023). BTM changes at week 16 predicted change in BMD by week 48 (R = −0.394, p = 0.003 for CTX; and R = −0.477, p<0.001 for P1NP).
The NRTI-sparing regimen RAL+DRV/r did not achieve similar week 48 virologic efficacy compared with TDF/FTC+DRV/r, but was better with regard to markers of bone health.
Trial Registration NCT 00677300
PMCID: PMC4149560  PMID: 25170938
10.  Human Infection with West Nile Virus, Xinjiang, China, 2011 
Emerging Infectious Diseases  2014;20(8):1421-1423.
PMCID: PMC4111179  PMID: 25062043
West Nile virus; viruses; human infection; encephalitis; Xinjiang; China
11.  Meta-Analysis of EGFR Tyrosine Kinase Inhibitors Compared with Chemotherapy as Second-Line Treatment in Pretreated Advanced Non-Small Cell Lung Cancer 
PLoS ONE  2014;9(7):e102777.
Since efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) versus chemotherapy in the treatment of patients with pretreated advanced non-small cell lung cancer (NSCLC) remain controversial, we performed a meta-analysis to compare them.
An internet search of several databases was performed, including PubMed, Embase, and the Cochrane database. Randomized trials that compared an EGFR-TKI with chemotherapy in the second-line setting were included. The outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade 3–4 toxicities. The PFS, OS for the EGFR mutation-positive (EGFR M+) and EGFR mutation-negative (EGFR M−) subgroups were pooled. The pooled hazard ratios (HRs) and odds ratios (ORs) with their corresponding confidence intervals (CIs) were calculated on the STATA software.
Our meta-analysis combined 3,825 patients from 10 randomized trials. Overall, EGFR-TKIs and second-line chemotherapy have equivalent efficacy in terms of PFS (HR, 1.03; 95%CI, 0.87–1.21; P = 0.73; I2 = 78.7%, Pheterogeneity<0.001), OS (HR, 1.00; 95%CI, 0.92–1.08; P = 0.90; I2 = 0.0%, Pheterogeneity = 0.88), and ORR (OR, 1.34; 95%CI, 0.86–2.08; P = 0.20; I2 = 73.1%, Pheterogeneity<0.001). However, subgroup analysis based on EGFR mutation status showed that second-line chemotherapy significantly improved PFS (HR, 1.35; 95%CI, 1.09–1.66; P = 0.01; I2 = 55.7%, Pheterogeneity = 0.046) for EGFR M− patients, whereas OS was equal (HR, 0.96; 95%CI, 0.77–1.19; P = 0.69; I2 = 0.0%, Pheterogeneity = 0.43); EGFR-TKIs significantly improved PFS (HR, 0.28; 95%CI, 0.15–0.53; P<0.001; I2 = 4.1%, Pheterogeneity = 0.35) for EGFR M+ patients, whereas OS was equal (HR, 0.86; 95%CI, 0.44–1.68; P = 0.65; I2 = 0.0%, Pheterogeneity = 0.77). Compared with chemotherapy, EGFR-TKIs led to more grade 3–4 rash, but less fatigue/asthenia disorder, leukopenia and thrombocytopenia.
Our analysis suggests that chemotherapy in the second-line setting can prolong PFS in EGFR M− patients, whereas it has no impact on OS. EGFR-TKIs seem superior over chemotherapy as second-line therapy for EGFR M+ patients. Our findings support obtaining information on EGFR mutational status before initiation of second-line treatment.
PMCID: PMC4100920  PMID: 25029199
13.  Pattern of Diagnostic Evaluation for the Causes of Pediatric Acute Liver Failure: An Opportunity for Quality Improvement 
The Journal of pediatrics  2009;155(6):801-806.e1.
To describe the frequency of diagnostic testing for the 4 most common causes of pediatric acute liver failure (PALF) (drugs, metabolic disease, autoimmune process, and infections) in indeterminate PALF within the PALF Study Group Database.
Study design
PALF was defined by severe hepatic dysfunction within 8 weeks of onset of illness, with no known underlying chronic liver disease in patients from birth through 17 years of age.
Of the 703 patients in the database, 329 (47%) had indeterminate PALF. In this group, a drug history was obtained in 325 (99%) urine toxicology screenings performed in 118 (36%) and acetaminophen level measured in 124 (38%) patients. No testing for common metabolic diseases was done in 179 (54%) patients. Anti-nuclear antibody, anti-smooth muscle antibody, and anti-liver kidney microsomal autoantibodies associated with autoimmunity were determined in 239 (73%), 233 (71%), and 208 (63%) patients, and no tests were obtained in 70 (21%). Testing was performed for hepatitis A virus, hepatitis B virus, and Epstein Barr virus in 80%, 86%, and 68%, respectively.
Current practice indicates that investigation for metabolic and autoimmune causes of PALF are infrequent in patients ultimately given a diagnosis of indeterminate acute liver failure. This offers an opportunity to improve diagnosis and potential treatment options in children with acute liver failure.
PMCID: PMC4035352  PMID: 19643443
14.  Hybrid Magnetic Cross-Linked Enzyme Aggregates of Phenylalanine Ammonia Lyase from Rhodotorula glutinis 
PLoS ONE  2014;9(5):e97221.
Novel hybrid magnetic cross-linked enzyme aggregates of phenylalanine ammonia lyase (HM-PAL-CLEAs) were developed by co-aggregation of enzyme aggregates with magnetite nanoparticles and subsequent crosslinking with glutaraldehyde. The HM-PAL-CLEAs can be easily separated from the reaction mixture by using an external magnetic field. Analysis by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) indicated that PAL-CLEAs were inlayed in nanoparticle aggregates. The HM-PAL-CLEAs revealed a broader limit in optimal pH compared to free enzyme and PAL-CLEAs. Although there is no big difference in Km of enzyme in CLEAs and HM-PAL-CLEAs, Vmax of HM-PAL-CLEAs is about 1.75 times higher than that of CLEAs. Compared with free enzyme and PAL-CLEAs, the HM-PAL-CLEAs also exhibited the highest thermal stability, denaturant stability and storage stability. The HM-PAL-CLEAs retained 30% initial activity even after 11 cycles of reuse, whereas PAL-CLEAs retained 35% of its initial activity only after 7 cycles. These results indicated that hybrid magnetic CLEAs technology might be used as a feasible and efficient solution for improving properties of immobilized enzyme in industrial application.
PMCID: PMC4019550  PMID: 24825453
15.  A Bayesian Extension of the Hypergeometric Test for Functional Enrichment Analysis 
Biometrics  2013;70(1):84-94.
Functional enrichment analysis is conducted on high-throughput data to provide functional interpretation for a list of genes or proteins that share a common property, such as being differentially expressed (DE). The hypergeometric P-value has been widely used to investigate whether genes from pre-defined functional terms, e.g., Gene Ontology (GO), are enriched in the DE genes. The hypergeometric P-value has three limitations: 1) computed independently for each term, thus neglecting biological dependence; 2) subject to a size constraint that leads to the tendency of selecting less-specific terms; 3) repeated use of information due to overlapping annotations by the true-path rule. We propose a Bayesian approach based on the non-central hypergeometric model. The GO dependence structure is incorporated through a prior on non-centrality parameters. The likelihood function does not include overlapping information. The inference about enrichment is based on posterior probabilities that do not have a size constraint. This method can detect moderate but consistent enrichment signals and identify sets of closely-related and biologically-meaningful functional terms rather than isolated terms. We also describe the basic ideas of assumption and implementation of different methods to provide some theoretical insights, which are demonstrated via a simulation study. A real application is presented.
PMCID: PMC3954234  PMID: 24320951
Functional enrichment analysis; Modular enrichment analysis; Hypergeometric P- value; Non-central hypergeometric distribution; Gene ontology
16.  IgG, IgM, and IgA Antinuclear Antibodies in Discoid and Systemic Lupus Erythematosus Patients 
The Scientific World Journal  2014;2014:171028.
IgG antinuclear antibodies (ANAs) are elevated in patients with systemic lupus erythematosus (SLE) compared with patients with discoid lupus erythematosus (DLE). To provide an expanded immunologic view of circulating ANAs in lupus patients, we compared the expressions of IgG, IgM, and IgA ANAs in DLE and SLE patients. In this cross-sectional study, sera from age-, gender-, and ethnic-matched SLE (N = 35), DLE (N = 23), and normal patients (N = 22) were tested for IgG, IgM, and IgA ANAs using enzyme-linked immunosorbent assays (ELISAs) and indirect immunofluorescence (IIF) with monkey esophagus as substrate. ELISAs showed elevated levels of IgG ANA, IgM ANA, and IgG/IgM ANA ratios in SLE patients compared with DLE and normal patients. IgA ANA expression was higher in SLE and DLE patients versus normal patients. IIF studies showed higher percentages of patients positive for IgG, IgM, and IgA ANAs in the SLE group. Higher IgG/IgM ANA ratios in SLE than DLE show enhanced class-switching and a more sustained humoral response in SLE. They also suggest a potential connection of IgM ANAs with disease containment.
PMCID: PMC3972853  PMID: 24741342
17.  Immunophenotype predicts outcome in pediatric acute liver failure 
We sought to determine if markers of T cell immune activation, including soluble interleukin 2 receptor alpha (sIL2Rα) levels predict outcome in pediatric acute liver failure (PALF) and might target potential candidates for immunomodulatory therapy.
We analyzed markers of immune activation in 77 patients with PALF enrolled in a multi-national, multi-center study. The outcomes were survival with native liver, liver transplantation, and death without transplantation within 21 days after enrollment.
Adjusting for multiple comparisons, only normalized serum sIL2Rα level differed significantly among the 3 outcomes, and was significantly higher in patients who died (p=0.02) or underwent liver transplantation (p=0.01) compared to those who survived with their native liver. The 37 patients with normal sIL2Rα levels all lived, 30 with their native liver. Of the 15 subjects with markedly high sIL2Rα (≥5000 IU/mL), 5 survived with their native liver, 2 died, and 8 underwent liver transplantation.
Evidence of immune activation is present in some patients who die or undergo liver transplantation. Patients with higher sIL2Rα levels were more likely to die or undergo liver transplantation within 21 days than those with lower levels. Identifying a subset of patients at risk for poor outcome may form the foundation for targeted clinical trials with immunomodulatory drugs.
PMCID: PMC3582763  PMID: 23111765
acute liver failure; sIL2Rα; immune activation; outcome
18.  3D absolute shape measurement of live rabbit hearts with a superfast two-frequency phase-shifting technique 
Optics Express  2013;21(5):5822-5832.
This paper presents a two-frequency binary phase-shifting technique to measure three-dimensional (3D) absolute shape of beating rabbit hearts. Due to the low contrast of the cardiac surface, the projector and the camera must remain focused, which poses challenges for any existing binary method where the measurement accuracy is low. To conquer this challenge, this paper proposes to utilize the optimal pulse width modulation (OPWM) technique to generate high-frequency fringe patterns, and the error-diffusion dithering technique to produce low-frequency fringe patterns. Furthermore, this paper will show that fringe patterns produced with blue light provide the best quality measurements compared to fringe patterns generated with red or green light; and the minimum data acquisition speed for high quality measurements is around 800 Hz for a rabbit heart beating at 180 beats per minute.
PMCID: PMC3601735  PMID: 23482151
(120.0120) Instrumentation, measurement, and metrology; (110.6880) Three-dimensional image acquisition; (320.7100) Ultrafast measurements; (120.5050) Phase measurement
19.  Association between serum homocysteine and arterial stiffness in elderly: a community-based study 
Arterial stiffness and homocysteine are both powerful predictors of cardiovascular disease, especially in older populations. Previous studies have investigated the association of homocysteine with arterial stiffness in human subjects, while the relationship between homocysteine and arterial stiffness in the elderly is still indefinite. The current study examined the association of homocysteine with arterial stiffness in Chinese community-based elderly persons.
We related serum levels of homocysteine to two measures of arterial stiffness (carotid-femoral pulse wave velocity (PWV) and carotid-radial PWV) in 780 participants (46.3% men, mean age 71.9 years (ranging 65–96 years old)) from two communities of Beijing, China. Arterial stiffness was measured within two days of the time of biomarker measurement.
In multiple-adjusted models, homocysteine levels were strongly associated with the carotid-femoral PWV (standardized β = 0.13, P < 0.001), even after adjustment for classical risk factors of cardiovascular disease. The association is also stronger when the carotid-femoral PWV is elevated above normal, whereas no significant association with homocysteine was observed for carotid-radial PWV.
In Chinese elderly persons, serum homocysteine levels are associated with alterations of aortic stiffness.
PMCID: PMC3981981  PMID: 24748879
The elderly; Homocysteine; Arterial stiffness; Pulse wave velocity
20.  Therapeutic Benefit of Bone Marrow–Derived Endothelial Progenitor Cell Transplantation after Experimental Aneurysm Embolization with Coil in Rats 
PLoS ONE  2014;9(2):e90069.
Aneurysm embolization with coil is now widely used clinically. However, the recurrence of aneurysms after embolization has always plagued neurosurgeons because the endothelial layer of the aneurysm neck loses its integrity after being embolized by coil. Bone marrow–derived endothelial progenitor cells (BM-EPCs) could be incorporated into injured endothelium and differentiate into mature endothelial cells during vascular repairing processes. The aim of our study is to explore the effects of BM-EPCs on aneurysm repairing and remodeling in a rat embolization model of abdominal aortic aneurysm. BM-EPC proliferation, migration and tube formation were not affected by super-paramagnetic iron oxide nanoparticle (SPIO) labeling compared to the controls (p>0.05). The number of SPIO-labeled cells greatly increased in EPC transplanted rats compared to that of phosphate buffered saline treated rats. SPIO-labeled EPC (SPIO-EPC) are mainly located in the aneurysm neck and surrounded by fibrous tissue. A histology study showed that the aneurysm orifice was closed with neointima and the aneurysm was filled with newly formed fibrous tissue. The SPIO-EPC accumulated in the aneurysm neck, which accelerated focal fibrous tissue remodeling, suggesting that BM-EPCs play a crucial role in repairing and remodeling the aneurysm neck orifice.
PMCID: PMC3938595  PMID: 24587209
21.  Sample Size Calculation for Comparing Time-Averaged Responses in K-Group Repeated-Measurement Studies 
Many clinical trials compare the efficacy of K (≥3) treatments in repeated measurement studies. However, the design of such trials have received relatively less attention from researchers. Zhang & Ahn (2012) derived a closed-form sample size formula for two-sample comparisons of time-averaged responses using the generalized estimating equation (GEE) approach, which takes into account different correlation structures and missing data patterns. In this paper, we extend the sample size formula to scenarios where K (≥3) treatments are compared simultaneously to detect time-averaged differences in treatment effect. A closed-form sample size formula based on the noncentral χ2 test statistic is derived. We conduct simulation studies to assess the performance of the proposed sample size formula under various correlation structures from a damped exponential family, random and monotone missing patterns, and different observation probabilities. Simulation studies show that empirical powers and type I errors are close to their nominal levels. The proposed sample size formula is illustrated using a real clinical trial example.
PMCID: PMC3505113  PMID: 23183937
22.  Handheld Shape Discrimination Hyperacuity Test on a Mobile Device for Remote Monitoring of Visual Function in Maculopathy 
Frequency monitoring of age-related macular degeneration (AMD) and diabetic retinopathy (DR) is crucial for timely intervention. This study evaluated a handheld shape discrimination hyperacuity (hSDH) test iPhone app designed for visual function self-monitoring in patients with AMD and DR.
One hundred subjects (27 visually normal, 37 with AMD, and 36 with DR) were included based on clinical documentation and visual acuity of 20/100 or better. The hSDH test was implemented on the iOS platform. A cross-sectional study was conducted to compare the hSDH test with a previously established desktop SDH (dSDH) test and to assess the effect of disease severity on the hSDH test. A user survey was also conducted to assess the usability of the hSDH test on the mobile device.
The hSDH test and dSDH test were highly correlated (r = 0.88, P < 0.0001). Bland-Altman analysis indicated no significant difference in hSDH and dSDH measurements. One-way ANOVA indicated that the mean hSDH measurement of the eyes with advanced AMD (n = 16) or with severe to very severe nonproliferative DR (NPDR) (n = 12) was significantly worse than that of the eyes with intermediate AMD (n = 11) or with mild to moderate NPDR (n = 11) (P < 0.0001). Ninety-eight percent of 46 patients (10 with AMD and 36 with DR) who completed the usability survey reported that the hSDH test was easy to use.
This study demonstrated that the hSDH test on a mobile device is comparable to PC-based testing methods. As a mobile app, it is intuitive to use, readily accessible, and sensitive to the severity of maculopathy. It has the potential to provide patients having maculopathy with a new tool to monitor their vision at home.
This study demonstrated that a handheld shape discrimination hyperacuity test is intuitive to use, low cost, and sensitive to the severity of maculopathy. This test implemented on a mobile device has the potential to provide patients having maculopathy with a new tool to monitor their vision at home.
PMCID: PMC3743459  PMID: 23860761
age-related macular degeneration; diabetic retinopathy; shape discrimination; visual acuity; remote vision self-testing
23.  Correlation between HER-2/neu(erbB-2) expression level and therapeutic effect of combination treatment with HERCEPTIN and chemotherapeutic agents in gastric cancer cell lines 
Although advanced gastric cancer has many limitations and response rate is marginal in chemotherapy. Overexpression of human epidermal growth factor receptor 2(HER-2/neu) gene and its protein are associated with increased cell division and a high rate of tumor growth and have been reported in several malignancies. Especially, approximately 30% of breast cancer patients have overexpression of HER-2/neu protein and the overexpression metastasize faster, induces resistance of the chemotherapy and down-regulate function of estrogen receptor. Recombinant humanized anti-HER2 antibody (Herceptin) inhibits proliferation of HER-2/neu overexpressing tumor cells and the use of that in combination in metastatic breast cancer have increased cytotoxicity of chemotherapeutic agents.
We evaluated the expression of HER-2/neu protein in gastric cell lines by FACS and then comparing the cytotoxicity in chemotherapeutics (doxorubicin, cisplatin, paclitaxel, 5-FU) alone and in combination with Herceptin according to the expression of HER-2/neu protein by MTT assay.
1. NCI-N87 (88%) gastric cancer cell line and SK-BR-3 (89%) breast cancer cell line with strong positivity of HER-2/neu expression. YBC-2 (55%) and YBC-3 (48%) gastric cancer cell line with intermediated, weak positivity respectively. Negative control U-87 MG (6%) brain cancer cell line were showed low expression of HER-2/neu. 2. Cell growth was dose-dependently inhibited in HER-2/neu positive, control cell line SK-BR-3 by Herceptin treatment but not observed in HER-2/neu negative control cell line U-87 MG. Effective growth inhibition was not observed in gastric cancer cell lines with single treatment of Herceptin, all cell lines observed the dose-dependent growth inhibition to chemotherapeutic agents (doxorubicin, cisplatin, paclitaxel and 5-FU). 3. Combination of Herceptin with doxorubicin observed synergistic effects in all cancer cell lines except YBC-3, combination of Herceptin with cisplatin observed NCI-N87 and SK-BR-3 and combination of Herceptin with paclitaxel observed synergistic effects in YBC-2. Combination of Herceptin with 5-FU observed antagonistic effects in all cancer cell lines.
According to HER-2/neu expression level, effect of anti-cancer agents was observed differently in combination of Herceptin with chemotherapeutic agents. This suggests that HER-2/neu expression level can be applied standard of combination drug selection in combination of Herceptin With chemotherapeutic agents in gastric cancer.
PMCID: PMC3915235  PMID: 24472145
HER-2/neu(erbB-2); HERCEPTIN; Gastric cancer; Combination treatment; CI
24.  Neuroprotective Effects of Tetramethylpyrazine against Dopaminergic Neuron Injury in a Rat Model of Parkinson's Disease Induced by MPTP 
Parkinson's disease (PD) is the second most prevalent progressive neurodegenerative disease. Although several hypotheses have been proposed to explain the pathogenesis of PD, apoptotic cell death and oxidative stress are the most prevalent mechanisms. Tetramethylpyrazine (TMP) is a biological component that has been extracted from Ligusticum wallichii Franchat (ChuanXiong), which exhibits anti-apoptotic and antioxidant roles. In the current study, we aimed to investigate the possible protective effect of TMP against dopaminergic neuron injury in a rat model of Parkinson's disease induced by MPTP and to elucidate probable molecular mechanisms. The results showed that TMP could notably prevent MPTP-induced dopaminergic neurons damage, reflected by improvement of motor deficits, enhancement of TH expression and the content of dopamine and its metabolite, DOPAC. We observed MPTP-induced activation of mitochondrial apoptotic death pathway, evidenced by up-regulation of Bax, down-regulation of Bcl-2, release of cytochrome c and cleavage of caspase 3, which was significantly inhibited by TMP. Moreover, TMP could prevent MPTP-increased TBARS level and MPTP-decreased GSH level, indicating the antioxidant role of TMP in PD model. And the antioxidant role of TMP attributes to the prevention of MPTP-induced reduction of Nrf2 and GCLc expression. In conclusion, in MPTP-induced PD model, TMP prevents the down-regulation of Nrf2 and GCLc, maintaining redox balance and inhibiting apoptosis, leading to the attenuation of dopaminergic neuron damage. The effectiveness of TMP in treating PD potentially leads to interesting therapeutic perspectives.
PMCID: PMC3979987  PMID: 24719552
Tetramethylpyrazine; Parkinson's disease; anti-apoptotic; antioxidant; MPTP.
25.  Silybin-Mediated Inhibition of Notch Signaling Exerts Antitumor Activity in Human Hepatocellular Carcinoma Cells 
PLoS ONE  2013;8(12):e83699.
Hepatocellular carcinoma (HCC) is a global health burden that is associated with limited treatment options and poor patient prognoses. Silybin (SIL), an antioxidant derived from the milk thistle plant (Silybum marianum), has been reported to exert hepatoprotective and antitumorigenic effects both in vitro and in vivo. While SIL has been shown to have potent antitumor activity against various types of cancer, including HCC, the molecular mechanisms underlying the effects of SIL remain largely unknown. The Notch signaling pathway plays crucial roles in tumorigenesis and immune development. In the present study, we assessed the antitumor activity of SIL in human HCC HepG2 cells in vitro and in vivo and explored the roles of the Notch pathway and of the apoptosis-related signaling pathway on the activity of SIL. SIL treatment resulted in a dose- and time-dependent inhibition of HCC cell viability. Additionally, SIL exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration, intracellular glutathione (GSH) levels and total antioxidant capability (T-AOC) but also by increases in the apoptotic index, caspase3 activity, and reactive oxygen species (ROS). Furthermore, SIL treatment decreased the expression of the Notch1 intracellular domain (NICD), RBP-Jκ, and Hes1 proteins, upregulated the apoptosis pathway-related protein Bax, and downregulated Bcl2, survivin, and cyclin D1. Notch1 siRNA (in vitro) or DAPT (a known Notch1 inhibitor, in vivo) further enhanced the antitumor activity of SIL, and recombinant Jagged1 protein (a known Notch ligand in vitro) attenuated the antitumor activity of SIL. Taken together, these data indicate that SIL is a potent inhibitor of HCC cell growth that targets the Notch signaling pathway and suggest that the inhibition of Notch signaling may be a novel therapeutic intervention for HCC.
PMCID: PMC3873967  PMID: 24386256

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