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1.  Factor inhibiting HIF1α (FIH-1) functions as a tumor suppressor in human colorectal cancer by repressing HIF1α pathway 
Cancer Biology & Therapy  2015;16(2):244-252.
Colorectal cancer (CRC) is one of the most common cancers worldwide. The molecular mechanisms underlying CRC development involve a multistep process with the accumulation of both genetic and epigenetic changes. To deeply understand CRC tumorigenesis and progression, advances in identification of novel mechanisms and key factors are therefore in an urgent need. Here, we examined the correlation of factor inhibiting HIF-1α (FIH-1) expression with clinicopathological features of CRC. The finding that FIH-1 was not only significantly decreased in tumor tissue but also was significantly correlated with tumor invading depth, lymph node involvement, and metastasis suggested the role of FIH-1 as a tumor suppressor in CRC development. To further support the above hypothesis, we performed both in vitro and in vivo experiments to identify the role of FIH-1 in CRC development. FIH-1 was found to inhibit CRC cell proliferation, migration, invasion, and colony formation in vitro. FIH-1 was also shown to repress LOVO xenograft tumor growth in vivo. To decipher the mechanism, we examined the expression level of HIF-1α and its target genes. We found that FIH-1 was able to inhibit HIF1α mediated transcription of GLUT1 and VEGF in CRC cells. The above observation points to the possibility that loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF1α and an alteration of HIF-1 targets such as GLUT-1 and VEGF. These findings highlight the critical role of FIH-1 in CRC and indicate FIH-1 functions as a tumor suppressor in human CRC by repressing HIF1α pathway.
doi:10.1080/15384047.2014.1002346
PMCID: PMC4622465  PMID: 25602156
colorectal cancer; FIH-1; HIF1α pathway; prognosis; progression; tumor suppressor; tumorigenesis
2.  Aptamer-CaCO3 nanostructures: A facile, pH-responsive, specific platform for targeted anticancer theranostics 
Chemistry, an Asian journal  2014;10(1):166-171.
Application of cancer theranostics depends on the development of multifunctional nanostructure platforms for accurate cell targeting and controlled drug release, imaging and therapy. In this work, a comprehensive, easily fabricated anticancer theranostic platform with high drug-loading capacity, termed aptamer-functionalized calcium carbonate (CaCO3) nanostructure (apt-CCN), is reported. Flow cytometry and confocal fluorescence microscopy studies demonstrated that apt-CCNs can specifically bind to target cancer cells, but not to control cells, and that they possess highly efficient internalization to target cancer cells. This smart nanostructure selectively reaches the lysosomes through receptor-mediated endocytosis and is responsive to the relatively low lysosome pH (4.5–5.5), facilitating the release of doxorubicin. The apt-CCN platform offers targeted and efficient drug transport, as well as target-specific delivery of imaging agents for cancer diagnosis and therapy.
doi:10.1002/asia.201403115
PMCID: PMC4323099  PMID: 25377905
aptamer; anticancer drugs; CaCO3 nanostructure; targeted delivery; theranostics
3.  Recent advances in the dark adaptation investigations 
Dark adaptation is a highly sensitive neural function and may be the first symptom of many status including the physiologic and pathologic entity, suggesting that it could be instrumental for diagnose. However, shortcomings such as the lack of standardized parameters, the long duration of examination, and subjective randomness would substantially impede the use of dark adaptation in clinical work. In this review we summarize the recent research about the dark adaptation, including two visual cycles-canonical and cone-specific visual cycle, affecting factors and the methods for measuring dark adaptation. In the opinions of authors, intensive investigations are needed to be done for the widely use of this significant visual function in clinic.
doi:10.3980/j.issn.2222-3959.2015.06.31
PMCID: PMC4651898  PMID: 26682182
dark adaptation; visual cycle; pigment regeneration; adaptometer
4.  Cytokine and Antibody Based Diagnostic Algorithms for Sputum Culture-Positive Pulmonary Tuberculosis 
PLoS ONE  2015;10(12):e0144705.
Background
Tuberculosis (TB) is one of the most serious infectious diseases globally and has high mortality rates. A variety of diagnostic tests are available, yet none are wholly reliable. Serum cytokines, although significantly and frequently induced by different diseases and thus good biomarkers for disease diagnosis and prognosis, are not sufficiently disease-specific. TB-specific antibody detection, on the other hand, has been reported to be highly specific but not sufficiently sensitive. In this study, our aim was to improve the sensitivity and specificity of TB diagnosis by combining detection of TB-related cytokines and TB-specific antibodies in peripheral blood samples.
Methods
TB-related serum cytokines were screened using a human cytokine array. TB-related cytokines and TB-specific antibodies were detected in parallel with microarray technology. The diagnostic performance of the new protocol for active TB was systematically compared with other traditional methods.
Results
Here, we show that cytokines I-309, IL-8 and MIG are capable of distinguishing patients with active TB from healthy controls, patients with latent TB infection, and those with a range of other pulmonary diseases, and that these cytokines, and their presence alongside antibodies for TB-specific antigens Ag14-16kDa, Ag32kDa, Ag38kDa and Ag85B, are specific markers for active TB. The diagnostic protocol for active TB developed here, which combines the detection of three TB-related cytokines and TB-specific antibodies, is highly sensitive (91.03%), specific (90.77%) and accurate (90.87%).
Conclusions
Our results show that combining detection of TB-related cytokines and TB-specific antibodies significantly enhances diagnostic accuracy for active TB, providing greater accuracy than conventional diagnostic methods such as interferon gamma release assays (IGRAs), TB antibody Colloidal Gold Assays and microbiological culture, and suggest that this diagnostic protocol has potential for clinical application.
doi:10.1371/journal.pone.0144705
PMCID: PMC4682626  PMID: 26674517
5.  Association between MDM2 SNP309 T>G polymorphism and the risk of bladder cancer: new data in a Chinese population and an updated meta-analysis 
OncoTargets and therapy  2015;8:3679-3690.
Objective
Human murine double minute 2 protein (MDM2) is mainly a negative regulator of p53 tumor suppressor pathway. We aimed to investigate the association between MDM2 SNP309 polymorphism and bladder cancer risk.
Methods
A total of 535 bladder cancer patients and 649 health controls were recruited for our study. MDM2 SNP309 T>G polymorphism was genotyped by polymerase chain reaction-ligase detection reaction method. Logistic regression was used to analyze the relationship between the genotype and susceptibility of bladder cancer. Kaplan–Meier estimates and log-rank test were obtained to analyze the association between the genotype and risk of recrudesce in nonmuscle-invasive bladder cancer patients. A multivariable Cox proportional hazards model was fitted to identify independent prognostic factors. To further investigate the association, we conducted a meta-analysis including six studies.
Results
The frequency of the MDM2 SNP309 T>G polymorphism showed no significant difference between cases and controls (all P>0.05). In the stratification analysis, the results showed that G allele carriers were prone to have a significant decrease in risk of low-grade bladder cancer (adjusted odds ratio: 0.613, 95% confidence interval: 0.427–0.881), and G variant was associated with a significantly reduced risk of recurrence in nonmuscle-invasive bladder cancer patients with or without chemotherapy (P<0.05). The results of the meta-analysis showed that G allele and GG genotype of MDM2 SNP309 polymorphism were significantly associated with increased risk of bladder cancer in Caucasians (both P<0.05), and no association was observed in total populations and Asians (P>0.05).
Conclusion
MDM2 SNP309 T>G polymorphism has no influence on bladder cancer risk in Asians, but this single nucleotide polymorphism may be associated with genetic susceptibility of bladder cancer among Caucasians.
doi:10.2147/OTT.S95353
PMCID: PMC4676618  PMID: 26672516
bladder cancer; MDM2; single nucleotide polymorphism; rs2279744; recurrence; meta-analysis
6.  Activation of the Mammalian Target of Rapamycin in the Rostral Ventromedial Medulla Contributes to the Maintenance of Nerve Injury-Induced Neuropathic Pain in Rat 
Neural Plasticity  2015;2015:394820.
The mammalian target of rapamycin (mTOR), a serine-threonine protein kinase, integrates extracellular signals, thereby modulating several physiological and pathological processes, including pain. Previous studies have suggested that rapamycin (an mTOR inhibitor) can attenuate nociceptive behaviors in many pain models, most likely at the spinal cord level. However, the mechanisms of mTOR at the supraspinal level, particularly at the level of the rostral ventromedial medulla (RVM), remain unclear. Thus, the aim of this study was to elucidate the role of mTOR in the RVM, a key relay region for the descending pain control pathway, under neuropathic pain conditions. Phosphorylated mTOR was mainly expressed in serotonergic spinally projecting neurons and was significantly increased in the RVM after spared nerve injury- (SNI-) induced neuropathic pain. Moreover, in SNI rat brain slices, rapamycin infusion both decreased the amplitude instead of the frequency of spontaneous excitatory postsynaptic currents and reduced the numbers of action potentials in serotonergic neurons. Finally, intra-RVM microinjection of rapamycin effectively alleviated established mechanical allodynia but failed to affect the development of neuropathic pain. In conclusion, our data provide strong evidence for the role of mTOR in the RVM in nerve injury-induced neuropathic pain, indicating a novel mechanism of mTOR inhibitor-induced analgesia.
doi:10.1155/2015/394820
PMCID: PMC4684879  PMID: 26770837
7.  A Cell-Targeted, Size-Photocontrollable, Nuclear-Uptake Nanodrug Delivery System for Drug-Resistant Cancer Therapy 
Nano Letters  2014;15(1):457-463.
The development of multidrug resistance (MDR) has become an increasingly serious problem in cancer therapy. The cell-membrane overexpression of P-glycoprotein (P-gp), which can actively efflux various anticancer drugs from the cell, is a major mechanism of MDR. Nuclear-uptake nanodrug delivery systems, which enable intranuclear release of anticancer drugs, are expected to address this challenge by bypassing P-gp. However, before entering the nucleus, the nanocarrier must pass through the cell membrane, necessitating coordination between intracellular and intranuclear delivery. To accommodate this requirement, we have used DNA self-assembly to develop a nuclear-uptake nanodrug system carried by a cell-targeted near-infrared (NIR)-responsive nanotruck for drug-resistant cancer therapy. Via DNA hybridization, small drug-loaded gold nanoparticles (termed nanodrugs) can self-assemble onto the side face of a silver–gold nanorod (NR, termed nanotruck) whose end faces were modified with a cell type-specific internalizing aptamer. By using this size-photocontrollable nanodrug delivery system, anticancer drugs can be efficiently accumulated in the nuclei to effectively kill the cancer cells.
doi:10.1021/nl503777s
PMCID: PMC4296921  PMID: 25479133
Nuclear uptake; photocontrollable size; drug-resistant cancer therapy; cell-targeted delivery; aptamer
8.  Endoscopic resection of tumors in the lower digestive tract 
As endoscopic technology has developed and matured, the endoscopic resection of gastrointestinal tract polyps has become a widely used treatment. Colorectal polyps are the most common type of polyp, which are best managed by early resection before the polyp undergoes malignant transformation. Methods for treating colorectal tumors are numerous, including argon plasma coagulation, endoscopic mucosal resection, endoscopic submucosal dissection, and laparoscopic-endoscopic cooperative surgery. In this review, we will highlight several currently used clinical endoscopic resection methods and how they are selected based on the characteristics of the targeted tumor. Specifically, we will focus on laparoscopic-endoscopic cooperative surgery.
doi:10.4253/wjge.v7.i17.1238
PMCID: PMC4658603  PMID: 26634039
Colorectal tumor; Endoscopic resection
9.  Metabolic engineering of Escherichia coli for poly(3-hydroxybutyrate) production via threonine bypass 
Background
Poly(3-hydroxybutyrate) (PHB), have been considered to be good candidates for completely biodegradable polymers due to their similar mechanical properties to petroleum-derived polymers and complete biodegradability. Escherichia coli has been used to simulate the distribution of metabolic fluxes in recombinant E. coli producing poly(3-hydroxybutyrate) (PHB). Genome-scale metabolic network analysis can reveal unexpected metabolic engineering strategies to improve the production of biochemicals and biofuels.
Results
In this study, we reported the discovery of a new pathway called threonine bypass by flux balance analysis of the genome-scale metabolic model of E. coli. This pathway, mainly containing the reactions for threonine synthesis and degradation, can potentially increase the yield of PHB and other acetyl-CoA derived products by reutilizing the CO2 released at the pyruvate dehydrogenase step. To implement the threonine bypass for PHB production in E. coli, we deregulated the threonine and serine degradation pathway and enhanced the threonine synthesis, resulting in 2.23-fold improvement of PHB titer. Then, we overexpressed glyA to enhance the conversion of glycine to serine and activated transhydrogenase to generate NADPH required in the threonine bypass.
Conclusions
The result strain TB17 (pBHR68) produced 6.82 g/L PHB with the yield of 0.36 g/g glucose in the shake flask fermentation and 35.92 g/L PHB with the yield of 0.23 g/g glucose in the fed-batch fermentation, which was almost 3.3-fold higher than the parent strain. The work outlined here shows that genome-scale metabolic network analysis can reveal novel metabolic engineering strategies for developing efficient microbial cell factories.
Electronic supplementary material
The online version of this article (doi:10.1186/s12934-015-0369-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12934-015-0369-3
PMCID: PMC4654888  PMID: 26589676
Genome-scale metabolic network; Threonine bypass; Strain optimization; Poly(3-hydroxybutyrate)
10.  Impact of lymphovascular invasion on recurrence and progression rates in patients with pT1 urothelial carcinoma of bladder after transurethral resection 
OncoTargets and therapy  2015;8:3401-3406.
Objective
To evaluate the clinical significance of lymphovascular invasion (LVI) on recurrence and progression rates in patients with pT1 urothelial carcinoma of bladder after transurethral resection.
Methods
This retrospective study was performed with 155 patients with newly diagnosed pT1 urothelial carcinoma of bladder who were treated with transurethral resection of bladder tumor at our institution from January 2006 to January 2010. The presence or absence of LVI was examined by pathologists. Chi-square test was performed to identify the correlations between LVI and other clinical and pathological features. Kaplan–Meier method was used to estimate the recurrence-free survival (RFS) and progression-free survival curves and difference was determined by the log-rank test. Univariate and multivariate analyses were performed to determine the predictive factors through a Cox proportional hazards analysis model.
Results
LVI was detected in a total of 34 patients (21.9%). While LVI was associated with high-grade tumors (P<0.001) and intravesical therapy (P=0.009). Correlations with age (P=0.227), sex (P=0.376), tumor size (P=0.969), tumor multiplicity (P=0.196), carcinoma in situ (P=0.321), and smoking (P=0.438) were not statistically significant. There was a statistically significant tendency toward higher recurrence rate and shorter RFS time in LVI-positive patients. However, no statistically significant differences were observed in progression rate between the two groups. Moreover, multivariate Cox proportional hazards analysis revealed that LVI, tumor size, and smoking were independent prognostic predictors of recurrence. The hazard ratios (95% confidence interval) were 2.042 (1.113–3.746, P=0.021), 1.817 (1.014–3.256, P=0.045), and 2.079 (1.172–3.687, P=0.012), respectively.
Conclusion
The presence of LVI in transurethral resection of bladder tumor specimens is significantly associated with higher recurrence rate and shorter RFS time in patients with newly diagnosed T1 urothelial carcinoma of the bladder. It is an independent prognostic predictor for disease recurrence. Thus, patients with LVI should be followed up closely.
doi:10.2147/OTT.S95609
PMCID: PMC4655960  PMID: 26604797
bladder urothelial carcinoma; TURBT; lymphovascular invasion; recurrence; progression
11.  A Modified Rife Algorithm for Off-Grid DOA Estimation Based on Sparse Representations 
Sensors (Basel, Switzerland)  2015;15(11):29721-29733.
In this paper we address the problem of off-grid direction of arrival (DOA) estimation based on sparse representations in the situation of multiple measurement vectors (MMV). A novel sparse DOA estimation method which changes MMV problem to SMV is proposed. This method uses sparse representations based on weighted eigenvectors (SRBWEV) to deal with the MMV problem. MMV problem can be changed to single measurement vector (SMV) problem by using the linear combination of eigenvectors of array covariance matrix in signal subspace as a new SMV for sparse solution calculation. So the complexity of this proposed algorithm is smaller than other DOA estimation algorithms of MMV. Meanwhile, it can overcome the limitation of the conventional sparsity-based DOA estimation approaches that the unknown directions belong to a predefined discrete angular grid, so it can further improve the DOA estimation accuracy. The modified Rife algorithm for DOA estimation (MRife-DOA) is simulated based on SRBWEV algorithm. In this proposed algorithm, the largest and sub-largest inner products between the measurement vector or its residual and the atoms in the dictionary are utilized to further modify DOA estimation according to the principle of Rife algorithm and the basic idea of coarse-to-fine estimation. Finally, simulation experiments show that the proposed algorithm is effective and can reduce the DOA estimation error caused by grid effect with lower complexity.
doi:10.3390/s151129721
PMCID: PMC4701356  PMID: 26610521
direction of arrival (DOA) estimation; sparse representations; eigenvalue decomposition (EVD); off-grid; Rife algorithm
12.  Development and validation of a LC–MS/MS method for quantification of hetrombopag for pharmacokinetics study 
SpringerPlus  2015;4:652.
Hetrombopag as the derivative of ethylidene hydrazine carboxamide was recently developed into a novel patented non-peptide thrombopoietin mimetic and thrombopoietin receptor agonist to treat idiopathic thrombocytopenic purpura. To study the pharmacokinetics of hetrombopag, a highly sensitive, rapid and reliable liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed and validated for determination of hetrombopag in rat plasma. After protein precipitation extraction, the chromatography separation of analyte and internal standard named eltrombopag as an marketed analog of hetrombopag was performed on an Synergi Polar-RP column at the flow rate of 0.5 mL/min, and the determination was conducted on an API4000 triple quadrupole mass spectrometry in the multiple reaction monitoring mode using the respective [M+H]+ ions m/z 459.2 → 200.9 for hetrombopag and m/z 443.2 → 229.0 for IS. The lower limit of quantification was established to be 1 ng/mL, and the linear scope of standard curve was 1–1000 ng/mL. Both the precision (RSD%) and accuracy (RE%) were within the acceptable criterion of below 15 %. The validated method was successfully applied to quantify hetrombopag in the rat plasma and investigate the pharmacokinetics.
doi:10.1186/s40064-015-1446-0
PMCID: PMC4628022  PMID: 26543786
Hetrombopag; Pharmacokinetics; Idiopathic thrombocytopenic purpura; LC–MS/MS
13.  Transient absorption microscopy of gold nanorods as spectrally orthogonal labels in live cells† 
Nanoscale  2014;6(18):10536-10539.
Gold nanorods (AuNRs) have shown great potential as bio-compatible imaging probes in various biological applications. Probing nanomaterials in live cells is essential to reveal the interaction between them. In this study, we used a transient absorption microscope to selectively image AuNRs in live cells. The transient absorption signals were monitored through lock-in amplification. This provides a new way of observing AuNRs with no interference from background autofluorescence.
doi:10.1039/c4nr03413a
PMCID: PMC4571198  PMID: 25098209
14.  Mechanism of QHF-cisplatin against hepatocellular carcinoma in a mouse model 
World Journal of Gastroenterology : WJG  2015;21(35):10126-10136.
AIM: To study the effects of QHF-cisplatin on H22 hepatocellular carcinoma (HCC) and their mechanisms of action.
METHODS: Sixty BALB/c mice were randomly divided into a model group (n = 48) and a normal control group (n = 12). An HCC xenograft tumor was created by injecting H22 cells directly into the liver parenchyma of the mice. The 48 BALB/c mice in the model group were randomly divided into four groups: QHF, DDP (cisplatin), QHF plus DDP, and model control. The inhibitory effects of these drugs on tumor growth were evaluated by calculating the rate of tumor growth inhibition. The mice were examined by observing their general condition, body weight and survival time. Changes in tumor tissue were observed under an optical microscope. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and α-fetoprotein (AFP) levels in serum were measured. Hepatocyte growth factor (HGF), c-mesenchymal-epithelial transition (c-Met) factor, phosphorylated (p)-c-Met, p38, p-p38, extracellular signal-regulated kinase (ERK), p-ERK and vascular endothelial growth factor (VEGF) levels were evaluated in tumor and liver tissues using western blotting.
RESULTS: Compared with the DDP group, a lower incidence of toxic reactions and a higher survival time were observed in the QHF plus DDP group. Tumor weight was significantly lower in the QHF, DDP and QHF plus DDP groups than in the model control group (0.24 ± 0.07, 0.18 ± 0.03 and 0.14 ± 0.01 g vs 0.38 ± 0.05 g, respectively), and the differences were statistically significant (P < 0.01). The rate of tumor growth inhibition in the QHF, DDP and QHF plus DDP groups was 38.7%, 52.6% and 63.5%, respectively. AST, ALT and AFP levels in serum were significantly lower in the QHF, DDP and QHF plus DDP groups compared to the model control group (P < 0.05). Similarly, HGF, p-c-Met, p-p38, p-ERK and VEGF levels in tumor tissue were significantly lower in the QHF, DDP and QHF plus DDP groups (P < 0.05).
CONCLUSION: QHF and DDP have an antiangiogenic effect on H22 HCC in mice. QHF inhibits tumor growth via blocking the HGF/c-Met signaling pathway, inhibiting p38, ERK and VEGF signaling.
doi:10.3748/wjg.v21.i35.10126
PMCID: PMC4572793  PMID: 26401077
QHF formula; Cisplatin; Hepatocellular carcinoma; H22 cells; Hepatocyte growth factor; c-Met
15.  Genetic polymorphisms in apoptosis-related genes and the prognosis of hepatocellular carcinoma 
American Journal of Cancer Research  2015;5(10):3249-3259.
The apoptotic pathway is important in the control of vital processes of hepatocellular carcinoma (HCC). In the current study, we aimed to determine whether apoptotic gene-related polymorphisms modified HCC prognosis. We genotyped 16 single nucleotide polymorphisms (SNPs) in 10 core genes (TP53, TP53INP1, TP53BP1, CDKN2A, CDKN1A, CDKN1B, MDM2, BAX, CCDN1 and BCL2) in the apoptotic pathway by using DNA from blood samples of 362 HCC patients receiving surgical resection of HCC tumor. The associations between genotypes/haplotypes of the 10 genes and overall survival (OS) of HCC patients were assessed using the Cox proportional hazards model. We found one CDKN1B haplotype CCT/ACT (constructed by rs36228499 C>A, rs34330 C>T and rs2066827 T>G) significantly associated with decreased OS of HCC patients, compared to the common haplotype ACT/CTT both in univariate analysis (P=0.013, HR=1.198, 95% CI: 1.039-1.381) and multivariate analysis (P=0.006, HR=1.224, 95% CI: 1.059-1.413). We also find two SNPs (rs560191 G>C and rs2602141 T>G) in TP53BP1 shown to be marginally significantly associated with decreased OS of HCC patients. However, none of the other SNPs or haplotypes were significantly associated with HCC OS. Our results illustrated the potential use of CDKN1B haplotype as a prognostic marker for HCC patients with surgical resection of tumor.
PMCID: PMC4656746  PMID: 26693075
Hepatocellular carcinoma; survival; apoptosis; CDKN1B; genetic polymorphisms
16.  Facile Surface Functionalization of Hydrophobic Magnetic Nanoparticles 
Journal of the American Chemical Society  2014;136(36):12552-12555.
Nonpolar phase synthesized hydrophobic nanocrystals show attractive properties and have demonstrated prominent potential in biomedical applications. However, the preparation of biocompatible nanocrystals is made difficult by the presence of hydrophobic surfactant stabilizer on their surfaces. To address this limitation, we have developed a facile, high efficiency, single-phase and low-cost method to convert hydrophobic magnetic nanoparticles (MNPs) to an aqueous phase using tetrahydrofuran, NaOH and 3,4-dihydroxyhydrocinnamic acid without any complicated organic synthesis. The as-transferred hydrophilic MNPs are water-soluble over a wide pH range (pH = 3–12), and the solubility is pH-controllable. Furthermore, the as-transferred MNPs with carboxylate can be readily adapted with further surface functionalization, varying from small molecule dyes to oligonucleotides and enzymes. Finally, the strategy developed here can easily be extended to other types of hydrophobic nanoparticles to facilitate biomedical applications of nanomaterials.
doi:10.1021/ja5060324
PMCID: PMC4160275  PMID: 25140614
17.  Advances in cancer pain from bone metastasis 
With the technological advances in cancer diagnosis and treatment, the survival rates for patients with cancer are prolonged. The issue of figuring out how to improve the life quality of patients with cancer has become increasingly prominent. Pain, especially bone pain, is the most common symptom in malignancy patients, which seriously affects the life quality of patients with cancer. The research of cancer pain has a breakthrough due to the development of the animal models of cancer pain in recent years, such as the animal models of mouse femur, humerus, calcaneus, and rat tibia. The establishment of several kinds of animal models related to cancer pain provides a new platform in vivo to investigate the molecular mechanisms of cancer pain. In this review, we focus on the advances of cancer pain from bone metastasis, the mechanisms involved in cancer pain, and the drug treatment of cancer pain in the animal models.
doi:10.2147/DDDT.S87568
PMCID: PMC4547660  PMID: 26316696
cancer pain from bone metastasis; animal models of cancer pain; molecular mechanisms; drug treatment
18.  Nanotechnology for treating osteoporotic vertebral fractures 
Osteoporosis is a serious public health problem affecting hundreds of millions of aged people worldwide, with severe consequences including vertebral fractures that are associated with significant morbidity and mortality. To augment or treat osteoporotic vertebral fractures, a number of surgical approaches including minimally invasive vertebroplasty and kyphoplasty have been developed. However, these approaches face problems and difficulties with efficacy and long-term stability. Recent advances and progress in nanotechnology are opening up new opportunities to improve the surgical procedures for treating osteoporotic vertebral fractures. This article reviews the improvements enabled by new nanomaterials and focuses on new injectable biomaterials like bone cements and surgical instruments for treating vertebral fractures. This article also provides an introduction to osteoporotic vertebral fractures and current clinical treatments, along with the rationale and efficacy of utilizing nanomaterials to modify and improve biomaterials or instruments. In addition, perspectives on future trends with injectable bone cements and surgical instruments enhanced by nanotechnology are provided.
doi:10.2147/IJN.S85037
PMCID: PMC4540116  PMID: 26316746
nanomaterials; osteoporosis; vertebral fracture; kyphoplasty; bone cement; pedicle screw; radiopacifier
19.  The Arabidopsis gene DIG6 encodes a large 60S subunit nuclear export GTPase 1 that is involved in ribosome biogenesis and affects multiple auxin-regulated development processes 
Journal of Experimental Botany  2015;66(21):6863-6875.
Highlight
DIG6 encodes a large 60S subunit GTPase 1 and affects ribosome biogenesis, and auxin response and homeostasis.
The circularly permuted GTPase large subunit GTPase 1 (LSG1) is involved in the maturation step of the 60S ribosome and is essential for cell viability in yeast. Here, an Arabidopsis mutant dig6 (drought inhibited growth of lateral roots) was isolated. The mutant exhibited multiple auxin-related phenotypes, which included reduced lateral root number, altered leaf veins, and shorter roots. Genetic mapping combined with next-generation DNA sequencing identified that the mutation occurred in AtLSG1-2. This gene was highly expressed in regions of auxin accumulation. Ribosome profiling revealed that a loss of function of AtLSG1-2 led to decreased levels of monosomes, further demonstrating its role in ribosome biogenesis. Quantitative proteomics showed that the expression of certain proteins involved in ribosome biogenesis was differentially regulated, indicating that ribosome biogenesis processes were impaired in the mutant. Further investigations showed that an AtLSG1-2 deficiency caused the alteration of auxin distribution, response, and transport in plants. It is concluded that AtLSG1-2 is integral to ribosome biogenesis, consequently affecting auxin homeostasis and plant development.
doi:10.1093/jxb/erv391
PMCID: PMC4623693  PMID: 26272902
AtLSG1; Arabidopsis; auxin homeostasis; expression pattern; map-based cloning; proteomics; ribosome biogenesis.
20.  Tri-Axial Accelerometer-Determined Daily Physical Activity and Sedentary Behavior of Suburban Community-Dwelling Older Japanese Adults 
Knowledge regarding accelerometer-derived physical activity (PA) and sedentary behavior (SED) levels is scarce for Japanese older adults. The aims of this study were therefore to 1) describe levels of PA and SED in Japanese community-dwelling older adults, using tri-axial accelerometer; 2) examine the variation of PA and SED with respect to sex, age, and body mass index (BMI). Participants of this study were from the baseline survey of the Sasaguri Genkimon Study, who were 65 years or older and not certified as those requiring long-term care. PA was assessed objectively for seven consecutive days using tri-axial accelerometer. A total of 1,739 participants (median age: 72 years, men: 38.0%) with valid PA data were included. Overall, participants in the present study spent 54.5% of their waking time being sedentary and 45.5% being active, of which 5.4% was moderate-to-vigorous physical activity (MVPA). Women accumulated more minutes of light physical activity (LPA) and MVPA compared with men. In contrast, men spent more time being sedentary. Mean steps per day did not differ between sexes. Furthermore, participants with higher BMI (BMI ≥25) had lower PA levels, and longer SED compared with those with lower BMI (BMI <). PA levels were lower and SED was longer with age. The present study is the first to demonstrate that the levels of PA and SED differed by sex, age, and BMI in Japanese community-dwelling older adults. In particular, women were more active compared with men, providing unique insight into the current level of PA in older adults. Data presented in the study will enable further investigation of additional determinants of PA and SED in order to develop effective population-based intervention strategies to promote PA and reduce prolonged SED in the Japanese population and possibly other rapidly aging societies.
Key pointsAccelerometer, that is capable to assess PA more precisely in large scale epidemiological studies, provides opportunity for improving understanding of daily PA in older adults.This study first demonstrated that the levels of PA and SED differed by sex, age, and BMI in Japanese community-dwelling older people.Women were more active compared with men, in terms of more minutes of MVPA.
PMCID: PMC4541113  PMID: 26336336
Tri-axial accelerometer; physical activity; sedentary behavior; community-based study; older adults
21.  Rapid and Sustainable Detoxication of Airborne Pollutants by Broccoli Sprout Beverage: Results of a Randomized Clinical Trial in China 
Broccoli sprouts are a convenient and rich source of the glucosinolate, glucoraphanin, which can generate the chemopreventive agent, sulforaphane, an inducer of glutathione S-transferases (GSTs) and other cytoprotective enzymes. A broccoli sprout-derived beverage providing daily doses of 600 μmol glucoraphanin and 40 μmol sulforaphane was evaluated for magnitude and duration of pharmacodynamic action in a 12-week randomized clinical trial. Two hundred and ninety-one study participants were recruited from the rural He-He Township, Qidong, in the Yangtze River delta region of China, an area characterized by exposures to substantial levels of airborne pollutants. Exposure to air pollution has been associated with lung cancer and cardiopulmonary diseases. Urinary excretion of the mercapturic acids of the pollutants, benzene, acrolein, and crotonaldehyde, were measured before and during the intervention using liquid chromatography tandem mass spectrometry. Rapid and sustained, statistically significant (p ≤ 0.01) increases in the levels of excretion of the glutathione-derived conjugates of benzene (61%), acrolein (23%), but not crotonaldehyde were found in those receiving broccoli sprout beverage compared with placebo. Excretion of the benzene-derived mercapturic acid was higher in participants who were GSTT1-positive compared to the null genotype, irrespective of study arm assignment. Measures of sulforaphane metabolites in urine indicated that bioavailability did not decline over the 12-week daily dosing period. Thus, intervention with broccoli sprouts enhances the detoxication of some airborne pollutants and may provide a frugal means to attenuate their associated long-term health risks.
doi:10.1158/1940-6207.CAPR-14-0103
PMCID: PMC4125483  PMID: 24913818
Air pollution; broccoli; sulforaphane; benzene; chemoprevention
22.  Accelerating Aerobic Sludge Granulation by Adding Dry Sewage Sludge Micropowder in Sequencing Batch Reactors 
Micropowder (20–250 µm) made from ground dry waste sludge from a municipal sewage treatment plant was added in a sequencing batch reactor (R2), which was fed by synthetic wastewater with acetate as carbon source. Compared with the traditional SBR (R1), aerobic sludge granulation time was shortened 15 days in R2. Furthermore, filamentous bacteria in bulking sludge were controlled to accelerate aerobic granulation and form large granules. Correspondingly, the SVI decreased from 225 mL/g to 37 mL/g. X-ray Fluorescence (XRF) analysis demonstrated that Al and Si from the micropowder were accumulated in granules. A mechanism hypotheses for the acceleration of aerobic granulation by adding dry sludge micropowder is proposed: added micropowder acts as nuclei to induce bacterial attachment; dissolved matters from the micropowder increase abruptly the organic load for starved sludge to control overgrown filamentous bacteria as a framework for aggregation; increased friction from the movement of micropowder forces the filaments which extend outwards to shrink for shaping granules.
doi:10.3390/ijerph120810056
PMCID: PMC4555328  PMID: 26308025
aerobic granulation; granule; filamentous bacteria; micropowder; dry sewage sludge
23.  Dynamic Electrochemical Membranes for Continuous Affinity Protein Separation 
Advanced functional materials  2014;24(27):4317-4323.
A membrane system with nm-scale thick electrodes is able to selectively bind genetically modified proteins and pump them across the membrane with sequential voltage pulses. The electrodes are located at the first 20nm of pore entrances to specifically capture targeted proteins and block non-specific protein transport through the pores during the binding cycle. During the release cycle, concentration of imidazole is controlled to keep the pore blocked while releasing proteins at the bottom edge of the electrode. A separation factor for GFP:BSA of 16 was achieved with observed GFP electrophoretic mobility of 2.54×10-6cm2v-1S-1. This non-optimized system with a membrane area of 0.75 cm2 has the same throughput as 1ml of commercially available chromatography columns showing viability as a continuous process. This system will enable continuous separation of expressed proteins directly from fermentation broths dramatically simplifying the separation process as well as reducing biopharmaceutical production costs.
doi:10.1002/adfm.201303707
PMCID: PMC4220452  PMID: 25383076
Nanoporous electrode; continuous separation; electrophoresis; dynamic membrane; Biomimetics
24.  Management of iatrogenic colorectal perforation: From surgery to endoscopy 
Iatrogenic colon perforation is one the most pernicious complications for patients undergoing endoscopic screening or therapy. It is a serious but rare complication of colonoscopy. However, with the expansion of the indications for endoscopic therapies for gastrointestinal diseases, the frequency of colorectal perforation has increased. The management of iatrogenic colorectal perforation is still a challenge for many endoscopists. The methods for treating this complication vary, including conservative treatment, surgical treatment, laparoscopy and endoscopy. In this review, we highlight the etiology, recognition and treatment of colorectal iatrogenic perforation. Specifically, we shed light on the endoscopic management of this rare complication.
doi:10.4253/wjge.v7.i8.819
PMCID: PMC4501973  PMID: 26191347
Iatrogenic perforation; Colorectum; Surgery; Laparoscopy; Endoscopy
25.  Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome 
Neuropsychopharmacology  2014;39(8):1955-1967.
Fragile X syndrome, caused by the mutation of the Fmr1 gene, is characterized by deficits of attention and learning ability. In the hippocampus of Fmr1 knockout mice (KO), long-term depression is enhanced whereas long-term potentiation (LTP) including late-phase LTP (L-LTP) is reduced or unaffected. Here we examined L-LTP in the anterior cingulate cortex (ACC) in Fmr1 KO mice by using a 64-electrode array recording system. In wild-type mice, theta-burst stimulation induced L-LTP that does not occur in all active electrodes/channels within the cingulate circuit and is typically detected in ∼75% of active channels. Furthermore, L-LTP recruited new responses from previous inactive channels. Both L-LTP and the recruitment of inactive responses were blocked in the ACC slices of Fmr1 KO mice. Bath application of metabotropic glutamate receptor 5 (mGluR5) antagonist or glycogen synthase kinase-3 (GSK3) inhibitors rescued the L-LTP and network recruitment. Our results demonstrate that loss of FMRP will greatly impair L-LTP and recruitment of cortical network in the ACC that can be rescued by pharmacological inhibition of mGluR5 or GSK3. This study is the first report of the network properties of L-LTP in the ACC, and provides basic mechanisms for future treatment of cortex-related cognitive defects in fragile X patients.
doi:10.1038/npp.2014.44
PMCID: PMC4059905  PMID: 24553731

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