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1.  On the importance of sensor height variation for detection of magnetic labels by magnetoresistive sensors 
Scientific Reports  2015;5:12282.
Magnetoresistive sensors are widely used for biosensing by detecting the signal from magnetic labels bound to a functionalized area that usually covers the entire sensor structure. Magnetic labels magnetized by a homogeneous applied magnetic field weaken and strengthen the applied field when they are over and outside the sensor area, respectively, and the detailed origin of the sensor signal in experimental studies has not been clarified. We systematically analyze the signal from both a single sensor stripe and an array of sensor stripes as function of the geometrical parameters of the sensor stripes as well as the distribution of magnetic labels over the stripes. We show that the signal from sensor stripes with a uniform protective coating, contrary to conventional wisdom in the field, is usually dominated by the contribution from magnetic labels between the sensor stripes rather than by the labels on top of the sensor stripes because these are at a lower height. We therefore propose a shift of paradigm to maximize the signal due to magnetic labels between sensor stripes. Guidelines for this optimization are provided and illustrated for an experimental case from the literature.
PMCID: PMC4508666  PMID: 26195089
2.  Expression of MMP-1/PAR-1 and patterns of invasion in oral squamous cell carcinoma as potential prognostic markers 
OncoTargets and therapy  2015;8:1619-1626.
Matrix metalloproteinase (MMP)-1 degrades type I collagen of the extracellular matrix and also activates protease activated receptor (PAR)-1 to induce angiogenesis. The aims of this study were to evaluate microvessel density (MVD) and the expression of PAR-1 and MMP-1 in oral squamous cell carcinoma (SCC) specimens with different patterns of invasion (POI) and to evaluate their association with clinical outcomes.
Seventy-four surgically obtained oral SCC samples were classified by POI according to hematoxylin-eosin staining. MVD and the localization and intensity of PAR-1 and MMP-1 expression were detected by immunohistochemistry.
Of the 74 oral SCC samples, 18, 5, 34, and 17 showed type I, II, III, and IV POI, respectively. MVD and expression levels of MMP-1 and PAR-1 differed between POI types I–II and POI types III–IV. Patients with low tumor expression of MMP-1 and PAR-1 and low MVD had a longer survival time than those with high tumor expression of MMP-1 and PAR-1. Moreover, the survival time of patients with POI types III–IV was shorter than that of patients with POI types I–II.
POI combined with expression levels of MMP-1 and PAR-1 may be a valuable tool for assessing the clinical prognosis of patients with oral SCC.
PMCID: PMC4498722  PMID: 26170698
oral squamous cell carcinoma; pattern of invasion; immunohistochemistry; clinical outcomes
3.  In-cell infection: a novel pathway for Epstein-Barr virus infection mediated by cell-in-cell structures 
Cell Research  2015;25(7):785-800.
Epstein-Barr virus (EBV) can infect both susceptible B lymphocytes and non-susceptible epithelial cells (ECs). Viral tropism analyses have revealed two intriguing means of EBV infection, either by a receptor-mediated infection of B cells or by a cell-to-cell contact-mediated infection of non-susceptible ECs. Herein, we report a novel “in-cell infection” mechanism for EBV infection of non-susceptible ECs through the formation of cell-in-cell structures. Epithelial CNE-2 cells were invaded by EBV-infected Akata B cells to form cell-in-cell structures in vitro. Such unique cellular structures could be readily observed in the specimens of nasopharyngeal carcinoma. Importantly, the formation of cell-in-cell structures led to the autonomous activation of EBV within Akata cells and subsequent viral transmission to CNE-2 cells, as evidenced by the expression of viral genes and the presence of virion particles in CNE-2 cells. Significantly, EBV generated from in-cell infected ECs displayed altered tropism with higher infection efficacy to both B cells and ECs. In addition to CNE-2 tumor cells, cell-in-cell structure formation could also mediate EBV infection of NPEC1-Bmi1 cells, an immortalized nasopharyngeal epithelial cell line. Furthermore, efficient infection by this mechanism involved the activation of the PI3K/AKT signaling pathway. Thus, our study identified “in-cell infection” as a novel mechanism for EBV infection. Given the diversity of virus-infected cells and the prevalence of cell-in-cell structures during chronic infection, we speculate that “in-cell infection” is likely a general mechanism for EBV and other viruses to infect non-susceptible ECs.
PMCID: PMC4493273  PMID: 25916549
cell-in-cell structures; in-cell infection; Epstein-Barr virus; tropism; PI3K/AKT pathway
4.  mTOR Directs Breast Morphogenesis through the PKC-alpha-Rac1 Signaling Axis 
PLoS Genetics  2015;11(7):e1005291.
Akt phosphorylation is a major driver of cell survival, motility, and proliferation in development and disease, causing increased interest in upstream regulators of Akt like mTOR complex 2 (mTORC2). We used genetic disruption of Rictor to impair mTORC2 activity in mouse mammary epithelia, which decreased Akt phosphorylation, ductal length, secondary branching, cell motility, and cell survival. These effects were recapitulated with a pharmacological dual inhibitor of mTORC1/mTORC2, but not upon genetic disruption of mTORC1 function via Raptor deletion. Surprisingly, Akt re-activation was not sufficient to rescue cell survival or invasion, and modestly increased branching of mTORC2-impaired mammary epithelial cells (MECs) in culture and in vivo. However, another mTORC2 substrate, protein kinase C (PKC)-alpha, fully rescued mTORC2-impaired MEC branching, invasion, and survival, as well as branching morphogenesis in vivo. PKC-alpha-mediated signaling through the small GTPase Rac1 was necessary for mTORC2-dependent mammary epithelial development during puberty, revealing a novel role for Rictor/mTORC2 in MEC survival and motility during branching morphogenesis through a PKC-alpha/Rac1-dependent mechanism.
Author Summary
The protein kinase mTOR is frequently activated in breast cancers, where it enhances cancer cell growth, survival, and metastastic spread to distant organs. Thus, mTOR is an attractive, clinically relevant molecular target for drugs designed to treat metastatic breast cancers. However, mTOR exists in two distinct complexes, mTORC1 and mTORC2, and the relative roles of each complex have not been elucidated. Moreover, as pathways that regulate normal tissue growth and development are often highjacked to promote cancer, understanding mTOR function in normal mammary epithelial development will likely provide insight into its role in tumor progression. In this study, we assessed the role of mTORC1 and mTORC2 complexes in normal mammary epithelial cell branching, survival, and invasion. Interestingly, while mTORC1 was not required for branching, survival and invasion of mammary epithelial cells, mTORC2 was necessary for these processes in both mouse and human models. Furthermore, we found that mTORC2 exerts its effects primarily through downstream activation of a PKC-alpha-Rac1 signaling axis rather than the more well-studied Akt signaling pathway. Our studies identify a novel role for the mTORC2 complex in mammary morphogenesis, including cell survival and motility, which are relevant to breast cancer progression.
PMCID: PMC4488502  PMID: 26132202
5.  High performance wash-free magnetic bioassays through microfluidically enhanced particle specificity 
Scientific Reports  2015;5:11693.
Magnetic biosensors have emerged as a sensitive and versatile platform for high performance medical diagnostics. These magnetic biosensors require well-tailored magnetic particles as detection probes, which need to give rise to a large and specific biological signal while showing very low nonspecific binding. This is especially important in wash-free bioassay protocols, which do not require removal of particles before measurement, often a necessity in point of care diagnostics. Here we show that magnetic interactions between magnetic particles and magnetized sensors dramatically impact particle transport and magnetic adhesion to the sensor surfaces. We investigate the dynamics of magnetic particles’ biomolecular binding and magnetic adhesion to the sensor surface using microfluidic experiments. We elucidate how flow forces can inhibit magnetic adhesion, greatly diminishing or even eliminating nonspecific signals in wash-free magnetic bioassays, and enhancing signal to noise ratios by several orders of magnitude. Our method is useful for selecting and optimizing magnetic particles for a wide range of magnetic sensor platforms.
PMCID: PMC4485157  PMID: 26123868
6.  Caspase-1 inhibitor ameliorates experimental autoimmune myasthenia gravis by innate dendric cell IL-1-IL-17 pathway 
IL-1β has been shown to play a pivotal role in autoimmunity. Cysteinyl aspartate-specific proteinase-1 (caspase-1) inhibitor may be an important drug target for autoimmune diseases. However, the effects of caspase-1 inhibitor on myasthenia gravis (MG) remain undefined.
To investigate the effects of caspase-1 inhibitor on experimental autoimmune myasthenia gravis (EAMG), an animal model of MG, caspase-1 inhibitor was administered to Lewis rats immunized with region 97–116 of the rat AChR α subunit (R97-116 peptide) in complete Freund’s adjuvant. The immunophenotypical characterization by flow cytometry and the levels of autoantibody by ELISA were carried out to evaluate the neuroprotective effect of caspase-1 inhibitor.
We found that caspase-1 inhibitor improved EAMG clinical symptom, which was associated with decreased IL-17 production by CD4+ T cells and γδ T cells, lower affinity of anti-R97-116 peptide IgG. Caspase-1 inhibitor decreased expression of CD80, CD86, and MHC class II on DCs, as well as intracellular IL-1β production from DCs. In addition, caspase-1 inhibitor treatment inhibited R97-116 peptide-specific cell proliferation and decreased follicular helper T cells relating to EAMG development.
Our results suggest that caspase-1 inhibitor ameliorates experimental autoimmune myasthenia gravis by innate DC IL-1-IL-17 pathway and provides new evidence that caspase-1 is an important drug target in the treatment of MG and other autoimmune diseases.
PMCID: PMC4470006  PMID: 26071315
Caspase-1 inhibitor; IL-1β; Dendric cell; Th17 cell; Follicular helper T cell; Experimental autoimmune myasthenia gravis
7.  MicroRNA-217 functions as a prognosis predictor and inhibits colorectal cancer cell proliferation and invasion via an AEG-1 dependent mechanism 
BMC Cancer  2015;15:437.
Recent studies have indicated the possible function of miR-217 in tumorigenesis. However, the roles of miR-217 in colorectal cancer (CRC) are still largely unknown.
We examined the expression of miR-217 and AEG-1 in 50 CRC tissues and the corresponding noncancerous tissues by qRT-PCR. The clinical significance of miR-217 was analyzed. CRC cell lines with miR-217 upregulation and AEG-1 silencing were established and the effects on tumor growth in vitro and in vivo were assessed. Dual-luciferase reporter gene assays were also performed to investigate the interaction between miR-217 and AEG-1.
Our data demonstrated that miR-217 was significantly downregulated in 50 pairs of colorectal cancer tissues. MiR-217 expression levels were closely correlated with tumor differentiation. Moreover, decreased miR-217 expression was also associated with shorter overall survival of CRC patients. MiR-217 overexpression significantly inhibited proliferation, colony formation and invasiveness of CRC cells by promoting apoptosis and G0/G1 phase arrest. Interestingly, ectopic miR-217 expression decreased AEG-1 expression and repressed luciferase reporter activity associated with the AEG-1 3′-untranslated region (UTR). AEG-1 silencing resulted in similar biological behavior changes to those associated with miR-217 overexpression. Finally, in a nude mouse xenografted tumor model, miR-217 overexpression significantly suppressed CRC cell growth.
Our findings suggest that miR-217 has considerable value as a prognostic marker and potential therapeutic target in CRC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1438-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4446846  PMID: 26016795
miR-217; AEG-1; colorectal cancer; proliferation; invasion
8.  Different Dynamic Patterns of β-Lactams, Quinolones, Glycopeptides and Macrolides on Mouse Gut Microbial Diversity 
PLoS ONE  2015;10(5):e0126712.
The adverse impact of antibiotics on the gut microbiota has attracted extensive interest, particularly due to the development of microbiome research techniques in recent years. However, a direct comparison of the dynamic effects of various types of antibiotics using the same animal model has not been available. In the present study, we selected six antibiotics from four categories with the broadest clinical usage, namely, β-lactams (Ceftriaxone Sodium, Cefoperazone/Sulbactam and meropenem), quinolones (ofloxacin), glycopeptides (vancomycin), and macrolides (azithromycin), to treat BALB/c mice. Stool samples were collected during and after the administration of antibiotics, and microbial diversity was analyzed through Illumina sequencing and bioinformatics analyses using QIIME. Both α and β diversity analyses showed that ceftriaxone sodium, cefoperazone/sulbactam, meropenem and vancomycin changed the gut microbiota dramatically by the second day of antibiotic administration whereas the influence of ofloxacin was trivial. Azithromycin clearly changed the gut microbiota but much less than vancomycin and the β-lactams. In general, the community changes induced by the three β-lactam antibiotics showed consistency in inhibiting Papillibacter, Prevotella and Alistipes while inducing massive growth of Clostridium. The low diversity and high Clostridium level might be an important cause of Clostridium difficile infection after usage of β-lactams. Vancomycin was unique in that it inhibited Firmicutes, mainly the genus Clostridium. On the other hand, it induced the growth of Escherichia and effect lasted for months afterward. Azithromycin and meropenem induced the growth of Enterococcus. These findings will be useful for understanding the potential adverse effects of antibiotics on the gut microbiome and ensuring their better usage.
PMCID: PMC4430517  PMID: 25970622
9.  Three-Dimensional Spheroid-Cultured Mesenchymal Stem Cells Devoid of Embolism Attenuate Brain Stroke Injury After Intra-Arterial Injection 
Stem Cells and Development  2013;23(9):978-989.
The therapeutic effect of mesenchymal stem cells (MSCs) in tissue repair/regeneration is substantially dampened by the loss of primitive properties and poor engraftment to target organs. In this study, the multipotency and cell sizes of human MSCs, which had been expanded in monolayer culture for several passages, were dramatically restored after an episode of three-dimensional (3D) spheroid culture. Unlike MSCs derived from monolayer, which caused embolism and blindness, MSCs derived from 3D spheroids did not cause vascular obstructions, after intra-carotid artery infusion in rats. Importantly, intra-carotid infusion of 1 million 3D spheroid MSCs in rats 24 h after middle cerebral artery occlusion and reperfusion resulted in engraftment of the cells into the lesion and significant (over 70%) reduction of infarct size along with restoration of neurologic function. Moreover, the enhanced effect of spheroid MSCs was coincided with significantly increased differentiation of the MSCs into neurons and markedly increased number of endogenous glial fibrillary acidic protein–positive neural progenitors in the peri-infarct boundary zone. However, the similarly administered monolayer MSCs resulted in a modest functional improvement. Our results suggest that 3D MSCs, in combination with intra-carotid delivery, may represent a novel therapeutic approach of MSCs for stroke.
PMCID: PMC3997073  PMID: 24341685
10.  Elevated Slit2 Activity Impairs VEGF-induced Angiogenesis and Tumor Neovascularization in EphA2-deficient Endothelium 
Molecular cancer research : MCR  2014;13(3):524-537.
Angiogenic remodeling during embryonic development and in adult tissue homeostasis is orchestrated by cooperative signaling between several distinct molecular pathways, which are often exploited by tumors. Indeed, tumors upregulate pro-angiogenic molecules while simultaneously suppressing angiostatic pathways in order to recruit blood vessels for growth, survival, and metastatic spread. Understanding how cancers exploit pro- and anti-angiogenic signals is a key step in developing new, molecularly targeted anti-angiogenic therapies. While EphA2, a receptor tyrosine kinase (RTK), is required for vascular endothelial growth factor (VEGF)-induced angiogenesis, the mechanism through which these pathways intersect remains unclear. Slit2 expression is elevated in EphA2-deficient endothelium, and here it is reported that inhibiting Slit activity rescues VEGF-induced angiogenesis in cell culture and in vivo, as well as VEGF-dependent tumor angiogenesis, in EphA2-deficient endothelial cells and animals. Moreover, blocking Slit activity or Slit2 expression in EphA2-deficient endothelial cells restores VEGF-induced activation of Src and Rac, both of which are required for VEGF-mediated angiogenesis. These data suggest that EphA2 suppression of Slit2 expression and Slit angiostatic activity enables VEGF-induced angiogenesis in vitro and in vivo, providing a plausible mechanism for impaired endothelial responses to VEGF in the absence of EphA2 function.
PMCID: PMC4416411  PMID: 25504371
EphA2; Slit2; VEGF; endothelium; tumor angiogenesis
11.  Titanium mesh cage fracture after lumbar reconstruction surgery: a case report and literature review 
Titanium mesh cage (TMC) was introduced recently to provide anterior structural support and interbody fusion without the need to harvest bone from the iliac crest. Because of its good mechanical behavior and satisfactory clinical outcomes, TMC is commonly used for lumbar burst fractures. Here, we present a female patient who underwent a posterior-anterior L4 corpectomy with TMC placement and developed a cage fracture after 42 months. The patient refused the revision surgery and asked for conservative treatment. At the 3-month follow-up, she reported doing well, with no complaints of back pain or leg pain. There were three cases of TMC fracture have been previously reported in the literature. Only one patient performed a revision surgery with an expandable titanium cage, and all this three patients experienced a good outcome during the follow-up period. TMC fracture is a rare complication of spinal surgery. Close observation or surgical treatment should be considered to improve patient outcomes. Although cage placement, instability, subsidence, and both stress shielding and necrotic bone in the cage appear to play key roles in the pathogenesis of this rare complication, the exact mechanism of this condition remains undetermined.
PMCID: PMC4483954  PMID: 26131138
Lumbar spine; titanium mesh cage; fracture; review
12.  A novel nanobody specific for respiratory surfactant protein A has potential for lung targeting 
Lung-targeting drugs are thought to be potential therapies of refractory lung diseases by maximizing local drug concentrations in the lung to avoid systemic circulation. However, a major limitation in developing lung-targeted drugs is the acquirement of lung-specific ligands. Pulmonary surfactant protein A (SPA) is predominantly synthesized by type II alveolar epithelial cells, and may serve as a potential lung-targeting ligand. Here, we generated recombinant rat pulmonary SPA (rSPA) as an antigen and immunized an alpaca to produce two nanobodies (the smallest naturally occurring antibodies) specific for rSPA, designated Nb6 and Nb17. To assess these nanobodies’ potential for lung targeting, we evaluated their specificity to lung tissue and toxicity in mice. Using immunohistochemistry, we demonstrated that these anti-rSPA nanobodies selectively bound to rat lungs with high affinity. Furthermore, we intravenously injected fluorescein isothiocyanate-Nb17 in nude mice and observed its preferential accumulation in the lung to other tissues, suggesting high affinity of the nanobody for the lung. Studying acute and chronic toxicity of Nb17 revealed its safety in rats without causing apparent histological alterations. Collectively, we have generated and characterized lung-specific nanobodies, which may be applicable for lung drug delivery.
PMCID: PMC4403696  PMID: 25926731
nanobodies; rSPA; phage-nanobody library; VHH; lung-targeting drugs
13.  Use of Genome-Wide Association Studies for Cancer Research and Drug Repositioning 
PLoS ONE  2015;10(3):e0116477.
Although genome-wide association studies have identified many risk loci associated with colorectal cancer, the molecular basis of these associations are still unclear. We aimed to infer biological insights and highlight candidate genes of interest within GWAS risk loci. We used an in silico pipeline based on functional annotation, quantitative trait loci mapping of cis-acting gene, PubMed text-mining, protein-protein interaction studies, genetic overlaps with cancer somatic mutations and knockout mouse phenotypes, and functional enrichment analysis to prioritize the candidate genes at the colorectal cancer risk loci. Based on these analyses, we observed that these genes were the targets of approved therapies for colorectal cancer, and suggested that drugs approved for other indications may be repurposed for the treatment of colorectal cancer. This study highlights the use of publicly available data as a cost effective solution to derive biological insights, and provides an empirical evidence that the molecular basis of colorectal cancer can provide important leads for the discovery of new drugs.
PMCID: PMC4372357  PMID: 25803826
14.  The Chondrogenic Induction Potential for Bone Marrow-Derived Stem Cells between Autologous Platelet-Rich Plasma and Common Chondrogenic Induction Agents: A Preliminary Comparative Study 
Stem Cells International  2015;2015:589124.
The interests in platelet-rich plasma (PRP) and their application in stem cell therapy have contributed to a better understanding of the basic biology of the prochondrogenesis effect on bone marrow-derived stem cells (BMSCs). We aimed at comparing the effect of autologous PRP with common chondrogenic induction agents (CCIAs) on the chondrogenic differentiation of BMSCs. Rabbit BMSCs were isolated and characterized by flow cytometry and differentiated towards adipocytes and osteoblasts. The chondrogenic response of BMSCs to autologous PRP and CCIAs which included transforming growth factor-β1 (TGF-β1), dexamethasone (DEX), and vitamin C (Vc) was examined by cell pellet culture. The isolated BMSCs after two passages highly expressed CD29 and CD44 but minimally expressed CD45. The osteogenic and adipogenic differentiation potentials of the isolated BMSCs were also confirmed. Compared with common CCIAs, autologous PRP significantly upregulated the chondrogenic related gene expression, including Col-2, AGC, and Sox-9. Osteogenic related gene expression, including Col-1 and OCN, was not of statistical significance between these two groups. Thus, our data shows that, compared with common chondrogenic induction agents, autologous PRP can be more effective in promoting the chondrogenesis of BMSCs.
PMCID: PMC4378611  PMID: 25861279
15.  Lentivirus-mediated RNA interference targeting UbcH10 reduces cell growth and invasion of human osteosarcoma cells via inhibition of Ki-67 and matrix metalloproteinases 
Oncology Letters  2015;9(5):2171-2176.
Osteosarcoma (OS) is the most commonly diagnosed primary malignancy affecting the bone. UbcH10 is a cancer-related E2-ubiquitin-conjugating enzyme. An overexpression of UbcH10 is significantly associated with tumor grade and cellular proliferation. However, limited evidence exists with regard to the biological function of UbcH10 in OS. The present study created a UbcH10 knockdown OS cell line using lentivirus-mediated RNA interference. The expression of UbcH10 was significantly reduced in UbcH10-targeted small hairpin RNA-expressing lentivirus OS cells. The downregulation of UbcH10 suppressed OS cell proliferation and colony formation ability via decreased Ki-67 expression. UbcH10 knockdown OS cells exhibited impaired invasion and migration abilities. Furthermore, knockdown of UbcH10 led to decreased levels of matrix metalloproteinase-3 and −9 in OS cells. The present study demonstrated the role of UbcH10 in OS cell proliferation, invasion and migration, which suggests that UbcH10 may be a potential candidate for OS therapy.
PMCID: PMC4467328  PMID: 26137034
UbcH10; matrix metalloproteinases; osteosarcoma; growth; invasion; Ki-67
16.  Possible Hepatotoxicity Associated With Intravenous Acetaminophen in a 36-Year-Old Female Patient 
Pharmacy and Therapeutics  2015;40(2):123-132.
A woman received intravenous (IV) acetaminophen every six hours (16 doses) for pain control. Tests showed high levels of markers for liver damage, but levels fell after the drug was stopped—raising the possibility of hepatotoxicity linked to IV acetaminophen.
We present a case of a 36-year-old female who came into the emergency department with right-side abdominal pain. She went to the operating room for a diagnostic laparoscopy and appendectomy. She received intravenous (IV) acetaminophen every six hours both preoperatively and postoperatively for pain control. The patient’s aspartate aminotransferase and alanine aminotransferase levels were elevated and peaked at 4,833 and 6,600 IU/L, respectively, from baselines of 14 and 15, respectively, while she was receiving 16 doses of IV acetaminophen. The patient was transferred to a regional liver transplant center for evaluation for a transplant. She was treated with IV N-acetylcysteine and discharged with a normal liver-function test without a transplant. This case report supports the possibility of hepatotoxicity associated with IV acetaminophen.
PMCID: PMC4315114  PMID: 25673962
intravenous acetaminophen; hepatotoxicity
17.  Significant Differences in the Clinicopathological Characteristics and Survival of Gastric Cancer Patients from Two Cancer Centers in China and Korea 
Journal of Gastric Cancer  2015;15(1):19-28.
To compare the clinicopathological data and long-term survival of gastric cancer patients in China and Korea.
Materials and Methods
Patients who had undergone gastrectomy for gastric cancer between 1998 and 2009 in 2 high-volume institutions in both China (n=1,637) and Korea (n=2,231) were retrospectively evaluated. Clinicopathological variables, overall survival (OS), progression-free survival (PFS), and surgery-related complications were assessed for all patients and compared between the 2 institutions.
Chinese patients included in the study were significantly older and had a significantly lower body mass index (BMI) than the Korean patients. Esophagogastric junction tumors were more frequent in Chinese patients. However, the number of patients with stage I gastric cancer, the number of harvested lymph nodes, and the number of total gastrectomies were significantly higher in the Korean population. Korean patients also presented with fewer undifferentiated tumors than Chinese patients. Furthermore, Korean patients had prolonged OS and PFS for stage III cancers only. BMI, tumor-node-metastasis (TNM) stage, tumor invasion, number of positive lymph nodes, and distant metastases were all independent factors affecting OS and PFS.
Although China and Korea are neighboring Asian countries, the clinicopathological characteristics of Chinese patients are significantly different from those of Korean patients. Korean gastric cancer patients had longer OS and PFS than Chinese patients. Influencing factors included TNM stage, tumor invasion, and lymph node metastasis.
PMCID: PMC4389093  PMID: 25861519
Stomach neoplasms; Korea; China; Clinicopathological characteristics; Survival
18.  Genetic diversity of Plasmodium vivax population before elimination of malaria in Hainan Province, China 
Malaria Journal  2015;14:78.
Hainan Province is one of the most severe endemic regions with high transmission of Plasmodium falciparum and Plasmodium vivax in China. However, the incidence of P. falciparum and P. vivax has dropped dramatically since 2007 and a national elimination malaria programme (NEMP) was launched after 2010. To better understand the genetic information on P. vivax population before elimination of malaria in Hainan Province, the extent of genetic diversity of P. vivax isolates in Hainan Province was investigated using four polymorphic genetic markers, including P. vivax merozoite surface proteins 1, 3α, and 3β (pvmsp-1, pvmsp-3α, and pvmsp-3β) and circumsporozoite protein (pvcsp).
Isolates of P. vivax (n = 27) from Hainan Province were collected from 2009 to 2010 and pvmsp-1 and pvcsp were analysed by DNA sequencing, respectively. Using polymerase chain reaction-restriction fragment length polymorphism were analysed in pvmsp-3α, and pvmsp-3β.
The DNA sequencing analysis on pvmsp1 revealed that there were three allele types: Salvador-1 (Sal-1), Belem and recombinant (R) types. Among them, Sal-1 type was a dominant strain with eight variant subtypes (88.9%), whereas R- (3.7%) and Belem-type strains (7.4%) had one variant subtypes, respectively. All the isolates carried pvcsp with VK210 type accounting for 85.2% (23/27 isolates) and VK247 type accounting for 14.8% (4/27). Only type A and type B alleles were successfully amplified in pvmsp-3α gene, and a high level of polymorphism was observed in pvmsp-3α. Considering pvmsp-3β gene, type A was the predominant type in 17 isolates (63%), whereas type B was dominant in only ten isolates (37%).
The present data indicate that there was high degree of genetic diversity among P. vivax population in Hainan Province of China during the pre-elimination stage of malaria, with 26 unique haplotypes observed among 27 samples.
PMCID: PMC4354742  PMID: 25888891
Plasmodium vivax; pvmsp-1; pvcsp; pvmsp-3α; pvmsp-3β; Hainan province; Elimination malaria; China
19.  Sensitivity of Plasmodium falciparum to Antimalarial Drugs in Hainan Island, China 
Pyronaridine and artesunate have been shown to be effective in falciparum malaria treatment. However, pyronaridine is rarely used in Hainan Island clinically, and artesunate is not widely used as a therapeutic agent. Instead, conventional antimalarial drugs, chloroquine and piperaquine, are used, explaining the emergence of chloroquine-resistant Plasmodium falciparum. In this article, we investigated the sensitivity of P. falciparum to antimalarial drugs used in Hainan Island for rational drug therapy. We performed in vivo (28 days) and in vitro tests to determine the sensitivity of P. falciparum to antimalarial drugs. Total 46 patients with falciparum malaria were treated with dihydroartemisinin/piperaquine phosphate (DUO-COTECXIN) and followed up for 28 day. The cure rate was 97.8%. The mean fever clearance time (22.5±10.6 hr) and the mean parasite clearance time (27.3±12.2 hr) showed no statistical significance with different genders, ages, temperatures, or parasite density (P>0.05). The resistance rates of chloroquine, piperaquine, pyronarididine, and artesunate detected in vitro were 71.9%, 40.6%, 12.5%, and 0%, respectively (P<0.0001). The resistance intensities decreased as follows: chloroquine>piperaquine>pyronarididine>artesunate. The inhibitory dose 50 (IC50) was 3.77×10-6 mol/L, 2.09×10-6 mol/L, 0.09×10-6 mol/L, and 0.05×10-6 mol/L, and the mean concentrations for complete inhibition (CIMC) of schizont formation were 5.60×10-6 mol/L, 9.26×10-6 mol/L, 0.55×10-6 mol/L, and 0.07×10-6 mol/L, respectively. Dihydroartemisinin showed a strong therapeutic effect against falciparum malaria with a low toxicity.
PMCID: PMC4384795  PMID: 25748707
Plasmodium falciparum; antimalarial; sensitivity; in vivo and in vitro test
20.  Safe distance between electrotome and recurrent laryngeal nerve: an experimental canine model 
Background: Various energy based surgical devices (ESD) like electrotome have been widely applied in thyroid surgery. This is the first canine model to determine the safety margin of using the electrotome near the recurrent laryngeal nerve (RLN) to prevent injury to this nerve during thyroid surgery. Methods: Eighteen healthy male dogs were divided equally into three groups according to the distance between electrotome application and the RLN: Group A (5 mm), Group B (3 mm), Group C (1 mm). The parameters of evoked electromyography (EEMG) of vocal muscles between right normal RLNs and left RLNs after electrotome application at a power of 30 W for 1 second in each group were recorded and compared. The acute microstructural morphological changes of the RLNs were observed immediately after the operation under electron microscope. Results: In Group B and Group C, after using the electrotome at a vertical distance of 3 mm or 1 mm from the left RLNs, the stimulating thresholds of left RLNs had a significant increase (P = 0.005; P = 0.002) compared with right normal RLNs, and there occurred obvious acute microstructural morphological changes under electron microscope for left RLNs. While there was no significant functional or histological changes for left RLNs after using the electrotome at a vertical distance of 5 mm from the RLN (P = 0.187) in Group A. Conclusions: When using the electrotome near the RLN at a power of 30W in thyroid surgery, a safety margin of more than 3 mm should be recommended.
PMCID: PMC4358511  PMID: 25785056
Thyroid surgery; electrotome; neuromonitoring; recurrent laryngeal nerve; safe distance
21.  Wafer-scale synthesis of monodisperse synthetic magnetic multilayer nanorods 
Nano letters  2013;14(1):333-338.
A double exposure technique has been used to fabricate nanoimprint stamps for making monodisperse nanorods with controllable lengths. The nanorod length is defined by a normal photolithography projection process whereas the nanorod width is defined by an edge-lithography process using a soft polydimethylsiloxane (PDMS) contact mask. Taking advantage of edge-lithography, the nanorod width can be less than the diffraction limit of the exposure light. Using these nanorod stamps, synthetic magnetic multilayer (SMM) nanorods have been fabricated using nanoimprint lithography, resulting in a length variation of ~3%. Nanorod magnetic properties have been characterized in both longitudinal and in-plane transverse directions of the nanorods. A theoretical model has been established to explain the magnetic responses and has revealed that both shape anisotropy and interlayer interactions are important in determining the properties of SMM nanorods.
PMCID: PMC3931460  PMID: 24329003
Nanorod; magnetic; synthesis; nanoimprint lithography; nano-patterning
22.  Fecal microbiota transplantation broadening its application beyond intestinal disorders 
Intestinal dysbiosis is now known to be a complication in a myriad of diseases. Fecal microbiota transplantation (FMT), as a microbiota-target therapy, is arguably very effective for curing Clostridium difficile infection and has good outcomes in other intestinal diseases. New insights have raised an interest in FMT for the management of extra-intestinal disorders associated with gut microbiota. This review shows that it is an exciting time in the burgeoning science of FMT application in previously unexpected areas, including metabolic diseases, neuropsychiatric disorders, autoimmune diseases, allergic disorders, and tumors. A randomized controlled trial was conducted on FMT in metabolic syndrome by infusing microbiota from lean donors or from self-collected feces, with the resultant findings showing that the lean donor feces group displayed increased insulin sensitivity, along with increased levels of butyrate-producing intestinal microbiota. Case reports of FMT have also shown favorable outcomes in Parkinson’s disease, multiple sclerosis, myoclonus dystonia, chronic fatigue syndrome, and idiopathic thrombocytopenic purpura. FMT is a promising approach in the manipulation of the intestinal microbiota and has potential applications in a variety of extra-intestinal conditions associated with intestinal dysbiosis.
PMCID: PMC4284325  PMID: 25574083
Fecal microbiota transplantation; Intestinal microbiota; Dysbiosis; Extra-intestinal disorders; Therapy
23.  Identification and Expression Analysis of Putative Chemosensory Receptor Genes in Microplitis mediator by Antennal Transcriptome Screening 
Host-seeking, ovipositional behavior and mating of insects are controlled mainly by odor perception through sensory organs such as antennae. Antennal chemoreception is extremely important for insect survival. Several antennal chemosensory receptors are involved in mediating the odor detection in insects, especially the odorant receptors (ORs) and ionotropic receptors (IRs), to ensure the specificity of the olfactory sensory neuron responses. In the present study, we identified the chemosensory receptor gene repertoire of the parasitoid wasp Microplitis mediator, a generalist endoparasitoid that infests more than 40 types of Lepidopterous larvae and is widely distributed in the Palaearctic region. By transcriptome sequencing of male and female antennae we identified 60 candidate odorant receptors, six candidate ionotropic receptors and two gustatory receptors in M. mediator. The full-length sequences of these putative chemosensory receptor genes were obtained by using the rapid amplification of cDNA ends PCR (RACE-PCR) method. We also conducted reverse transcription PCR (RT-PCR) combined with real-time quantitative PCR (qPCR) for investigating the expression profiles of these chemosensory receptor genes in olfactory and non-olfactory tissues. The tissue- and sex-biased expression patterns may provide insights into the roles of the chemosensory receptor in M. mediator. Our findings support possible future study of the chemosensory behavior of M. mediator at the molecular level.
PMCID: PMC4466455  PMID: 26078716
Microplitis mediator; chemosensory receptor gene; odorant receptor; ionotropic receptor; gustatory receptor; expression profile
24.  Biological and clinical significance of epigenetic silencing of MARVELD1 gene in lung cancer 
Scientific Reports  2014;4:7545.
Epigenetic silence in cancer frequently altered signal-transduction pathways during the early stages of tumor development. Recent progress in the field of cancer epigenetics has led to new opportunities for diagnosis and treatment of cancer. We previously demonstrated that novel identified nuclear factor MARVELD1 was widely expressed in human tissues, but down-regulated by promoter methylation in multiple cancers. This study was carried out to determine the biological and clinical significance of MARVELD1 gene silencing in lung cancer. Here, we found the reduced MARVELD1 expression significantly correlated with diagnostic histopathology and malignant degree of lung cancers. DNA hypermethylation and histone deacetylation synergistically inactivated MARVELD1 gene in lung cancer cells. Moreover, MARVELD1 modulated the efficiency of nonsense-mediated mRNA decay (NMD) through interaction with NMD core factor SMG1. The decreased MARVELD1 level in lung cancer reduces NMD efficiency through diminishing the association between NMD complex component UPF1/SMG1 and premature termination codons containing mRNA (PTC-mRNA). The results suggested that MARVELD1 silencing is an appealing diagnostic biomarker for lung cancer and epigenetic silencing of MARVELD1 gene links with the regulatory mechanism of NMD pathway in lung cancer, which may be required for tumorigenesis.
PMCID: PMC4269892  PMID: 25520033
25.  Neutrophils with protumor potential could efficiently suppress tumor growth after cytokine priming and in presence of normal NK cells 
Oncotarget  2014;5(24):12621-12634.
In tumor-bearing state, the function of neutrophils is converted from tumor-suppressing to tumor-promoting. Here we report that priming with IFN-γ and TNF-α could convert the potential of neutrophils from tumor-promoting to tumor-suppressing. The neutrophils with protumor potential have not lost their responsiveness to IFN-γ and TNF-α. After priming with IFN-γ and TNF-α, the potential of the neutrophils to express Bv8 and Mmp9 genes was reduced. Conversely, the tumor-promotional neutrophils recovered the expression of Rab27a and Trail, resumed the activation levels of PI3K and p38 MAPK pathways in response to stimuli, and expressed higher levels of IL-18 and NK-activating ligands such as RAE-1, MULT-1, and H60. Therefore, the anti-tumor function of the neutrophils was augmented, including the cytotoxicity to tumor cells, the capability of degranulation, and the capacity to activate NK cells. Since the function of NK cells is impaired in tumor-bearing state, the administration of normal NK cells could significantly augment the efficiency of tumor therapy based on neutrophil priming. These findings highlight the reversibility of neutrophil function in tumor-bearing state, and suggest that neutrophil priming by IFN-γ/TNF-α might be a potential approach to eliminate residual tumor cells in comprehensive strategy for tumor therapy.
PMCID: PMC4350330  PMID: 25587026
neutrophils; protumor potential; priming; cytokines; NK cells

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