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1.  Anti-tumor effect of 5-aza-2'-deoxycytidine by inhibiting telomerase activity in hepatocellular carcinoma cells 
AIM: To investigate the effect of the demethylating reagent 5-aza-2’-deoxycitidine (DAC) on telomerase activity in hepatocellular carcinoma (HCC) cell lines, SMMC-7721 and HepG2.
METHODS: The related gene expression in cell lines was examined by real-time reverse transcription-polymerase chain reaction and Western blotting analysis. The telomerase activity was examined by telomeric repeat amplification protocol-enzyme-linked immunosorbent assay and DNA methylation was determined by methylation-specific polymerase chain reaction.
RESULTS: The telomerase activity was significantly reduced in both cell lines treated with DAC, accompanied by downregulation of telomerase reverse transcriptase (hTERT). We also observed the effect of DAC on the methylation status of hTERT promoter and the expression of regulatory genes, such as c-myc, p15, p16, p21, E2F1, and WT1. The methylation status of hTERT promoter could be reversed in SMMC-7721 by DAC, but not in HepG2 cells. However, p16 expression could be reactivated by demethylation of its promoter, and c-Myc expression was repressed in both cell lines. Moreover, DAC could enhance the sensitivity to the chemotherapeutic agents, such as cisplatin, by induction of apoptosis of HCC cells.
CONCLUSION: The DAC exerts its anti-tumor effects in HCC cells by inhibiting the telomerase activity.
doi:10.3748/wjg.v18.i19.2334
PMCID: PMC3353367  PMID: 22654424
5-aza-2’-deoxycitidine; Telomerase; Hepatocellular carcinoma; DNA methylation
2.  Multiscale limited penetrable horizontal visibility graph for analyzing nonlinear time series 
Scientific Reports  2016;6:35622.
Visibility graph has established itself as a powerful tool for analyzing time series. We in this paper develop a novel multiscale limited penetrable horizontal visibility graph (MLPHVG). We use nonlinear time series from two typical complex systems, i.e., EEG signals and two-phase flow signals, to demonstrate the effectiveness of our method. Combining MLPHVG and support vector machine, we detect epileptic seizures from the EEG signals recorded from healthy subjects and epilepsy patients and the classification accuracy is 100%. In addition, we derive MLPHVGs from oil-water two-phase flow signals and find that the average clustering coefficient at different scales allows faithfully identifying and characterizing three typical oil-water flow patterns. These findings render our MLPHVG method particularly useful for analyzing nonlinear time series from the perspective of multiscale network analysis.
doi:10.1038/srep35622
PMCID: PMC5069474  PMID: 27759088
3.  Transplantation of vascular endothelial growth factor-modified neural stem/progenitor cells promotes the recovery of neurological function following hypoxic-ischemic brain damage 
Neural Regeneration Research  2016;11(9):1456-1463.
Neural stem/progenitor cell (NSC) transplantation has been shown to effectively improve neurological function in rats with hypoxic-ischemic brain damage. Vascular endothelial growth factor (VEGF) is a signaling protein that stimulates angiogenesis and improves neural regeneration. We hypothesized that transplantation of VEGF-transfected NSCs would alleviate hypoxic-ischemic brain damage in neonatal rats. We produced and transfected a recombinant lentiviral vector containing the VEGF165 gene into cultured NSCs. The transfected NSCs were transplanted into the left sensorimotor cortex of rats 3 days after hypoxic-ischemic brain damage. Compared with the NSCs group, VEGF mRNA and protein expression levels were increased in the transgene NSCs group, and learning and memory abilities were significantly improved at 30 days. Furthermore, histopathological changes were alleviated in these animals. Our findings indicate that transplantation of VEGF-transfected NSCs may facilitate the recovery of neurological function, and that its therapeutic effectiveness is better than that of unmodified NSCs.
doi:10.4103/1673-5374.191220
PMCID: PMC5090849  PMID: 27857750
nerve regeneration; vascular endothelial growth factor; transfection; neural stem/progenitor cells; transplantation; hypoxic-ischemic brain damage; cerebral cortex; animal model; neuroprotection; neural regeneration
4.  Trafficking Highways to the Intercalated Disc: New Insights Unlocking the Specificity of Connexin 43 Localization 
Cell communication & adhesion  2014;21(1):43-54.
With each heartbeat, billions of cardiomyocytes work in concert to propagate the electrical excitation needed to effectively circulate blood. Regulated expression and timely delivery of connexin proteins to form gap junctions at the specialized cell – cell contact region, known as the intercalated disc, is essential to ventricular cardiomyocyte coupling. We focus this review on several regulatory mechanisms that have been recently found to govern the lifecycle of connexin 43 (Cx43), the short-lived and most abundantly expressed connexin in cardiac ventricular muscle. The Cx43 lifecycle begins with gene expression, followed by oligomerization into hexameric channels, and then cytoskeletal-based transport toward the disc region. Once delivered, hemichannels interact with resident disc proteins and are organized to effect intercellular coupling. We highlight recent studies exploring regulation of Cx43 localization to the intercalated disc, with emphasis on alternatively translated Cx43 isoforms and cytoskeletal transport machinery that together regulate Cx43 gap junction coupling between cardiomyocytes.
doi:10.3109/15419061.2013.876014
PMCID: PMC4950511  PMID: 24460200
Connexin 43; internal translation; transcription; autoregulation; trafficking; cytoskeleton; intercalated disc; microtubules; actin
5.  Complex network analysis of phase dynamics underlying oil-water two-phase flows 
Scientific Reports  2016;6:28151.
Characterizing the complicated flow behaviors arising from high water cut and low velocity oil-water flows is an important problem of significant challenge. We design a high-speed cycle motivation conductance sensor and carry out experiments for measuring the local flow information from different oil-in-water flow patterns. We first use multivariate time-frequency analysis to probe the typical features of three flow patterns from the perspective of energy and frequency. Then we infer complex networks from multi-channel measurements in terms of phase lag index, aiming to uncovering the phase dynamics governing the transition and evolution of different oil-in-water flow patterns. In particular, we employ spectral radius and weighted clustering coefficient entropy to characterize the derived unweighted and weighted networks and the results indicate that our approach yields quantitative insights into the phase dynamics underlying the high water cut and low velocity oil-water flows.
doi:10.1038/srep28151
PMCID: PMC4910115  PMID: 27306101
6.  Establishment and application of a real-time loop-mediated isothermal amplification system for the detection of CYP2C19 polymorphisms 
Scientific Reports  2016;6:26533.
Single-nucleotide polymorphisms (SNPs) represent the most widespread type of genetic variation (approximately 90%) in the human genome, and the demand to overcome such variation has received more attention now than ever before. The capacity to rapidly assess SNPs that correlate with disease predisposition, drug efficacy and drug toxicity is a key step for the development of personalized medicine. In this work, a rapid one-step SNP detection method, real-time loop-mediated isothermal amplification (RT-LAMP), was first applied for CYP2C19 polymorphisms testing. The optimized method was established with specifically designed primers for target amplification by real-time detection in approximately 30 min under isothermal conditions. RT-LAMP amplified few copies of template to produce significant amounts of product and quantitatively detected human DNA with compatible specificity and sensitivity. The success in the establishment of this RT-LAMP protocol for CYP2C19 polymorphism testing is significant for the extension of this technique for the detection of other SNPs, which will further facilitate the development of personalized medicine.
doi:10.1038/srep26533
PMCID: PMC4887897  PMID: 27246657
7.  A 14-3-3 Mode-1 Binding Motif Initiates Gap Junction Internalization during Acute Cardiac Ischemia 
Traffic (Copenhagen, Denmark)  2014;15(6):684-699.
Altered phosphorylation and trafficking of connexin 43 (Cx43) during acute ischemia contributes to arrhythmogenic gap junction remodeling, yet the critical sequence and accessory proteins necessary for Cx43 internalization remain unresolved. 14-3-3 proteins can regulate protein trafficking, and a 14-3-3 mode-1 binding motif is activated upon phosphorylation of Ser373 of the Cx43 C-terminus. We hypothesized that Cx43Ser373 phosphorylation is important to pathologic gap junction remodeling. Immunofluorescence in human heart reveals enrichment of 14-3-3 proteins at intercalated discs, suggesting interaction with gap junctions. Knockdown of 14-3-3τ in cell lines increases gap junction plaque size at cell-cell borders. Cx43S373A mutation prevents Cx43/14-3-3 complexing and stabilizes Cx43 at the cell surface, indicating avoidance of degradation. Using Langendorff-perfused mouse hearts we detect phosphorylation of newly internalized Cx43 at Ser373 and Ser368 within 30 minutes of no-flow ischemia. Phosphorylation of Cx43 at Ser368 by PKC and Ser255 by MAPK has previously been implicated in Cx43 internalization. The Cx43S373A mutant is resistant to phosphorylation at both these residues and does not undergo ubiquitination, revealing Ser373 phosphorylation as an upstream gate-keeper of a post-translational modification cascade necessary for Cx43 internalization. Cx43Ser373 phosphorylation is a potent target for therapeutic interventions to preserve gap junction coupling in the stressed myocardium.
doi:10.1111/tra.12169
PMCID: PMC4278178  PMID: 24612377
Connexin; Gap Junction; 14-3-3; Ischemia; Endocytosis
8.  Diffuse-type giant cell tumor of the tendon sheath in the temporal region incidentally diagnosed due to a temporal tumor: A report of two cases and review of the literature 
Oncology Letters  2015;10(2):1179-1183.
Diffuse-type tenosynovial giant cell tumor (D-GCTS) is a rare benign lesion that not only frequently occurs in the fingers, but also along the tendon sheaths of the foot and ankle. The present study reports the cases of two middle-aged patients that were diagnosed with D-GCTS. The presentation of the D-GCTS lesions was extremely rare, as the tumors were located in the temporal fossa and threatened the skull base and external auditory canal. There were similarities and differences between the two patients in their clinical symptoms, disease progressions and invading sites. The patients' disease course occurred unnoticed with the absence of pain, was protracted and became infiltrative. However, the female patient was admitted to the hospital due to the occurrence of pain in the left temporal region, and the male patient presented at the doctor due to a painless left temporal mass and external auditory canal bleeding. Therefore, the operation area of the two patients was not the same. This type of illness should be considered in the differential diagnosis for masses occurring in the temporal region. Total tumor removal is the best treatment for D-GCTS, and the careful monitoring of recurrence can achieve a good clinical outcome subsequent to the surgical resection.
doi:10.3892/ol.2015.3288
PMCID: PMC4509145  PMID: 26622648
diffuse type tenosynovial giant cell tumor; the temporal fossa; skull base; external auditory canal; clinical and pathological
9.  Expression levels of B7-H3 and TLT-2 in human oral squamous cell carcinoma 
Oncology Letters  2015;10(2):1063-1068.
The aim of the present study was to investigate the role of immune regulatory molecules B7-H3 [also known as cluster of differentiation 276] and triggering receptor expressed on myeloid cell-like transcript-2 (TLT-2) in patients with oral squamous cell carcinoma (OSCC). Human OSCC samples were obtained from 76 patients (female, 32; male, 44; age range, 23–81 years; median age, 50.9 years) that underwent resection for OSCC at Peking University Shenzhen Hospital (Shenzhen, China) between 2007 and 2010. In addition, control oral mucosal samples were obtained from 76 healthy individuals (female, 36; male, 40; age range, 21–62 years; median age, 45.3 years) during wisdom tooth extraction. Protein and gene expression levels of B7-H3 and TLT-2 were determined by immunohistochemical analysis and reverse transcription-polymerase chain reaction (RT-PCR). In the healthy oral mucosa samples, B7-H3 expression was identified to be weak, while the expression of TLT-2 was only detected sporadically in the cell membrane and cytoplasm. By contrast, the two regulatory molecules were widely expressed in the aforementioned localizations in human OSCC specimens upon immunohistochemical examination. Furthermore, quantitative RT-PCR confirmed the presence of significantly higher B7-H3 and TLT-2 expression levels in OSCC specimens compared with the oral mucosa of healthy individuals. The significantly higher expression levels of B7-H3 and TLT-2 in human OSCC specimens may indicate an inhibitory role of these molecules in the antitumoral immune response. To investigate interactions between these two molecules and individual antitumoral immune response in OSCC patients, prospective clinical studies with an adequate sample size are required.
doi:10.3892/ol.2015.3274
PMCID: PMC4509374  PMID: 26622626
B7-H3/cluster of differentiation 276; triggering receptor expressed on myeloid cell-like transcript-2; tumor immunity; oral squamous cell carcinoma
10.  A micropatterning approach for imaging Cx43 dynamic trafficking to cell-cell borders 
FEBS letters  2014;588(8):1439-1445.
The precise expression and timely delivery of connexin 43 (Cx43) proteins to form gap junctions are essential for electrical coupling of cardiomyocytes. Growing evidence supports a cytoskeletal-based trafficking paradigm for Cx43 delivery directly to adherens junctions at the intercalated disc. A limitation of Cx43 localization assays in cultured cells, in which cell-cell contacts are essential, is the inability to control for cell geometry or reproducibly generate contact points. Here we present a micropatterned cell pairing system well suited for live microscopy to examine how the microtubule and actin cytoskeleton confer specificity to Cx43 trafficking to precisely defined cell-cell junctions. This system can also be adapted for other cell types and used to study dynamic intracellular movements of other proteins important for cell-cell communication‥
doi:10.1016/j.febslet.2014.01.002
PMCID: PMC3989419  PMID: 24444605
connexin 43; micropatterning; trafficking; cytoskeleton
11.  Cardiac Spliced BIN1 Folds T-tubule Membrane, Controlling Ion Flux and Limiting Arrhythmia 
Nature medicine  2014;20(6):624-632.
Cardiomyocyte T-tubules are important for regulating ionic flux. Bridging Integrator 1 (BIN1) is a T-tubule protein associated with calcium channel trafficking that is down-regulated in failing hearts. Here we find that cardiac T-tubules normally contain dense protective inner membrane folds that are formed by a cardiac spliced isoform of BIN1. In mice with cardiac Bin1 deletion, T-tubule folding is decreased which does not change overall cardiomyocyte morphology, but frees diffusion of local extracellular calcium and potassium ions, prolonging action potential duration, and increasing susceptibility to ventricular arrhythmias. We also find that T-tubule inner folds are rescued only by the BIN1 isoform BIN1+13+17, which promotes N-WASP dependent actin polymerization to stabilize T-tubule membrane at cardiac Z-discs. In conclusion, BIN1+13+17 recruits actin to fold T-tubule membrane, creating a fuzzy space that protectively restricts ionic flux. When BIN1+13+17 is decreased, as occurs in acquired cardiomyopathy, T-tubule morphology is altered and arrhythmias can result.
doi:10.1038/nm.3543
PMCID: PMC4048325  PMID: 24836577
12.  Altered regional homogeneity in experimentally induced low back pain: a resting-state fMRI study 
Background
Functional imaging studies have indicated that patients with low back pain can have significant reductions in cerebral cortex grey matter. However, the mechanisms governing the nociceptive pathways in the human brain are unclear. The aim of this study was to use functional magnetic resonance imaging (fMRI) and regional homogeneity (ReHo) to investigate changes in resting-state brain activity in subjects that experienced experimentally induced low back pain.
Methods
Healthy subjects (n = 15) underwent fMRI (3.0 T) at baseline and during painful stimulation (intramuscular injection of 3% hypertonic saline).
Results
Compared to the scans conducted at baseline, scans conducted during experimentally induced low back pain showed increased ReHo on the right side in the medial prefrontal cortex, precuneus, insula, parahippocampal gyrus and cerebellum (posterior lobe), but decreased ReHo in the primary somatosensory cortex, anterior cingulate cortex and parahippocampal gyrus on the left side. The right inferior parietal lobule also showed a decreased ReHo (P < 0.05, cluster threshold ≥10).
Conclusions
These findings suggest that abnormally spontaneous resting-state activity in some brain regions may be associated with pain processing. These changes in neural activity may contribute to the recognition, execution, memory and emotional processing of acute low back pain.
doi:10.1186/1743-0003-11-115
PMCID: PMC4237877  PMID: 25080831
Low back pain; Functional magnetic resonance imaging; Resting state; Regional homogeneity
13.  Multilayered Regulation of Cardiac Ion Channels 
Biochimica et biophysica acta  2012;1833(4):876-885.
Essential to beat-to-beat heart function is the ability for cardiomyocytes to propagate electrical excitation and generate contractile force. Both excitation and contractility depend on specific ventricular ion channels, which include the L-type calcium channel (LTCC) and the connexin 43 (Cx43) gap junction. Each of these two channels is localized to a distinct subdomain of the cardiomyocyte plasma membrane. In this review, we focus on regulatory mechanisms that govern the lifecycles of LTCC and Cx43, from their biogenesis in the nucleus to directed delivery to T-tubules and intercalated discs, respectively. We discuss recent findings on how alternative promoter usage, tissue-specific transcription, and alternative splicing determine precise ion channel expression levels within a cardiomyocyte. Moreover, recent work on microtubule and actin-dependent trafficking for Cx43 and LTCC are introduced. Lastly, we discuss how human cardiac disease phenotypes can be attributed to defects in distinct mechanisms of channel regulation at the level of gene expression and channel trafficking.
doi:10.1016/j.bbamcr.2012.10.020
PMCID: PMC3568256  PMID: 23103513
connexin 43; calcium channel; directed targeting; cytoskeleton; gene expression
14.  Actin Cytoskeleton Rest Stops Regulate Anterograde Traffic of Connexin 43 Vesicles to the Plasma Membrane 
Circulation research  2012;110(7):978-989.
Rationale
The intracellular trafficking of connexin 43 (Cx43) hemichannels presents opportunities to regulate cardiomyocyte gap junction coupling. Although it is known that Cx43 hemichannels are transported along microtubules to the plasma membrane, the role of actin in Cx43 forward trafficking is unknown.
Objective
We explored whether the actin cytoskeleton is involved in Cx43 forward trafficking.
Methods and Results
High-resolution imaging reveals that Cx43 vesicles colocalize with nonsarcomeric actin in adult cardiomyocytes. Live-cell fluorescence imaging reveals Cx43 vesicles as stationary or traveling slowly (average speed 0.09 μm/s) when associated with actin. At any time, the majority (81.7%) of vesicles travel at subkinesin rates, suggesting that actin is important for Cx43 transport. Using Cx43 containing a hemagglutinin tag in the second extracellular loop, we developed an assay to detect transport of de novo Cx43 hemichannels to the plasma membrane after release from Brefeldin A-induced endoplasmic reticulum/Golgi vesicular transport block. Latrunculin A (for specific interference of actin) was used as an intervention after reinitiation of vesicular transport. Disruption of actin inhibits delivery of Cx43 to the cell surface. Moreover, using the assay in primary cardiomyocytes, actin inhibition causes an 82% decrease (P<0.01) in de novo endogenous Cx43 delivery to cell–cell borders. In Langendorff-perfused mouse heart preparations, Cx43/β-actin complexing is disrupted during acute ischemia, and inhibition of actin polymerization is sufficient to reduce levels of Cx43 gap junctions at intercalated discs.
Conclusions
Actin is a necessary component of the cytoskeleton-based forward trafficking apparatus for Cx43. In cardiomyocytes, Cx43 vesicles spend a majority of their time pausing at nonsarcomeric actin rest stops when not undergoing microtubule-based transport to the plasma membrane. Deleterious effects on this interaction between Cx43 and the actin cytoskeleton during acute ischemia contribute to losses in Cx43 localization at intercalated discs.
doi:10.1161/CIRCRESAHA.111.257964
PMCID: PMC3621031  PMID: 22328533
actin; connexin 43; cytoskeletal dynamics; gap junctions; trafficking
15.  Nutritional status deteriorates as the severity of diabetic foot ulcers increases and independently associates with prognosis 
The prognosis for diabetic foot ulcers (DFUs) remains poor. Nutritional status has not been identified as one of the factors affecting the outcome of DFUs. Therefore, indicators correlated with nutritional status and outcome were analyzed to investigate their relationship. A total of 192 hospitalized patients with Wagner grade 1–5 ulcers and 60 patients with Wagner grade 0 ulcers (all had type 2 diabetes) were assessed by the following: subjective global assessment (SGA), anthropometric measurements, biochemical indicators and physical examinations to evaluate nutritional status, severity of infection and complications. Patient outcome was recorded as healing of the ulcer and the patients were followed up for 6 months or until the wound was healed. The percentage of malnutrition was 62.0% in the DFU patients. The SGA was closely correlated with infection (r=0.64), outcome (r=0.37) and BMI (r=−0.36), all P<0.001. The risk of poor outcome increased with malnutrition [odds ratio (OR), 10.6, P<0.001]. The nutritional status of the DFU patients was independently correlated with the severity of infection and outcome (both P<0.001) and Wagner grades and nutritional status (SGA) were independent risk factors for patient outcome (both P<0.001). Nutritional status deteriorated as the severity of the DFU increased, and malnutrition was a predictor of poor prognosis.
doi:10.3892/etm.2012.780
PMCID: PMC3524099  PMID: 23251271
nutritional status; diabetic foot ulcers; complication; infection
16.  Inhibition of autophagy enhances anticancer effects of bevacizumab in hepatocarcinoma 
Angiogenesis inhibitors have long been considered desirable anticancer agents. However, it was found that many tumors could develop resistance to antiangiogenesis inhibitors. Antiangiogenic therapy results in metabolic stress. Autophagy is an important survival mechanism in cancer cells under metabolic stress; however, it remains unknown if autophagy contributes to antiangiogenesis resistance. In this study, we reported that bevacizumab treatment reduced the development of new blood vessels and inhibited cell growth in xenografts of hepatocellular carcinoma (HCC) tumors. Bevacizumab treatment also upregulated expression of the autophagy-related genes (Beclin1 and LC3) and increased autophagosome formation. Our in vitro studies demonstrated that autophagy inhibition significantly increased apoptosis of HCC cells during nutrient starvation or hypoxia. In addition, the combined treatment of an autophagy inhibitor and bevacizumab markedly inhibited the tumor growth of HCC xenografts, led to enhanced apoptosis, and impaired the proliferation of tumor cells compared with treatment with either drug alone. Furthermore, autophagy inhibition led to enhanced reactive oxygen species (ROS) generation in HCC cells exposed to nutrient starvation or hypoxia in vitro and increased DNA oxidative damage in vivo. Antioxidants reduced nutrient starvation or the hypoxia-induced cell death of HCC cells after autophagy inhibition. Our results suggest that autophagy modulates ROS generation and contributes to cell survival under metabolic stress. Therefore, autophagy inhibition may be a novel way of increasing the efficicacy of antiangiogenic agents in the treatment of HCC.
Electronic supplementary material
The online version of this article (doi:10.1007/s00109-012-0966-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s00109-012-0966-0
PMCID: PMC3611041  PMID: 23052483
Hepatocarcinoma; Antiangiogenesis; Autophagy; Metabolic stress; Apoptosis
17.  Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide 
BMC Medicine  2012;10:98.
Background
The endotoxin level in the portal and peripheral veins of hepatocellular carcinoma (HCC) patients is higher and lipopolysaccharide (LPS), a cell wall constituent of gram-negative bacteria, has been reported to inhibit tumor growth. However, in this study, we found that LPS-induced toll-like receptor 4 (TLR4) signaling was involved in tumor invasion and survival, and the molecular mechanism was investigated,
Methods
Four HCC cell lines and a splenic vein metastasis of the nude mouse model were used to study the invasion ability of LPS-induced HCC cells and the epithelia-mesenchymal transition (EMT) in vitro and in vivo. A total of 106 clinical samples from HCC patients were used to evaluate TLR4 expression and analyze its association with clinicopathological characteristics
Results
The in vitro and in vivo experiments demonstrated that LPS could significantly enhance the invasive potential and induce EMT in HCC cells with TLR4 dependent. Further studies showed that LPS could directly activate nuclear factor kappa B (NF-κB) signaling through TLR4 in HCC cells. Interestingly, blocking NF-κB signaling significantly inhibited transcription factor Snail expression and thereby inhibited EMT occurrence. High expression of TLR4 in HCC tissues was strongly associated with both poor cancer-free survival and overall survival in patients.
Conclusions
Our results indicate that TLR4 signaling is required for LPS-induced EMT, tumor cell invasion and metastasis, which provide molecular insights for LPS-related pathogenesis and a basis for developing new strategies against metastasis in HCC.
doi:10.1186/1741-7015-10-98
PMCID: PMC3482562  PMID: 22938142
Toll-like receptor 4; Epithelial-mesenchymal transition; Lipopolysaccharide; Human hepatocellular carcinoma
18.  CD133+CXCR4+ colon cancer cells exhibit metastatic potential and predict poor prognosis of patients 
BMC Medicine  2012;10:85.
Background
Colorectal cancer (CRC), which frequently metastasizes to the liver, is one of the three leading causes of cancer-related deaths worldwide. Growing evidence suggests that a subset of cells exists among cancer stem cells. This distinct subpopulation is thought to contribute to liver metastasis; however, it has not been fully explored in CRC yet.
Methods
Flow cytometry analysis was performed to detect distinct subsets with CD133 and CXCR4 markers in human primary and metastatic CRC tissues. The 'stemness' and metastatic capacities of different subpopulations derived from the colon cancer cell line HCT116 were compared in vitro and in vivo. The roles of epithelial-mesenchymal transition (EMT) and stromal-cell derived factor-1 (SDF-1) in the metastatic process were also investigated. A survival curve was used to explore the correlation between the content of CD133+CXCR4+ cancer cells and patient survival.
Results
In human specimens, the content of CD133+CXCR4+ cells was higher in liver metastases than in primary colorectal tumors. Clonogenic and tumorigenic cells were restricted to CD133+ cells in the HCT116 cell line, with CXCR4 expression having no impact on the 'stemness' properties. We found that CD133+CXCR4+ cancer cells had a high metastatic capacity in vitro and in vivo. Compared with CD133+CXCR4- cells, CD133+CXCR4+ cancer cells experienced EMT, which contributed partly to their metastatic phenotype. We then determined that SDF-1/CXCL12 treatment could further induce EMT in CD133+CXCR4+ cancer cells and enhance their invasive behavior, while this could not be observed in CD133+CXCR4- cancer cells. Blocking SDF-1/CXCR4 interaction with a CXCR4 antagonist, AMD3100 (1,10-[1,4-phenylenebis(methylene)]bis-1,4,8,11 -tetraazacyclotetradecane octahydrochloride), inhibited metastatic tumor growth in a mouse hepatic metastasis model. Finally, a high percentage of CD133+CXCR4+ cells in human primary CRC was associated with a reduced two-year survival rate.
Conclusions
Strategies targeting the SDF-1/CXCR4 interaction may have important clinical applications in the suppression of colon cancer metastasis. Further investigations on how high expression of CXCR4 and EMT occur in this identified cancer stem cell subset are warranted to provide insights into our understanding of tumor biology.
doi:10.1186/1741-7015-10-85
PMCID: PMC3424958  PMID: 22871210
colorectal cancer; cancer stem cell; CXCR4; epithelial-mesenchymal transition; liver metastasis
19.  Effect of Anti-Obesity Drug on Cardiovascular Risk Factors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2012;7(6):e39062.
Background
Anti-obesity drugs are widely used to prevent the complications of obesity, however, the effects of anti-obesity drugs on cardiovascular risk factors are unclear at the present time. We carried out a comprehensively systematic review and meta-analysis to assess the effects of anti-obesity drugs on cardiovascular risk factors.
Methodology and Principal Findings
We systematically searched Medline, EmBase, the Cochrane Central Register of Controlled Trials, reference lists of articles and proceedings of major meetings for relevant literatures. We included randomized placebo-controlled trials that reported the effects of anti-obesity drugs on cardiovascular risk factors compared to placebo. Overall, orlistat produced a reduction of 2.39 kg (95%CI-3.34 to −1.45) for weight, a reduction of 0.27 mmol/L (95%CI: −0.36 to −0.17) for total cholesterol, a reduction of 0.21 mmol/L (95%CI: −0.30 to −0.12) for LDL, a reduction of 0.12 mmol/L (95%CI: −0.20 to −0.04) for fasting glucose, 1.85 mmHg reduction (95%CI: −3.30 to −0.40) for SBP, and a reduction of 1.49 mmHg (95%CI: −2.39 to −0.58) for DBP. Sibutramine only showed effects on weight loss and triglycerides reduction with statistical significances. Rimonabant was associated with statistically significant effects on weight loss, SBP reduction and DBP reduction. No other significantly different effects were identified between anti-obesity therapy and placebo.
Conclusion/Significance
We identified that anti-obesity therapy was associated with a decrease of weight regardless of the type of the drug. Orlistat and rimonabant could lead to an improvement on cardiovascular risk factors. However, Sibutramine may have a direct effect on cardiovascular risk factors.
doi:10.1371/journal.pone.0039062
PMCID: PMC3380040  PMID: 22745703
20.  Steroids in the Treatment of IgA Nephropathy to the Improvement of Renal Survival: A Systematic Review and Meta-Analysis 
PLoS ONE  2011;6(4):e18788.
Background
Studies have shown that steroids can improve kidney survival and decrease the risk of proteinuria in patients with Immunoglobulin A nephropathy, but the overall benefit of steroids in the treatment of Immunoglobulin A nephropathy remains controversial. The aim of this study was to evaluate the benefits and risks of steroids for renal survival in adults with Immunoglobulin A nephropathy.
Methodology and Principal Findings
We searched the Cochrane Renal Group Specialized Register, Cochrane Controlled Trial Registry, MEDLINE and EMBASE databases. All eligible studies were measuring at least one of the following outcomes: end-stage renal failure, doubling of serum creatinine and urinary protein excretion. Fifteen relevant trials (n = 1542) that met our inclusion criteria were identified. In a pooled analysis, steroid therapy was associated with statistically significant reduction of the risk in end-stage renal failure (RR: 0.46, 95% CI: 0.27 to 0.79), doubling of serum creatinine (RR = 0.34, 95%CI = 0.15 to 0.77) and reduced urinary protein excretion (MD = −0.47g/day, 95%CI = −0.64 to −0.31).
Conclusions/Significance
We identified that steroid therapy was associated with a decrease of proteinuria and with a statistically significant reduction of the risk in end-stage renal failure. Moreover, subgroup analysis also suggested that long-term steroid therapy had a higher efficiency than standard and short term therapy.
doi:10.1371/journal.pone.0018788
PMCID: PMC3075273  PMID: 21533280
21.  Diaqua­(5-methyl-1H-pyrazole-3-carboxyl­ato)(4-nitro­benzoato)copper(II) 
In the title complex, [Cu(C7H4NO4)(C5H5N2O2)(H2O)2], the CuII ion is coordinated in a slightly distorted square-pyramidal enviroment. The basal plane is formed by an N atom and an O atom from a 5-methyl-1H-pyrazole-3-carboxyl­ate ligand and by two O atoms from two water ligands. The apical position is occupied by a carboxylate O atom from a 4-nitro­benzoate ligand. In the crystal structure, inter­molecular O—H⋯O and N—H⋯O hydrogen bonds link complex moleclues, forming extended chains parallel to the a axis.
doi:10.1107/S160053680900169X
PMCID: PMC2968408  PMID: 21581806
22.  3-Chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)picolinic acid–triphenyl­phosphine oxide (1/1) 
In the title 1:1 adduct, C11H10ClN3O2·C18H15OP, the dihedral angle between the pyridine and pyrazole rings is 10.3 (2)°. The two components of the adduct are linked by an O—H⋯O hydrogen bond.
doi:10.1107/S160053680802045X
PMCID: PMC2962060  PMID: 21203144
23.  (3,6-Dichloro­pyridin-2-yl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone 
In the crystal structure of the title compound, C11H9Cl2N3O, mol­ecules are held together by short inter­molecular Cl⋯Cl contacts [3.319 (1) Å] and C—H⋯N hydrogen bonds, forming two-dimensional networks parallel to (01).
doi:10.1107/S1600536808015006
PMCID: PMC2961666  PMID: 21202861
24.  3,6-Dichloro-N-(4,6-dichloro­pyrimidin-2-yl)picolinamide 
In the title compound, C10H4Cl4N4O, the pyridine and pyrimidine rings are nearly perpendicular to each other, the dihedral angle between them being 86.60 (10)°. In the crystal structure, the N and O atoms in the amide group are involved in inter­molecular hydrogen bonds, forming a one-dimensional chain along the c axis.
doi:10.1107/S1600536808010325
PMCID: PMC2961186  PMID: 21202357
25.  Chlorido(1,10-phenanthroline)(1H-1,2,4-triazole-3-carboxyl­ato)copper(II) 
The title complex, [Cu(C3H2N3O2)Cl(C12H8N2)], crystallizes with two independent mol­ecules in the asymmetric unit. Each CuII atom is coordinated by an N atom and an O atom from the bidentate 1H-1,2,4-triazole-3-carboxyl­ate ligand, two N atoms from the 1,10-phenanthroline ligand, and the Cl atom. The coordination geometry is based on a ClN3O square pyramid. In the crystal structure, the mol­ecules are linked by inter­molecular N—H⋯O hydrogen bonds.
doi:10.1107/S160053680706299X
PMCID: PMC2914951  PMID: 21200641

Results 1-25 (25)