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1.  3-Ketone-4,6-diene ceramide analogs exclusively induce apoptosis in chemo-resistant cancer cells 
Bioorganic & medicinal chemistry  2014;22(4):1412-1420.
Multidrug-resistance is a major cause of cancer chemotherapy failure in clinical treatment. Evidence shows that multidrug-resistant cancer cells are as sensitive as corresponding regular cancer cells under the exposure to anticancer ceramide analogs. In this work we designed five new ceramide analogs with different backbones, in order to test the hypothesis that extending the conjugated system in ceramide analogs would lead to an increase of their anticancer activity and selectivity towards resistant cancer cells. The analogs with the 3-ketone-4,6-diene backbone show the highest apoptosis-inducing efficacy. The most potent compound, analog 406, possesses higher pro-apoptotic activity in chemo-resistant cell lines MCF-7TN-R and NCI/ADR-RES than the corresponding chemo-sensitive cell lines MCF-7 and OVCAR-8, respectively. However, this compound shows the same potency in inhibiting the growth of another pair of chemo-sensitive and chemo-resistant cancer cells, MCF-7 and MCF-7/Dox. Mechanism investigations indicate that analog 406 can induce apoptosis in chemo-resistant cancer cells through the mitochondrial pathway. Cellular glucosylceramide synthase assay shows that analog 406 does not interrupt glucosylcer-amide synthase in chemo-resistant cancer cell NCI/ADR-RES. These findings suggest that due to certain intrinsic properties, ceramide analogs’ pro-apoptotic activity is not disrupted by the normal drug-resistance mechanisms, leading to their potential use for overcoming cancer multidrug-resistance.
doi:10.1016/j.bmc.2013.12.065
PMCID: PMC3967587  PMID: 24457089
Ceramide; Glucosylceramide synthase (GCS); P-glycoprotein; Multidrug resistance; Anti-cancer drugs
2.  TARGETED THERAPY OF SPINAL CORD GLIOMA WITH A GENETICALLY-MODIFIED SALMONELLA TYPHIMURIUM 
Cell proliferation  2009;43(1):41-48.
Objective
Spinal cord tumors are highly malignant and often lead to paralysis and death mainly due to their infiltrative nature, high recurrence rate, and limited treatment options. In this study, we measured the antitumor efficacy of the Salmonella typhimurium A1-R tumor-targeting strain, administered systemically or intrathecally, to spinal cord cancer in orthotopic mouse models.
Materials and Methods
Tumor fragments of U87-RFP were implanted by surgical orthotopic implantation into the dorsal site of the spinal cord. Five and ten days after transplantation, 8 mice in each group were treated with A1-R (2 × 107 cfu / 200μl i.v. injection or 2 × 106 cfu / 10μl intrathecal injection).
Results
The untreated mice showed progressive paralysis beginning at 6 days after tumor transplantation and developed complete paralysis between 18 to 25 days. The mice treated i.v. with A1-R had an onset of paralysis at approximately 11 days and at day-30, 5 mice developed complete paralysis, while other 3 mice had partial paralysis. Mice treated via intrathecal injection of A1-R had an onset of paralysis at approximately 18 days and one mouse was still not paralyzed at day-30. Only one mouse developed complete paralysis at day 30 in this group. The intrathecally-treated animals had a significant increase in survival over the i.v.-treated group as well as the control group.
Conclusions
These results suggest that S. typhimurium A1-R monotherapy can effectively treat spinal cord glioma.
doi:10.1111/j.1365-2184.2009.00652.x
PMCID: PMC4299869  PMID: 19922490
Salmonella typhimurium A1-R; auxotroph; GFP; RFP; spinal cord tumor; targeted therapy imaging
3.  Successful management of acute myeloid leukemia transformed from chronic myelomonocytic leukemia in the elderly by a combination regimen of decitabine and cytarabine, aclarubicin and granulocyte colony-stimulating factor: A case report 
Oncology Letters  2015;9(3):1217-1220.
Despite advances in the treatment of acute myeloid leukemia (AML) in recent years, the outcome of elderly AML patients with antecedent hematological disorders remains unsatisfactory. The present study describes a case of complete remission in an elderly patient with AML transformed from chronic myelomonocytic leukemia (CMML) and the treatment of the case with decitabine in combination with cytarabine, aclarubicin and granulocyte colony-stimulating factor (CAG). A 70-year-old male was admitted with fever, pruritus and weakness that had been apparent for two weeks, and a two-year history of monocytosis (22.5–27.0%). Further examinations revealed a hemoglobin level of 106 g/l, a white blood cell count of 39.52×109/l, a platelet count of 81×109/l, Y chromosome loss and uniparental disomy on chromosomes 4q, 2q and 19p. The patient was diagnosed with AML transformed from CMML, with cytogenetic anomalies. A combination regimen of decitabine and CAG was administered. Subsequent to one cycle, the patient achieved complete remission. The patient was then followed up with three courses of the same regimen and achieved clinical remission, with no evidence of AML relapse. The present study suggests that a combination of low-dose decitabine and CAG may offer a novel and potentially effective treatment regimen for elderly AML patients.
doi:10.3892/ol.2015.2870
PMCID: PMC4315126  PMID: 25663885
acute myeloid leukemia; chronic myeloid leukemia; decitabine; cytarabine; aclarubicin and granulocyte colony-stimulating factor; single nucleotide polymorphism
4.  Validation and implementation of a liquid chromatography/tandem mass spectrometry assay to quantitate ON 01910.Na, a mitotic progression modulator, in human plasma 
A reverse-phase high performance liquid chromatographic method with tandem mass spectrometry (LC-MS/MS) was developed and validated for the quantitation of ON 01910.Na, a novel synthetic benzyl styryl sulfone, in human plasma. The assay involved a simple sample preparation with acetonitrile protein precipitation. ON 01910.Na and the internal standard temazepam were separated on a Waters X-Terra™ MS C18 column with mobile phase of acetonitrile containing 0.1% formic acid /10 mM ammonium acetate (55:45, v/v) using isocratic flow at 0.2 mL/min for 5 minutes. The analytes were monitored by tandem-mass spectrometry with electrospray positive ionization. Two calibration curves were generated over the range of 10–2000 ng/mL and 100–20000 ng/mL. The lower limit of quantitation (LLOQ) was 10 ng/mL for ON 01910.Na in human plasma. The accuracy and within- and between-day precisions were within the acceptance criteria for bioanalytical assays. ON 01910.Na was found stable in plasma at −70°C for at least 1 year. The method was successfully applied to characterize the plasma concentration-time profiles of ON 01910.Na in the cancer patients in the phase I study.
doi:10.1016/j.jchromb.2007.05.047
PMCID: PMC4286291  PMID: 17588831
ON 01910.Na; high performance liquid chromatography (HPLC); mass spectrometry (MS); LC-MS/MS; pharmacokinetics
5.  MiR-125a-3p Regulates Glioma Apoptosis and Invasion by Regulating Nrg1 
PLoS ONE  2015;10(1):e0116759.
The current study was designed to examine the functional role and mechanism of miR-125a-3p in glioma development. Quantitative RT-PCR was used to evaluate miR-125a-3p expression in 60 glioma cases of different malignant grades. Then, the clinic pathologic significance of miR-125a-3p expression was determined in combination with the prognosis of the patients. In addition, the effects and mechanisms of miR-125a-3p on the proliferation, apoptosis and invasion of glioma cells were further investigated. The results showed that the expression of miR-125a-3p was decreased significantly in most malignant glioma samples relative to normal brain tissues and glioma tissues of low-malignant degree. Further kaplan-meier survival analysis showed that the lower expression of miR-125a-3p was associated with a poor prognosis of GBM patients. Functional analysis showed that the reintroduction of miR-125a-3p into glioblastoma cell lines induces markedly the apoptosis and suppresses the proliferation and migration of glioblastoma cells in vitro and in vivo. Luciferase assay and Western blot analysis revealed that Nrg1 is a direct target of miR-125a-3p. Furthermore, an increased expression of Nrg1 could reverse the effects of overexpression of miR-125a-3p on the proliferation, apoptosis and migration of glioblastoma cells. These findings suggest that miR-125a-3p performed an important role in glioma development mediated by directly regulating the expression of Nrg1. This study also provides a potential target for diagnosis and treatment of malignant glioma.
doi:10.1371/journal.pone.0116759
PMCID: PMC4283963  PMID: 25560389
6.  Genepleio Software for Effective Estimation of Gene Pleiotropy from Protein Sequences 
BioMed Research International  2015;2015:269150.
Though pleiotropy, which refers to the phenomenon of a gene affecting multiple traits, has long played a central role in genetics, development, and evolution, estimation of the number of pleiotropy components remains a hard mission to accomplish. In this paper, we report a newly developed software package, Genepleio, to estimate the effective gene pleiotropy from phylogenetic analysis of protein sequences. Since this estimate can be interpreted as the minimum pleiotropy of a gene, it is used to play a role of reference for many empirical pleiotropy measures. This work would facilitate our understanding of how gene pleiotropy affects the pattern of genotype-phenotype map and the consequence of organismal evolution.
doi:10.1155/2015/269150
PMCID: PMC4299487  PMID: 25629041
7.  Bioanalytical method for evaluating the pharmacokinetics of the GCP-II inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) 
2-Phosphonomethyl pentanedioic acid (2-PMPA) is a potent and selective inhibitor of glutamate carboxypeptidase-II, an enzyme which catabolizes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to N-acetylaspartate (NAA) and glutamate. 2-PMPA demonstrates robust efficacy in numerous animal models of neurological disease, however its pharmacokinetics has not yet been fully described. 2-PMPA is a highly polar compound with multiple negative charges causing significant challenges for analysis in biological matrices. Here we report a derivatization method for the acidic groups that involved protein precipitation with acetonitrile followed by reaction with N-tert-butyldimethysilyl-N-methyltrifluoroacetamide (MTBSTFA). The silylated analyte with transitions (683→551.4) and the internal standard (669→537.2) were monitored by tandem mass spectrometry with electrospray positive ionization mode. The method was subsequently used to evaluate 2-PMPA pharmacokinetics in rats. Intraperitoneal administration of 100 mg/kg 2-PMPA resulted in maximum concentration in plasma of 275 μg/mL at 0.25 h. The half-life, area under the curve, apparent clearance, and volume of distribution were 0.64 h, 210 μg×h/mL, 7.93 mL/min/kg, and 0.44 L/kg, respectively. The tissue/plasma ratios in brain, sciatic nerve and dorsal root ganglion were 0.018, 0.120 and 0.142 respectively. In summary, a sensitive analytical method for 2-PMPA is reported that can be employed for similarly charged molecules.
doi:10.1016/j.jpba.2013.08.028
PMCID: PMC3891469  PMID: 24055700
2-PMPA; glutamate carboxypeptidase-II; derivatization; pharmacokinetics; brain/plasma ratio
8.  A bis-Benzylidine Piperidone Targeting Proteasome Ubiquitin Receptor RPN13/ADRM1 as a therapy for cancer 
Cancer cell  2013;24(6):10.1016/j.ccr.2013.11.001.
The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of ubiquitin receptor RPN13 in the 19S regulatory particle and inhibits proteasome function, triggering rapid accumulation of polyubiquitinated proteins. Multiple myeloma (MM) lines, even those resistant to bortezomib, were sensitive to RA190 via endoplasmic reticulum stress-related apoptosis. RA190 stabilized targets of human papillomavirus (HPV) E6 oncoprotein, and preferentially killed HPV-transformed cells. After oral (p.o.) or intraperitoneal (i.p.) dosing of mice, RA190 distributed to plasma and major organs excepting brain, and inhibited proteasome function in skin and muscle. RA190 administration profoundly reduced growth of multiple myeloma and ovarian cancer xenografts, and oral RA190 treatment retarded HPV16+ syngeneic mouse tumor growth, without impacting spontaneous HPV-specific CD8+ T cell responses, suggesting its therapeutic potential.
doi:10.1016/j.ccr.2013.11.001
PMCID: PMC3881268  PMID: 24332045
Multiple Myeloma; Cervical Cancer; Ovarian Cancer; Proteasome Inhibitors; Ubiquitin Proteasome System (UPS); UPS-stress; RPN13; ubiquitin receptor
9.  SNP rs6265 Regulates Protein Phosphorylation and Osteoblast Differentiation and Influences BMD in Humans 
Bone Mineral Density (BMD) is major index for diagnosing osteoporosis. PhosSNPs are non-synonymous SNPs that affect protein phosphorylation. The relevance and significance of phosSNPs to BMD and osteoporosis is unknown. This study aims to identify and characterize phosSNPs significant for BMD in humans. We conducted a pilot genome-wide phosSNP association study for BMD in three independent population samples, involving ~5,000 unrelated individuals. We identified and replicated three phosSNPs associated with both spine BMD and hip BMD in Caucasians. Association with hip BMD for one of these phosSNPs, i.e., rs6265 (major/minor allele: G/A) in BDNF gene, was also suggested in Chinese. Consistently in both ethnicities, individuals carrying AA genotype have significant lower hip BMD than carriers of GA and GG genotypes. Through in vitro molecular and cellular studies, we found that compared to osteoblastic cells transfected with wild-type BDNF-Val66 (encoded with allele G at rs6265), transfection of variant BDNF-Met66 (encoded with allele A at rs6265) significantly decreased BDNF protein phosphorylation (at amino acid residue T62), expression of osteoblastic genes (OPN, BMP2, and ALP), and osteoblastic activity. The findings are consistent with and explain our prior observations in general human populations. We conclude that phosSNP rs6265, via regulating BDNF protein phosphorylation and osteoblast differentiation, influence hip BMD in humans. This study represents our first endeavor to dissect the functions of phosSNPs in bone, which might stimulate extended large-scale studies on bone or similar studies on other human complex traits and diseases.
doi:10.1002/jbmr.1997
PMCID: PMC4127979  PMID: 23712400
BMD; SNP; protein phosphorylation; BDNF; osteoblast
10.  Molecular Actions of Ovarian Cancer G Protein-Coupled Receptor 1 Caused by Extracellular Acidification in Bone 
Extracellular acidification occurs under physiologic and pathologic conditions, such as exercise, ischemia, and inflammation. It has been shown that acidosis has various adverse effects on bone. In recent years there has been increasing evidence which indicates that ovarian cancer G protein-coupled receptor 1 (OGR1) is a pH-sensing receptor and mediates a variety of extracellular acidification-induced actions on bone cells and other cell types. Recent studies have shown that OGR1 is involved in the regulation of osteoclast differentiation, survival, and function, as well as osteoblast differentiation and bone formation. Moreover, OGR1 also regulates acid-induced apoptosis of endplate chondrocytes in intervertebral discs. These observations demonstrate the importance of OGR1 in skeletal development and metabolism. Here, we provide an overview of OGR1 regulation ofosteoclasts, osteoblasts, and chondrocytes, and the molecular actions of OGR1 induced by extracellular acidification in the maintenance of bone health.
doi:10.3390/ijms151222365
PMCID: PMC4284713  PMID: 25479080
extracellular acidification; OGR1; osteoclasts; osteoblasts; endplate chondrocytes
11.  Extranodal follicular dendritic cell sarcoma of the soft palate: a case report 
Follicular dentritic cell sarcoma (FDCS) is an extremely rare malignant neoplasm arising from the accessory cells of the lymph nodes, the follicular dendritic cells. They commonly occur in the lymph nodes, but have also been reported at extranodal sites. Because of its rarity, FDCS is not easily to make a diagnosis by clinicians or pathologists. Herein, we report a soft palate tumor in a 59-year-old female, with a history of tonsillectomy. Pharynx MRI scan revealed a 4.7×3.0×3.5 cm mass at the right side of the parapharyngeal space. The pathology results returned as Follicular dentritic cell sarcoma. The patient underwent a tumorectomy and adjuvant postoperative radiotherapy. The patient was free of disease 1 year after the end of the treatment. The FDCS is an infrequent nonlymphoid malignant tumor accounting for less than 1% of all head and neck tumors. The immunohistochemical technique is essential for accurately identifying this class of tumour.
PMCID: PMC4314020
Follicular dentritic cell sarcoma; softpalate; immunohistochemistry; CD21; CD23
12.  Efficacy of tumor-targeting Salmonella typhimurium A1-R in combination with anti-angiogenesis therapy on a pancreatic cancer patient-derived orthotopic xenograft (PDOX) and cell line mouse models 
Oncotarget  2014;5(23):12346-12357.
The aim of the present study was to examine the efficacy of tumor-targeting Salmonella typhimurium A1-R treatment following anti-vascular endothelial growth factor (VEGF) therapy on VEGF-positive human pancreatic cancer. A pancreatic cancer patient-derived orthotopic xenograft (PDOX) that was VEGF-positive and an orthotopic VEGF-positive human pancreatic cancer cell line (MiaPaCa-2-GFP) as well as a VEGF-negative cell line (Panc-1) were tested. Nude mice with these tumors were treated with gemcitabine (GEM), bevacizumab (BEV), and S. typhimurium A1-R. BEV/GEM followed by S. typhimurium A1-R significantly reduced tumor weight compared to BEV/GEM treatment alone in the PDOX and MiaPaCa-2 models. Neither treatment was as effective in the VEGF-negative model as in the VEGF-positive models. These results demonstrate that S. typhimurium A1-R following anti-angiogenic therapy is effective on pancreatic cancer including the PDOX model, suggesting its clinical potential.
PMCID: PMC4322966  PMID: 25402324
Pancreatic cancer; Salmonella typhimurium A1-R; patient-derived orthotopic xenograft (PDOX); orthotopic; nude mice; GFP; VEGF; anti-angiogenic therapy; bevacizumab; gemcitabine
13.  Chd5 orchestrates chromatin remodeling during sperm development 
Nature communications  2014;5:3812.
One of the most remarkable chromatin remodeling processes occurs during spermiogenesis, the post-meiotic phase of sperm development during which histones are replaced with sperm-specific protamines to repackage the genome into the highly compact chromatin structure of mature sperm. Here we identify Chromodomain helicase DNA binding protein 5 (Chd5) as a master regulator of the histone-to-protamine chromatin remodeling process. Chd5 deficiency leads to defective sperm chromatin compaction and male infertility in mice, mirroring the observation of low CHD5 expression in testes of infertile men. Chd5 orchestrates a cascade of molecular events required for histone removal and replacement, including histone 4 (H4) hyperacetylation, histone variant expression, nucleosome eviction, and DNA damage repair. Chd5 deficiency also perturbs expression of transition proteins (Tnp1/Tnp2) and protamines (Prm1/2). These findings define Chd5 as a multi-faceted mediator of histone-to-protamine replacement and depict the cascade of molecular events underlying chromatin remodeling during this process of extensive chromatin remodeling.
doi:10.1038/ncomms4812
PMCID: PMC4151132  PMID: 24818823
14.  Statistical analysis of twenty years (1993 to 2012) of data from mainland China’s first intervention center for children with autism spectrum disorder 
Molecular Autism  2014;5:52.
Background
Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and interaction, and restrictive and repetitive patterns of behavior, interests or activities. This study aimed to analyze trends in ASD diagnosis and intervention in 20 years of data from the Beijing Stars and Rain Education Institute for Autism (SR), the first autism intervention center in mainland China, and from a recent survey of members of the Heart Alliance, an industry association of autism intervention centers in China.
Methods
We analyzed the registration data at the SR from 1993 to 2012 for a total of 2,222 children who had a parent-reported diagnosis of ASD and 612 of ‘autistic tendencies’. Most of the children who were the primary focus of our analyses were age six and under. We also analyzed results of a survey we conducted in 2013 of 100 member centers of the Heart Alliance. Generalized Estimating Equations, multiple linear regression and the Mann-Whitney test were used for data analysis. Statistically significant findings are reported here.
Results
The number of hospitals where SR children received their diagnosis increased from several in the early 1990s to 276 at present. The proportion of ‘autistic tendencies’ diagnosis increased 2.04-fold from 1998 to 2012 and was higher for children diagnosed at a younger age. The mean age at first diagnosis of ASD or ‘autistic tendencies’ decreased by 0.27 years every decade. A higher level of parental education was statistically significantly associated with an earlier diagnosis of the child. The mean parental age at childbirth increased by about 1.48 years per decade, and the mean maternal age was 1.40 and 2.10 years higher than that in the national population censuses of 2000 and 2010, respectively. At the time of the survey 3,957 children with ASD were being trained at the 100 autism intervention centers. Ninety-seven of these centers opened after the year 2000. Economically underdeveloped regions are still underserved.
Conclusions
This study revealed encouraging trends and remaining challenges in ASD diagnosis and intervention among children at the SR over the past 20 years and the 100 autism intervention centers in China at present.
Electronic supplementary material
The online version of this article (doi:10.1186/2040-2392-5-52) contains supplementary material, which is available to authorized users.
doi:10.1186/2040-2392-5-52
PMCID: PMC4332440
Autism spectrum disorder; Diagnosis; Intervention; Parental age; China
15.  Hypomethylation and overexpression of ITGAL (CD11a) in CD4+ T cells in systemic sclerosis 
Clinical Epigenetics  2014;6(1):25.
Background
The pathogenesis and etiology of systemic sclerosis (SSc) are complex and poorly understood. To date, several studies have demonstrated that the activation of the immune system undoubtedly plays a pivotal role in SSc pathogenesis. Activated immune effector T cells contribute to the release of various pro-inflammatory cytokines and drive the SSc-specific autoantibody responses. This, and a profibrotic environment, are all-important components of abnormal active immune responses that can lead to pathological disorders of SSc. CD11a is essential to inflammatory and immune responses, regulating adhesive and co-stimulatory interactions between CD4+ T cells and other cells. Although CD11a is overexpressed in SSc patients, the mechanisms leading to this overexpression and its consequences remain unclear. DNA methylation, a main epigenetic modification, plays an important role in the regulation of gene expression and is involved in the pathogenesis of autoimmune diseases. This work aims to investigate the effect of DNA demethylation on CD11a expression in SSc CD4+ T cells and to determine its functional significance. CD11a expression was measured using RT-PCR and flow cytometry. Bisulfite sequencing was used to determine the methylation status of the CD11a regulatory region. CD4+ T cells were co-cultured with antigen-presenting cells, B cells, or fibroblasts with and without anti-CD11a, and proliferation of CD4+ T cells, IgG production by B cells, and expression levels of COL1A2 mRNA by fibroblasts were evaluated.
Results
Elevated CD11a expression levels were observed in CD4+ T cells from SSc patients; these levels were found to be positively correlated with disease activity. The methylation levels of the CD11a regulatory sequences were lower in SSc patients than in controls and inversely correlated with CD11a mRNA expression. Treatment of CD4+ T cells with 5-azacytidine (5-azaC) decreased CD11a promoter methylation and caused CD11a overexpression. SSc CD4+ T cells and 5-azaC-treated CD4+ T cells showed increased proliferation of CD4+ T cells, increased production of IgG by co-cultured B cells, and induced expression of COL1A2 mRNA by co-cultured fibroblasts. These stimulatory effects were abrogated by anti-CD11a.
Conclusions
Demethylation of CD11a regulatory elements and subsequent CD11a overexpression in CD4+ T cells may mediate immunological abnormalities and fibrotic processes in SSc.
doi:10.1186/1868-7083-6-25
PMCID: PMC4237764  PMID: 25414732
CD11a; CD4+ T cells; COL1A2; DNA methylation; Systemic sclerosis
16.  Celastrol Stimulates Hypoxia-Inducible Factor-1 Activity in Tumor Cells by Initiating the ROS/Akt/p70S6K Signaling Pathway and Enhancing Hypoxia-Inducible Factor-1α Protein Synthesis 
PLoS ONE  2014;9(11):e112470.
Celastrol, a tripterine derived from the traditional Chinese medicine plant Tripterygium wilfordii Hook F. (“Thunder of God Vine”), has been reported to have multiple effects, such as anti-inflammation, suppression of tumor angiogenesis, inhibition of tumor growth, induction of apoptosis and protection of cells against human neurodegenerative diseases. However, the mechanisms that underlie these functions are not well defined. In this study, we reported for the first time that Celastrol could induce HIF-1α protein accumulation in multiple cancer cell lines in an oxygen-independent manner and that the enhanced HIF-1α protein entered the nucleus and promoted the transcription of the HIF-1 target genes VEGF and Glut-1. Celastrol did not influence HIF-1α transcription. Instead, Celastrol induced the accumulation of the HIF-1α protein by inducing ROS and activating Akt/p70S6K signaling to promote HIF-1α translation. In addition, we found that the activation of Akt by Celastrol was transient. With increased exposure time, inhibition of Hsp90 chaperone function by Celastrol led to the subsequent depletion of the Akt protein and thus to the suppression of Akt activity. Moreover, in HepG2 cells, the accumulation of HIF-1α increased the expression of BNIP3, which induced autophagy. However, HIF-1α and BNIP3 did not influence the cytotoxicity of Celastrol because the main mechanism by which Celastrol kills cancer cells is through stimulating ROS-mediated JNK activation and inducing apoptosis. Furthermore, our data showed that the dose required for Celastrol to induce HIF-1α protein accumulation and enhance HIF-1α transcriptional activation was below its cytotoxic threshold. A cytotoxic dose of Celastrol for cancer cells did not display cytotoxicity in LO2 normal human liver cells, which indicated that the novel functions of Celastrol in regulating HIF-1 signaling and inducing autophagy might be used in new applications, such as in anti-inflammation and protection of cells against human neurodegenerative diseases. Future studies regarding these applications are required.
doi:10.1371/journal.pone.0112470
PMCID: PMC4226555  PMID: 25383959
17.  Effect of Copper Treatment on the Composition and Function of the Bacterial Community in the Sponge Haliclona cymaeformis 
mBio  2014;5(6):e01980-14.
ABSTRACT
Marine sponges are the most primitive metazoan and host symbiotic microorganisms. They are crucial components of the marine ecological system and play an essential role in pelagic processes. Copper pollution is currently a widespread problem and poses a threat to marine organisms. Here, we examined the effects of copper treatment on the composition of the sponge-associated bacterial community and the genetic features that facilitate the survival of enriched bacteria under copper stress. The 16S rRNA gene sequencing results showed that the sponge Haliclona cymaeformis harbored symbiotic sulfur-oxidizing Ectothiorhodospiraceae and photosynthetic Cyanobacteria as dominant species. However, these autotrophic bacteria decreased substantially after treatment with a high copper concentration, which enriched for a heterotrophic-bacterium-dominated community. Metagenomic comparison revealed a varied profile of functional genes and enriched functions, including bacterial motility and chemotaxis, extracellular polysaccharide and capsule synthesis, virulence-associated genes, and genes involved in cell signaling and regulation, suggesting short-period mechanisms of the enriched bacterial community for surviving copper stress in the microenvironment of the sponge. Microscopic observation and comparison revealed dynamic bacterial aggregation within the matrix and lysis of sponge cells. The bacteriophage community was also enriched, and the complete genome of a dominant phage was determined, implying that a lytic phage cycle was stimulated by the high copper concentration. This study demonstrated a copper-induced shift in the composition of functional genes of the sponge-associated bacterial community, revealing the selective effect of copper treatment on the functions of the bacterial community in the microenvironment of the sponge.
IMPORTANCE
This study determined the bacterial community structure of the common sponge Haliclona cymaeformis and examined the effect of copper treatment on the community structure and functional gene composition, revealing that copper treatment had a selective effect on the functions of the bacterial community in the sponge. These findings suggest that copper pollution has an ecological impact on the sponge symbiont. The analysis showed that the untreated sponges hosted symbiotic autotrophic bacteria as dominant species, and the high-concentration copper treatment enriched for a heterotrophic bacterial community with enrichment for genes important for bacterial motility, supplementary cellular components, signaling and regulation, and virulence. Microscopic observation showed obvious bacterial aggregation and a reduction of sponge cell numbers in treated sponges, which suggested the formation of aggregates to reduce the copper concentration. The enrichment for functions of directional bacterial movement and supplementary cellular components and the formation of bacterial aggregates and phage enrichment are novel findings in sponge studies.
doi:10.1128/mBio.01980-14
PMCID: PMC4222105  PMID: 25370493
18.  Multi-Fault Detection of Rolling Element Bearings under Harsh Working Condition Using IMF-Based Adaptive Envelope Order Analysis 
Sensors (Basel, Switzerland)  2014;14(11):20320-20346.
When operating under harsh condition (e.g., time-varying speed and load, large shocks), the vibration signals of rolling element bearings are always manifested as low signal noise ratio, non-stationary statistical parameters, which cause difficulties for current diagnostic methods. As such, an IMF-based adaptive envelope order analysis (IMF-AEOA) is proposed for bearing fault detection under such conditions. This approach is established through combining the ensemble empirical mode decomposition (EEMD), envelope order tracking and fault sensitive analysis. In this scheme, EEMD provides an effective way to adaptively decompose the raw vibration signal into IMFs with different frequency bands. The envelope order tracking is further employed to transform the envelope of each IMF to angular domain to eliminate the spectral smearing induced by speed variation, which makes the bearing characteristic frequencies more clear and discernible in the envelope order spectrum. Finally, a fault sensitive matrix is established to select the optimal IMF containing the richest diagnostic information for final decision making. The effectiveness of IMF-AEOA is validated by simulated signal and experimental data from locomotive bearings. The result shows that IMF-AEOA could accurately identify both single and multiple faults of bearing even under time-varying rotating speed and large extraneous shocks.
doi:10.3390/s141120320
PMCID: PMC4279485  PMID: 25353982
rolling element bearing; multi-fault diagnosis; time-varying rotating speed; fault sensitive matrix
19.  Premelanosome-negative inflammatory angiomyolipoma of liver with expression of cathepsin K and TFE3 
We report the first case of inflammatory variant of hepatic angiomyolipoma (AML) with expression of transcription factor E3 (TFE3) protein but negativity for HMB45 and melan A in a 62-year-old female. Imaging studies revealed a tumor in the left lobe of liver, sized 5.8 cm in maximum diameter. Microscopically, the lesion was composed of large polygonal or epithelioid cells with copious eosinophilic granular cytoplasm. There was a very prominent stromal lymphoplasmacytic infiltrate. Immunohistochemically, the tumor cells showed very strong and diffuse positivity for smooth muscle actin, and cathepsin K, while S-100 protein, keratin, desmin, HMB45 and Melan-A are negative. However, there was multifocal and very convincing nuclear positivity for TFE3, thus confirms the diagnosis.
PMCID: PMC4270569  PMID: 25550868
Liver; angiomyolipoma; inflammatory; epithelioid tumor; TFE3; cathepsin K; differential diagnosis
20.  Comparison of Efficacy and Toxicity of Traditional Chinese Medicine (TCM) Herbal Mixture LQ and Conventional Chemotherapy on Lung Cancer Metastasis and Survival in Mouse Models 
PLoS ONE  2014;9(10):e109814.
Unlike Western medicine that generally uses purified compounds and aims to target a single molecule or pathway, traditional Chinese medicine (TCM) compositions usually comprise multiple herbs and components that are necessary for efficacy. Despite the very long-time and wide-spread use of TCM, there are very few direct comparisons of TCM and standard cytotoxic chemotherapy. In the present report, we compared the efficacy of the TCM herbal mixture LQ against lung cancer in mouse models with doxorubicin (DOX) and cyclophosphamide (CTX). LQ inhibited tumor size and weight measured directly as well as by fluorescent-protein imaging in subcutaneous, orthotopic, spontaneous experimental metastasis and angiogenesis mouse models of lung cancer. LQ was efficacious against primary and metastatic lung cancer without weight loss and organ toxicity. In contrast, CTX and DOX, although efficacious in the lung cancer models caused significant weight loss, and organ toxicity. LQ also had anti-angiogenic activity as observed in lung tumors growing in nestin-driven green fluorescent protein (ND-GFP) transgenic nude mice, which selectively express GFP in nascent blood vessels. Survival of tumor-bearing mice was also prolonged by LQ, comparable to DOX. In vitro, lung cancer cells were killed by LQ as observed by time-lapse imaging, comparable to cisplatinum. LQ was more potent to induce cell death on cancer cell lines than normal cell lines unlike cytotoxic chemotherapy. The results indicate that LQ has non-toxic efficacy against metastatic lung cancer.
doi:10.1371/journal.pone.0109814
PMCID: PMC4186882  PMID: 25286158
21.  Non-commutativity and Local Indistinguishability of Quantum States 
Scientific Reports  2014;4:6336.
We study the local indistinguishability problem of quantum states. By introducing an easily calculated quantity, non-commutativity, we present an criterion which is both necessary and sufficient for the local indistinguishability of a complete set of pure orthogonal product states. A constructive distinguishing procedure to obtain the concrete local measurements and classical communications is given. The non-commutativity of ensembles can be also used to characterize the quantumness for classical-quantum or quantum-classical correlated states.
doi:10.1038/srep06336
PMCID: PMC4160716  PMID: 25208830
22.  Comparison of efficacy of Salmonella typhimurium A1-R and chemotherapy on stem-like and non-stem human pancreatic cancer cells 
Cell Cycle  2013;12(17):2774-2780.
The XPA1 human pancreatic cancer cell line is dimorphic, with spindle stem-like cells and round non-stem cells. We report here the in vitro IC50 values of stem-like and non-stem XPA1 human pancreatic cells cells for: (1) 5-fluorouracil (5-FU), (2) cisplatinum (CDDP), (3) gemcitabine (GEM), and (4) tumor-targeting Salmonella typhimurium A1-R (A1-R). IC50 values of stem-like XPA1 cells were significantly higher than those of non-stem XPA1 cells for 5-FU (P = 0.007) and CDDP (P = 0.012). In contrast, there was no difference between the efficacy of A1-R on stem-like and non-stem XPA1 cells. In vivo, 5-FU and A1-R significantly reduced the tumor weight of non-stem XPA1 cells (5-FU; P = 0.028; A1-R; P = 0.011). In contrast, only A1-R significantly reduced tumor weight of stem-like XPA1 cells (P = 0.012). The combination A1-R with 5-FU improved the antitumor efficacy compared with 5-FU monotherapy on the stem-like cells (P = 0.004). The results of the present report indicate A1-R is a promising therapy for chemo-resistant pancreatic cancer stem-like cells.
doi:10.4161/cc.25872
PMCID: PMC3899191  PMID: 23966167
Salmonella typhimurium; amino acid auxotrophy; selective tumor targeting; pancreatic cancer; stem cell; chemoresistance; RFP; GFP; fluorescence imaging; confocal microscopy
23.  Elevated pretreatment serum globulin albumin ratio predicts poor prognosis for advanced non-small cell lung cancer patients 
Journal of Thoracic Disease  2014;6(9):1261-1270.
Background
The aim of the present study was to explore the association between the pretreatment globulin albumin ratio (GAR) and the survival of advanced non-small cell lung cancer (NSCLC) patients.
Methods
Patients hospitalized between January 2007 and December 2010 were enrolled and eliminated according to the inclusion and exclusion criteria. GAR was defined as the absolute globulin value divided by the absolute albumin value. Chi-squared test was performed to compare clinical characteristics in different groups. Kaplan-Meier and Cox regression model were used to determine independent prognostic factors. A P value of ≤0.05 was considered to be statistically significant.
Results
Total 316 patients were finally enrolled. The median progression free survival (PFS) and overall survival (OS) were 210.0 and 430.0 days, respectively. The statistical analyses indicated that pretreatment GAR >0.58 [hazard ratio (HR) =1.52, 95% confidence interval (95% CI): 1.12-2.08, P=0.008 for PFS, HR =1.65, 95% CI: 1.20-2.26, P=0.002 for OS], and pretreatment albumin ≤35 g/L (HR =2.09, 95% CI: 1.20-3.65, P=0.003 for PFS, HR =1.92, 95% CI: 1.10-3.36, P=0.022 for OS) were independent prognostic factors for both PFS and OS.
Conclusions
Our study first established a connection between pretreatment GAR and advanced NSCLC patients, suggesting that GAR was an independent prognostic factor and could be the biomarker for prognosis.
doi:10.3978/j.issn.2072-1439.2014.07.13
PMCID: PMC4178101  PMID: 25276368
Globulin albumin ratio (GAR); prognostic factor; non-small cell lung cancer (NSCLC)
24.  Resting-state functional connectivity abnormalities in patients with obsessive–compulsive disorder and their healthy first-degree relatives 
Background
Obsessive–compulsive disorder (OCD) is a common, heritable neuropsychiatric disorder, hypothetically underpinned by dysfunction of brain cortical–striatal–thalamic–cortical (CSTC) circuits; however, the extent of brain functional abnormalities in individuals with OCD is unclear, and the genetic basis of this disorder is poorly understood. We determined the whole brain functional connectivity patterns in patients with OCD and their healthy first-degree relatives.
Methods
We used resting-state fMRI to measure functional connectivity strength in patients with OCD, their healthy first-degree relatives and healthy controls. Whole brain functional networks were constructed by measuring the temporal correlations of all brain voxel pairs and further analyzed using a graph theory approach.
Results
We enrolled 39 patients with OCD, 20 healthy first-degree relatives and 39 healthy controls in our study. Compared with healthy controls, patients with OCD showed increased functional connectivity primarily within the CSTC circuits and decreased functional connectivity in the occipital cortex, temporal cortex and cerebellum. Moreover, patients with OCD and their first-degree relatives exhibited overlapping increased functional connectivity strength in the bilateral caudate nucleus, left orbitofrontal cortex (OFC) and left middle temporal gyrus.
Limitations
Potential confounding factors, such as medication use, heterogeneity in symptom clusters and comorbid disorders, may have impacted our findings.
Conclusion
Our preliminary results suggest that patients with OCD have abnormal resting-state functional connectivity that is not limited to CSTC circuits and involves abnormalities in additional large-scale brain systems, especially the limbic system. Moreover, resting-state functional connectivity strength abnormalities in the left OFC, bilateral caudate nucleus and left middle temporal gyrus may be neuroimaging endophenotypes for OCD.
doi:10.1503/jpn.130220
PMCID: PMC4160359  PMID: 24866415
25.  Retrieval-balloon-assisted enterography for ERCP after Billroth II gastroenterostomy and Braun anastomosis 
World Journal of Gastroenterology : WJG  2014;20(31):10921-10926.
AIM: To describe an optimal route to the Braun anastomosis including the use of retrieval-balloon-assisted enterography.
METHODS: Patients who received a Billroth II gastroenterostomy (n = 109) and a Billroth II gastroenterostomy with Braun anastomosis (n = 20) between January 2009 and May 2013 were analyzed in this study. Endoscopic retrograde cholangiopancreatography (ERCP) was performed under fluoroscopic control using a total length of 120 cm oblique-viewing duodenoscope with a 3.7-mm diameter working channel. For this procedure, we used a triple-lumen retrieval balloon catheter in which a 0.035-inch guidewire could be inserted into the “open-channel” guidewire lumen while the balloon could be simultaneously injected and inflated through the other 2 lumens.
RESULTS: For the patients with Billroth II gastroenterostomy and Braun anastomosis, successful access to the papilla was gained in 17 patients (85%) and there was therapeutic success in 16 patients (80%). One patient had afferent loop perforation, but postoperative bleeding did not occur. For Billroth II gastroenterostomy, there was failure in accessing the papilla in 15 patients (13.8%). ERCP was unsuccessful because of tumor infiltration (6 patients), a long afferent loop (9 patients), and cannulation failure (4 patients). The papilla was successfully accessed in 94 patients (86.2%), and there was therapeutic success in 90 patients (82.6%). Afferent loop perforation did not occur in any of these patients. One patient had hemorrhage 2 h after ERCP, which was successfully managed with conservative treatment.
CONCLUSION: Retrieval-balloon-assisted enterography along an optimal route may improve the ERCP success rate after Billroth II gastroenterostomy and Braun anastomosis.
doi:10.3748/wjg.v20.i31.10921
PMCID: PMC4138472  PMID: 25152595
Retrieval-balloon-assisted enterography; Billroth II gastroenterostomy; Braun anastomosis; Optimal enterography route; Gastrojejunal anastomosis; Efferent loop; Endoscopic retrograde cholangiopancreatography; Duodenoscope; Enterography success rate; Therapeutic success rate

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