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1.  Alcohol consumption in 0.5 million people from 10 diverse regions of China: prevalence, patterns and socio-demographic and health-related correlates 
Millwood, Iona Y | Li, Liming | Smith, Margaret | Guo, Yu | Yang, Ling | Bian, Zheng | Lewington, Sarah | Whitlock, Gary | Sherliker, Paul | Collins, Rory | Chen, Junshi | Peto, Richard | Wang, Hongmei | Xu, Jiujiu | He, Jian | Yu, Min | Liu, Huilin | Chen, Zhengming | Li, Liming | Chen, Zhengming | Chen, Junshi | Collins, Rory | Wu, Fan | Peto, Richard | Chen, Zhengming | Lancaster, Garry | Yang, Xiaoming | Williams, Alex | Smith, Margaret | Yang, Ling | Chang, Yumei | Millwood, Iona | Chen, Yiping | Zhang, Qiuli | Lewington, Sarah | Whitlock, Gary | Guo, Yu | Zhao, Guoqing | Bian, Zheng | Wu, Lixue | Hou, Can | Pang, Zengchang | Wang, Shaojie | Zhang, Yun | Zhang, Kui | Liu, Silu | Zhao, Zhonghou | Liu, Shumei | Pang, Zhigang | Feng, Weijia | Wu, Shuling | Yang, Liqiu | Han, Huili | He, Hui | Pan, Xianhai | Wang, Shanqing | Wang, Hongmei | Hao, Xinhua | Chen, Chunxing | Lin, Shuxiong | Hu, Xiaoshu | Zhou, Minghao | Wu, Ming | Wang, Yeyuan | Hu, Yihe | Ma, Liangcai | Zhou, Renxian | Xu, Guanqun | Dong, Baiqing | Chen, Naying | Huang, Ying | Li, Mingqiang | Meng, Jinhuai | Gan, Zhigao | Xu, Jiujiu | Liu, Yun | Wu, Xianping | Gao, Yali | Zhang, Ningmei | Luo, Guojin | Que, Xiangsan | Chen, Xiaofang | Ge, Pengfei | He, Jian | Ren, Xiaolan | Zhang, Hui | Mao, Enke | Li, Guanzhong | Li, Zhongxiao | He, Jun | Liu, Guohua | Zhu, Baoyu | Zhou, Gang | Feng, Shixian | Gao, Yulian | He, Tianyou | Jiang, Li | Qin, Jianhua | Sun, Huarong | Liu, Liqun | Yu, Min | Chen, Yaping | Hu, Zhixiang | Hu, Jianjin | Qian, Yijian | Wu, Zhiying | Chen, Lingli | Liu, Wen | Li, Guangchun | Liu, Huilin | Long, Xiangquan | Xiong, Youping | Tan, Zhongwen | Xie, Xuqiu | Peng, Yunfang
Background Drinking alcohol has a long tradition in Chinese culture. However, data on the prevalence and patterns of alcohol consumption in China, and its main correlates, are limited.
Methods During 2004–08 the China Kadoorie Biobank recruited 512 891 men and women aged 30–79 years from 10 urban and rural areas of China. Detailed information on alcohol consumption was collected using a standardized questionnaire, and related to socio-demographic, physical and behavioural characteristics in men and women separately.
Results Overall, 76% of men and 36% of women reported drinking some alcohol during the past 12 months, with 33% of men and 2% of women drinking at least weekly; the prevalence of weekly drinking in men varied from 7% to 51% across the 10 study areas. Mean consumption was 286 g/week and was higher in those with less education. Most weekly drinkers habitually drank spirits, although this varied by area, and beer consumption was highest among younger drinkers; 37% of male weekly drinkers (12% of all men) reported weekly heavy drinking episodes, with the prevalence highest in younger men. Drinking alcohol was positively correlated with regular smoking, blood pressure and heart rate. Among male weekly drinkers, each 20 g/day alcohol consumed was associated with 2 mmHg higher systolic blood pressure. Potential indicators of problem drinking were reported by 24% of male weekly drinkers.
Conclusion The prevalence and patterns of drinking in China differ greatly by age, sex and geographical region. Alcohol consumption is associated with a number of unfavourable health behaviours and characteristics.
PMCID: PMC3733702  PMID: 23918852
Alcohol; drinking; cohort study; descriptive analysis; China
2.  Generation of Med28 Specific Monoclonal Antibodies 
Med28 plays a role in transcription, signal transduction, and cell proliferation. The overexpression of med28 is associated with tumor progression in in vitro and in vivo models. Recently it has been reported that the elevated expression of med28 is associated with poor outcome in women with breast cancer. The expression level of med28 in in vitro and in vivo was examined by using anti-rabbit polyclonal antibody in previous reports. In this study, we report for the first time the generation and characterization of four monoclonal antibodies against med28 through immunoblotting, immunofluorescence microscopy, immunoprecipitation, and immunohistochemical analyses. These antibodies will be useful in detecting med28 in in vitro and in vivo.
PMCID: PMC4350139  PMID: 25723281
3.  cis p-tau: early driver of brain injury and tauopathy blocked by antibody 
Nature  2015;523(7561):431-436.
Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD), whose defining pathologic features include tauopathy made of phosphorylated tau (p-tau). However, tauopathy has not been detected in early stages after TBI and how TBI leads to tauopathy is unknown. Here we find robust cis p-tau pathology after sport- and military-related TBI in humans and mice. Acutely after TBI in mice and stress in vitro, neurons prominently produce cis p-tau, which disrupts axonal microtubule network and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, termed “cistauosis”, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis p-tau is a major early driver after TBI and leads to tauopathy in CTE and AD, and cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.
PMCID: PMC4718588  PMID: 26176913
4.  Low-photon-number optical switch and AND/OR logic gates based on quantum dot-bimodal cavity coupling system 
Scientific Reports  2016;6:19001.
We propose a new scheme based on quantum dot-bimodal cavity coupling system to realize all-optical switch and logic gates in low-photon-number regime. Suppression of mode transmission due to the destructive interference effect is theoretically demonstrated by driving the cavity with two orthogonally polarized pulsed lasers at certain pulse delay. The transmitted mode can be selected by designing laser pulse sequence. The optical switch with high on-off ratio emerges when considering one driving laser as the control. Moreover, the AND/OR logic gates based on photon polarization are achieved by cascading the coupling system. Both proposed optical switch and logic gates work well in ultra-low energy magnitude. Our work may enable various applications of all-optical computing and quantum information processing.
PMCID: PMC4707446  PMID: 26750557
5.  Hairy Canola (Brasssica napus) re-visited: Down-regulating TTG1 in an AtGL3-enhanced hairy leaf background improves growth, leaf trichome coverage, and metabolite gene expression diversity 
BMC Plant Biology  2016;16:12.
Through evolution, some plants have developed natural resistance to insects by having hairs (trichomes) on leaves and other tissues. The hairy trait has been neglected in Brassica breeding programs, which mainly focus on disease resistance, yield, and overall crop productivity. In Arabidopsis, a network of three classes of proteins consisting of TTG1 (a WD40 repeat protein), GL3 (a bHLH factor) and GL1 (a MYB transcription factor), activates trichome initiation and patterning. Introduction of a trichome regulatory gene AtGL3 from Arabidopsis into semi-glabrous Brassica napus resulted in hairy canola plants which showed tolerance to flea beetles and diamondback moths; however plant growth was negatively affected. In addition, the role of BnTTG1 transcription in the new germplasm was not understood.
Here, we show that two ultra-hairy lines (K-5-8 and K-6-3) with BnTTG1 knock-down in the hairy AtGL3+ B. napus background showed stable enhancement of trichome coverage, density, and length and restored wild type growth similar to growth of the semi-glabrous Westar plant. In contrast, over-expression of BnTTG1 in the hairy AtGL3+ B. napus background gave consistently glabrous plants of very low fertility and poor stability, with only one glabrous plant (O-3-7) surviving to the T3 generation. Q-PCR trichome gene expression data in leaf samples combining several leaf stages for these lines suggested that BnGL2 controlled B. napus trichome length and out-growth and that strong BnTTG1 transcription together with strong GL3 expression inhibited this process. Weak expression of BnTRY in both glabrous and trichome-bearing leaves of B. napus in the latter Q-PCR experiment suggested that TRY may have functions other than as an inhibitor of trichome initiation in the Brassicas. A role for BnTTG1 in the lateral inhibition of trichome formation in neighbouring cells was also proposed for B. napus. RNA sequencing of first leaves identified a much larger array of genes with altered expression patterns in the K-5-8 line compared to the hairy AtGL3+B. napus background (relative to the Westar control plant). These genes particularly included transcription factors, protein degradation and modification genes, but also included pathways that coded for anthocyanins, flavonols, terpenes, glucosinolates, alkaloids, shikimates, cell wall biosynthesis, and hormones. A 2nd Q-PCR experiment was conducted on redox, cell wall carbohydrate, lignin, and trichome genes using young first leaves, including T4 O-3-7-5 plants that had partially reverted to yield two linked growth and trichome phenotypes. Most of the trichome genes tested showed to be consistant with leaf trichome phenotypes and with RNA sequencing data in three of the lines. Two redox genes showed highest overall expression in K-5-8 leaves and lowest in O-3-7-5 leaves, while one redox gene and three cell wall genes were consistently higher in the two less robust lines compared with the two robust lines.
The data support the strong impact of BnTTG1 knockdown (in the presence of strong AtGL3 expression) at restoring growth, enhancing trichome coverage and length, and enhancing expression and diversity of growth, metabolic, and anti-oxidant genes important for stress tolerance and plant health in B. napus. Our data also suggests that the combination of strong (up-regulated) BnTTG1 expression in concert with strong AtGL3 expression is unstable and lethal to the plant.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0680-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4704247  PMID: 26739276
Brassica napus; GL3 and TTG1 manipulation; Trichome patterning and growth; Broad metabolic gene expression changes; Q-PCR and RNA sequencing
6.  Lyn Delivers Bacteria to Lysosomes for Eradication through TLR2-Initiated Autophagy Related Phagocytosis 
PLoS Pathogens  2016;12(1):e1005363.
Extracellular bacteria, such as Pseudomonas aeruginosa and Klebsiella pneumoniae, have been reported to induce autophagy; however, the role and machinery of infection-induced autophagy remain elusive. We show that the pleiotropic Src kinase Lyn mediates phagocytosis and autophagosome maturation in alveolar macrophages (AM), which facilitates eventual bacterial eradication. We report that Lyn is required for bacterial infection-induced recruitment of autophagic components to pathogen-containing phagosomes. When we blocked autophagy with 3-methyladenine (3-MA) or by depleting Lyn, we observed less phagocytosis and subsequent bacterial clearance by AM. Both morphological and biological evidence demonstrated that Lyn delivered bacteria to lysosomes through xenophagy. TLR2 initiated the phagocytic process and activated Lyn following infection. Cytoskeletal trafficking proteins, such as Rab5 and Rab7, critically facilitated early phagosome formation, autophagosome maturation, and eventual autophagy-mediated bacterial degradation. These findings reveal that Lyn, TLR2 and Rab modulate autophagy related phagocytosis and augment bactericidal activity, which may offer insight into novel therapeutic strategies to control lung infection.
Author Summary
It is vital to establish the mechanistic basis for initiation of host defenses and immune responses that are required to eliminate bacterial infection. This line of inquiry will increase knowledge of bacterial pathogenesis and uncover new insights that can enhance design and effectiveness of novel therapeutics. We demonstrate that TLR-2 is required for inducing Lyn activity in host defense against Pa infection through assistance in autophagosome maturation, and may link autophagy to phagocytosis in a TLR-2-Lyn-dependent manner. Thus, these results may further help to alleviate human acute lung injury/adult respiratory distress syndrome (ALI/ARDS) caused by Gram-negative bacteria.
PMCID: PMC4703367  PMID: 26735693
7.  Prognostic Value of SPARC in Patients with Pancreatic Cancer: A Systematic Review and Meta-Analysis 
PLoS ONE  2016;11(1):e0145803.
There is a heated debate on whether the prognostic value of SPARC is favorable or unfavorable. Thus, we carried out a meta-analysis evaluating the relationship between SPARC expression and the prognosis of patients with pancreatic cancer.
We searched PubMed, EMBASE and Web of Science for relevant articles. The pooled hazard ratios (HRs) and corresponding 95%CI of overall survival (OS) were calculated to evaluate the prognostic value of SPARC expression in patients with pancreatic cancer. We also performed subgroup analyses.
With 1623 patients pooled from 10 available studies, the incorporative HR showed an unfavorable prognosis of patients with pancreatic cancer in the multivariate analysis (HR = 1.55, 95%CI: 1.11–2.17, P = 0.01), but not in univariate analysis (HR = 1.41, 95%CI: 0.47–4.21, P = 0.54) and estimate (HR = 1.24, 95%CI: 0.72–2.13, P = 0.44). And this adverse impact could also be found in the subgroup analyses in multivariate analysis, especially in the stroma (HR = 1.53, 95%CI: 1.05–2.24, P = 0.03). However, the combined HR had the highly significant heterogeneity. No obvious publication bias was found.
SPARC might be an unfavorable indicator in patients with pancreatic cancer, especially in the stroma. More and further researches should be conducted to reveal the prognostic value of SPARC.
PMCID: PMC4701416  PMID: 26731428
8.  Thrombospondin-1 restrains neutrophil granule serine protease function and regulates the innate immune response during Klebsiella pneumoniae infection 
Mucosal immunology  2014;8(4):896-905.
Neutrophil elastase (NE) and cathepsin G (CG) contribute to intracellular microbial killing but, if left unchecked and released extracellularly, promotes tissue damage. Conversely, mechanisms that constrain neutrophil serine protease activity protect against tissue damage but may have the untoward effect of disabling the microbial killing arsenal. The host elaborates thrombospondin-1 (TSP-1), a matricellular protein released during inflammation, but its role during neutrophil activation following microbial pathogen challenge remains uncertain. Mice deficient in thrombospondin-1 (thbs1−/−) showed enhanced lung bacterial clearance, reduced splenic dissemination, and increased survival compared with WT controls during intrapulmonary Klebsiella pneumoniae infection. More effective pathogen containment was associated with reduced burden of inflammation in thbs1−/− mouse lungs compared with WT controls. Lung NE activity was increased in thbs1−/− mice following Klebsiella pneumoniae challenge, and thbs1−/− neutrophils showed enhanced intracellular microbial killing that was abrogated with recombinant TSP-1 administration or WT serum. Thbs1−/− neutrophils exhibited enhanced NE and CG enzymatic activity and a peptide corresponding to amino acid residues 793–801 within the type 3 repeats domain of TSP-1 bridled neutrophil proteolytic function and microbial killing in vitro. Thus, TSP-1 restrains proteolytic action during neutrophilic inflammation elicited by Klebsiella pneumoniae, providing a mechanism that may regulate the microbial killing arsenal.
PMCID: PMC4465063  PMID: 25492474
thrombospondin-1; neutrophil; bacterial killing; Klebsiella pneumoniae
9.  Cell Wall Pectin and its Methyl-esterification in Transition Zone Determine Al Resistance in Cultivars of Pea (Pisum sativum) 
The initial response of plants to aluminum (Al) is the inhibition of root elongation, while the transition zone is the most Al sensitive zone in the root apex, which may sense the presence of Al and regulate the responses of root to Al toxicity. In the present study, the effect of Al treatment (30 μM, 24 h) on root growth, Al accumulation, and properties of cell wall of two pea (Pisum sativum L.) cultivars, cv Onward (Al-resistant) and cv Sima (Al-sensitive), were studied to disclose whether the response of root transition zone to Al toxicity determines Al resistance in pea cultivars. The lower relative root elongation (RRE) and higher Al content were founded in cv Sima compared with cv Onward, which were related to Al-induced the increase of pectin in root segments of both cultivars. The increase of pectin is more prominent in Al-sensitive cultivar than in Al-resistant cultivar. Aluminum toxicity also induced the increase of pectin methylesterases (PME), which is 2.2 times in root transition zone in Al-sensitive cv Sima to that of Al resistant cv Onward, thus led to higher demethylesterified pectin content in root transition zone of Al-sensitive cv Sima. The higher demethylesterified pectin content in root transition zone resulted in more Al accumulation in the cell wall and cytosol in Al-sensitive cv Sima. Our results provide evidence that the increase of pectin content and PME activity under Al toxicity cooperates to determine Al sensitivity in root transition zone that confers Al resistance in cultivars of pea (Pisum sativum).
PMCID: PMC4734104  PMID: 26870060
pea; aluminum sensitivity; transition zone; cell wall pectin; degree of pectin methyl-esterification; pectin methylesterase activity
10.  Genomic analysis of Luteimonas abyssi XH031T: insights into its adaption to the subseafloor environment of South Pacific Gyre and ecological role in biogeochemical cycle 
BMC Genomics  2015;16:1092.
Luteimonas abyssi XH031T, which was previously isolated from subseafloor environment of the South Pacific Gyre (SPG), was an aerobic, gram-negative bacterium, and was identified to be a novel species of the genus Luteimonas in the family of Xanthomonadaceae. The nutrients utilization and metabolic mechanisms of XH031T indicate its plasticity. In view of the above characteristics, its genome was sequenced, and an in-depth analysis of the XH031T genome was performed to elucidate its adaption to extreme ecological environment.
Various macromolecules including polysaccharide, protein, lipid and DNA could be degraded at low temperature by XH031T under laboratory conditions, and its degradation abilities to starch, gelatin and casein were considerably strong. Genome sequence analysis indicated that XH031T possesses extensive enzyme-encoding genes compared with four other Luteimonas strains. In addition, intricate systems (such as two-component regulatory systems, secretion systems, etc.), which are often used by bacteria to modulate the interactions of bacteria with their environments, were predicted in the genome of XH031T. Genes encoding a choline-glycine betaine transporter and 99 extracellular peptidases featured with halophilicity were predicted in the genome, which might help the bacterium to adapt to the salty marine environment. Moreover, there were many gene clusters in the genome encoding ATP-binding cassette superfamily transporters, major facilitator superfamily transporters and cytochrome P450s that might function in the process of various substrate transportation and metabolisms. Furthermore, drug resistance genes harbored in the genome might signify that XH031T has evolved hereditary adaptation to toxic environment. Finally, the annotation of metabolic pathways of the elements (such as carbon, nitrogen, sulfur, phosphor and iron) in the genome elucidated the degradation of organic matter in the deep sediment of the SPG.
The genome analysis showed that XH031T had genetic advantages to adapt to subseafloor environment. The material metabolism manifests that the strain may play an important ecological role in the biogeochemical cycle of the SPG, and various cold-adapted extracelluar enzymes produced by the strain may have significant value in application.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-2326-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4687298  PMID: 26690083
Luteimonas abyssi; Genomic analysis; Genetic advantages; Ecological role
11.  Changes in vitreous VEGF, bFGF and fibrosis in proliferative diabetic retinopathy after intravitreal bevacizumab 
To evaluate the relationship between intravitreal bevacizumab (IVB) treatment and the levels of vitreous vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and vitreous-retina surface fibrosis in patients with proliferative diabetic retinopathy (PDR).
This study was a prospective, open-label, controlled, randomized clinical trial. Sixty-eight eyes of PDR patients (n=53) and macular hole patients (n=15) were enrolled in this study. Thirty-four eyes of the PDR patients received IVB before vitrectomy. Twenty-three of the 34 PDR patients received IVB treatment 5d before vitrectomy (subgroup a), and 11 of the 34 PDR patients received IVB treatment greater than 2wk prior to vitrectomy (subgroup b). Nineteen of the PDR patients did not receive IVB treatment at any time prior to vitrectomy. The levels of bFGF and VEGF in vitreous samples were measured using enzyme-linked immunosorbent assay (ELISA) and the degree of vitreoretinal fibrosis was characterized using clinical data and data obtained intra-operatively.
In PDR patients, VEGF and bFGF levels were significantly increased compared to non-PDR (control) subject's eyes (P<0.01). In PDR patients, vitreous VEGF levels were significantly decreased following IVB treatment compared to PDR patients that did not receive IVB treatment (P<0.01). The degree of vitreoretinal fibrosis was significantly increased in subgroup b compared to subgroup a(P<0.05) and to patients that did not receive IVB (P<0.05). Vitreous bFGF levels were significantly greater in subgroup b than subgroup a (P<0.01) or in patients who did not receive IVB treatment (P<0.05). A Spearman's rank correlation test indicated that higher levels of vitreous bFGF, but not VEGF, correlated with the degree of vitreoretinal fibrosis.
We found that bFGF levels increase in PDR patient's vitreous after IVB treatment longer than two weeks prior to vitrectomy and correlated with the degree of fibrosis after IVB treatment. These findings suggest vitreous fibrosis is increased in PDR patients after IVB treatment may be due to increased levels of bFGF.
PMCID: PMC4651889  PMID: 26682173
proliferative diabetic retinopathy; vascular endothelial growth factor; basic fibroblast growth factor; fibrosis; bevacizumab
12.  Bioengineered implantable scaffolds as a tool to study stromal-derived factors in metastatic cancer models 
Cancer research  2014;74(24):7229-7238.
Modeling the hematogenous spread of cancer cells to distant organs poses one of the greatest challenges in the study of human metastasis. Both tumor-cell intrinsic properties as well as interactions with reactive stromal cells contribute to this process, but identification of relevant stromal signals has been hampered by the lack of models allowing characterization of the metastatic niche. Here we describe an implantable bioengineered scaffold, amenable to in vivo imaging, ex vivo manipulation and serial transplantation for the continuous study of human metastasis in mice. Orthotopic or systemic inoculation of tagged human cancer cells into the mouse leads to the release of circulating tumor cells (CTCs) into the vasculature, which seed the scaffold, initiating a metastatic tumor focus. Mouse stromal cells can be readily recovered and profiled, revealing differential expression of cytokines, such as IL-1β, from tumor-bearing versus unseeded scaffolds. Finally, this platform can be used to test the effect of drugs on suppressing initiation of metastatic lesions. This generalizable model to study cancer metastasis may thus identify key stromal-derived factors with important implications for basic and translational cancer research.
PMCID: PMC4267901  PMID: 25339351
Bioengineered scaffold; metastasis; stroma; microenvironment; IL-1β
13.  Myocardia ischemia associated with a myocardial bridge with no significant atherosclerotic stenosis 
Myocardial bridge refers to the myocardial tissue with which the coronary artery is partly covered. Though it has long been regarded to be benign, patients with myocardial bridges may present with myocardial ischemia, acute coronary syndromes, coronary spasm, sudden cardiac arrest or even sudden death.
Case presentation
In present study, we reviewed four cases with myocardial bridge and no stenosis of coronary artery, which included acute coronary syndrome and sudden cardiac arrest.
These cases indicated that cardiac events in patients with myocardial bridge may be associated with coronary spasm, myocardial supply/demand mismatch or cardiac arrest.
Electronic supplementary material
The online version of this article (doi:10.1186/s12872-015-0158-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4673761  PMID: 26646509
Myocardial bridge; Electrocardiogram; Coronary angiography
14.  Inequality trends of health workforce in different stages of medical system reform (1985-2011) in China 
The aim of this study was to identify whether policies in different stages of medical system reform had been effective in decreasing inequalities and increasing the density of health workers in rural areas in China between 1985 and 2011.
With data from China Health Statistics Yearbooks from 2004 to 2012, we measured the Gini coefficient and the Theil L index across the urban and rural areas from 1985 to 2011 to investigate changes in inequalities in the distributions of health workers, doctors, and nurses by states, regions, and urban-rural stratum and account for the sources of inequalities.
We found that the overall inequalities in the distribution of health workers decreased to the lowest in 2000, then increased gently until 2011. Nurses were the most unequally distributed between urban-rural districts among health workers. Most of the overall inequalities in the distribution of health workers across regions were due to inequalities within the rural-urban stratum.
Discussions and conclusions
Different policies and interventions in different stages would result in important changes in inequality in the distribution of the health workforce. It was also influenced by other system reforms, like the urbanization, education, and employment reforms in China. The results are useful for the Chinese government to decide how to narrow the gap of the health workforce and meet its citizens’ health needs to the maximum extent.
PMCID: PMC4673776  PMID: 26645960
Inequality; Health workforce; Medical system reform
15.  Amplification of 1q21 and Other Abnormalities in Multiple Myeloma Patients from a Tertiary Hospital in Singapore 
Much effort has been made to stratify multiple myeloma patients for targeted therapy. However, responses have been varied and improved patient stratifications are needed. Forty-five diagnostic samples from multiple myeloma patients (median age 65 years) were stratified cytogenetically as 15 having non-hyperdiploidy, 20 having hyperdiploidy and 10 having a normal karyotype. Fluorescence in situ hybridization (FISH) assays with FGFR3/IGH, CCND1/IGH, IGH/MAF, RB1 and TP53 probes on bone marrow samples showed that IGH rearrangements were the most common abnormality in the non-hyperdiploid group but these were also found among hyperdiploid patients and patients with normal cytogenetics. Of these, FGFR3/IGH rearrangements were most frequent. Deletion of RB1/monosomy 13 was the most common genetic abnormality across the three groups and was significantly higher among non-hyperdiploid compared to hyperdiploid patients. On the other hand, the study recorded a low incidence of TP53 deletion/monosomy 17. The FGFR3/IGH fusion was frequently seen with RB1 deletion/monosomy 13. FISH with 1p36/1q21 and 6q21/15q22 probes showed that amplification of 15q22 was seen in all of the hyperdiploid patients while amplification of 1q21, Amp(1q21), characterized non-hyperdiploid patients. In contrast, deletions of 1p36 and 6q21 were very rare events. Amp(1q21), FGFR3/IGH fusion, RB1 deletion/monosomy 13, and even TP53 deletion/monosomy 17 were seen in some hyperdiploid patients, suggesting that they have a less than favorable prognosis and require closer monitoring.
PMCID: PMC4243399  PMID: 25435723
Amp(1q21); FISH panel; Hyperdiploidy; Non-hyperdiploidy
16.  Luoyutong Treatment Promotes Functional Recovery and Neuronal Plasticity after Cerebral Ischemia-Reperfusion Injury in Rats 
Luoyutong (LYT) capsule has been used to treat cerebrovascular diseases clinically in China and is now patented and approved by the State Food and Drug Administration. In this retrospective validation study we investigated the ability of LYT to protect against cerebral ischemia-reperfusion injury in rats. Cerebral ischemia-reperfusion injury was induced by middle cerebral artery occlusion followed by reperfusion. Capsule containing LYT (high dose and medium dose) as treatment group and Citicoline Sodium as positive control treatment group were administered daily to rats 30 min after reperfusion. Treatment was continued for either 3 days or 14 days. A saline solution was administered to control animals. Behavior tests were performed after 3 and 14 days of treatment. Our findings revealed that LYT treatment improved the neurological outcome, decreased cerebral infarction volume, and reduced apoptosis. Additionally, LYT improved neural plasticity, as the expression of synaptophysin, microtubule associated protein, and myelin basic protein was upregulated by LYT treatment, while neurofilament 200 expression was reduced. Moreover, levels of brain derived neurotrophic factor and basic fibroblast growth factor were increased. Our results suggest that LYT treatment may protect against ischemic injury and improve neural plasticity.
PMCID: PMC4678236  PMID: 26697095
17.  High MicroRNA-370 Expression Correlates with Tumor Progression and Poor Prognosis in Breast Cancer 
Journal of Breast Cancer  2015;18(4):323-328.
Deregulation of microRNA-370 (miR-370) has been reported in various cancers, in which it can act as either an oncogene or a tumor suppressor gene. However, the clinicopathologic significance of miR-370 expression in breast cancer has not been studied.
The expression of miR-370 was determined with quantitative real-time polymerase chain reaction in 60 formalin-fixed, paraffin-embedded primary breast cancer tissues. Additionally, the protein expression levels of previously known targets of miR-370, such as FOXM1, FOXO1, and FOXO3a, were detected using immunohistochemistry. Finally, we analyzed its correlation with target protein expression, clinicopathologic features, and clinical outcome.
High levels of miR-370 expression correlated with lymph node metastasis (p=0.009), advanced stage (p=0.002), and frequent perineural invasion (p=0.042). Moreover, patients with high miR-370 expression had poor disease-free survival compared with the low-expression group. However, no correlation was observed between miR-370 and its target protein expression.
Our results indicate that upregulation of miR-370 in breast cancer is correlated with breast cancer progression and that it might be a potential biomarker for predicting clinical outcomes.
PMCID: PMC4705083  PMID: 26770238
Breast neoplasms; MicroRNA-370; Prognosis; Real-time polymerase chain reaction
18.  Turner syndrome with spinal hemorrhage due to vascular malformation 
Turner syndrome (TS) is a relatively common chromosomal disorder and is associated with a range of comorbidities involving the cardiovascular system. Vascular abnormalities, in particular, are a common finding in cases of TS. However, dissection involving the vertebral arteries is rare. Here, we report the case of a 9-year-old girl with TS who had been treated with growth hormone replacement therapy for the past 3 years. She presented with weakness of both lower legs, and was ultimately diagnosed with spinal hemorrhage due to vascular malformation. We treated her with intravenous high dose dexamethasone (0.6 mg/kg) and she could walk without assistance after 6 days of treatment. In conclusion, when a patient with TS shows sudden weakness of the lower limbs, we should consider the possibility of spinal vessel rupture and try to take spine magnetic resonance imaging as soon as possible. We suggest a direction how to make a proper diagnosis and management of sudden vertebral artery hemorrhage in patients with TS.
PMCID: PMC4722165  PMID: 26817012
Turner syndrome; Vascular malformations; Vertebral artery dissection
19.  ATAD2 Overexpression Identifies Colorectal Cancer Patients with Poor Prognosis and Drives Proliferation of Cancer Cells 
ATPase family AAA domain-containing 2 (ATAD2) has been identified as a critical modulator involved in cell proliferation and invasion. The purpose of this study was to explore the expression of ATAD2 in CRC tissues as well as its relationship with degree of malignancy. Data containing three independent investigations from Oncomine database demonstrated that ATAD2 is overexpressed in CRC compared with normal tissue, and similar result was also found in 32 pairs of CRC tissues by qPCR. The protein expression of ATAD2 was examined in six CRC cell lines and 300 CRC specimens. The results showed that high expression of ATAD2 was significantly correlated with tumor size (P < 0.001), serum CEA (P = 0.012), lymph node metastasis (P = 0.018), liver metastasis (P = 0.025), and clinical stage (P = 0.004). Kaplan-Meier method suggested that higher ATAD2 protein expression significantly associated with the overall survival (OS) of CRC patients (P < 0.001) and was an independent predictor of poor OS. Functional studies showed that suppression of ATAD2 expression with siRNA could significantly inhibit the growth in SW480 and HCT116 cells. These results indicated that ATAD2 could serve as a prognostic marker and a therapeutic target for CRC.
PMCID: PMC4677176  PMID: 26697062
20.  Relationship between virological response and FIB-4 index in chronic hepatitis B patients with entecavir therapy 
World Journal of Gastroenterology  2015;21(43):12421-12429.
AIM: To investigate whether long-term low-level hepatitis B virus (HBV) DNA influences dynamic changes of the FIB-4 index in chronic hepatitis B (CHB) patients receiving entecavir (ETV) therapy with partial virological responses.
METHODS: We retrospectively analyzed 231 nucleos(t)ide (NA) naïve CHB patients from our previous study (NCT01926288) who received continuous ETV or ETV maleate therapy for three years. The patients were divided into partial virological response (PVR) and complete virological response (CVR) groups according to serum HBV DNA levels at week 48. Seventy-six patients underwent biopsies at baseline and at 48 wk. The performance of the FIB-4 index and area under the receiver operating characteristic (AUROC) curve for predicting fibrosis were determined for the patients undergoing biopsy. The primary objective of the study was to compare the cumulative probabilities of virological responses between the two groups during the treatment period. The secondary outcome was to observe dynamic changes of the FIB-4 index between CVR patients and PVR patients.
RESULTS: For hepatitis B e antigen (HBeAg)-positive patients (n = 178), the cumulative probability of achieving undetectable levels at week 144 was 95% and 69% for CVR and PVR patients, respectively (P < 0.001). In the Cox proportional hazards model, a lower pretreatment serum HBV DNA level was an independent factor predicting maintained viral suppression. The cumulative probability of achieving undetectable levels of HBV DNA for HBeAg-negative patients (n = 53) did not differ between the two groups. The FIB-4 index efficiently identified fibrosis, with an AUROC of 0.80 (95%CI: 0.69-0.89). For HBeAg-positive patients, the FIB-4 index was higher in CVR patients than in PVR patients at baseline (1.89 ± 1.43 vs 1.18 ± 0.69, P < 0.001). There was no significant difference in the reduction of the FIB-4 index between the CVR and PVR groups from weeks 48 to 144 (-0.11 ± 0.47 vs -0.13 ± 0.49, P = 0.71). At week 144, the FIB-4 index levels were similar between the two groups (1.24 ± 0.87 vs 1.02 ± 0.73, P = 0.06). After multivariate logistic regression analysis, a lower baseline serum HBV DNA level was associated with improvement of liver fibrosis. In HBeAg-negative patients, the FIB-4 index did not differ between the two groups.
CONCLUSION: The cumulative probabilities of HBV DNA responses showed significant differences between CVR and PVR HBeAg-positive CHB patients undergoing entecavir treatment for 144 wk. However, long-term low-level HBV DNA did not deteriorate the FIB-4 index, which was used to evaluate liver fibrosis, at the end of three years.
PMCID: PMC4649125  PMID: 26604649
Chronic hepatitis B; Hepatitis B virus DNA; Entecavir; Partial virological response; Liver fibrosis; FIB-4 index
21.  Annexin A2 binds to endosomes and negatively regulates TLR4-triggered inflammatory responses via the TRAM-TRIF pathway 
Scientific Reports  2015;5:15859.
Lipopolysaccharide (LPS) derived from Gram-negative bacteria activates plasma membrane signaling via Toll-like receptor 4 (TLR4) on host cells and triggers innate inflammatory responses, but the underlying mechanisms remain to be fully elucidated. Here we reveal a role for annexin A2 (AnxA2) in host defense against infection as anxa2−/− mice were highly susceptible to Gram-negative bacteria-induced sepsis with enhanced inflammatory responses. Computing analysis and biochemical experiments identified that constitutive AnxA2 expression facilitated TLR4 internalization and its subsequent translocation into early endosomal membranes. It activated the TRAM-dependent endosomal signaling, leading to the release of anti-inflammatory cytokines. Importantly, AnxA2 deficiency prolonged TLR4-mediated signaling from the plasma membrane, which was attributable to pro-inflammatory cytokine production (IL-6, TNFα and IL-1β). Thus, AnxA2 directly exerted negative regulation of inflammatory responses through TLR4-initiated TRAM-TRIF pathway occurring on endosomes. This study reveals AnxA2 as a critical regulator in infection-initiated inflammation, which protects the host from excessive inflammatory damage.
PMCID: PMC4630631  PMID: 26527544
22.  Genomic insight into Aquimarina longa SW024T: its ultra-oligotrophic adapting mechanisms and biogeochemical functions 
BMC Genomics  2015;16:772.
South Pacific Gyre (SPG) is the largest and clearest gyre in the world, where the concentration of surface chlorophyll a and primary production are extremely low. Aquimarina longa SW024T was isolated from surface water of the SPG center. To understand how this bacterium could survive in this ultra-oligotrophic oceanic environment and its function in biogeochemical cycle, we sequenced the genome of A. longa SW024T and performed extensive genomic analyses.
Genomic DNA was extracted and sequenced using Illumina Hiseq 2000 and Miseq platform. Genome annotation, genomic comparison and phylogenetic analyses were performed with the use of multiple bioinformatics tools like: BLAST+ 2.2.24, Glimmer3.0, RAST server, Geneious 4.8.5, ClustalW2 and MEGA5. Physiological and morphological features were tested by bacterial culture, electron microscopy, fluorescence microscopy and exopolysaccharides extraction.
Analysis of seven Aquimarina genomes and 30 other genomes of Flavobacteriaceae isolated from seawater showed that most of the strains had low DNA G + C contents, and Aquimarina had larger genomes than other strains. Genome comparison showed varying genomic properties among seven Aquimarina genomes, including genome sizes and gene contents, which may warrant their specific adaptive strategies. Genome of A. longa SW024T was further compared with the genomes of two other Aquimarina species which were also isolated from the SPG and A. longa SW024T appeared to have much more genes related to replication, recombination and repair. As a copiotroph, A. longa SW024T is long in length, and possesses large genome size and diverse transporters. However, it has also evolved many properties to survive in the oligotrophic marine environment. This bacterium grew better on solid medium than in liquid medium, suggesting it may be liable to attach to particle surfaces in order to survive in the nutrient-limiting environment. Gliding motility and the capacity to degrade various polymers possibly allow the bacterium to grow on detritus particles and use polymeric substances as carbon and energy sources. Moreover, genes related to carbon, nitrogen, and sulfur metabolisms were identified, which showed that A. longa SW024T might be involved in various elemental cycles.
Genomic comparison of Aquimarina genus exhibits comprehensive capabilities of the strains to adapt to diverse marine environments. The genomic characteristics of A. longa SW024T reveal that it evolves various strategies to cope with both copiotrophic and ultra-oligotrophic marine environment, which provides a better understanding of the survival abilities of bacteria in prevalent and even extreme oceanic environments. Furthermore, carbon, nitrogen and sulfur utilization of A. longa SW024T may represent its potential functions in the global biogeochemical cycle.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-2005-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4603819  PMID: 26459873
Aquimarina longa; Genome analysis; Genome comparison; Oligotrophic bacterium
23.  Protection mechanism of early hyperbaric oxygen therapy in rats with permanent cerebral ischemia 
Journal of Physical Therapy Science  2015;27(10):3271-3274.
[Purpose] The purpose of this study was to investigate whether early hyperbaric oxygen is useful in rats with permanent cerebral ischemia, and whether its mechanism relates to the inhibition of the tumor necrosis factor-alpha-protein kinase C-alpha pathway. [Subjects] Healthy, male Sprague-Dawley rats (N = 108) were the subjects. [Methods] After middle cerebral artery occlusion models were successfully made, rats were randomly divided into sham-operated, cerebral ischemia, and hyperbaric oxygen groups. At 4 and 12 hours after modeling, the volume of cerebral infarction was determined by triphenyltetrazolium chloride staining, and brain water content was measured using the dry and wet method. The expression of tumor necrosis factor-alpha and protein kinase C-alpha in the ischemic penumbra tissue was measured using Western blot analysis. [Results] The data showed that at 4 and 12 hours after modeling, cerebral infarct volume and brain water content decreased in the hyperbaric oxygen group, and expression of tumor necrosis factor-alpha and phospho-protein kinase C-alpha in the ischemic penumbra tissue also decreased. [Conclusion] Our study demonstrates that early hyperbaric oxygen therapy has protective effects on brain tissue after cerebral ischemia, possibly via inhibition of tumor necrosis factor-alpha and phospho-protein kinase C-alpha.
PMCID: PMC4668181  PMID: 26644690
Hyperbaric oxygen therapy; Cerebrovascular protection; Cerebral ischemic rats
24.  Electrospun and woven silk fibroin/poly(lactic-co-glycolic acid) nerve guidance conduits for repairing peripheral nerve injury 
Neural Regeneration Research  2015;10(10):1635-1642.
We have designed a novel nerve guidance conduit (NGC) made from silk fibroin and poly(lactic-co-glycolic acid) through electrospinning and weaving (ESP-NGCs). Several physical and biological properties of the ESP-NGCs were assessed in order to evaluate their biocompatibility. The physical properties, including thickness, tensile stiffness, infrared spectroscopy, porosity, and water absorption were determined in vitro. To assess the biological properties, Schwann cells were cultured in ESP-NGC extracts and were assessed by morphological observation, the MTT assay, and immunohistochemistry. In addition, ESP-NGCs were subcutaneously implanted in the backs of rabbits to evaluate their biocompatibility in vivo. The results showed that ESP-NGCs have high porosity, strong hydrophilicity, and strong tensile stiffness. Schwann cells cultured in the ESP-NGC extract fluids showed no significant differences compared to control cells in their morphology or viability. Histological evaluation of the ESP-NGCs implanted in vivo indicated a mild inflammatory reaction and high biocompatibility. Together, these data suggest that these novel ESP-NGCs are biocompatible, and may thus provide a reliable scaffold for peripheral nerve repair in clinical application.
PMCID: PMC4660758  PMID: 26692862
nerve regeneration; peripheral nerve injury; poly(lactic-co-glycolic acid); electrospinning; silk fibroin; biocompatibility; nerve guidance conduit; weaving
25.  Thyroid dysfunction in Chinese hepatitis C patients: Prevalence and correlation with TPOAb and CXCL10 
AIM: To investigate the relationship among pretreatment serum CXC chemokine ligand 10 (CXCL10), thyroid peroxidase antibody (TPOAb) levels and thyroid dysfunction (TD) in Chinese hepatitis C patients.
METHODS: One hundred and thirty-nine treatment-naive genotype 1 chronic hepatitis C patients with no history of TD or treatment with thyroid hormones were enrolled in this study. Patients underwent peginterferon alfa-2a/ribavirin (PegIFNα-2a/RBV) treatment for 48 wk, followed by detection of clinical factors at each follow-up point. Hepatitis C virus (HCV) antibodies were analyzed using microsomal chemiluminescence, and serum HCV RNA was measured by real-time PCR assay at 0, 4, 12, 24 and 48 wk after the initiation of therapy and 24 wk after the end of therapy. To assess thyroid function, serum thyroid stimulating hormone (TSH), free thyroxine (FT4), free triodothyronine (FT3) and TPOAb/thyroglobulin antibody (TGAb) levels were determined using chemiluminescent immunoassays every 3 mo. Serum CXCL10 levels were determined at baseline.
RESULTS: The prevalence of TD was 18.0%. Twenty-one (84.0%) out of twenty-five patients exhibited normal thyroid function at week 24 after therapy. The rate of sustained virological response to PegIFNα-2a/RBV in our study was 59.0% (82/139), independent of thyroid function. Pretreatment serum CXCL10 levels were significantly increased in patients with euthyroid status compared with patients with TD (495.2 ± 244.2 pg/mL vs 310.0 ± 163.4 pg/mL, P = 0.012). Patients with TD were more frequently TPOAb-positive than non-TD (NTD) patients (24.2% vs 12.3%, P = 0.047) at baseline. Three of the one hundred and fifteen patients without TPOAb at baseline developed TD at the end of treatment (37.5% vs 2.6%, P = 0.000). Female patients exhibited an increased risk for developing TD compared with male patients (P = 0.014).
CONCLUSION: Lower pretreatment serum CXCL10 levels are associated with TD, and TD prevalence increases in female patients and patients who are positive for TPOAb at baseline.
PMCID: PMC4562961  PMID: 26361424
Thyroid dysfunction; Thyroid peroxidase antibody; CXC chemokine ligand 10; Peginterferon alfa-2a/ribavirin; China

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