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2.  Scientometric trends and knowledge maps of global health systems research 
Background
In the last few decades, health systems research (HSR) has garnered much attention with a rapid increase in the related literature. This study aims to review and evaluate the global progress in HSR and assess the current quantitative trends.
Methods
Based on data from the Web of Science database, scientometric methods and knowledge visualization techniques were applied to evaluate global scientific production and develop trends of HSR from 1900 to 2012.
Results
HSR has increased rapidly over the past 20 years. Currently, there are 28,787 research articles published in 3,674 journals that are listed in 140 Web of Science subject categories. The research in this field has mainly focused on public, environmental and occupational health (6,178, 21.46%), health care sciences and services (5,840, 20.29%), and general and internal medicine (3,783, 13.14%). The top 10 journals had published 2,969 (10.31%) articles and received 5,229 local citations and 40,271 global citations. The top 20 authors together contributed 628 papers, which accounted for a 2.18% share in the cumulative worldwide publications. The most productive author was McKee, from the London School of Hygiene & Tropical Medicine, with 48 articles. In addition, USA and American institutions ranked the first in health system research productivity, with high citation times, followed by the UK and Canada.
Conclusions
HSR is an interdisciplinary area. Organization for Economic Co-operation and Development countries showed they are the leading nations in HSR. Meanwhile, American and Canadian institutions and the World Health Organization play a dominant role in the production, collaboration, and citation of high quality articles. Moreover, health policy and analysis research, health systems and sub-systems research, healthcare and services research, health, epidemiology and economics of communicable and non-communicable diseases, primary care research, health economics and health costs, and pharmacy of hospital have been identified as the mainstream topics in HSR fields. These findings will provide evidence of the current status and trends in HSR all over the world, as well as clues to the impact of this popular topic; thus, helping scientific researchers and policy makers understand the panorama of HSR and predict the dynamic directions of research.
doi:10.1186/1478-4505-12-26
PMCID: PMC4065315  PMID: 24903126
Global trend; Health systems research; Knowledge mapping; Scientometric; Web of Science
3.  Analysis of PRICKLE1 in human cleft palate and mouse development demonstrates rare and common variants involved in human malformations 
Palate development is shaped by multiple molecular signaling pathways, including the Wnt pathway. In mice and humans, mutations in both the canonical and noncanonical arms of the Wnt pathway manifest as cleft palate, one of the most common human birth defects. Like the palate, numerous studies also link different Wnt signaling perturbations to varying degrees of limb malformation; for example, shortened limbs form in mutations of Ror2,Vangl2looptail and, in particular, Wnt5a. We recently showed the noncanonical Wnt/planar cell polarity (PCP) signaling molecule Prickle1 (Prickle like 1) also stunts limb growth in mice. We now expanded these studies to the palate and show that Prickle1 is also required for palate development, like Wnt5a and Ror2. Unlike in the limb, the Vangl2looptail mutation only aggravates palate defects caused by other mutations. We screened Filipino cleft palate patients and found PRICKLE1 variants, both common and rare, at an elevated frequency. Our results reveal that in mice and humans PRICKLE1 directs palate morphogenesis; our results also uncouple Prickle1 function from Vangl2 function. Together, these findings suggest mouse and human palate development is guided by PCP-Prickle1 signaling that is probably not downstream of Vangl2.
doi:10.1002/mgg3.53
PMCID: PMC3960056  PMID: 24689077
Cleft palate; Prickle1; Shh; Vangl2
4.  Lignans from the bark of Eucommia ulmoides inhibited Ang II-stimulated extracellular matrix biosynthesis in mesangial cells 
Chinese Medicine  2014;9:8.
Background
Tree bark of Eucommia ulmoides Oliv., (commonly well-known as “Du-zhong” in China), has been used to treat hypertension, hypercholesterolemia, hyperglycemia, hepatic fibrosis and renal injury. This study aims to investigate the effects of lignans extracted from the bark of Eucommia ulmoides Oliv. on Ang II-induced proliferation and extracellular matrix biosynthesis in rat mesangial cells.
Methods
Rat mesangial cells (RMCs) were cultured in vitro and divided into six groups (control, Ang II, losartan, and low, middle and high concentration lignans groups). RMC proliferation was measured by MTT assay. RT-qPCR and western blotting were used to detect mRNA and protein expression of collagen type I (Col I), collagen type III (Col III), collagen type IV (Col IV), fibronectin and aldose reductase (AR).
Results
Cellular proliferation induced by Ang II was significantly suppressed by Eucommia lignans of different concentrations (P = 0.034, P < 0.001, and P < 0.001). Treatment of cells with Ang II increased Col I, Col III, Col IV, and fibronectin mRNA expression, which was observed at the protein level (P < 0.001, P < 0.001, P = 0.004, and P = 0.004, respectively). The increased mRNA expression and protein levels of Col I, Col III, Col IV, and fibronectin were diminished remarkably with by treatment Eucommia lignans, and elevated AR expression stimulated by Ang II was significantly inhibited by Eucommia lignans.
Conclusions
Eucommia lignans (Du-zhong) inhibited Ang II-stimulated extracellular matrix biosynthesis in mesangial cells.
doi:10.1186/1749-8546-9-8
PMCID: PMC3937011  PMID: 24524265
5.  Evolution and Development of the Tetrapod Auditory System: an Organ of Corti-Centric Perspective 
Evolution & development  2013;15(1):63-79.
The tetrapod auditory system transmits sound through the outer and middle ear to the organ of Corti or other sound pressure receivers of the inner ear where specialized hair cells translate vibrations of the basilar membrane into electrical potential changes that are conducted by the spiral ganglion neurons to the auditory nuclei. In other systems, notably the vertebrate limb, a detailed connection between the evolutionary variations in adaptive morphology and the underlying alterations in the genetic basis of development has been partially elucidated. In this review, we attempt to correlate evolutionary and partially characterized molecular data into a cohesive perspective of the evolution of the mammalian organ of Corti out of the tetrapod basilar papilla. We propose a stepwise, molecularly partially characterized transformation of the ancestral, vestibular developmental program of the vertebrate ear. This review provides a framework to decipher both discrete steps in development and the evolution of unique functional adaptations of the auditory system. The combined analysis of evolution and development establishes a powerful cross-correlation where conclusions derived from either approach become more meaningful in a larger context not possible through exclusively evolution or development centered perspectives.
doi:10.1111/ede.12015
PMCID: PMC3918746  PMID: 23331918
6.  Ulinastatin Preconditioning Attenuates Inflammatory Reaction of Hepatic Ischemia Reperfusion Injury in Rats via High Mobility Group Box 1(HMGB1) Inhibition 
Objective It has been found that ulinastatin (UTI) can attenuate hepatic injury in a rat model of ischemia reperfusion (IR), but the specific mechanism is unclear. This study aims to investigate possible pathomechanism of ulinastatin in reducing the inflammatory response after hepatic IR.
Methods A male sprague-dawley(SD) rat model of hepatic ischemia reperfusion injury was used. The rats were randomly divided into 4 groups on average, which were 0.9% saline and IR group as control, ulinastatin preconditioning (UPC) group, UPC+rHMGB1 (recombinant HMGB1) group and UPC +anti-HMGB1 group. Serum aminotransferases, TNF-α, IL-1 and Myeloperoxidase (MPO) levels were measured. Histopathology examination and apoptotic cell detection and the different expression of HMGB1 protein were also assessed.
Results Serum levels of aminotransferases, cytokines and hepatic MPO in UPC and UPC+anti-HMGB1 groups were significantly lower than those in control group (p<0.05). Decreased histologic damage and apoptosis were also seen in these two groups (p<0.05).
Conclusions HMGB1 expressions in UPC and UPC+anti-HMGB1 groups were significantly lower than those in the two control groups (p<0.05), pretreatment with ulinastatin attenuated liver IR injury by reducing HMGB1 expression through its anti-inflammatory effects.
doi:10.7150/ijms.7861
PMCID: PMC3936027  PMID: 24578610
Ulinastatin; Preconditioning; High mobility group box 1 protein (HMGB1); Ischemia reperfusion
7.  Circulating microRNAs: A Potential Role in Diagnosis and Prognosis of Acute Myocardial Infarction 
Disease markers  2013;35(5):561-566.
Rapid and correct diagnosis of acute myocardial infarction (AMI) plays a crucial role in saving patients' life. Although some biomarkers (such as cardiac troponin and creatine kinase) are available for AMI diagnosis so far, there is still a clinical need for novel biomarkers, which can reliably rule in or rule out AMI immediately on admission. Circulating microRNAs (miRNAs) are a potential choice for novel biomarkers in AMI diagnosis and prognosis with high sensitivity and specificity. Circulating microRNAs are endogenous miRNAs that are detectable in whole blood, serum, or plasma in a highly stable form. Until now, around 20 circulating miRNAs were reported to be closely associated with AMI. In this minireview, we summarized recent available data on the correlation between circulating miRNAs and AMI. Some miRNAs, such as miR-208, miR-499, miR-133, and miR-1, were given special attention, since they may have a potential prospect in diagnosis and prognosis of AMI.
doi:10.1155/2013/217948
PMCID: PMC3821917  PMID: 24249943
8.  The role of 14,15-dihydroxyeicosatrienoic acid levels in inflammation and its relationship to lipoproteins 
Background
14,15-Epoxyeicosatrienoic acids (14,15-EETs) generated from arachidonic acid by cytochrome P450 epoxygenases have beneficial effects in certain cardiovascular diseases, and increased 14,15-EET levels protect the cardiovascular system. 14,15-EETs are rapidly hydrolyzed by soluble epoxide hydrolase (sEH) to the corresponding 14,15-dihydroxyeicosatrienoic acids (14,15-DHETs), which are generally less biologically active but more stable metabolite. A functionally relevant polymorphism of the CYP2J2 gene is independently associated with an increased risk of coronary heart disease (CHD), and the major CYP2J2 product is 14,15-EETs. 14,15-DHETs can be considered a relevant marker of CYP2J2 activity. Therefore, the aim of the present study was to evaluate the plasma 14,15-DHET levels to reflect the 14,15-EET levels in an indirectly way in patients with CHD, and to highlight the growing body of evidence that 14,15-EETs also play a role in anti-inflammatory and lipid-regulating effects in patients with CHD. This was achieved by investigating the relationship between 14,15-DHETs and high-sensitivity C-reactive protein (hs-CRP) and blood lipoproteins.
Methods
Samples of peripheral venous blood were drawn from 60 patients with CHD and 60 healthy controls. A 14,15-DHET enzyme-linked immunosorbent assay kit (14,15-DHET ELISA kit) was used to measure the plasma 14,15-DHET levels. Hs-CRP, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein-cholesterol levels were measured.
Results
14,15-DHET levels (2.53 ± 1.60 ng/mL) were significantly higher in patients with CHD as compared with those of the healthy controls (1.65 ± 1.54 ng/mL, P < 0.05). There was a significant positive correlation between 14,15-DHETs and hs-CRP levels (R = 0.286, P = 0.027). However, there was no significant correlation between 14,15-DHETs and blood lipoproteins (all, P > 0.05).
Conclusions
Increased plasma 14,15-DHET levels reflect the decreased of 14,15-EET levels in an indirectly way. Indicated that decreased plasma 14,15-EET levels might be involved in the inflammatory reaction process in atherosclerosis.
doi:10.1186/1476-511X-12-151
PMCID: PMC3874761  PMID: 24148690
Coronary heart disease; Atherosclerosis; 14,15-epoxyeicosatrienoic acids; 14,15-dihydroxyeicosatrienoic acids; Inflammation; Lipoproteins
9.  Generation of diffraction-free optical beams using wrinkled membranes 
Scientific Reports  2013;3:2775.
Wrinkling has become a well developed bottom-up technique to make artificial surface textures in about the last decade. However, application of the optical properties of long range ordered wrinkles has been limited to one dimensional gratings to date. We report the demonstration of macroscopic optical focusing using wrinkled membranes, in which concentric wrinkle rings on a gold-PDMS bilayer membrane convert collimated illuminations to diffraction-free focused beams. Beam diameters of 300–400 μm have been observed in the visible range, which are dominantly limited by the eccentricity of the current devices. Based upon agreement between theoretical and experimental results on eccentricity effects, we predict a decrease of the beam diameter to no more than around 50 μm, if eccentricity is eliminated.
doi:10.1038/srep02775
PMCID: PMC3784948  PMID: 24072139
10.  A rapid fluorescent screening method for cellular sensitivity to anti-cancer compound 
Cytotechnology  2012;64(4):451-457.
The tetrazolium salts (MTT, XTT, MTS, WST) based colorimetric assay or resazurin based fluorimetric assay are currently typical methods for cell sensitivity determination to anticancer compounds. We presented here a new rapid method for this purpose. This method uses a fluorescent dye named DCFH-DA which is previously taken as a intracellular probe for measurement of H2O2 levels within a cell. The application basis for this method lies in two facts: the membrane permeable feature of the final metabolite of DCFH-DA inside a cell, and the linearity relationship between cell number and H2O2 level. The results showed that there was a perfect association between cell number and fluorescent intensity determined by the DCFH-DA method, no matter whether using resuspended or adherent cells, and further 50% concentration of inhibition (IC50) comparison between data obtained by DCFH-DA method or MTT method using a positive known anticancer compound Baicalin showed that there were no significant differences in cellular sensitivity determination to compound Baicalin though there existed a relatively higher coefficient of variation of IC50 by the DCFH-DA method than that by the MTT method. Thus our data indicate that DCFH-DA might not only be a fine reagent for determination of H2O2 levels in cells but also an ideal fluorescent dye for cellular sensitivity test of anti-cancer compounds, and may be suitable for primary high-throughput drugs screening.
Electronic supplementary material
The online version of this article (doi:10.1007/s10616-011-9423-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s10616-011-9423-0
PMCID: PMC3397105  PMID: 22476562
DCFH-DA; MTT; Anti-cancer compound; Cell sensitivity; Baicalin
11.  Factors Associated with Serological Cure and the Serofast State of HIV-Negative Patients with Primary, Secondary, Latent, and Tertiary Syphilis 
PLoS ONE  2013;8(7):e70102.
Background
Some syphilis patients remain in a serologically active state after the recommended therapy. We currently know too little about the characteristics of this serological response.
Methods
We conducted a cohort study using the clinical database from Zhongshan Hospital, Medical College of Xiamen. In total, 1,327 HIV-negative patients with primary, secondary, latent, and tertiary syphilis were enrolled. Bivariate and multivariate analyses were utilised to identify factors associated with a serological cure and serofast state in syphilis patients one year after therapy. Chi-square tests were used to determine the differences in the serological cure rate across different therapy time points.
Results
One year after the recommended therapy, 870 patients achieved a serological cure, and 457 patients (34.4%) remained in the serofast state. The serological cure rate increased only within the first 6 months. The bivariate analysis indicated that male or younger patients had a higher likelihood of a serological cure than female or older patients. Having a baseline titre ≤1∶2 or ≥1∶64 was associated with an increased likelihood of a serological cure. The serological cure rate decreased for the different disease stages in the order of primary, secondary, latent, and tertiary syphilis. A distinction should be drawn between early and late syphilis. The multivariate analysis indicated that a serological cure was significantly associated with the disease phase, gender, age, and baseline rapid plasma reagin (RPR) titre.
Conclusions
The serofast state is common in clinical work. After one year of the recommended therapy, quite a few syphilis patients remained RPR positive. The primary endpoint of the study indicated that disease phase, gender, age and baseline RPR titre were crucial factors associated with a serological cure.
doi:10.1371/journal.pone.0070102
PMCID: PMC3720935  PMID: 23894598
12.  Sp100A promotes chromatin decondensation at a cytomegalovirus-promoter–regulated transcription site 
Molecular Biology of the Cell  2013;24(9):1454-1468.
Sp100 isoforms differentially regulate a CMV-promoter–regulated transcription site, which can be visualized in single cells. Sp100A promotes decondensation and increases lysine acetylation. However, it cannot overcome Daxx- and ATRX-mediated repression, indicating that PML-NB/ND10 factors function within a regulatory hierarchy.
Promyelocytic leukemia nuclear bodies (PML-NBs)/nuclear domain 10s (ND10s) are nuclear structures that contain many transcriptional and chromatin regulatory factors. One of these, Sp100, is expressed from a single-copy gene and spliced into four isoforms (A, B, C, and HMG), which differentially regulate transcription. Here we evaluate Sp100 function in single cells using an inducible cytomegalovirus-promoter–regulated transgene, visualized as a chromatinized transcription site. Sp100A is the isoform most strongly recruited to the transgene array, and it significantly increases chromatin decondensation. However, Sp100A cannot overcome Daxx- and α-thalassemia mental retardation, X-linked (ATRX)–mediated transcriptional repression, which indicates that PML-NB/ND10 factors function within a regulatory hierarchy. Sp100A increases and Sp100B, which contains a SAND domain, decreases acetyl-lysine regulatory factor levels at activated sites, suggesting that Sp100 isoforms differentially regulate transcription by modulating lysine acetylation. In contrast to Daxx, ATRX, and PML, Sp100 is recruited to activated arrays in cells expressing the herpes simplex virus type 1 E3 ubiquitin ligase, ICP0, which degrades all Sp100 isoforms except unsumoylated Sp100A. The recruitment Sp100A(K297R), which cannot be sumoylated, further suggests that sumoylation plays an important role in regulating Sp100 isoform levels at transcription sites. This study provides insight into the ways in which viruses may modulate Sp100 to promote their replication cycles.
doi:10.1091/mbc.E12-09-0669
PMCID: PMC3639056  PMID: 23485562
13.  The Role of Antigen Cross-Presentation From Leukemia Blasts on Immunity to the Leukemia-Associated Antigen PR1 
Cross-presentation is an important mechanism by which exogenous tumor antigens are presented to elicit immunity. Since neutrophil elastase (NE) and proteinase-3 (P3) expression is increased in myeloid leukemia, we investigated whether NE and P3 are cross-presented by dendritic cells (DC) and B-cells, and whether the NE and P3 source determines immune outcomes. We show that NE and P3 are elevated in leukemia patient serum and that levels correlate with remission status. We demonstrate cellular uptake of NE and P3 into lysosomes, ubiquitination and proteasome processing for cross-presentation. Using anti-PR1/HLA-A2 monoclonal antibody, we provide direct evidence that B-cells cross-present soluble and leukemia-associated NE and P3, while DCs cross-present only leukemia-associated NE and P3. Cross-presentation occurred at early time points but was not associated with DC or B-cell activation, suggesting that NE and P3 cross-presentation may favor tolerance. Furthermore, we show aberrant subcellular localization of NE and P3 in leukemia blasts to compartments that share common elements of the classical MHC class I antigen-presenting pathway, which may facilitate cross-presentation. Our data demonstrate distinct mechanisms for cross-presentation of soluble and cell-associated NE and P3, which may be valuable in understanding immunity to PR1 in leukemia.
doi:10.1097/CJI.0b013e31824b3b14
PMCID: PMC3326226  PMID: 22495388
neutrophil elastase; proteinase 3; cross-presentation; leukemia; PR1; myeloid
14.  Anesthetic management of conjoined twins undergoing one-stage surgical separation: A single center experience 
Objective: To summarize our experience in the anesthetic management of conjoined twins undergoing one-stage surgical separation.
Methodology: Medical records of conjoined twins admitted to our hospital for treatment and considered for surgical separation from 1996 to present were retrospectively reviewed. Four cases of conjoined twins underwent one-stage surgical separation under general anesthesia. Preoperative evaluation was performed to determine the extent of anatomical conjunction and associated anomalies. Anesthesia was simultaneously induced in all conjoined twins. The intubation procedure was successfully performed with the head slightly rotated to each baby’s side, followed by the administration of vecuronium. Anesthetic agents were administered according to the estimated weight of each baby. One case of conjoined twins underwent surgical separation with cardiopulmonary bypass due to shared hearts.
Results: All conjoined twins were successfully separated. No significant respiratory or cardiac events occurred during surgery except for one twin, which died after separation because of complicated congenital heart disease.
Conclusions : Accurate preoperative evaluation, respiratory and circulatory management, and close cooperation of the multidisciplinary team are important aspects of anesthetic management of conjoined twins surgery.
PMCID: PMC3809258  PMID: 24353566
Conjoined twins; Separation; Anesthetic management; Surgery
15.  Role of VPO1, a newly identified heme-containing peroxidase, in ox-LDL induced endothelial cell apoptosis 
Free radical biology & medicine  2011;51(8):1492-1500.
Myeloperoxidase (MPO) is an important enzyme involved in the genesis and development of atherosclerosis. Vascular peroxidase 1 (VPO1) is a newly discovered member of the peroxidase family that is mainly expressed in vascular endothelial cells and smooth muscle cells and has structural characteristics and biological activity similar to those of MPO. Our specific aims were to explore the effects of VPO1 on endothelial cell apoptosis induced by oxidized low-density lipoprotein (ox-LDL) and the underlying mechanisms. The results showed that ox-LDL induced endothelial cell apoptosis and the expression of VPO1 in endothelial cells in a concentration- and time-dependent manner concomitant with increased intracellular reactive oxygen species (ROS) and hypochlorous acid (HOCl) generation, and up-regulated protein expression of the NADPH oxidase gp91phox subunit and phosphorylation of p38 MAPK. All these effects of ox-LDL were inhibited by VPO1 gene silencing and NADPH oxidase gp91phox subunit gene silencing or by pretreatment with the NADPH oxidase inhibitor apocynin or diphenyliodonium. The p38 MAPK inhibitor SB203580 or the caspase-3 inhibitor DEVD-CHO significantly inhibited ox-LDL-induced endothelial cell apoptosis, but had no effect on intracellular ROS and HOCl generation or the expression of NADPH oxidase gp91phox subunit or VPO1. Collectively, these findings suggest for the first time that VPO1 plays a critical role in ox-LDL-induced endothelial cell apoptosis and that there is a positive feedback loop between VPO1/HOCl and the now-accepted dogma that the NADPH oxidase/ROS/p38 MAPK/caspase-3 pathway is involved in ox-LDL-induced endothelial cell apoptosis.
doi:10.1016/j.freeradbiomed.2011.07.004
PMCID: PMC3570029  PMID: 21820048
VPO1; MPO; NADPH oxidase; Apoptosis; Endothelial cells; Free radicals
16.  Wnt10b Promotes Differentiation of Mouse Hair Follicle Melanocytes 
Previous research has revealed that Wnt10b activates canonical Wnt signaling, which is integral to melanocyte differentiation in hair follicles (HFs). However, the function of Wnt10b in HF melanocytes remains poorly understood. We determined using Dct-LacZ transgenic mice that Wnt10b is mainly expressed near and within melanocytes of the hair bulbs during the anagen stage of the hair cycle. We also found that Wnt10b promotes an increase in melanocyte maturation and pigmentation in the hair bulbs of the mouse HF. To further explore the potential functions of Wnt10b in mouse HF melanocytes, we infected iMC23 cells with Ad-Wnt10b to overexpress Wnt10b. We demonstrated that Wnt10b promotes the differentiation of melanocytes by activating canonical Wnt signaling in melanocytes.
doi:10.7150/ijms.6170
PMCID: PMC3619118  PMID: 23569433
Wnt10b; Wnt/β-catenin signaling; Hair follicle; Melanocyte; Differentiation.
17.  Wnt5a Inhibits the Proliferation and Melanogenesis of Melanocytes 
Wnt5a, which is a noncanonical Wnt molecule, has been shown to be involved in a variety of developmental processes and cellular functions. In this study, we used “melan-a” cells as a cell model to investigate the effects of Wnt5a on melanocyte proliferation and melanogenesis, and to elucidate the possible mechanisms involved. We infected melan-a cells with recombinant Wnt5a adenoviruses to express Wnt5a protein and to simulate the Wnt5a processing environment. MTT assay and BrdU incorporation assay revealed that Wnt5a significantly inhibited the proliferation of melan-a cells. Melanin content and tyrosinase activity assays showed that Wnt5a was an inhibitor of melanin synthesis. Furthermore, RT-PCR and Western blot showed that this suppressive effect depended on noncanonical Wnt/Ror2 pathway activation and accessed the inhibition of the canonical Wnt pathway. The above results provided a novel insight into the role of Wnt5a and its related signaling in melanocyte homeostasis.
doi:10.7150/ijms.5664
PMCID: PMC3619119  PMID: 23569434
Wnt5a; melanocyte; proliferation; melanogenesis; Wnt/Ror2 pathway.
18.  Adenovirus-Mediated Wnt5a Expression Inhibits the Telogen-To-Anagen Transition of Hair Follicles in Mice 
The canonical Wnt/β-catenin pathway plays an important role in hair cycle induction. Wnt5a is a non-canonical Wnt family member that generally antagonizes canonical Wnt signaling in other systems. In hair follicles, Wnt5a and canonical Wnt are both expressed in cells in the telogen stage. Wnt5a has been shown to be critical for controlling hair cell fate. However, the role that Wnt5a plays in the transition from the telogen to anagen stage is unknown. In this study, using whole-mount in situ hybridization, we show that Wnt5a is produced by several other cell types, excluding dermal papilla cells, throughout the hair cycle. For example, Wnt5a is expressed in bulge and secondary hair germ cells in the telogen stage. Our studies focused on the depilated 8-week-old mouse as a synchronized model of hair growth. Interestingly, overexpression of adenovirus Wnt5a in the dorsal skin of mice led to the elongation of the telogen stage and inhibition of the initiation of the anagen stage. However, following an extended period of time, four pelage hair types grew from hairless skin that was induced by Wnt5a, and the structure of these new hair shafts was normal. Using microarray analysis and quantitative arrays, we showed that the expression of β-catenin and some target genes of canonical Wnt signaling decreased after Wnt5a treatment. These data demonstrate that Wnt5a may inhibit the telogen stage to maintain a quiescent state of the hair follicle.
doi:10.7150/ijms.6137
PMCID: PMC3675505  PMID: 23781137
Wnt5a; Hair growth; Wnt signaling pathway; Hair cycle.
19.  Combining multiple serum biomarkers in tumor diagnosis: A clinical assessment 
Molecular and Clinical Oncology  2012;1(1):153-160.
The present study aimed to assess the diagnostic/prognostic value of various clinical tumor markers, including carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratin 19 (CYFRA21-1), α-fetoprotein (AFP), carbohydrate antigen-125 (CA-125), carbohydrate antigen-19.9 (CA-19.9) and ferritin, individually or in combination. The electro-chemiluminescence immunization method was performed to detect the levels of seven tumor markers in 560 cancer patients and 103 healthy subjects for comparison. The serum levels of the seven markers measured in cancer patients were higher compared to healthy subjects (P<0.05 for AFP and P<0.001 for the remaining six markers). Different markers had different sensitivity towards different types of tumors. Combining more markers significantly increased the ratios of positive diagnosis in the tumors. The diagnostic sensitivities of combining seven markers were particularly high in digestive, urinary and skeletal tumors (82, 92 and 83%, respectively). Gynecological tumors have exhibited a constant yet relatively low positive diagnosis irrespective of the use of a single marker or combined markers. However, the increase in sensitivity when combining markers was accompanied by a decrease in specificity. Generally, combining more markers increased the tumor detection rates, while a combination of the seven markers provided the highest detection rate. Combined detection showed a particularly high sensitivity in detecting respiratory, digestive and urinary system tumors, with the lowest sensitivity observed in gynecological tumors. As a result, combining tumor markers may play an important role in early tumor detection/diagnosis while the loss of specificity can be tolerated.
doi:10.3892/mco.2012.23
PMCID: PMC3956235  PMID: 24649139
tumor marker; diagnosis; lung cancer; carcinoembryonic antigen; neuron-specific enolase; cytokeratin 19
20.  The molecular basis of making spiral ganglion neurons and connecting them to hair cells of the organ of Corti 
Hearing research  2011;278(1-2):21-33.
The bipolar spiral ganglion neurons predominantly delaminate from the growing cochlear duct and migrate to Rosenthal’s canal. They project radial fibers to innervate the organ of Corti (type I neurons to inner hair cells, type II neurons to outer hair cells) and also project tonotopically to the cochlear nuclei. The early differentiation of these neurons requires transcription factors to regulate migration, pathfinding and survival. Neurog1 null mice lack formation of neurons. Neurod1 null mice show massive cell death combined with aberrant central and peripheral projections. Prox1 protein is necessary for proper type II neuron process navigation, which is also affected by the neurotrophins Bdnf and Ntf3. Neurotrophin null mutants show specific patterns of neuronal loss along the cochlea but remaining neurons compensate by expanding their target area. All neurotrophin mutants have reduced radial fiber growth proportional to the degree of loss of neurotrophin alleles. This suggests a simple dose response effect of neurotrophin concentration. Keeping overall concentration constant, but misexpressing one neurotrophin under regulatory control of another one results in exuberant fiber growth not only of vestibular fibers to the cochlea but also of spiral ganglion neurons to outer hair cells suggesting different effectiveness of neurotrophins for spiral ganglion neurite growth. Finally, we report here for the first time that losing all neurons in double null mutants affects extension of the cochlear duct and leads to formation of extra rows of outer hair cells in the apex, possibly by disrupting the interaction of the spiral ganglion with the elongating cochlea.
doi:10.1016/j.heares.2011.03.002
PMCID: PMC3130837  PMID: 21414397
ear; spiral ganglion; development; neuronal survival
21.  Krüppel-Like Factor 8 Is a New Wnt/Beta-Catenin Signaling Target Gene and Regulator in Hepatocellular Carcinoma 
PLoS ONE  2012;7(6):e39668.
Krüppel-like factor 8 (KLF8) plays important role in cell cycle and oncogenic transformation. Here we report the mechanisms by which KLF8 crosstalks with Wnt/β-catenin signaling pathway and regulates hepatocellular carcinoma (HCC) cells proliferation. We show that overexpression of KLF8 and nucleus accumulation of β-catenin in the human HCC samples are positively correlated. More importantly, KLF8 protein levels plus nucleus accumulation of β-catenin levels were significantly elevated in high-grade HCC compared to low-grade HCC. Using HCC HepG2 cells we find that, on the one hand both protein and mRNA of KLF8 are up-regulated under Wnt3a stimulation, on the other hand overexpression of KLF8 increases the cytoplasm and nucleus accumulation of β-catenin, recruits p300 to β-catenin/T-cell factor 4 (TCF4) transcription complex, enhances TOP flash report gene transcription, and induces Wnt/β-catenin signaling target genes c-Myc, cyclin D1 and Axin1 expression. Knockdown of KLF8 using shRNA inhibits Wnt3a induced transcription of TOP flash report gene and expression of c-Myc, cyclin D1 and Axin1. Knockdown of β-catenin by shRNA rescues the enhanced HepG2 and Hep3B cells proliferation ability induced by overexpression of KLF8.
doi:10.1371/journal.pone.0039668
PMCID: PMC3384617  PMID: 22761862
22.  Concomitant lung metastasis in patients with advanced hepatocellular carcinoma 
AIM: To investigate the clinical features and prognostic factors of advanced hepatocellular carcinoma (HCC) patients presenting with lung metastasis at initial diagnosis.
METHODS: Between 2001 and 2010, we recruited 76 consecutive HCC patients initially presenting with lung metastasis, without co-existing metastasis from other sites. These patients were divided into three groups: untreated group (n = 22), single treatment group (n = 19), and combined treatment group (n = 35).
RESULTS: Metastasis of bilateral lung lobes was common and noted in 35 patients (46.1%), and most of patients (59/76, 77.6%) presented with multiple lung metastatic nodules. Nineteen patients (25.0%) received single-method treatment, including hepatectomy in 4, transcatheter arterial chemoembolization in 6, radiotherapy in 5, and oral sorafenib in 4. Thirty-five patients (46.1%) received combined treatment modalities. The overall median survival of the all patients was 8.7 ± 0.6 mo; 4.1 ± 0.3, 6.3 ± 2.5 and 18.6 ± 3.9 mo, respectively in the untreated group, single treatment group and combined treatment group, respectively, with a significant difference (log-rank test, P < 0.001). Multivariate analysis revealed that Child-Pugh score, the absence or presence of portal vein tumor thrombus, and treatment modality were three independent prognostic factors affecting survival of patients with advanced HCC and concomitant lung metastasis.
CONCLUSION: Combined treatment modalities tend to result in a better survival as compared with the conservative treatment or single treatment modality for HCC patients initially presenting with lung metastasis.
doi:10.3748/wjg.v18.i20.2533
PMCID: PMC3360452  PMID: 22654451
Hepatocellular carcinoma; Lung metastasis; Prognosis; Survival; Prognostic factor
23.  Descriptive data on cancerous lung lesions detected by auto-fluorescence bronchoscope: A five-year study 
Annals of Thoracic Medicine  2012;7(1):21-25.
BACKGROUND:
Auto-fluorescence bronchoscopy (AFB) has been used for the identification and localization of intra-epithelial pre-neoplastic and neoplastic lesions within the bronchus.
OBJECTIVES:
To determine the applicability of AFB for the detection and localization of precancerous and cancerous lesions, in addition to analyzing the morphologic presentation, their association to histological type and the variation between genders.
METHODS:
A five-year study involving 4983 patients, who underwent routine bronchoscopy [B] examination in a local tertiary teaching hospital, was done. The B examination was performed under intratracheal lidocaine, and samples were obtained using suitable approach. One thousand four hundred and eighty-five pathologically confirmed lung cancer patients were included in the study. The following parameters were studied: Morphological presentation, biopsy sites, histology. Differences between the groups were analyzed using Chi square test.
RESULT:
One thousand four hundred and eighty-five patients who had hyperplasia or neoplastic lesions were further confirmed as lung cancer pathologically. Lung cancer was more commonly found in the right lung (51.58% vs. 42.82%). The lesion occurred more frequently in the upper lobe than the lower lobe (44.17% vs. 22.42%). Male patients with squamous cell carcinoma showed upper lobe involvement more commonly, while the left main bronchus was more commonly involved in female patients. Adenocarcinoma mostly involved lesion of the upper lobe. Squamous cell carcinoma and small cell carcinoma were the major proliferative types (80.15% and 76.16% respectively).
CONCLUSION:
AFB is efficient in the detection of pre-invasive and invasive lung lesions. The morphological presentation is associated to the histological type. There is variation in the presentation and histology of cancerous lung lesions between genders.
doi:10.4103/1817-1737.91559
PMCID: PMC3277036  PMID: 22347346
Auto-fluorescence bronchoscopy; gender; invasive lesion; lung cancer; screening
24.  Isoflurane Preconditioning at Clinically Relevant Doses Induce Protective Effects of Heme Oxygenase-1 on Hepatic Ischemia Reperfusion in Rats 
BMC Gastroenterology  2011;11:31.
Background
Activation of heme oxygenase-1 (HO-1) has been proved to reduce damages to the liver in ischemia reperfusion injury. The objective of present study was to determine whether clinic relevant doses of isoflurane treatment could be sufficient to activate HO-1 inducing, which confers protective effect against hepatic ischemia-reperfusion injury.
Methods
The hepatic artery and portal vein to the left and the median liver lobes of forty male Sprague-Dawley rats were occluded for 60 minutes. Reperfusion was allowed for 4 hours before the animal subjects were sacrificed. Six groups (n = 12) were included in the study. A negative control group received sham operation and positive control group a standard ischemia-reperfusion regimen. The third group was pretreated with isoflurane prior to the ischemia-reperfusion. The fourth group received an HO-1 inhibitor zinc protoporphyrin (Znpp) prior to the isoflurane pretreatment and the ischemia-reperfusion. The fifth group received Znpp alone before ischemia-reperfusion procedure, and the sixth group was administrated with a HO-1 inducer hemin prior to IR. HO-1 in the liver was measured using an enzymatic activity assay, a Western blot analysis, as well as immunohistochemical method. Extent of liver damage was estimated by determination of the serum transaminases, liver lipid peroxidation and hepatic histology. Infiltration of the liver by neutrophils was measured using a myeloperoxidase activity assay. TNFα mRNA in the liver was measured using RT-PCR.
Results
Isoflurane pretreatment significantly attenuated the hepatic injuries and inflammatory responses caused by the ischemia reperfusion. Selectively inhibiting HO-1 with ZnPP completed blocked the protective effects of isoflurane. Inducing HO-1 with hemin alone produced protective effects similar in magnitude to that of isoflurane.
Conclusions
Clinic relevant doses of isoflurane attenuate ischemia reperfusion injury in rats by increasing the HO-1 expression and activity.
doi:10.1186/1471-230X-11-31
PMCID: PMC3088533  PMID: 21453462
25.  Results of the proximal femoral nail anti-rotation (PFNA) in elderly Chinese patients 
International Orthopaedics  2009;33(5):1441-1444.
A prospective study is presented of 87 unstable intertrochanteric fractures treated with the proximal femoral nail anti-rotation (PFNA) with a follow-up of one year. Of the patients 76% were female. The average age was 75.3 years. The fracture was treated by closed reduction and intramedullary fixation. Pre-injury activity level was recovered in 77% of the patients. Fractures united in all patients. Mechanical failure and cut-out were not observed. A technical problem related to the mismatch of the proximal end of the nail was observed in 11 cases. Nine patients presented with thigh pain due to the redundant proximal end of the nail. The results of the PFNA were satisfactory in most elderly Chinese patients. However, the proximal end of the nail was not matched with the specific anatomy of some short elderly patients. Further modifications of the nail are necessary for the elderly Chinese population.
doi:10.1007/s00264-009-0776-3
PMCID: PMC2899136  PMID: 19367404

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