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1.  Population Pharmacokinetic-Pharmacodynamic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis 
To evaluate the exposure-response relationships for efficacy and safety of voriconazole and anidulafungin in adult patients with invasive aspergillosis (IA), a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from a phase 3, prospective, double-blind, comparative study evaluating voriconazole and anidulafungin combination therapy versus voriconazole (and placebo) monotherapy. Anidulafungin/placebo treatment duration was 2 to 4 weeks, and voriconazole treatment duration was 6 weeks. Efficacy (6-week all-causality mortality and 6-week global response [n = 176]) and safety (hepatic [n = 238], visual [n = 199], and psychiatric [n = 183] adverse events [AEs]) endpoints were analyzed separately using a binary logistic regression model. In IA patients receiving voriconazole monotherapy, no positive associations between voriconazole exposure and efficacy or safety were identified. In IA patients receiving combination therapy, no positive associations between voriconazole or anidulafungin exposures and efficacy were identified. The 6-week survival rate tended to increase as anidulafungin treatment duration increased; this finding should be considered with caution. Additionally, in IA patients receiving combination therapy, a positive association between voriconazole and anidulafungin exposures (area under the curve [AUC] and trough concentration [Cmin]) and hepatic AEs was established; a weak positive association between voriconazole exposure (AUC and Cmin) and psychiatric AEs was also established, but no association between voriconazole exposure and visual AEs was identified. Besides the drug exposures, no other covariates (i.e., CYP2C19 genotype status, age, weight, body mass index, sex, race, or neutropenia status) were identified as significant predictors of the efficacy and safety endpoints in IA patients. This study was registered on (NCT00531479).
PMCID: PMC4126689  PMID: 24914120
2.  Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis 
To assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC0–12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on (NCT00531479).
PMCID: PMC4136065  PMID: 24913161
3.  SEARS: A Seamless Dose Escalation/Expansion with Adaptive Randomization Scheme 
Standard drug development conducts phase I dose finding and phase II dose expansion sequentially and separately. Information between the two phases is rarely shared. Administratively, such a sequential process is time consuming and burdensome.
We propose SEARS, a seamless design that combines phase I dose escalation based on toxicity with phase II dose expansion and dose comparison based on efficacy. SEARS allows extension from phase I to phase II under one design with no gap in between, and employs a dynamic and parallel procedure involving simultaneous dose escalation, dose graduation, and adaptive randomization.
SEARS integrates three components into a seamless scheme. Specifically, in phase I, SEARS applies the mTPI method to monitor dose escalation based on toxicity outcome. Doses that show promising efficacy and safety are immediately graduated from phase I and placed to a phase II stage in which patients are adaptively randomized based on efficacy outcome. Phase I dose escalation, dose graduation, and phase II adaptive randomization proceed simultaneously throughout the entire trial.
Examples are given comparing SEARS with two other designs, in which superior performance of SEARS is demonstrated. An important and promising finding is that SEARS reduces sample sizes without losing power. R program and demo slides of SEARS can be obtained at
We assume that the binary efficacy and toxicity response can be measured in the same time frame. This is often achievable with surrogate efficacy markers in practice.
PMCID: PMC4281526  PMID: 24137041
Bayesian adaptive designs; Graduation rule; Phase I; Phase II; Seamless
5.  Urinary Metabolite Profiling Offers Potential for Differentiation of Liver-Kidney Yin Deficiency and Dampness-Heat Internal Smoldering Syndromes in Posthepatitis B Cirrhosis Patients 
Zheng is the basic theory and essence of traditional Chinese medicine (TCM) in diagnosing diseases. However, there are no biological evidences to support TCM Zheng differentiation. In this study we elucidated the biological alteration of cirrhosis with TCM “Liver-Kidney Yin Deficiency (YX)” or “Dampness-Heat Internal Smoldering (SR)” Zheng and the potential of urine metabonomics in TCM Zheng differentiation. Differential metabolites contributing to the intergroup variation between healthy controls and liver cirrhosis patients were investigated, respectively, and mainly participated in energy metabolism, gut microbiota metabolism, oxidative stress, and bile acid metabolism. Three metabolites, aconitate, citrate, and 2-pentendioate, altered significantly in YX Zheng only, representing the abnormal energy metabolism. Contrarily, hippurate and 4-pyridinecarboxylate altered significantly in SR Zheng only, representing the abnormalities of gut microbiota metabolism. Moreover, there were significant differences between two TCM Zhengs in three metabolites, glycoursodeoxycholate, cortolone-3-glucuronide, and L-aspartyl-4-phosphate, among all differential metabolites. Metabonomic profiling, as a powerful approach, provides support to the understanding of biological mechanisms of TCM Zheng stratification. The altered urinary metabolites constitute a panel of reliable biological evidence for TCM Zheng differentiation in patients with posthepatitis B cirrhosis and may be used for the potential biomarkers of TCM Zheng stratification.
PMCID: PMC4312628  PMID: 25667596
6.  The responsive expression of a chitinase gene in the ridgetail white prawn Exopalaemon carinicauda against Vibrio anguillarum and WSSV challenge 
Cell Stress & Chaperones  2014;19(4):549-558.
Chitinases are essential enzymes for crustaceans and participates in several biological processes, such as nutrient digestion, morphogenesis, pathogenesis, and pathogen defense. In the present study, the full-length cDNA of Chi (named EcChi) was cloned from the hemocytes of ridgetail white prawn Exopalaemon carinicauda by rapid amplification of cDNA ends methods. The full-length cDNA of EcChi was 1,319 bp, including contains a 5′-untranslated region (UTR) of 42 bp, 3′-UTR of 101 bp with a poly (A) tail, an open-reading frame of 1,176 bp, encoding a 391-amino acid polypeptide with the predicted molecular weight of 43.71 kDa and estimated isoelectric point of 4.78. Sequence analysis revealed that the conserved chitinases family 18 active site was predicted in the amino acid sequence of EcChi. BLAST analysis revealed that amino acids of EcChi shared high identity (61–77 %) with that of other crustaceans. Quantitative real-time PCR analysis indicated that EcChi could be detected in all the tested tissues, and strongly expressed in hepatopancreas of E. carinicauda. After challenged with Vibrio anguillarum and WSSV, EcChi transcripts both in hemocytes and hepatopancreas increased significantly in the first 3 h, respectively. These results indicated that EcChi might be involved in the innate immune responses to V. anguillarum and WSSV in E. carinicauda.
PMCID: PMC4041943  PMID: 24408604
Exopalaemon carinicauda; Chitinase (Chi); Vibrio anguillarum; White spot syndrome virus (WSSV); Immune response
7.  Super-resolution imaging of C-type lectin spatial rearrangement within the dendritic cell plasma membrane at fungal microbe contact sites 
Frontiers in physics  2014;2:46.
Dendritic cells express DC-SIGN and CD206, C-type lectins (CTLs) that bind a variety of pathogens and may facilitate pathogen uptake for subsequent antigen presentation. Both proteins form punctate membrane nanodomains (∼80 nm) on naïve cells. We analyzed the spatiotemporal distribution of CTLs following host-fungal particle contact using confocal microscopy and three distinct methods of cluster identification and measurement of receptor clusters in super-resolution datasets: DBSCAN, Pair Correlation and a custom implementation of the Getis spatial statistic. Quantitative analysis of confocal and super-resolution images demonstrated that CTL nanodomains become concentrated in the contact site relative to non-contact membrane after the first hour of exposure and established that this recruitment is sustained out to 4 h. DC-SIGN nanodomains in fungal contact sites exhibit a 70% area increase and a 38% decrease in interdomain separation. Contact site CD206 nanodomains possess 90% greater area and 42% lower interdomain separation relative to non-contact regions. Contact site CTL clusters appear as disk-shaped domains of approximately 150–175 nm in diameter. The increase in length scale of CTL nanostructure in contact sites suggests that the smaller nanodomains on resting membranes may merge during fungal recognition, or that they become packed closely enough to achieve sub-resolution inter-domain edge separations of <30 nm. This study provides evidence of local receptor spatial rearrangements on the nanoscale that occur in the plasma membrane upon pathogen binding and may direct important signaling interactions required to recognize and respond to the presence of a relatively large pathogen.
PMCID: PMC4262399  PMID: 25506589
CD206; DC-SIGN; dendritic cell; dSTORM; mannan; zymosan
8.  Risk Factors for Postural Tachycardia Syndrome in Children and Adolescents 
PLoS ONE  2014;9(12):e113625.
Postural tachycardia syndrome (POTS) is prevalent in children and adolescents and has a great impact on health. But its risk factors have not been fully understood. This study aimed to explore possible risk factors for children and adolescents with POTS.
Methods and Findings
600 children and adolescents (test group) aged 7–18 (11.9±3.0) years old, 259 males and 341 females, were recruited for identifying its risk factors. Another 197 subjects aged from 7 to 18 (11.3±2.3) years old were enrolled in the validation group. Heart rate (HR) and blood pressure (BP) were monitored during upright test. Risk factors were analyzed and sensitivity and specificity for predicting POTS were tested via receiver operating characteristic curve. Among 600 subjects, 41 were confirmed with POTS patients (6.8%) based on clinical manifestation and upright test. The results showed a significant difference in daily water intake, the daily sleeping hours, supine HR, HR increment and maximum HR during upright test between POTS and the unaffected children (P<0.05). Likelihood of POTS would increase by 1.583 times if supine HR was increased by 10 beats/min (95%CI 1.184 to 2.116, P<0.01), by 3.877 times if a child's water intake was less than 800 ml/day (95%CI 1.937 to 7.760, P<0.001), or by 5.905 times (95%CI 2.972 to 11.733, P<0.001) if sleeping hours were less than 8 hours/day. Supine HR, daily water intake and sleeping hours showed the capability of predicting POTS in children and adolescents with an AUC of 83.9% (95% CI: 78.6%–89.1%), sensitivity of 80.5% and specificity of 75%. Furthermore, in validation group, predictive sensitivity and specificity were 73.3% and 72.5%.
Faster supine HR, less water intake and shorter sleeping hours were identified as risk factors for POTS.
PMCID: PMC4256207  PMID: 25474569
9.  Interferon-Inducible Cholesterol-25-Hydroxylase Inhibits Hepatitis C Virus Replication via Distinct Mechanisms 
Scientific Reports  2014;4:7242.
Cholesterol 25-hydroxylase (CH25H) as an interferon-stimulated gene (ISG) has recently been shown to exert broad antiviral activity through the production of 25-hydroxycholesterol (25HC), which is believed to inhibit the virus-cell membrane fusion during viral entry. However, little is known about the function of CH25H on HCV infection and replication and whether antiviral function of CH25H is exclusively mediated by 25HC. In the present study, we have found that although 25HC produced by CH25H can inhibit HCV replication, CH25H mutants lacking the hydroxylase activity still carry the antiviral activity against HCV but not other viruses such as MHV-68. Further studies have revealed that CH25H can interact with the NS5A protein of HCV and inhibit its dimer formation, which is essential for HCV replication. Thus, our work has uncovered a novel mechanism by which CH25H restricts HCV replication, suggesting that CH25H inhibits viral infection through both 25HC-dependent and independent events.
PMCID: PMC4252895  PMID: 25467815
10.  Effect of anterior cervical discectomy and fusion on adjacent segments in rabbits 
This study is to investigate the effect of anterior cervical discectomy with internal fixation and fusion at different levels on adjacent segments in rabbits. Sixty New Zealand rabbits were randomly divided into four groups, one control group and three model groups, with 15 in each group. Each group underwent anterior cervical internal fixation and fusion at C3-4, C4-5, and C5-6 levels respectively. X-ray film was examined three, six and nine months after fusion to observe the changes in intervertebral space and endplate of adjacent segment. Immunohistochemistry was utilized to evaluate the effects of different fusion methods on adjacent segments of spine. As time went by, in model groups, the majority of cartilage endplates were calcified, as examined by X-ray. Immunohistochemical results of the intervertebral disc showed that the expression levels of collagen type II in nucleus pulposus were decreased significantly, while the expression levels collagen type I in annular fibrosus were increased. And collagen type I tends to replace collagen type II gradually in nucleus pulposus as time goes by. The change in collagen between upper and lower adjacent segments at C3-4 and C4-5 showed no statistical significance after fixation and fusion (p > 0.05). But for C5-6, the change showed statistical significance (p < 0.05). Cervical internal fixation and fusion can induce intervertebral disc degeneration of adjacent segment in rabbits, and cervical internal fixation and fusion operated at different levels may result in different effects on adjacent segments of cervical intervertebral disc.
PMCID: PMC4276202  PMID: 25550944
Cervical vertebra; adjacent segment; internal fixation and fusion; intervertebral disc
11.  An ER-associated miRNA signature predicts prognosis in ER-positive breast cancer 
Breast cancer patients with positive estrogen receptor (ER) have a better prognosis. However, no prognostic miRNA signature was reported in the ER-positive breast cancer. The aim of the study was to identify and assess the prognostic significance of a miRNA signature in ER-positive breast cancer.
Two cohorts from The Cancer Genome Atlas (TCGA) dataset were used as training (n =596) and testing set (n =319). Differential expression profiling was identified in the training set. And the prognostic value of the miRNA signature was then assessed in the two cohorts.
A total of 14 miRNAs were observed to be associated with the status of ER by significance analysis of microarrays (SAM) in the training set. Patients were characterized as high score or low score group according to the calculated risk scores from each miRNA. And patients in high score group had worse overall survival compared with those in low score group both in the training and testing set.
Our study revealed a miRNA signature including 14 miRNAs associated with ER status which could act as a prognostic marker in ER-positive breast cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-014-0094-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4232612  PMID: 25373603
Breast cancer; ER status; miRNA signature; prognosis
12.  The complex jujube genome provides insights into fruit tree biology 
Nature Communications  2014;5:5315.
The jujube (Ziziphus jujuba Mill.), a member of family Rhamnaceae, is a major dry fruit and a traditional herbal medicine for more than one billion people. Here we present a high-quality sequence for the complex jujube genome, the first genome sequence of Rhamnaceae, using an integrated strategy. The final assembly spans 437.65 Mb (98.6% of the estimated) with 321.45 Mb anchored to the 12 pseudo-chromosomes and contains 32,808 genes. The jujube genome has undergone frequent inter-chromosome fusions and segmental duplications, but no recent whole-genome duplication. Further analyses of the jujube-specific genes and transcriptome data from 15 tissues reveal the molecular mechanisms underlying some specific properties of the jujube. Its high vitamin C content can be attributed to a unique high level expression of genes involved in both biosynthesis and regeneration. Our study provides insights into jujube-specific biology and valuable genomic resources for the improvement of Rhamnaceae plants and other fruit trees.
The jujube is a major dry fruit crop in China and is commonly used for medicinal purposes. Here the authors sequence the genome and transcriptome of the most widely cultivated jujube cultivar, Dongzao, and highlight the genetic and molecular basis of agronomically important jujube traits, such as vitamin C content.
PMCID: PMC4220462  PMID: 25350882
13.  Adenosine A2A receptor deficiency alleviates blast-induced cognitive dysfunction 
Traumatic brain injury (TBI), particularly explosive blast-induced TBI (bTBI), has become the most prevalent injury among military personnel. The disruption of cognitive function is one of the most serious consequences of bTBI because its long-lasting effects prevent survivors fulfilling their active duty and resuming normal civilian life. However, the mechanisms are poorly understood and there is no treatment available. This study investigated the effects of adenosine A2A receptor (A2AR) on bTBI-induced cognitive deficit, and explored the underlying mechanisms. After being subjected to moderate whole-body blast injury, mice lacking the A2AR (A2AR knockout (KO)) showed less severity and shorter duration of impaired spatial reference memory and working memory than wild-type mice did. In addition, bTBI-induced cortical and hippocampal lesions, as well as proinflammatory cytokine expression, glutamate release, edema, cell loss, and gliosis in both early and prolonged phases of the injury, were significantly attenuated in A2AR KO mice. The results suggest that early injury and chronic neuropathological damages are important mechanisms of bTBI-induced cognitive impairment, and that the impairment can be attenuated by preventing A2AR activation. These findings suggest that A2AR antagonism is a potential therapeutic strategy for mild-to-moderate bTBI and consequent cognitive impairment.
PMCID: PMC3824177  PMID: 23921902
adenosine; brain trauma; cognitive impairment; experimental; neuroprotection
14.  Microbubbles coupled to methotrexate-loaded liposomes for ultrasound-mediated delivery of methotrexate across the blood–brain barrier 
Methotrexate (MTX) is the single most effective agent for the treatment of primary central nervous system lymphoma. Currently, the delivery of MTX to the brain is achieved by high systemic doses, which cause severe long-term neurotoxicity, or intrathecal administration, which is highly invasive and may lead to infections or hemorrhagic complications. Acoustically active microbubbles have been developed as drug carriers for the noninvasive and brain-targeted delivery of therapeutics. However, their application is limited by their low drug-loading capacity. To overcome this limitation, we prepared microbubbles coupled to MTX-loaded liposomes using ZHIFUXIAN, a novel type of microbubbles with a superior safety profile and long circulation time. MTX-liposome-coupled microbubbles had a high drug-loading capacity of 8.91%±0.86%, and their size (2.64±0.93 μm in diameter) was suitable for intravenous injection. When used with ultrasound, they showed more potent in vitro cytotoxicity against Walker-256 cancer cells than MTX alone or MTX-loaded liposomes. When Sprague-Dawley rats were exposed to sonication, administration of these MTX-liposome-coupled microbubbles via the tail vein led to targeted disruption of the blood–brain barrier without noticeable tissue or capillary damage. High-performance liquid chromatography analysis of the brain MTX concentration showed that MTX delivery to the brain followed the order of MTX-liposome-coupled microbubbles + ultrasound (25.3±2.4 μg/g) > unmodified ZHIFUXIAN + MTX + ultrasound (18.6±2.2 μg/g) > MTX alone (6.97±0.75 μg/g) > MTX-liposome-coupled microbubbles (2.92±0.39 μg/g). Therefore, treatment with MTX-liposome-coupled microbubbles and ultrasound resulted in a significantly higher brain MTX concentration than all other treatments (P<0.01). These results suggest that MTX-liposome-coupled microbubbles may hold great promise as new and effective therapies for primary central nervous system lymphoma and other central nervous system malignancies.
PMCID: PMC4211917  PMID: 25364248
methotrexate; microbubbles; ultrasound; liposomes; blood–brain barrier
15.  Meta-Analysis of the Prognostic Value of Smad4 Immunohistochemistry in Various Cancers 
PLoS ONE  2014;9(10):e110182.
Accumulating evidence indicates that Smad4 (DPC4) plays a fundamental role in the development and prognosis of several types of cancer. The objective of this study was to conduct a meta-analysis to evaluate whether the loss of Smad4 staining could serve as a prognostic marker.
A comprehensive meta-analysis was conducted using major useful databases to determine the relationship between the immunohistochemical detection of Smad4 and the survival of patients with various cancers. We used hazard ratios (HRs) with 95% confidence interval (CIs) as the effect estimation to evaluate the association of Smad4 with overall survival (OS), cancer-specific survival (CSS) or recurrence-free survival (RFS). The relationship between the clinical characteristics of patients and Smad4 was also evaluated using the odds ratio (OR).
A total of 7570 patients from 26 studies were included in the analysis. The pooled results showed that loss of Smad4 staining was a negative predictor of OS with an HR of 1.97 (95% CI: 1.55–2.51; Pheterogeneity<0.001) and CSS/RFS (HR = 1.81; 95% CI: 1.30–2.54; Pheterogeneity<0.001). In addition, loss of Smad4 staining was more likely to be found in older (OR = 1.69, 95% CI: 1.09–2.61; Pheterogeneity = 0.648) colorectal cancer patients with a late tumor stage (OR = 2.31, 95% CI: 1.71–3.10; Pheterogeneity = 0.218) and in gastric cancer patients with lymph node metastasis (OR = 2.11, 95% CI: 1.03–4.34; Pheterogeneity = 0.038).
Based on these results, our meta-analysis provided evidence that loss of Smad4 staining could act as an unfavorable biomarker in the prognosis of various cancers and should be used as a powerful tool in future clinical trials.
PMCID: PMC4198206  PMID: 25333693
16.  Chromosome aberrations and spermatogenic disorders in mice with Robertsonian translocation (11; 13) 
Objective: To determine the diagnostic features of Robertsonian (Rob) translocation (11; 13) in mice and the mechanisms underlying the effect on spermatogenesis and reproductive decline. Methods: A Rob translocation (11; 13) mouse model was established by cross-breeding, and confirmed by chromosome analysis. Chromosome aberrations and translocation patterns were identified in mice with Rob translocation (11; 13) by fluorescence in situ hybridization (FISH). Spermatogenic disorders were investigated at different stages of spermatogenesis. Immunofluorescent analysis was performed on sections of testis and epididymis specimens during spermatogenic meiosis. The weight of the testes and reproductive decline were recorded. Results: The crossed Rob translocation (11; 13) mouse has 39 chromosomes, including a fusion chromosome (included chromosomes 11 and 13) using dual color FISH. There was no difference in the distribution pattern of SYCP3 and γH2AX in spermatocytes between Rob translocation and wild-type mice; however, round haploid spermatids presented characteristic morphologic changes of apoptosis and the number of haploid spermatids was decreased. Furthermore, the immature germ cells were released into the epididymis and the number of mature sperm was reduced. Conclusions: Chromosome aberrations and spermatogenic disorders may result from apoptosis of round haploid spermatids and a reduced number of mature sperm in Rob translocation (11; 13) mice. Abnormal sperm and reduced number of sperm may be one of the main reasons for reproductive decline and male infertility in Rob translocation (11; 13) mice.
PMCID: PMC4270519  PMID: 25550810
Infertility; spermatogenesis; Robertsonian translocation; mouse
17.  Can Serum Glypican-3 Be a Biomarker for Effective Diagnosis of Hepatocellular Carcinoma? A Meta-Analysis of the Literature 
Disease Markers  2014;2014:127831.
Objective. This review is to evaluate the diagnostic value of serum GPC3 for hepatocellular carcinoma (HCC) due to conflicting results reported. Methods. NCBI PubMed and Embase were comprehensively searched for studies that have used serum GPC3 level as a diagnostic index for HCC. The quality of the included studies was assessed. Subgroup analyses were conducted to evaluate the sensitivity and specificity of GPC3 as a HCC marker. Statistical analysis was performed with the software STATA version 12.0. Results. A total of 22 studies were included. The qualities of included studies were relatively poor. Among them, 18 studies have shown that serum GPC3 is a specific biomarker for HCC, and the pooled sensitivity and specificity of these studies were 69 and 93%, respectively. The other 4 studies have reported conflicting results, which were not caused by races, infection status of HBV and HCV, or assay reagents but due to one common experimental design of enrolling liver cirrhosis patients as control subjects. Conclusions. This meta-analysis indicates that serum GPC3 is elevated in HCC patients compared with healthy individuals, but more studies are needed to evaluate its effectiveness to differentially diagnose HCC and liver cirrhosis.
PMCID: PMC4214040  PMID: 25378766
18.  Bmi-1 induces radioresistance by suppressing senescence in human U87 glioma cells 
Oncology Letters  2014;8(6):2601-2606.
Radiotherapy is the main locoregional control modality for a number of types of malignant tumors, including glioblastoma. However, radiotherapy fails to prevent recurrence in numerous patients due to the intrinsic radioresistance of cancer cells. Cell senescence is significant in tumor suppressor mechanisms and is closely associated with the radioresistance of cancer cells. Bmi-1 has been proposed to be an oncogene that can induce anti-senescence in tumor cells. The present study investigated the response of U87 glioma cells to radiation exposure and the role of Bmi-1 in the response following radiotherapy. Cell apoptosis and cell cycle distribution were assessed using flow cytometry, and a SA-β-Gal stain was used to observe the senescence ratio of U87 cells following radiation. The expression of Bmi-1 in U87 cells exposed to different doses of radiation was evaluated by western blot analysis. X-ray radiation was found to inhibit U87 cell proliferation through the induction of senescence rather than apoptosis. Following exposure to radiation, the cell cycle distribution was dysregulated, with an increased number of cells in the G2/M phase, and the expression of Bmi-1 was upregulated, particularly when a dose of ≥6 Gy was administered. The results indicated that senescence is the main mechanism by which U87 cell growth is inhibited following radiation. In addition, Bmi-1 may be significant in increasing the radioresistance of glioma cells by enabling cell senescence.
PMCID: PMC4214493  PMID: 25364434
glioma; Bmi-1; senescence; radiation
19.  A Randomized Phase II Trial of Fludarabine/Melphalan 100 versus Fludarabine/Melphalan 140 followed by Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Multiple Myeloma 
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for multiple myeloma (MM); however, due to high-treatment related mortality (TRM) its role is not well defined.
Patients with newly diagnosed, relapsed, or primary refractory myeloma were enrolled in a randomized phase II trial of two reduced intensity conditioning regimens, fludarabine 120 mg/m2+ melphalan 100 mg/m2(FM100) versus fludarabine 120 mg/m2+ melphalan 140 mg/m2(FM140) before allo-HCT from related or unrelated donors.
Fifty patients underwent allo-HCT using FM100 (N=23) or FM140 (N=27) conditioning between April 2002 and 2011. There were no significant differences between FM100 and FM140 in time to neutrophil engraftment (p=0.21), acute grade II-IV GVHD (p=1.0), chronic GVHD (p=0.24), response rate (p=1.0), TRM (13% versus 15%, p=1.0), median progression-free survival (PFS), 11.7 versus 8.4 months, p=0.12, and median overall survival (OS), 35.1 versus19.7 months, p=0.38. Cumulative incidence of disease progression in FM100 and FM140 was 43% and 70%, respectively (p=0.08). Recurrent disease was the most common cause of death for both FM100 (26%) and FM140 (44%), p=0.24. On multivariate analysis, disease status at allo-HCT, complete response or very good partial response (VGPR) was significantly associated with longer PFS (15.6 versus 9.6 months in patients with < VGPR, p=0.05). OS was similar across all variables.
We conclude that FM 100 and FM140 may result in similar patient outcomes after allo-HCT for MM.
PMCID: PMC4157818  PMID: 23872222
Myeloma; Allogeneic transplantation; Reduced intensity conditioning; Fludarabine; Melphalan
20.  Martensitic transformation of FeNi nanofilm induced by interfacial stress generated in FeNi/V nanomultilayered structure 
Nanoscale Research Letters  2014;9(1):440.
FeNi/V nanomultilayered films with different V layer thicknesses were synthesized by magnetron sputtering. By adjusting the thickness of the V layer, different interfacial compressive stress were imposed on FeNi layers and the effect of interfacial stress on martensitic transformation of the FeNi film was investigated. Without insertion of V layers, the FeNi film exhibits a face-centered cubic (fcc) structure. With the thickness of V inserted layers up to 1.5 nm, under the coherent growth structure in FeNi/V nanomultilayered films, FeNi layers bear interfacial compressive stress due to the larger lattice parameter relative to V, which induces the martensitic transformation of the FeNi film. As the V layer thickness increases to 2.0 nm, V layers cannot keep the coherent growth structure with FeNi layers, leading to the disappearance of interfacial compressive stress and termination of the martensitic transformation in the FeNi film. The interfacial compressive stress-induced martensitic transformation of the FeNi nanofilm is verified through experiment. The method of imposing and modulating the interfacial stress through the epitaxial growth structure in the nanomultilayered films should be noticed and utilized.
PMCID: PMC4154052  PMID: 25232296
FeNi alloy; Multilayer thin films; Martensitic phase transformation; Interfacial stress; Epitaxial growth
21.  Malignant transformation of testicular teratoma: A chemoresistant phenotype 
Urologic oncology  2008;26(6):595-599.
To review our experience in the management of malignant transformation of teratoma (MTT).
Materials and methods
Nine patients with MTT were identified from January 1980 to August 2005, with all pathological specimens re-reviewed by a single genitourinary pathologist.
Two patients presented with clinical stage I disease in which malignant transformation occurred within the primary testis tumor (rhabdomyosarcoma in 1 and adenocarcinoma in 1). These patients underwent a primary retroperitoneal lymph node dissection (RPLND). No viable tumor was identified in the specimen, and both patients were alive without disease at 16 months follow-up. Of the remaining 7 patients, the clinical stages were IIA (N = 1), IIB (N = 3), and III (N = 3), and all were treated with chemotherapy followed by RPLND. The MTT histology of these RPLND specimens consisted of adenocarcinoma (N = 3), rhabdomyosarcoma (N = 2), angiosarcoma (N = 1), and astrocytoma (N = 1). Following preoperative chemotherapy, a significant radiologic response (defined as more than a 25% reduction in maximum tumor circumferential diameter) was demonstrated in 1 patient, and normalization of serum tumor markers was demonstrated in 6. At a mean follow-up of 5 years, 3 of these 7 patients were alive with no evidence of disease, 1 had persistent disease, and 3 had died of disease, and their median disease-specific survival duration was 4.6 years.
In our experience, MTT is significantly resistant to current chemotherapeutic regimens, as demonstrated by its poor radiologic response to treatment. Alternative therapeutic strategies targeted to MTT are thus needed.
PMCID: PMC4121060  PMID: 18367105
Malignant transformation; Teratoma; Postchemotherapy Retroperitoneal lymph node dissection; Testis cancer
22.  Trends in the Incidence and Management of Acute Myocardial Infarction From 1999 to 2008: Get With the Guidelines Performance Measures in Taiwan 
The American Heart Association Get With the Guidelines (GWTG) program has improved care quality of acute myocardial infarction (AMI) with important implications for other countries in the world. This study evaluated the incidence and care of AMI in Taiwan and assessed the compliance of GWTG in Taiwan.
Methods and Results
We used the Taiwan National Health Insurance Research Database (1999–2008) to identify hospitalized patients ≥18 years of age presenting with AMI. The temporal trends of annual incidence and care quality of AMI were evaluated. The age‐adjusted incidence of AMI (/100 000 person‐years) increased from 28.0 in 1999 to 44.4 in 2008 (P<0.001). The use of guideline‐based medications for AMI was evaluated. The use of dual antiplatelet therapy (DAPT) increased from 65% in 2004 to 83.9% in 2008 (P<0.001). Angiotensin‐converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) was used in 72.6% in 2004 and 71.7% in 2008 (P=NS) and β‐blocker was used in 60% in 2004 and 59.7% in 2008 (P=NS). Statin use increased from 32.1% to 50.1% from 2004 to 2008 (P<0.001). The in‐hospital mortality decreased from 15.9% in 1999 to 12.3% in 2008 (P<0.0001). Multivariable analysis showed that DAPT, ACE inhibitor/ARB, β‐blocker, and statin use during hospitalization were all associated with reduced in‐hospital mortality in our AMI patients.
AMI incidence was increasing, but the guideline‐based medications for AMI were underutilized in Taiwan. Quality improvement programs, such as GWTG, should be promoted to improve AMI care and outcomes in Taiwan.
PMCID: PMC4310397  PMID: 25112555
epidemiology; incidence; myocardial infarction; population
23.  Outcome Analysis of 9-Gauge Magnetic Resonance Imaging-Guided Vacuum-Assisted Core Needle Breast Biopsies 
To correlate 9-gauge Magnetic Resonance imaging-guided Vacuum-Assisted breast Biopsy (MRVAB) with surgical histology to determine the upgrade rate and to correlate the frequency of MRVAB cancer diagnosis with breast MRI indications and enhancement characteristics of targeted lesions.
Materials and Methods
The HIPAA compliant study was approved by the institutional review board. A database search was performed of all MRVABs performed from January 1, 2005 to September 31, 2010. The breast MRI indications, history, age, risk factors, lesion size, enhancement characteristics, pathology at MRVAB and at surgery were documented. Fisher's exact test and Analysis of Variance were used for statistical analysis.
A total of 218 lesions underwent MRVAB in 197 women (mean age 52 years, range 28 - 76 years), of which 85 (39%) had surgical correlation. (R1, #3) There were 48/218 (22%) malignant, 133/218 (61%) benign, and 37/218 (17%) high-risk lesions at MRVAB. Ten (12%) of 85 lesions were upgraded to malignancy at surgery, with a final malignancy rate of 25%. The frequency of malignancy was significantly higher in patients presenting for diagnostic (50/177, 28%) versus screening (4/41, 10%, P<0.05) evaluation, patients with ipsilateral cancer (22/49, 45%, P<0.001), lesions with washout kinetics (34/103, 33%, P < 0.05); and relatively higher in lesions with non-mass-like enhancement (26/76, 34%, P=0.07), which represented ductal carcinoma in situ in the majority (17/26, 65%, P<0.005).
Patients with ipsilateral cancer who have additional suspicious lesions identified on MRI require careful evaluation and biopsy to exclude additional sites of cancer that may impact surgical management.
PMCID: PMC4111151  PMID: 22268171
24.  Prognostic Value of miR-21 in Various Cancers: An Updating Meta-Analysis 
PLoS ONE  2014;9(7):e102413.
Recently, more and more studies investigated the value of microRNA (miRNA) as a diagnostic or prognostic biomarker in various cancers. MiR-21 was found dysregulated in almost all types of cancers. While the prognostic role of miR-21 in many cancers has been studied, the results were not consistent.
We performed a meta-analysis to investigate the correlation between miR-21 and survival of general cancers by calculating pooled hazard ratios (HR) and 95% confidence intervals (CI).
The pooled results of 63 published studies showed that elevated miR-21 was a predictor for poor survival of general carcinomas, with pooled HR of 1.91 (95%CI: 1.66–2.19) for OS, 1.42 (95% CI: 1.16–1.74) for DFS and 2.2 (95% CI: 1.64–2.96) for RFS/CSS. MiR-21 was also a prognostic biomarker in the patients who received adjuvant therapy, with pooled HR of 2.4 (95%CI: 1.18–4.9) for OS.
Our results showed that miR-21 could act as a significant biomarker in the prognosis of various cancers. Further studies are warranted before the application of the useful biomarker in the clinical.
PMCID: PMC4097394  PMID: 25019505
25.  Incidence and natural history of pure red cell aplasia in major ABO-mismatched haematopoietic cell transplantation 
British journal of haematology  2013;160(6):798-805.
Major ABO mismatching is not considered a contraindication to allogeneic haematopoietic stem cell transplantation (HSCT). Modern reduced-intensity conditioning and reduced-toxicity regimens cause much less myeloablation than conventional myeloablative regimens, such as cyclophosphamide with busulfan or total body irradiation, which may affect the incidence of pure red cell aplasia (PRCA). We estimated the incidence and described the natural history of PRCA in patients with major ABO-mismatched donor stem cells. Between 2007 and 2008, 161 (27% of all patients undergoing HSCT) underwent allogeneic HSCT with major ABO-mismatched stem cells and 12 (7·5%) of these patients developed PRCA. Thirty and ninety day T-cell and myeloid cell chimerism and neutrophil and platelet engraftment did not differ between patients who developed PRCA and those who did not. The only risk factor associated with PRCA was the use of a fludarabine/busulfan conditioning regimen. All patients with PRCA needed red cell transfusion for several months after HSCT resulting in significant iron overload. Pure red cell aplasia resolved spontaneously in the majority (seven patients) but only resolved after stopping tacrolimus in three patients. Hence, after major ABO-mismatched HSCT, the incidence of PRCA was 7·5% and it resolved spontaneously or after withdrawal of immunosuppression in the majority of patients.
PMCID: PMC4078723  PMID: 23330820
pure red cell aplasia; allogeneic hematopoietic stem cell transplantation; major ABO incompatibility; blood groups

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