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1.  Age of asthma onset and vulnerability to ambient air pollution: an observational population-based study of adults from Southern Taiwan 
Background
Late-onset asthma (onset > 12 years) is pathologically distinct from early-onset asthma. The mechanism of air pollution is not a classic allergic inflammation and could have differential effect on late-onset and early-onset asthma. However, there is little known about the association of onset-age phenotype and air pollution. In this population-based study, we aimed to determine the association of asthma severity outcomes and air pollution regarding age at onset of asthma.
Methods
In 2004, we conducted a cross-sectional questionnaire survey about respiratory health among schoolchildren’s parents randomly selected from 94 of 816 elementary and middle schools in southern Taiwan. Participants ever having typical asthma symptoms were enrolled. We used kriging method to estimate individual exposure to ambient air pollution in the preceding year before the year of asthma severity survey. Ordered logistic regression was used to determine the association of exposure and asthma severity scores. Age at asthma onset of 12 years was used as a cut-off to define early- or late-onset asthma.
Results
The study surveyed 35,682 participants. Data from 23,551 participants remained satisfactory with a response rate of 66 %. Among 20,508 participants aged 26–50 years, 703 questionnaire-determined asthmatics were identified and included for analysis. Using the median of PM10 (66 μg/m3) as a cut-off, those exposed to higher PM10 were more likely to have higher severity scores (OR = 1.74; 95 % CI, 1.13 – 2.70) only for asthmatics with asthma onset at > 12 years.
Conclusions
In adulthood, exposure to PM10 has a greater effect on late-onset asthma than early-onset asthma and deserves greater attention among ambient air pollutants.
Electronic supplementary material
The online version of this article (doi:10.1186/s12890-016-0218-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12890-016-0218-0
PMCID: PMC4837625  PMID: 27094099
Adult asthma; Air pollution; Particulate matter; Phenotype
2.  Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs 
Nature Communications  2016;7:11215.
Circular RNAs (circRNAs) represent a class of widespread and diverse endogenous RNAs that may regulate gene expression in eukaryotes. However, the regulation and function of human circRNAs remain largely unknown. Here we generate ribosomal-depleted RNA sequencing data from six normal tissues and seven cancers, and detect at least 27,000 circRNA candidates. Many of these circRNAs are differently expressed between the normal and cancerous tissues. We further characterize one abundant circRNA derived from Exon2 of the HIPK3 gene, termed circHIPK3. The silencing of circHIPK3 but not HIPK3 mRNA significantly inhibits human cell growth. Via a luciferase screening assay, circHIPK3 is observed to sponge to 9 miRNAs with 18 potential binding sites. Specifically, we show that circHIPK3 directly binds to miR-124 and inhibits miR-124 activity. Our results provide evidence that circular RNA produced from precursor mRNA may have a regulatory role in human cells.
Circular RNAs are formed from exon back-splicing, the significance of these endogenous RNAs is beginning to be unraveled. Here, the authors identify thousands of circular RNAs differentially expressed between normal and cancer tissues and show that an abundant circular RNA generated from HIPK3 regulates cell growth.
doi:10.1038/ncomms11215
PMCID: PMC4823868  PMID: 27050392
3.  Genome-wide identification and developmental expression profiling of long noncoding RNAs during Drosophila metamorphosis 
Scientific Reports  2016;6:23330.
An increasing number of long noncoding RNAs (lncRNAs) have been discovered with the recent advances in RNA-sequencing technologies. lncRNAs play key roles across diverse biological processes, and are involved in developmental regulation. However, knowledge about how the genome-wide expression of lncRNAs is developmentally regulated is still limited. We here performed a whole-genome identification of lncRNAs followed by a global expression profiling of these lncRNAs during development in Drosophila melanogaster. We combined bioinformatic prediction of lncRNAs with stringent filtering of protein-coding transcripts and experimental validation to define a high-confidence set of Drosophila lncRNAs. We identified 1,077 lncRNAs in the given transcriptomes that contain 43,967 transcripts; among these, 646 lncRNAs are novel. In vivo expression profiling of these lncRNAs in 27 developmental processes revealed that the expression of lncRNAs is highly temporally restricted relative to that of protein-coding genes. Remarkably, 21% and 42% lncRNAs were significantly upregulated at late embryonic and larval stage, the critical time for developmental transition. The results highlight the developmental specificity of lncRNA expression, and reflect the regulatory significance of a large subclass of lncRNAs for the onset of metamorphosis. The systematic annotation and expression analysis of lncRNAs during Drosophila development form the foundation for future functional exploration.
doi:10.1038/srep23330
PMCID: PMC4800424  PMID: 26996731
4.  The miR-20-Rest-Wnt signaling axis regulates neural progenitor cell differentiation 
Scientific Reports  2016;6:23300.
Increasing evidence suggests that three dimensional (3-D) cell cultures are an improvement over traditional two dimensional (2-D) cell cultures. Current researches have extensively focused on the study of utilizing biomaterial-based 3-D culture systems to study and direct stem-cell fate both in vitro and in vivo. Here in our study, we screened the differential expression patterns of miRNAs between 2-D cultured and 3-D cultured NPCs using microarray analysis. Among these differentially expressed miRNAs, miR-20 was found to increase during differentiation of NPCs. Specifically, the facilitative effect on neural differentiation of miR-20 is mediated, at least in part by directly target the Rest gene, which is essential for preventing neural differentiation and maintaining NPCs self-renewal. Furthermore, the expression of miR-20 was decreased when the WNT pathway was inhibited by knock down of β-catenin or by exogenous Dkk protein, whereas it increased when the WNT pathway was activated by exogenous Wnt3a protein. Overall, miR-20, Rest and Wnt signaling are suggested to be involved in a regulatory circuit that can modulate the neural differention of NPCs. This novel regulatory circuit provides additional insight into how microRNAs interact with signaling molecules during neural differentiation of NPCs, allowing for fine-tuning of intricate cellular processes.
doi:10.1038/srep23300
PMCID: PMC4800422  PMID: 26996236
5.  Antiallergic Phorbol Ester from the Seeds of Aquilaria malaccensis 
The Aquilaria malaccensis (Thymelaeaceae) tree is a source of precious fragrant resin, called agarwood, which is widely used in traditional medicines in East Asia against diseases such as asthma. In our continuous search for active natural products, A. malaccensis seeds ethanolic extract demonstrated antiallergic effect with an IC50 value less than 1 µg/mL. Therefore, the present research aimed to purify and identify the antiallergic principle of A. malaccensis through a bioactivity-guided fractionation approach. We found that phorbol ester-rich fraction was responsible for the antiallergic activity of A. malaccensis seeds. One new active phorbol ester, 12-O-(2Z,4E,6E)-tetradeca-2,4,6-trienoylphorbol-13-acetate, aquimavitalin (1) was isolated. The structure of 1 was assigned by means of 1D and 2D NMR data and high-resolution mass spectrometry (HR-MS). Aquimavitalin (1) showed strong inhibitory activity in A23187- and antigen-induced degranulation assay with IC50 values of 1.7 and 11 nM, respectively, with a therapeutic index up to 71,000. The antiallergic activities of A. malaccensis seeds and aquimavitalin (1) have never been revealed before. The results indicated that A. malaccensis seeds and the pure compound have the potential for use in the treatment of allergy.
doi:10.3390/ijms17030398
PMCID: PMC4813253  PMID: 27007372
Aquilaria malaccensis seeds; antiallergic; degranulation; phorbol ester; bioactivity-guided fractionation
6.  A collagen-binding EGFR antibody fragment targeting tumors with a collagen-rich extracellular matrix 
Scientific Reports  2016;6:18205.
Many tumors over-express collagen, which constitutes the physical scaffold of tumor microenvironment. Collagen has been considered to be a target for cancer therapy. The collagen-binding domain (CBD) is a short peptide, which could bind to collagen and achieve the sustained release of CBD-fused proteins in collagen scaffold. Here, a collagen-binding EGFR antibody fragment was designed and expressed for targeting the collagen-rich extracellular matrix in tumors. The antibody fragment (Fab) of cetuximab was fused with CBD (CBD-Fab) and expressed in Pichia pastoris. CBD-Fab maintained antigen binding and anti-tumor activity of cetuximab and obtained a collagen-binding ability in vitro. The results also showed CBD-Fab was mainly enriched in tumors and had longer retention time in tumors in A431 s.c. xenografts. Furthermore, CBD-Fab showed a similar therapeutic efficacy as cetuximab in A431 xenografts. Although CBD-Fab hasn’t showed better therapeutic effects than cetuximab, its smaller molecular and special target may be applicable as antibody–drug conjugates (ADC) or immunotoxins.
doi:10.1038/srep18205
PMCID: PMC4756367  PMID: 26883295
7.  Protective Efficacy of Adenovirus/Protein Vaccines Against SIV Challenges in Rhesus Monkeys 
Science (New York, N.Y.)  2015;349(6245):320-324.
Preclinical studies of viral vector-based HIV-1 vaccine candidates have previously shown partial protection against stringent virus challenges in rhesus monkeys. In this study, we evaluated the protective efficacy of adenovirus serotype 26 (Ad26) vector priming followed by boosting with a purified envelope (Env) glycoprotein. Rhesus monkeys primed with Ad26 vectors expressing SIVsmE543 Env/Gag/Pol antigens and boosted with AS01B-adjuvanted SIVmac32H Env gp140 demonstrated complete protection in 50% of vaccinated animals against a series of repetitive, heterologous, intrarectal SIVmac251 challenges that infected all controls. Protective efficacy correlated with the functionality of Env-specific antibody responses. Comparable protection was also observed with a similar Ad/Env vaccine against repetitive, heterologous, intrarectal SHIV-SF162P3 challenges. These data demonstrate robust protection by Ad/Env vaccines against acquisition of stringent virus challenges in rhesus monkeys.
doi:10.1126/science.aab3886
PMCID: PMC4653134  PMID: 26138104
8.  Study of transpedicular screw fixation on spine development in a piglet model 
Background
Transpedicular screws may cause damage to the cartilage in the neural arch of the vertebra, and give continuous pressure to the skeleton besides the vertebral body. The aim of this study is to examine the morphological change of the vertebral body at fixation sites and development of the vertebral body after fixation.
Methods
A piglet model was used to study the influence of transpedicular screw fixation on spine development. Transpedicular screw fixation was adjusted to meet specific requirements of surgery on piglet. The screws and plates were placed at L1–L3 vertebral plates via routine surgical approach. Scoliosis and kyphosis Cobb angles were measured.
Results
Anatomical characteristics of 6-week-old piglets fit the transpedicular screw system, and can meet the requirements of related studies. Transpedicular screw fixation system has no significant influence on the development of canalis vertebralis. Fixation did not cause developmental stenosis of canalis vertebralis and damage to spinal cord or nerve root. However, transpedicular screw fixation significantly impacted the development of the spine: it shortened the spine by curtailing the length of the vertebral body and intervertebral space. Our results also suggested that slow growth of epiphyseal plate may contribute to the shortening of the vertebral body.
Conclusion
Transpedicular screw fixation system is beneficial for fixation of the developing spine. It may not cause scoliosis but could lead to change of cervical curvature.
doi:10.1186/s13018-015-0302-9
PMCID: PMC4712474  PMID: 26762190
Transpedicular screw fixation; Spine development; A piglet model; Canalis vertebralis
9.  Effect of the cytoplasmic domain on antigenic characteristics of HIV-1 envelope glycoprotein 
Science (New York, N.Y.)  2015;349(6244):191-195.
A major goal for HIV-1 vaccine development is the production of an immunogen to mimic native, functional HIV-1 envelope trimeric spikes (Env) on the virion surface. We lack a reliable description of a native, functional trimer, however, because of inherent instability and heterogeneity in most preparations. We describe here two conformationally homogeneous Envs derived from difficult-to-neutralize primary isolates. All their non-neutralizing epitopes are fully concealed and independent of their proteolytic processing. Most broadly neutralizing antibodies (bnAbs) recognize these native trimers. Truncation of their cytoplasmic tail has little effect on membrane fusion, but it diminishes binding to trimer-specific bnAbs while exposing non-neutralizing epitopes. These results yield a more accurate antigenic picture than hitherto possible of a genuinely untriggered and functional HIV-1 Env; they can guide effective vaccine development.
doi:10.1126/science.aaa9804
PMCID: PMC4701381  PMID: 26113642
10.  Melodic Pitch Perception and Lexical Tone Perception in Mandarin-Speaking Cochlear Implant Users 
Ear and hearing  2015;36(1):102-110.
Objectives
To examine the relationship between lexical tone perception and melodic pitch perception in Mandarin-speaking cochlear implant (CI) users, and to investigate the influence of previous acoustic hearing on CI users’ speech and music perception.
Design
Lexical tone perception and melodic contour identification (MCI) were measured in 21 prelingual and 11 postlingual young (age: 6–26 years old) Mandarin-speaking CI users. Lexical tone recognition was measured for four tonal patterns: Tone 1 (flat F0), Tone 2 (rising F0), Tone 3 (falling-rising F0), and Tone 4 (falling F0). MCI was measured using 9 five-note melodic patterns that contained changes in pitch contour, as well as different semitone spacing between notes.
Results
Lexical tone recognition was generally good (overall mean = 81% correct), and there was no significant difference between subject groups. MCI performance was generally poor (mean = 23% correct). MCI performance was significantly better for postlingual (mean = 32% correct) than for prelingual CI participants (18% correct). After correcting for outliers, there was no significant correlation between lexical tone recognition and MCI performance for prelingual or post-lingual CI participants. Age at deafness was significantly correlated with MCI performance only for postlingual participants. CI experience was significantly correlated with MCI performance for both prelingual and postlingual participants. Duration of deafness was significantly correlated with tone recognition only for prelingual participants.
Conclusions
Despite the prevalence of pitch cues in Mandarin, the present CI participants had great difficulty perceiving melodic pitch. The availability of amplitude and duration cues in lexical tones most likely compensated for the poor pitch perception observed with these CI listeners. Previous acoustic hearing experience seemed to benefit postlingual CI users’ melodic pitch perception. Longer CI experience was associated with better MCI performance for both subject groups, suggesting that CI users’ music perception may improve as they gain experience with their device.
doi:10.1097/AUD.0000000000000086
PMCID: PMC4272610  PMID: 25099401
11.  Suicide and Ambient Temperature in East Asian Countries: A Time-Stratified Case-Crossover Analysis 
Background
A limited number of studies suggest that ambient temperature contributes to suicide; these studies typically focus on a single nation and use temporally and spatially aggregated data.
Objective
We evaluated the association between ambient temperature and suicide in multiple cities in three East Asian countries.
Methods
A time-stratified case-crossover method was used to explore the relationship between temperature and suicide, adjusting for potential time-varying confounders and time-invariant individual characteristics. Sex- and age-specific associations of temperature with suicide were estimated, as were interactions between temperature and these variables. A random-effects meta-analysis was used to estimate country-specific pooled associations of temperature with suicide.
Results
An increase in temperature corresponding to half of the city-specific standard deviation was positively associated with suicide in most cities, although average suicide rates varied substantially. Pooled country-level effect estimates were 7.8% (95% CI: 5.0, 10.8%) for a 2.3°C increase in ambient temperature in Taiwan, 6.8% (95% CI: 5.4, 8.2%) for a 4.7°C increase in Korea, and 4.5% (95% CI: 3.3, 5.7%) for a 4.2°C increase in Japan. The association between temperature and suicide was significant even after adjusting for sunshine duration; the association between sunshine and suicide was not significant. The associations were greater among men than women in 12 of the 15 cities although not significantly so. There was little evidence of a consistent pattern of associations with age. In general, associations were strongest with temperature on the same day or the previous day, with little evidence of associations with temperature over longer lags (up to 5 days).
Conclusions
We estimated consistent positive associations between suicide and elevated ambient temperature in three East Asian countries, regardless of country, sex, and age.
Citation
Kim Y, Kim H, Honda Y, Guo YL, Chen BY, Woo JM, Ebi KL. 2016. Suicide and ambient temperature in East Asian countries: a time-stratified case-crossover analysis. Environ Health Perspect 124:75–80; http://dx.doi.org/10.1289/ehp.1409392
doi:10.1289/ehp.1409392
PMCID: PMC4710603  PMID: 26069051
12.  Optimizing a Male Reproductive Aging Mouse Model by d-Galactose Injection 
The d-galactose (d-gal)-injected animal model, which is typically established by administering consecutive subcutaneous d-gal injections to animals for approximately six or eight weeks, has been frequently used for aging research. In addition, this animal model has been demonstrated to accelerate aging in the brain, kidneys, liver and blood cells. However, studies on aging in male reproductive organs that have used this animal model remain few. Therefore, the current study aimed to optimize a model of male reproductive aging by administering d-gal injections to male mice and to determine the possible mechanism expediting senescence processes during spermatogenesis. In this study, C57Bl/6 mice were randomized into five groups (each containing 8–10 mice according to the daily intraperitoneal injection of vehicle control or 100 or 200 mg/kg dosages of d-gal for a period of six or eight weeks). First, mice subjected to d-gal injections for six or eight weeks demonstrated considerably decreased superoxide dismutase activity in the serum and testis lysates compared to those in the control group. The lipid peroxidation in testis also increased in the d-gal-injected groups. Furthermore, the d-gal-injected groups exhibited a decreased ratio of testis weight/body weight and sperm count compared to the control group. The percentages of both immotile sperm and abnormal sperm increased considerably in the d-gal-injected groups compared to those of the control group. To determine the genes influenced by the d-gal injection during murine spermatogenesis, a c-DNA microarray was conducted to compare testicular RNA samples between the treated groups and the control group. The d-gal-injected groups exhibited RNA transcripts of nine spermatogenesis-related genes (Cycl2, Hk1, Pltp, Utp3, Cabyr, Zpbp2, Speer2, Csnka2ip and Katnb1) that were up- or down-regulated by at least two-fold compared to the control group. Several of these genes are critical for forming sperm-head morphologies or maintaining nuclear integration (e.g., cylicin, basic protein of sperm head cytoskeleton 2 (Cylc2), casein kinase 2, alpha prime interacting protein (Csnka2ip) and katanin p80 (WD40-containing) subunit B1 (Katnb1)). These results indicate that d-gal-injected mice are suitable for investigating male reproductive aging.
doi:10.3390/ijms17010098
PMCID: PMC4730340  PMID: 26771610
aging; male infertility; mouse model
13.  Roles of palmitoylation and the KIKK membrane-targeting motif in leukemogenesis by oncogenic KRAS4A 
Background
We have previously shown that palmitoylation is essential for NRAS leukemogenesis, suggesting that targeting RAS palmitoylation may be an effective therapy for NRAS-related cancers. For KRAS-driven cancer, although much research has been focused on the KRAS4B splice variant, which does not undergo palmitoylation, KRAS4A has recently been shown to play an essential role in the development of carcinogen-induced lung cancer in mice and to be widely expressed in human cancers. However, the role of palmitoylation in KRAS4A tumorigenesis is not clear.
Methods
The expression of KRAS4A in KRAS-mutated leukemia cell lines and acute myeloid leukemia (AML) cells were checked using western blotting and reverse transcriptions-quantitative polymerase chain reaction (RT-qPCR) analysis, respectively. The leukemogenic potentials of oncogenic KRAS4A and its palmitoylation-defective mutants were examined by a mouse bone marrow transduction and transplantation model and the in vitro transformation assays. The activation of the RAS downstream signaling pathways and the membrane localizations of the KRAS4A and its mutants were analyzed via western blot analysis and confocal microscopy, respectively.
Results
We show here that KRAS4A is expressed in human leukemia cell lines and in AML cells harboring KRAS mutations and that mutation at the palmitoylation site of oncogenic KRAS4A significantly abrogates its leukemogenic potential. However, unlike NRAS, palmitoylation-defective KRAS4A still induces leukemia in mice, albeit with a much longer latency. Using NRAS/KRAS4A chimeric constructs, we found that the KIKK motif of KRAS4A contributes to the transforming activity of KRAS4A. Mutations at both palmitoylation site and the KIKK motif abolish the ability of oncogenic KRAS4A to induce leukemia in mice.
Conclusions
Our studies suggest that therapies targeting RAS palmitoylation may also be effective in treating KRAS4A associated malignancies and that interfering the KIKK membrane-targeting motif would enhance the therapeutic effectiveness.
doi:10.1186/s13045-015-0226-1
PMCID: PMC4696201  PMID: 26715448
RAS; Leukemogenesis; Drug target; Plasma membrane translocation; Signal transduction
14.  Individual Variability and Test-Retest Reliability Revealed by Ten Repeated Resting-State Brain Scans over One Month 
PLoS ONE  2015;10(12):e0144963.
Individual differences in mind and behavior are believed to reflect the functional variability of the human brain. Due to the lack of a large-scale longitudinal dataset, the full landscape of variability within and between individual functional connectomes is largely unknown. We collected 300 resting-state functional magnetic resonance imaging (rfMRI) datasets from 30 healthy participants who were scanned every three days for one month. With these data, both intra- and inter-individual variability of six common rfMRI metrics, as well as their test-retest reliability, were estimated across multiple spatial scales. Global metrics were more dynamic than local regional metrics. Cognitive components involving working memory, inhibition, attention, language and related neural networks exhibited high intra-individual variability. In contrast, inter-individual variability demonstrated a more complex picture across the multiple scales of metrics. Limbic, default, frontoparietal and visual networks and their related cognitive components were more differentiable than somatomotor and attention networks across the participants. Analyzing both intra- and inter-individual variability revealed a set of high-resolution maps on test-retest reliability of the multi-scale connectomic metrics. These findings represent the first collection of individual differences in multi-scale and multi-metric characterization of the human functional connectomes in-vivo, serving as normal references for the field to guide the use of common functional metrics in rfMRI-based applications.
doi:10.1371/journal.pone.0144963
PMCID: PMC4694646  PMID: 26714192
16.  Modification of sperm morphology during long-term sperm storage in the reproductive tract of the Chinese soft-shelled turtle, Pelodiscus sinensis 
Scientific Reports  2015;5:16096.
Sperm storage in vivo extends the time window for fertilisation in several animal species, from a few days to several years. The underlying storage mechanisms, however, are largely unknown. In this study, spermatozoa from the epididymis and oviduct of Chinese soft-shelled turtles were investigated to identify potentially relevant morphological features and transformations at different stages of sperm storage. Large cytoplasmic droplets (CDs) containing lipid droplets (LDs) were attached to the midpiece of most spermatozoa in the epididymis, without migrating down the sperm tail. However, they were absent from the oviductal spermatozoa, suggesting that CDs with LDs may be a source of endogenous energy for epididymal spermatozoa. The onion-like mitochondria recovered their double-membrane morphology, with typical cristae, within the oviduct at a later stage of storage, thus implying that mitochondrial metabolism undergoes alterations during storage. Furthermore, a well developed fibrous sheath on the long principal piece was the integrating ultrastructure for glycolytic enzymes and substrates. These novel morphological characteristics may allow turtle spermatozoa to use diverse energy metabolism pathways at different stages of storage.
doi:10.1038/srep16096
PMCID: PMC4633597  PMID: 26537569
17.  Effect of Cellular Location of Human Carboxylesterase 2 on CPT-11 Hydrolysis and Anticancer Activity 
PLoS ONE  2015;10(10):e0141088.
CPT-11 is an anticancer prodrug that is clinically used for the treatment of metastatic colorectal cancer. Hydrolysis of CPT-11 by human carboxylesterase 2 (CE2) generates SN-38, a topoisomerase I inhibitor that is the active anti-tumor agent. Expression of CE2 in cancer cells is under investigation for the tumor-localized activation of CPT-11. CE2 is normally expressed in the endoplasmic reticulum of cells but can be engineered to direct expression of active enzyme on the plasma membrane or as a secreted form. Although previous studies have investigated different locations of CE2 expression in cancer cells, it remains unclear if CE2 cellular location affects CPT-11 anticancer activity. In the present study, we directly compared the influence of CE2 cellular location on substrate hydrolysis and CPT-11 cytotoxicity. We linked expression of CE2 and enhanced green fluorescence protein (eGFP) via a foot-and-mouth disease virus 2A (F2A) peptide to facilitate fluorescence-activated cell sorting to achieve similar expression levels of ER-located, secreted or membrane-anchored CE2. Soluble CE2 was detected in the medium of cells that expressed secreted and membrane-anchored CE2, but not in cells that expressed ER-retained CE2. Cancer cells that expressed all three forms of CE2 were more sensitive to CPT-11 as compared to unmodified cancer cells, but the membrane-anchored and ER-retained forms of CE2 were consistently more effective than secreted CE2. We conclude that expression of CE2 in the ER or on the membrane of cancer cells is suitable for enhancing CPT-11 anticancer activity.
doi:10.1371/journal.pone.0141088
PMCID: PMC4624787  PMID: 26509550
18.  Danhong injection in the treatment of chronic stable angina: study protocol for a randomized controlled trial 
Trials  2015;16:474.
Background
Chronic stable angina is a leading cause of death worldwide. Danhong injection, a complementary alternative medicine for chronic stable angina, has been demonstrated to be effective in numerous studies and is widely prescribed to patients. However, the methodological quality of most prior studies was found to be, in general, low. Therefore, we designed this randomized controlled trial to evaluate the efficacy and safety of using Danhong injection to treat chronic stable angina.
Methods/design
This is a randomized multicentre, double-blind, placebo-controlled, adaptive clinical trial. A total of 870 patients meeting the eligibility criteria will be randomly assigned into either the Danhong injection or the placebo group in a 2:1 ratio. Participants will then undergo a 2-week treatment regimen and a 76-day follow-up period. Because this is an adaptive trial, two interim analyses are prospectively planned. These will be performed after one-third and two-thirds of the patients, respectively, have completed the trial. Based on the results of these interim analyses, a data monitoring committee will determine how to modify aspects of the study without undermining the validity and integrity of the trial. The primary outcome measure is the proportion of patients who show a clinically significant change, which is defined as at least a 20-point improvement in angina frequency score on the Seattle Angina Questionnaire, which will be administered on day 30. Other secondary efficacy and safety outcomes will also be assessed.
Discussion
This trial will provide high-quality evidence regarding the use of Danhong injection to treat chronic stable angina.
Trial registration
ClinicalTrials.gov: NCT01681316.
doi:10.1186/s13063-015-0998-1
PMCID: PMC4618746  PMID: 26489511
Chinese medicine; Chronic stable angina; Danhong injection; Randomized controlled trial
19.  Combination of BCL-2 and MYC protein expression improves high-risk stratification in diffuse large B-cell lymphoma 
OncoTargets and therapy  2015;8:2645-2650.
Purpose
To evaluate whether the addition of two biological markers (MYC and BCL-2 protein overexpression) improves the stratification of high-risk patients with diffuse large B-cell lymphoma (DLBCL).
Method
Seven risk factors were identified at diagnosis, and a maximum of 7 points were assigned to each patient. The patients were classified according to four risk groups: low (0–1), low-intermediate (2–3), high-intermediate (4), and high (5–7). Only high-risk patients with DLBCL were included in this analysis. We retrospectively examined 20 cases from 2008 to 2013 at the Nanjing Drum Tower Hospital.
Results
The median expression of MYC protein was 60%, and 17 of 20 (65%) evaluable cases overexpressed MYC. The median expression of BCL-2 protein was also 60%. Eighteen of 20 (90%) evaluable cases showed BCL-2 overexpression. Additionally, 12 out of 20 cases (60%) demonstrated coexpression of MYC and BCL-2 proteins. The percentages of overall survival and progression-free survival at the median follow-up time (36 months) were 33.3%±16.1% and 16.9%±13.5%, respectively. By comparison, nine, four, and 20 patients were classified as high risk based on the International Prognostic Index (IPI), National Comprehensive Cancer Network(NCCN)-IPI, and revised IPI criteria, respectively. According to the IPI and NCCN-IPI stratification, the risk groups demonstrated closely overlapping survival curves. In addition, four out of 20 cases were identified as low-intermediate risk according to the NCCN-IPI criteria.
Conclusion
The addition of MYC and BCL-2 protein expression to the IPI could identify a subset of DLBCL patients with high-risk clinicopathological characteristics and poor clinical outcome.
doi:10.2147/OTT.S86093
PMCID: PMC4583112  PMID: 26425100
diffuse large B-cell lymphoma; MYC; BCL-2; International Prognostic Index
20.  Effect of Traditional Chinese Exercise on Gait and Balance for Stroke: A Systematic Review and Meta-Analysis 
PLoS ONE  2015;10(8):e0135932.
Objective
A systematic review is conducted to determine the effect of traditional Chinese exercise for patients with stroke.
Methods
Studies are obtained from PubMed, Embase, Cochrane Library, EBSCO, Web of Science, and CNKI. Only randomized controlled trials were left to evaluate the effects of traditional Chinese exercise for patients with stroke, and with no limits on study data or language. The primary outcome was the Berg balance score (BBS), Functional walking scale. And a random-effects model was used to calculate the pooled mean difference (MD) with 95% confidence interval (CI).
Results
A total of 9 studies on 820 participants conform to the inclusion criteria, whereas eight studies on 704 participants are used as data sources for the meta-analysis, all trials were published between 2004 and 2013. The BBS indicates that the efficacy of traditional Chinese exercise on balance of patients with stroke is better than that of other training or no training in short term [MD (95%CI) = 11.85 [5.41, 18.30], P < 0.00001]. And the short physical performance battery, Functional walking scale, limit of stability were observed significant differences on balance (p<0.05) and gait (p<0.05) between traditional Chinese exercise and other exercises or no exercise. In addition, there is an article showed that some other form (physiotherapy exercises focused on balance) significantly improved balance ability for stroke patients compared to tai chi chuan practice (Berg test = 0.01, Romberg, and standing on one leg).
Conclusion
In our meta analysis, the positive findings of this study suggest traditional Chinese exercise has beneficial effects on the balance ability in short term. However, we drew the conclusion according to the extreme heterogeneity, and evidence of better quality and from a larger sample size is required. Because of the inconsistent outcomes, there are short of enough good evidence for patients with stroke to prove the effects of traditional Chinese exercise on gait.
Systematic Review Registration
http://www.crd.york.ac.uk/PROSPERO PROSPERO registration number: CRD42013006474.
doi:10.1371/journal.pone.0135932
PMCID: PMC4546302  PMID: 26291978
21.  Exenatide once-weekly injection for the treatment of type 2 diabetes in Chinese patients: current perspectives 
Glucagon-like peptide-1 (GLP-1) analogs, such as exenatide, have played an important role as antidiabetic medications in the treatment of type 2 diabetes (T2DM). Like most other hypoglycemic agents, exenatide has a number of actions, including lowering blood glucose, promoting weight loss, improving insulin resistance, and protecting islet β-cells. Although GLP-1 analogs, combined with other antidiabetic medications, have excellent performance in T2DM, some side effects and imperfections limit its use in clinical practice. Since 2012, a new generation GLP-1 agent, exenatide once weekly (QW), has been available for patients with T2DM in the USA, but not as yet in the People’s Republic of China. Previous data indicate that exenatide QW achieves better fasting glucose reductions than sitagliptin or exenatide twice daily, whilst appearing non-inferior to pioglitazone and achieving less reductions than insulin glargine. Exenatide QW was better at improving average postprandial glucose than sitagliptin or titrated insulin glargine, but was inferior to exenatide twice daily. Additionally exenatide QW has a better effect in terms of weight loss than other glycemic medications. Exenatide QW can also reduce blood lipids and lower blood pressure. Accordingly, exenatide QW is cost-effective, achieves good clinical outcomes, and has acceptable side effects, indicating that it has promising prospects for future use in the People’s Republic of China.
doi:10.2147/TCRM.S81088
PMCID: PMC4539087  PMID: 26309403
diabetes; glycemic control; exenatide once weekly
22.  Fish Oil Supplementation does not Reduce Risks of Gestational Diabetes Mellitus, Pregnancy-Induced Hypertension, or Pre-Eclampsia: A Meta-Analysis of Randomized Controlled Trials 
Background
The effects of gestational supplementation with fish oil on risks for gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), and pre-eclampsia (PE) have not been confirmed. In this study, a meta-analysis was performed to evaluate the effect of fish oil supplementation on these gestational complications.
Material/Methods
Randomized controlled human trials that investigated the effects of fish oil supplementation in pregnant women were identified by a systematic search of Medline, Embase, and Cochrane’s Library, and references of related reviews and studies up to December 2014. Relative risks (RRs) for GDM, PIH, and PE were the outcomes of interest. Fixed-effects or random-effects models were applied according to the heterogeneity.
Results
Thirteen comparisons from 11 published articles, including more than 5000 participants, were included. The results showed that fish oil supplementation was not associated with reduced risks for GDM (RR=1.06, 95% confidence interval [CI]: 0.85–1.32, p=0.60), PIH (RR=1.03, 95% CI: 0.89–1.20, p=0.66), or PE (RR=0.93, 95% CI: 0.74–1.16, p=0.51). No statistically significant heterogeneity was detected for the comparison of each outcome. The effects of fish oil on these gestational complications were consistent between women with low-risk and high-risk pregnancies.
Conclusions
Gestational supplementation with fish oil during the second or third trimester of pregnancy is not associated with reduced risks for GDM, PIH, or PE. Other possible benefits of fish oil supplementation during pregnancy warrant further evaluation.
doi:10.12659/MSM.894033
PMCID: PMC4544354  PMID: 26256041
Diabetes, Gestational; Fish Oils; Pre-Eclampsia
23.  Inhibition of lung cancer cells A549 and H460 by curcuminoid extracts and nanoemulsions prepared from Curcuma longa Linnaeus 
The objectives of this study were to explore the inhibition mechanism of lung cancer cells A549 and H460 by curcuminoid extracts and nanoemulsions prepared from Curcuma longa Linnaeus. In addition, human bronchus epithelial cell line BEAS-2B (normal cell) was selected for comparison. A high-performance liquid chromatography (HPLC) method was developed to separate and quantify the various curcuminoids in C. longa extract, including curcumin (1,714.5 μg/mL), demethoxycurcumin (1,147.4 μg/mL), and bisdemethoxycurcumin (190.2 μg/mL). A high-stability nanoemulsion composed of Tween 80, water, and curcuminoid extract was prepared, with mean particle size being 12.6 nm. The cell cycle was retarded at G2/M for both the curcuminoid extract and nanoemulsion treatments; however, the inhibition pathway may be different. H460 cells were more susceptible to apoptosis than A549 cells for both curcuminoid extract and nanoemulsion treatments. Growth of BEAS-2B remained unaffected for both the curcuminoid extract and nanoemulsion treatments, with a concentration range from 1 to 4 μg/mL. Also, the activities of caspase-3, caspase-8, and caspase-9 followed a dose-dependent increase for both A549 and H460 cells for both the treatments, accompanied by a dose-dependent increase in cytochrome C expression and a dose-dependent decrease in CDK1 expression. Interestingly, a dose-dependent increase in cyclin B expression was shown for A549 cells for both the treatments, while a reversed trend was found for H460 cells. Both mitochondria and death receptor pathways may be responsible for apoptosis of both A549 and H460 cells.
doi:10.2147/IJN.S87225
PMCID: PMC4531038  PMID: 26345201
curcuminoid extract; curcuminoid nanoemulsion; Curcuma longa Linnaeus; lung cancer cell; cell cycle; apoptosis mechanism
24.  Whole-Body Vibration Exercise for Knee Osteoarthritis: A Systematic Review and Meta-Analysis 
Objectives. To assess the effects of WBV exercise on patients with KOA. Methods. Eight databases including Pubmed, EMBASE, Cochrane Library, CINAHL, Web of Science, the Physiotherapy Evidence Database, CNKI, and Wanfang were searched up to November 2014. Randomized controlled trials (RCTs) of WBV for KOA were eligible. The outcomes were pain intensity, functional performances, self-reported status, adverse events, and muscle strength. A meta-analysis was conducted. Results. Five trials with 168 participants provided data for the meta-analysis. No significant difference was shown in pain intensity and self-reported status between WBV and other forms of exercise. Improvement in functional performance (evaluated by BBS; WMD, 2.96; 95% CI, 1.29 to 4.62; P = 0.0005) was greater in WBV group, but the other parameters of functional performance (including 6MWT and TGUG) revealed no statistically significant difference. Adverse events were only reported in one trial and no significant difference was discovered in muscle strength. The overall quality of evidence was very low. Conclusion. Currently there is only limited evidence that suggested that WBV is effective in the treatment of KOA. Large, well-designed RCTs with better designs are needed.
doi:10.1155/2015/758147
PMCID: PMC4540999  PMID: 26347287
25.  Composite primary breast diffuse large B-cell lymphoma and T lymphoblastic leukemia/lymphoma: report of a case and review of literature 
We reported a rare case of composite diffuse large B-cell lymphoma and T lymphoblastic leukemia/lymphoma (T-LBL) in a 46-year-old woman with progressive enlargement of the breast lump. The patient initially sought care at a local hospital with a single left breast lump without any other physical examination findings. Histopathological analysis of which revealed a diffuse infiltration of tumor cells that were rich in cytoplasm with vesicular chromatin and prominent nucleoli. Further analysis of immunohistochemistry showed a cluster of neoplastic cells which express B-cell markers: CD19, CD20 (weak), CD79a, PAX5 and BCL-2, but negative for T-cell markers such as CD2, CD3, CD5 and CD7. PET-CT showed evidence of lymphadenopathy and splenomegaly, which may indicate lymphoma infiltration. Then a biopsy of bone marrow showed typical features of T-LBL. The aberrant terminal deoxynucleotidyl transferase (TDT) and cCD3 positive T-cell population that lack surface CD10 and CD19 were identified by flow cytometric immunophenotyping. Polymerase chain reaction analysis of the T-cell receptor gamma gene and IgH gene revealed a clonal rearrangement and confirming T-cell clonality. Fluorescence in-situ hybridization (FISH) revealed a deletion of the P53 gene in these T-neoplastic cells may indicate a bad outcome of such disease. Neither the large B-cells nor T-cells were positive for Epstein-Barr virus encoded RNA.
PMCID: PMC4583961  PMID: 26464729
Composite lymphoma; primary breast diffuse large B-cell lymphoma; T-lyphoblastic leukimia/lymphoma

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