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1.  Cell surface glycan engineering of neural stem cells augments neurotropism and improves recovery in a murine model of multiple sclerosis 
Glycobiology  2015;25(12):1392-1409.
Neural stem cell (NSC)-based therapies offer potential for neural repair in central nervous system (CNS) inflammatory and degenerative disorders. Typically, these conditions present with multifocal CNS lesions making it impractical to inject NSCs locally, thus mandating optimization of vascular delivery of the cells to involved sites. Here, we analyzed NSCs for expression of molecular effectors of cell migration and found that these cells are natively devoid of E-selectin ligands. Using glycosyltransferase-programmed stereosubstitution (GPS), we glycan engineered the cell surface of NSCs (“GPS-NSCs”) with resultant enforced expression of the potent E-selectin ligand HCELL (hematopoietic cell E-/L-selectin ligand) and of an E-selectin-binding glycoform of neural cell adhesion molecule (“NCAM-E”). Following intravenous (i.v.) injection, short-term homing studies demonstrated that, compared with buffer-treated (control) NSCs, GPS-NSCs showed greater neurotropism. Administration of GPS-NSC significantly attenuated the clinical course of experimental autoimmune encephalomyelitis (EAE), with markedly decreased inflammation and improved oligodendroglial and axonal integrity, but without evidence of long-term stem cell engraftment. Notably, this effect of NSC is not a universal property of adult stem cells, as administration of GPS-engineered mouse hematopoietic stem/progenitor cells did not improve EAE clinical course. These findings highlight the utility of cell surface glycan engineering to boost stem cell delivery in neuroinflammatory conditions and indicate that, despite the use of a neural tissue-specific progenitor cell population, neural repair in EAE results from endogenous repair and not from direct, NSC-derived cell replacement.
PMCID: PMC4634313  PMID: 26153105
exofucosylation; glycan engineering; HCELL; multiple sclerosis; neural stem cell
2.  p120 Catenin suppresses basal epithelial cell extrusion in invasive pancreatic neoplasia 
Cancer research  2016;76(11):3351-3363.
Aberrant regulation of cellular extrusion can promote invasion and metastasis. Here, we identify molecular requirements for early cellular invasion using a premalignant mouse model of pancreatic cancer with conditional knockout of p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high grade PanIN lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes, which is mediated in part through nuclear factor-kB (NF-kB) signaling. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, retain epithelial morphology, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by activation of S1P/S1pr2 signaling. In the context of oncogenic Kras, p120 catenin loss significantly reduces expression of genes mediating S1P/S1pr2 signaling in vivo and in vitro, and this effect is mediated at least in part through activation of NF-kB. These results provide insight into mechanisms controlling early events in the metastatic process and suggest that p120 catenin and S1P/S1pr2 signaling enhance cancer progression by regulating epithelial cell invasion.
PMCID: PMC4891257  PMID: 27032419
pancreatic cancer; epithelial extrusion; p120 catenin; adherens junctions; invasion; pancreatitis
3.  Bioimage classification with subcategory discriminant transform of high dimensional visual descriptors 
BMC Bioinformatics  2016;17:465.
Bioimage classification is a fundamental problem for many important biological studies that require accurate cell phenotype recognition, subcellular localization, and histopathological classification. In this paper, we present a new bioimage classification method that can be generally applicable to a wide variety of classification problems. We propose to use a high-dimensional multi-modal descriptor that combines multiple texture features. We also design a novel subcategory discriminant transform (SDT) algorithm to further enhance the discriminative power of descriptors by learning convolution kernels to reduce the within-class variation and increase the between-class difference.
We evaluate our method on eight different bioimage classification tasks using the publicly available IICBU 2008 database. Each task comprises a separate dataset, and the collection represents typical subcellular, cellular, and tissue level classification problems. Our method demonstrates improved classification accuracy (0.9 to 9%) on six tasks when compared to state-of-the-art approaches. We also find that SDT outperforms the well-known dimension reduction techniques, with for example 0.2 to 13% improvement over linear discriminant analysis.
We present a general bioimage classification method, which comprises a highly descriptive visual feature representation and a learning-based discriminative feature transformation algorithm. Our evaluation on the IICBU 2008 database demonstrates improved performance over the state-of-the-art for six different classification tasks.
PMCID: PMC5112644  PMID: 27852213
Microscopy imaging; Classification; Subcategory model; Discriminative feature transform
4.  Evaluation of site-specific lateral inclusion zone for vapor intrusion based on an analytical approach 
Journal of hazardous materials  2015;298:221-231.
In 2002, U.S. EPA proposed a general buffer zone of approximately 100 feet (30 m) laterally to determine which buildings to include in vapor intrusion (VI) investigations. However, this screening distance can be threatened by factors such as extensive surface pavements. Under such circumstances, EPA recommended investigating soil vapor migration distance on a site-specific basis. To serve this purpose, we present an analytical model (AAMLPH) as an alternative to estimate lateral VI screening distances at chlorinated compound-contaminated sites. Based on a previously introduced model (AAML), AAMLPH is developed by considering the effects of impervious surface cover and soil geology heterogeneities, providing predictions consistent with the three-dimensional (3-D) numerical simulated results. By employing risk-based and contribution-based screening levels of subslab concentrations (50 and 500 µg/m3, respectively) and source-to-subslab attenuation factor (0.001 and 0.01, respectively), AAMLPH suggests that buildings greater than 30 m from a plume “boundary” can still be affected by VI in the presence of any two of the three factors, which are high source vapor concentration, shallow source and significant surface cover. This finding justifies the concern that EPA has expressed about the application of the 30 m lateral separation distance in the presence of physical barriers (e.g., asphalt covers or ice) at the ground surface.
PMCID: PMC4777972  PMID: 26057584
Vapor intrusion; lateral inclusion zone; analytical approach; surface cover; layering
5.  Genome-wide Association Mapping of Cold Tolerance Genes at the Seedling Stage in Rice 
Rice  2016;9:61.
Rice is a temperature-sensitive crop and its production is severely affected by low temperature in temperate and sub-tropical regions. To understand the genetic basis of cold tolerance in rice, we evaluated the cold tolerance at the seedling stage (CTS) of 295 rice cultivars in the rice diversity panel 1 (RDP1), these cultivars were collected from 82 countries.
The evaluations revealed that both temperate and tropical japonica rice cultivars are more tolerant to cold stress than indica and AUS cultivars. Using the cold tolerance phenotypes and 44 K SNP chip dataset of RDP1, we performed genome-wide association mapping of quantitative trait loci (QTLs) for CTS. The analysis identified 67 QTLs for CTS that are located on 11 chromosomes. Fifty-six of these QTLs are located in regions without known cold tolerance-related QTLs.
Our study has provided new information on the genetic architecture of rice cold tolerance and has also identified highly cold tolerant cultivars and CTS-associated SNP markers that will be useful rice improvement.
Electronic supplementary material
The online version of this article (doi:10.1186/s12284-016-0133-2) contains supplementary material, which is available to authorized users.
PMCID: PMC5110459  PMID: 27848161
Oryza sativa; Cold tolerance; Quantitative trait locus (QTL); GWAS
7.  Web-based Real-Time Case Finding for the Population Health Management of Patients With Diabetes Mellitus: A Prospective Validation of the Natural Language Processing–Based Algorithm With Statewide Electronic Medical Records 
JMIR Medical Informatics  2016;4(4):e37.
Diabetes case finding based on structured medical records does not fully identify diabetic patients whose medical histories related to diabetes are available in the form of free text. Manual chart reviews have been used but involve high labor costs and long latency.
This study developed and tested a Web-based diabetes case finding algorithm using both structured and unstructured electronic medical records (EMRs).
This study was based on the health information exchange (HIE) EMR database that covers almost all health facilities in the state of Maine, United States. Using narrative clinical notes, a Web-based natural language processing (NLP) case finding algorithm was retrospectively (July 1, 2012, to June 30, 2013) developed with a random subset of HIE-associated facilities, which was then blind tested with the remaining facilities. The NLP-based algorithm was subsequently integrated into the HIE database and validated prospectively (July 1, 2013, to June 30, 2014).
Of the 935,891 patients in the prospective cohort, 64,168 diabetes cases were identified using diagnosis codes alone. Our NLP-based case finding algorithm prospectively found an additional 5756 uncodified cases (5756/64,168, 8.97% increase) with a positive predictive value of .90. Of the 21,720 diabetic patients identified by both methods, 6616 patients (6616/21,720, 30.46%) were identified by the NLP-based algorithm before a diabetes diagnosis was noted in the structured EMR (mean time difference = 48 days).
The online NLP algorithm was effective in identifying uncodified diabetes cases in real time, leading to a significant improvement in diabetes case finding. The successful integration of the NLP-based case finding algorithm into the Maine HIE database indicates a strong potential for application of this novel method to achieve a more complete ascertainment of diagnoses of diabetes mellitus.
PMCID: PMC5124114  PMID: 27836816
electronic medical record; natural language processing; diabetes mellitus; data mining
8.  Long non-coding RNA GAS5 controls human embryonic stem cell self-renewal by maintaining NODAL signalling 
Nature Communications  2016;7:13287.
Long non-coding RNAs (lncRNAs) are known players in the regulatory circuitry of the self-renewal in human embryonic stem cells (hESCs). However, most hESC-specific lncRNAs remain uncharacterized. Here we demonstrate that growth-arrest-specific transcript 5 (GAS5), a known tumour suppressor and growth arrest-related lncRNA, is highly expressed and directly regulated by pluripotency factors OCT4 and SOX2 in hESCs. Phenotypic analysis shows that GAS5 knockdown significantly impairs hESC self-renewal, but its overexpression significantly promotes hESC self-renewal. Using RNA sequencing and functional analysis, we demonstrate that GAS5 maintains NODAL signalling by protecting NODAL expression from miRNA-mediated degradation. Therefore, we propose that the above pluripotency factors, GAS5 and NODAL form a feed-forward signalling loop that maintains hESC self-renewal. As this regulatory function of GAS5 is stem cell specific, our findings also indicate that the functions of lncRNAs may vary in different cell types due to competing endogenous mechanisms.
Long non-coding RNAs (lncRNA) are known to regulate human embryonic stem cell (hESC) self-renewal. Here, the authors identify lncRNA growth-arrest-specific transcript 5 (GAS5) that regulates pluripotency via modulation of NODAL signalling to maintain self-renewal in hESCs.
PMCID: PMC5097163  PMID: 27811843
10.  Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo 
Cancer Biology & Therapy  2015;16(12):1784-1793.
MK-1775 is the first-in-class selective Wee1 inhibitor which has been demonstrated to synergize with CHK1 inhibitors in various malignancies. In this study, we report that the pan-histone deacetylase inhibitor (HDACI) panobinostat synergizes with MK-1775 in acute myeloid leukemia (AML), a malignancy which remains a clinical challenge and requires more effective therapies. Using both AML cell line models and primary patient samples, we demonstrated that panobinostat and MK-1775 synergistically induced proliferation arrest and cell death. We also demonstrated that panobinostat had equal anti-leukemic activities against primary AML blasts derived from patients either at initial diagnosis or at relapse. Interestingly, treatment with panobinostat alone or in combination with MK-1775 resulted in decreased Wee1 protein levels as well as downregulation of the CHK1 pathway. shRNA knockdown of CHK1 significantly sensitized AML cells to MK-1775 treatment, while knockdown of Wee1 significantly enhanced both MK-1775- and panobinostat-induced cell death. Our results demonstrate that panobinostat synergizes with MK-1775 in AML cells, at least in part through downregulation of CHK1 and/or Wee1, providing compelling evidence for the clinical development of the combination treatment in AML.
PMCID: PMC4847803  PMID: 26529495
Acute myeloid leukemia; CHK1; MK-1775; Panobinostat; Wee1
11.  Hippocampal Wnt3a is Necessary and Sufficient for Contextual Fear Memory Acquisition and Consolidation 
Cerebral Cortex (New York, NY)  2014;25(11):4062-4075.
The Wnt signaling pathway plays critical roles in development. However, to date, the role of Wnts in learning and memory in adults is still not well understood. Here, we aimed to investigate the roles and mechanisms of Wnts in hippocampal-dependent contextual fear conditioning (CFC) memory formation in adult mice. CFC training induced the secretion and expression of Wnt3a and the activation of its downstream Wnt/Ca2+ and Wnt/β-catenin signaling pathways in the dorsal hippocampus (DH). Intrahippocampal infusion of Wnt3a antibody impaired CFC acquisition and consolidation, but not expression. Using the Wnt antagonist sFRP1 or the canonical Wnt inhibitor Dkk1, we found that Wnt/Ca2+ and Wnt/β-catenin signaling pathways were involved in acquisition and consolidation, respectively. Moreover, we found Wnt3a signaling is not only necessary but also sufficient for CFC memory. Intrahippocampal infusion of exogenous Wnt3a could enhance acquisition and consolidation of CFC. Overexpression of constitutively active β-catenin in the DH could rescue the deficit in CFC memory consolidation, but not acquisition induced by Wnt3a antibody injection, which suggests β-catenin signaling pathway acts downstream of Wnt3a to mediate CFC memory consolidation. Our study may help further the understanding of the precise regulation of Wnt3a in differential memory phases depending on divergent signaling pathways.
PMCID: PMC4626827  PMID: 24904070
acquisition; consolidation; dorsal hippocampus; memory; Wnt3a
12.  Preventive effects of β-cryptoxanthin against cadmium-induced oxidative stress in the rat testis 
Asian Journal of Andrology  2016;18(6):920-924.
β-cryptoxanthin (CRY), a major carotenoid of potential interest for health, is obtained naturally from orange vegetables and fruits. A few research studies have reported that CRY could decrease oxidative stress and germ cell apoptosis. The purpose of this study was to examine the effects of CRY on acute cadmium chloride (CdCl2)-induced oxidative damage in rat testes. For this study, 24 rats were divided into four groups, one of which serves as a control group that received intraperitoneal (i.p.) injections of corn oil and physiological saline. The other rats were i.p. injected with CRY (10 μg kg−1) every 8 h, beginning 8 h before CdCl2 (2.0 mg kg−1) treatment. The pathological and TUNEL findings revealed that CRY ameliorated the Cd-induced testicular histological changes and germ cell apoptosis in the rats. Furthermore, the Cd-induced decrease in the testicular testosterone (T) level was attenuated after CRY administration (P < 0.05). The administration of CRY significantly reversed the Cd-induced increases in the lipid peroxide (LPO) and malondialdehyde (MDA) levels (P < 0.01). The testicular antioxidants superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) were decreased by treatment with Cd alone but were restored by CRY co-treatment. These results demonstrated that the application of CRY can enhance the tolerance of rats to Cd-induced oxidative damage and suggest that it has promised as a pharmacological agent to protect against Cd-induced testicular toxicity.
PMCID: PMC5109889  PMID: 27101804
apoptosis; cadmium chloride; cryptoxanthin; oxidative stress; rat; testicular damage; testosterone
13.  Application of RNAi-induced gene expression profiles for prognostic prediction in breast cancer 
Genome Medicine  2016;8:114.
Homologous recombination (HR) is the primary pathway for repairing double-strand DNA breaks implicating in the development of cancer. RNAi-based knockdowns of BRCA1 and RAD51 in this pathway have been performed to investigate the resulting transcriptomic profiles. Here we propose a computational framework to utilize these profiles to calculate a score, named RNA-Interference derived Proliferation Score (RIPS), which reflects cell proliferation ability in individual breast tumors. RIPS is predictive of breast cancer classes, prognosis, genome instability, and neoadjuvant chemosensitivity. This framework directly translates the readout of knockdown experiments into potential clinical applications and generates a robust biomarker in breast cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-016-0363-3) contains supplementary material, which is available to authorized users.
PMCID: PMC5084341  PMID: 27788678
Homologous recombination pathway; Gene knockdown profiles; Cell proliferation; Cancer prognosis; Neoadjuvant chemotherapy; Genomic instability
14.  Responses of the summer Asian-Pacific zonal thermal contrast and the associated evolution of atmospheric circulation to transient orbital changes during the Holocene 
Scientific Reports  2016;6:35816.
This study investigates the response of large-scale atmospheric circulation over the Asian-Pacific sector and precipitation over eastern China to transient orbital changes during the Holocene summer using an intermediate-complexity climate model. Corresponding to variations in the incoming solar radiation, the eddy sea level pressure (SLP) exhibited an out-of-phase relationship between the North Pacific and the Eurasian landmass that was similar to the present-day Asia-Pacific Oscillation (APO) pattern and was defined as the paleo-APO. Its index presented an increasing trend, which implies the enhancement of a zonal thermal contrast between Asia and the North Pacific. Associated with the strengthening of the paleo-APO was the westward shift in North Pacific high pressure. Accordingly, there was less/more summer precipitation over both the middle reach of the Yangtze River and Southwest China/over North China. The high-resolution stalagmite δ18O records further support this decrease in the model precipitation. Along with the strengthening of paleo-APO from the early Holocene to the present, the eddy SLP anomalies exhibited a decreasing/increasing trend over the Eurasian landmass/the North Pacific, with a phase change of approximately 4.5 ka BP, and they both moved westward. Meanwhile, a less rainfall belt over eastern China exhibited northward propagation from southern China.
PMCID: PMC5078810  PMID: 27779217
15.  rLj-RGD3, a Novel Recombinant Toxin Protein from Lampetra japonica, Protects against Cerebral Reperfusion Injury Following Middle Cerebral Artery Occlusion Involving the Integrin-PI3K/Akt Pathway in Rats 
PLoS ONE  2016;11(10):e0165093.
The RGD-toxin protein Lj-RGD3 is a naturally occurring 118 amino acid peptide that can be obtained from the salivary gland of the Lampetra japonica fish. This unique peptide contains 3 RGD (Arg-Gly-Asp) motifs in its primary structure. Lj-RGD3 is available in recombinant form (rLj-RGD3) and can be produced in large quantities using DNA recombination techniques. The pharmacology of the three RGD motif-containing peptides has not been studied. This study investigated the protective effects of rLj-RGD3, a novel polypeptide, against ischemia/reperfusion-induced damage to the brain caused by middle cerebral artery occlusion (MCAO) in a rat stroke model. We also explored the mechanism by which rLj-RGD3 acts by measuring protein and mRNA expression levels, with an emphasis on the FAK and integrin-PI3K/Akt anti-apoptosis pathways.
rLj-RGD3 was obtained from the buccal secretions of Lampetra japonica using gene recombination technology. Sprague Dawley (SD) rats were randomly divided into the following seven groups: a sham group; a vehicle-treated (VT) group; 100.0 μg·kg-1, 50.0 μg·kg-1 and 25.0 μg·kg-1 dose rLj-RGD3 groups; and two positive controls, including 1.5 mg·kg-1 Edaravone (ED) and 100.0 μg·kg-1 Eptifibatide (EP). MCAO was induced using a model consisting of 2 h of ischemia and 24 h of reperfusion. Behavioral changes were observed in the normal and operation groups after focal cerebral ischemia/reperfusion was applied. In addition, behavioral scores were evaluated at 4 and 24 h after reperfusion. Brain infarct volumes were determined based on 2,3,5-triphenyltetrazolium chloride (TTC) staining. Pathological changes in brain tissues were observed using hematoxylin and eosin (H&E) staining. Moreover, neuronal apoptosis was detected using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assays. We determined the expression levels of focal adhesion kinase (FAK), phosphatidyl inositol 3-kinase (PI3K), protein kinase B (Akt, PKB), caspase-3 and Bcl-2 in the brain using western blot analysis and RT-PCR assays. The research protocol was approved by the Institutional Ethics Committee of Dalian Medical University.
The behavioral scores and cerebral infarct volumes of the rLj-RGD3 groups were markedly lower at 4 and 24 h/RF. The rLj-RGD3 protein significantly ameliorated pathological changes in the brain and reduced the number of apoptotic neurons. Furthermore, the FAK and PI3K/Akt pathways were activated. rLj-RGD3 significantly increased the expression of FAK, p-FAK and Bcl-2 proteins. In contrast, caspase-3 expression was inhibited.
We conclude that recombinant Lampetra japonica RGD-peptide (rLj-RGD3) exerts a protective effect against cerebral ischemia/reperfusion injury in the brain. In addition, the mechanism of this protection is associated with the activation of the integrin-PI3K/Akt pathway. These results provide a theoretical foundation and an experimental basis for using RGD peptides as novel drugs for treating ischemic cerebral vascular diseases in addition to promoting the research and development of marine biotechnology drugs.
PMCID: PMC5074578  PMID: 27768719
16.  The astrocytic transporter SLC7A10 (Asc-1) mediates glycinergic inhibition of spinal cord motor neurons 
Scientific Reports  2016;6:35592.
SLC7A10 (Asc-1) is a sodium-independent amino acid transporter known to facilitate transport of a number of amino acids including glycine, L-serine, L-alanine, and L-cysteine, as well as their D-enantiomers. It has been described as a neuronal transporter with a primary role related to modulation of excitatory glutamatergic neurotransmission. We find that SLC7A10 is substantially enriched in a subset of astrocytes of the caudal brain and spinal cord in a distribution corresponding with high densities of glycinergic inhibitory synapses. Accordingly, we find that spinal cord glycine levels are significantly reduced in Slc7a10-null mice and spontaneous glycinergic postsynaptic currents in motor neurons show substantially diminished amplitudes, demonstrating an essential role for SLC7A10 in glycinergic inhibitory function in the central nervous system. These observations establish the etiology of sustained myoclonus (sudden involuntary muscle movements) and early postnatal lethality characteristic of Slc7a10-null mice, and implicate SLC7A10 as a candidate gene and auto-antibody target in human hyperekplexia and stiff person syndrome, respectively.
PMCID: PMC5069678  PMID: 27759100
17.  Design and Synthesis of Novel Bivalent Ligands (MOR and DOR) by Conjugation of Enkephalin Analogues with 4-Anilidopiperidine Derivatives 
We describe the design and synthesis of novel bivalent ligands based on the conjugation of 4-anilidopiperidine derivatives with enkephalin analogues. The design of non-peptide analogues is explored with 5-amino substituted tetrahydronaphthalen-2yl)methyl containing 4-anilidopiperidine derivatives, while non-peptide-peptide ligands are explored by conjugating the C-terminus of enkephalin analogues (H-Xxx-DAla-Gly-Phe-OH) to the amino group of 4-anilidopiperidine small molecule derivatives with and without a linker. These novel bivalent ligands are evaluated for biological activities at μ and δ opioid receptors. They exhibit very good affinities at μ and δ opioid receptors, and potent agonist activities in MVD and GPI assays. Among these the lead bivalent ligand 17 showed excellent binding affinities (0.1 nM and 0.5 nM) at μ and δ opioid receptors respectively, and was found to have very potent agonist activities in MVD (56 +/- 5.9 nM) and GPI (4.6 +/− 1.9 nM) assays. In vivo the lead bivalent ligand 17 exhibited a short duration of action (< 15 min) comparable to 4-anilidopiperidine derivatives, and moderate analgesic activity. The ligand 17 has limited application against acute pain but may have utility in settings where a highly reversible analgesic is required.
Graphical abstract
PMCID: PMC4642889  PMID: 26323872
Opioids; Opioid receptors; bivalent ligands; enkephalins
18.  Nosocomial outbreak of KPC-2- and NDM-1-producing Klebsiella pneumoniae in a neonatal ward: a retrospective study 
BMC Infectious Diseases  2016;16:563.
The spread of resistance to carbapenems among Enterobacteriaceae has become a major public health problem in recent years. In this study, we describe an outbreak of Klebsiella pneumoniae in the neonatal ward. First, we aimed to study the drug resistance, genetic relatedness, and transmission mechanism of carbapenem-resistant K. pneumoniae; second, we implemented infection control measures to contain the outbreak.
We investigated 27 non-repetitive strains isolated from neonates and five strains cultured from around the neonatal ward. Polymerase chain reaction (PCR), the agar dilution method, and multilocus sequence typing (MLST) were used to analyze the resistance gene(s), antimicrobial susceptibility, and homology, respectively. Health-care personnel education, hand hygiene, outer gown changing, and infected patient isolation were strictly enforced.
Our antimicrobial susceptibility results show that all strains were multidrug-resistant. MLST and PCR results revealed that, in this study, all of the KPC-2-producing strains are Sequence Type (ST) 11 (ST11) (n = 22) and all of the NDM-1-producing strains are ST20 (n = 4) or ST888 (n = 1). The environmental strains were identified as KPC-2-positive K. pneumoniae ST11 (n = 3) and NDM-1-positive K. pneumoniae ST20 (n = 2). The percentages of isolates with the extended-spectrum-β-lactamases CTX-M-15, blaCTX-M-14, blaTEM-1 were 9.4, 84.3, and 68.8 %, respectively. AmpC β-lactamase genes were not detected in our isolates.
KPC-2-positive K. pneumoniae ST11 and NDM-1-positive K. pneumoniae ST20 were associated with this outbreak. The identification of these isolates in samples from radiant warmers and nurses suggests that hospital cross-transmission played a role in this outbreak. Active infection control measures were effective for controlling this multidrug-resistant K. pneumoniae outbreak.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-016-1870-y) contains supplementary material, which is available to authorized users.
PMCID: PMC5062924  PMID: 27733128
Multidrug-Resistant; Klebsiella pneumoniae; KPC-2; NDM-1; Nosocomial Infection; Neonate
20.  The Growth of SGC-7901 Tumor Xenografts Was Suppressed by Chinese Bayberry Anthocyanin Extract through Upregulating KLF6 Gene Expression 
Nutrients  2016;8(10):599.
To investigate the antitumor effect of anthocyanins extracted from Chinese bayberry fruit (Myrica rubra Sieb. et Zucc.), a nude mouse tumor xenograft model was established. Treatments with C3G (cyanidin-3-glucoside, an anthocyanin) significantly suppressed the growth of SGC-7901 tumor xenografts in a dose-dependent manner. Immunohistochemical staining showed a significant increase in p21 expression, indicating that the cell cycle of tumor xenografts was inhibited. qPCR screening showed that C3G treatment up-regulated the expression of the KLF6 gene, which is an important tumor suppressor gene inactivated in many human cancers. Western blot showed that C3G treatments markedly increased KLF6 and p21 protein levels, inhibited CDK4 and Cyclin D1 expression, but did not notably change the expression of p53. These results indicated that KLF6 up-regulates p21 in a p53-independent manner and significantly reduces tumor proliferation. This study provides important information for the possible mechanism of C3G-induced antitumor activity against gastric adenocarcinoma in vivo.
PMCID: PMC5083987  PMID: 27690088
Chinese bayberry; anthocyanin; SGC-7901 cell; tumor xenograft; KLF6 gene
21.  Prostaglandin I2 upregulates the expression of anterior pharynx‐defective‐1α and anterior pharynx‐defective‐1β in amyloid precursor protein/presenilin 1 transgenic mice 
Aging Cell  2016;15(5):861-871.
Cyclooxygenase‐2 (COX‐2) has been recently identified to be involved in the pathogenesis of Alzheimer's disease (AD). Yet, the role of an important COX‐2 metabolic product, prostaglandin (PG) I2, in the pathogenesis of AD remains unknown. Using human‐ and mouse‐derived neuronal cells as well as amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice as model systems, we elucidated the mechanism of anterior pharynx‐defective (APH)‐1α and pharynx‐defective‐1β induction. In particular, we found that PGI 2 production increased during the course of AD development. Then, PGI 2 accumulation in neuronal cells activates PKA/CREB and JNK/c‐Jun signaling pathways by phosphorylation, which results in APH‐1α/1β expression. As PGI 2 is an important metabolic by‐product of COX‐2, its suppression by NS398 treatment decreases the expression of APH‐1α/1β in neuronal cells and APP/PS1 mice. More importantly, β‐amyloid protein (Aβ) oligomers in the cerebrospinal fluid (CSF) of APP/PS1 mice are critical for stimulating the expression of APH‐1α/1β, which was blocked by NS398 incubation. Finally, the induction of APH‐1α/1β was confirmed in the brains of patients with AD. Thus, these findings not only provide novel insights into the mechanism of PGI 2‐induced AD progression but also are instrumental for improving clinical therapies to combat AD.
PMCID: PMC5013024  PMID: 27240539
β‐amyloid protein; anterior pharynx‐defective‐1α/1β; APP/PS1; cyclooxygenase‐2; prostaglandin I2
22.  Protective Effects of Gallic Acid Against NiSO4-Induced Toxicity Through Down-Regulation of the Ras/ERK Signaling Pathway in Beas-2B Cells 
This study aimed to explore the preventive effects of gallic acid (GA) on the toxicity induced by NiSO4 in Beas-2B cells.
Beas-2B cell viability was measured by MTT assay. The degree of oxidative stress was detected by measuring the levels of reactive oxygen species (ROS) and lipid peroxide (LPO). The rate of apoptosis was measured by flow cytometry. Ras/ERK-related protein levels were analyzed by Western blot analysis, which including Ras, ERK, c-Myc, PARP, and PARP cleavage.
MTT assay showed that NiSO4 induced cytotoxicity, while GA had a protective role against toxicity. Additionally, GA could reduce the apoptotic cell number and the level of ROS in Beas-2B cells induced by NiSO4. Western blot analysis demonstrated that NiSO4 could up-regulate the related protein in the Ras/ERK signaling pathway. Furthermore, we observed that GA could alleviate the toxicity of NiSO4 through regulating protein changes in the Ras/ERK signaling pathway.
Preventive effects of GA on NiSO4-induced cytotoxicity in Beas-2B cells may be through the Ras/ERK signaling pathways.
PMCID: PMC5042120  PMID: 27676106
Gallic Acid; Nickel; Preventive Medicine
23.  Cyclooxygenase-2 is associated with malignant phenotypes in human lung cancer 
Oncology Letters  2016;12(5):3836-3844.
The objective of the present study was to investigate whether cyclooxygenase-2 (COX-2) is associated with malignancy, and to investigate its molecular mechanisms in human lung cancer tumor malignancy. The present study used RNA interference (RNAi) methodology and celecoxib, a COX-2 inhibitor, to investigate the effect of COX-2 knockdown on the proliferation and invasion abilities of lung cancer cells and the molecular mechanisms involved. Human lung adenocarcinoma A549-si10 and LTEP-A2 cells transfected with a specific small interfering RNA (A549-si10 and LTEP-A2-si10, respectively) grew more slowly compared with parental cell lines and cells transfected with pU6. The colony formation of A549-si10 and LTEP-A2-si10 cells was also reduced. In addition, A549-si10 and LTEP-A2-si10 cells were characterized by decreased metastatic and invasive abilities. The proliferation and invasive potential of parental A549 and LTEP-A2 cells was inhibited following treatment with celecoxib. In vivo, a COX-2 knockdown resulted in a decrease of proliferation and reduction of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2) and endothelial growth factor receptor (EGFR) expression in A549 xenografts. In conclusion, the present study revealed that COX-2 plays a extremely important role in tumor growth, infiltration and metastasis via the regulation of VEGF, MMP-2 and EGRF expression. Therefore, COX-2 is a potential therapeutic target for lung cancer.
PMCID: PMC5104181  PMID: 27895738
COX-2; lung cancer; malignant phenotype; celecoxib
24.  Alternative Splice Variants Modulates Dominant-Negative Function of Helios in T-Cell Leukemia 
PLoS ONE  2016;11(9):e0163328.
The molecular defects which lead to multistep incidences of human T-cell leukemia have yet to be identified. The DNA-binding protein Helios (known as IKZF2), a member of the Ikaros family of Krüppel-like zinc-finger proteins, functions pivotally in T-cell differentiation and activation. In this study, we identify three novel short Helios splice variants which are T-cell leukemic specific, and demonstrate their dominant-negative function. We then test the cellular localization of distinct Helios isoforms, as well as their capability to form heterodimer with Ikaros, and the association with complexes comprising histone deacetylase (HDAC). In addition, the ectopic expression of T-cell leukemic Helios isoforms interferes with T-cell proliferation and apoptosis. The gene expression profiling and pathway analysis indicated the enrichment of signaling pathways essential for gene expression, translation, cell cycle checkpoint, and response to DNA damage stimulus. These data indicate the molecular function of Helios to be involved in the leukemogenesis and phenotype of T-cell leukemia, and also reveal Helios deregulation as a novel marker for T-cell leukemia.
PMCID: PMC5040427  PMID: 27681508
25.  Web-Based Evaluation System to Measure Learning Effectiveness in Kampo Medicine 
Measuring the learning effectiveness of Kampo Medicine (KM) education is challenging. The aim of this study was to develop a web-based test to measure the learning effectiveness of KM education among medical students (MSs). We used an open-source Moodle platform to test 30 multiple-choice questions classified into 8-type fields (eight basic concepts of KM) including “qi-blood-fluid” and “five-element” theories, on 117 fourth-year MSs. The mean (±standard deviation [SD]) score on the web-based test was 30.2 ± 11.9 (/100). The correct answer rate ranged from 17% to 36%. A pattern-based portfolio enabled these rates to be individualized in terms of KM proficiency. MSs with scores higher (n = 19) or lower (n = 14) than mean ± 1SD were defined as high or low achievers, respectively. Cluster analysis using the correct answer rates for the 8-type field questions revealed clear divisions between high and low achievers. Interestingly, each high achiever had a different proficiency pattern. In contrast, three major clusters were evident among low achievers, all of whom responded with a low percentage of or no correct answers. In addition, a combination of three questions accurately classified high and low achievers. These findings suggest that our web-based test allows individual quantitative assessment of the learning effectiveness of KM education among MSs.
PMCID: PMC5055925  PMID: 27738440

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