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Find video protocols related to scientific articles indexed in Pubmed.
GSK-3?-regulated N-acetyltransferase 10 is involved in colorectal cancer invasion.
Clin. Cancer Res.
PUBLISHED: 06-30-2014
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NAT10 (N-acetyltransferase 10) is a nucleolar protein, but may show subcellular redistribution in colorectal carcinoma. In this study, we evaluated membranous staining of NAT10 in colorectal carcinoma and its clinical implications, and explored the mechanism of regulation of NAT10 redistribution.
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Cultivation and characterization of limbal epithelial stem cells on contact lenses with a feeder layer: toward the treatment of limbal stem cell deficiency.
Cornea
PUBLISHED: 05-29-2014
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Limbal epithelial sheets are used to promote corneal surface reconstruction after the detection of limbal epithelial stem cell deficiency. The aim of this study was to evaluate a novel combination of limbal stem cells (LSCs) maintained on contact lenses (CLs) in the presence of a 3T3 feeder cell layer regarding preservation of stem cell phenotype and the potential use for future in vivo transplantation.
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Estrogen receptor ?-coupled Bmi1 regulation pathway in breast cancer and its clinical implications.
BMC Cancer
PUBLISHED: 02-19-2014
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Bmi1 has been identified as an important regulator in breast cancer, but its relationship with other signaling molecules such as ER? and HER2 is undetermined.
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PTEN interacts with histone H1 and controls chromatin condensation.
Cell Rep
PUBLISHED: 02-14-2014
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Chromatin organization and dynamics are integral to global gene transcription. Histone modification influences chromatin status and gene expression. PTEN plays multiple roles in tumor suppression, development, and metabolism. Here, we report on the interplay of PTEN, histone H1, and chromatin. We show that loss of PTEN leads to dissociation of histone H1 from chromatin and decondensation of chromatin. PTEN deletion also results in elevation of histone H4 acetylation at lysine 16, an epigenetic marker for chromatin activation. We found that PTEN and histone H1 physically interact through their C-terminal domains. Disruption of the PTEN C terminus promotes the chromatin association of MOF acetyltransferase and induces H4K16 acetylation. Hyperacetylation of H4K16 impairs the association of PTEN with histone H1, which constitutes regulatory feedback that may reduce chromatin stability. Our results demonstrate that PTEN controls chromatin condensation, thus influencing gene expression. We propose that PTEN regulates global gene transcription profiling through histones and chromatin remodeling.
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PTEN?, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism.
Cell Metab.
PUBLISHED: 01-07-2014
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PTEN is one of the most frequently mutated genes in human cancer. It is known that PTEN has a wide range of biological functions beyond tumor suppression. Here, we report that PTEN?, an N-terminally extended form of PTEN, functions in mitochondrial metabolism. Translation of PTEN? is initiated from a CUG codon upstream of and in-frame with the coding region of canonical PTEN. Eukaryotic translation initiation factor 2A (eIF2A) controls PTEN? translation, which requires a CUG-centered palindromic motif. We show that PTEN? induces cytochrome c oxidase activity and ATP production in mitochondria. TALEN-mediated somatic deletion of PTEN? impairs mitochondrial respiratory chain function. PTEN? interacts with canonical PTEN to increase PINK1 protein levels and promote energy production. Our studies demonstrate the importance of eIF2A-mediated alternative translation for generation of protein diversity in eukaryotic systems and provide insights into the mechanism by which the PTEN family is involved in multiple cellular processes.
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Endogenous IgG affects the cell biology of RPE cells and involves the TLR4 pathway.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 10-10-2013
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RPE is a key component of the blood-ocular barrier (BOB) and is equipped with immunological molecules such as toll-like receptors (TLRs) and complement receptors, which together orchestrate the innate and adaptive immunity of the eye. Immunoglobulin G (IgG) in the aqueous humor and vitreous body has traditionally been thought to be derived from serum via transcytosis across the BOB. Our previous work validated production of endogenous IgG by RPE cells locally. However, the function and role of this IgG in the intraocular immunity is poorly understood.
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Neuron-derived IgG Protects Neurons from Complement-dependent Cytotoxicity.
J. Histochem. Cytochem.
PUBLISHED: 08-26-2013
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Passive immunity of the nervous system has traditionally been thought to be predominantly due to the blood-brain barrier. This concept must now be revisited based on the existence of neuron-derived IgG. The conventional concept is that IgG is produced solely by mature B lymphocytes, but it has now been found to be synthesized by murine and human neurons. However, the function of this endogenous IgG is poorly understood. In this study, we confirm IgG production by rat cortical neurons at the protein and mRNA levels, with 69.0 ± 5.8% of cortical neurons IgG-positive. Injury to primary-culture neurons was induced by complement leading to increases in IgG production. Blockage of neuron-derived IgG resulted in more neuronal death and early apoptosis in the presence of complement. In addition, Fc?RI was found in microglia and astrocytes. Expression of Fc?R I in microglia was increased by exposure to neuron-derived IgG. Release of NO from microglia triggered by complement was attenuated by neuron-derived IgG, and this attenuation could be reversed by IgG neutralization. These data demonstrate that neuron-derived IgG is protective of neurons against injury induced by complement and microglial activation. IgG appears to play an important role in maintaining the stability of the nervous system.
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Tonsillar Crypt Epithelium Is an Important ExtraCentral Nervous System Site for Viral Replication in EV71 Encephalomyelitis.
Am. J. Pathol.
PUBLISHED: 07-20-2013
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Enterovirus 71 (EV71; family Picornaviridae, species human Enterovirus A) usually causes hand, foot, and mouth disease, which may rarely be complicated by fatal encephalomyelitis. We investigated extracentral nervous system (CNS) tissues capable of supporting EV71 infection and replication, and have correlated tissue infection with expression of putative viral entry receptors, scavenger receptor B2 (SCARB2), and P-selectin glycoprotein ligand-1 (PSGL-1). Formalin-fixed, paraffin-embedded CNS and extra-CNS tissues from seven autopsy cases were examined by IHC and in situ hybridization to evaluate viral antigens and RNA. Viral receptors were identified with IHC. In all seven cases, the CNS showed stereotypical distribution of inflammation and neuronal localization of viral antigens and RNA, confirming the clinical diagnosis of EV71 encephalomyelitis. In six cases in which tonsillar tissues were available, viral antigens and/or RNA were localized to squamous epithelium lining the tonsillar crypts. Tissues from the gastrointestinal tract, pancreas, mesenteric nodes, spleen, and skin were all negative. Our novel findings strongly suggest that tonsillar crypt squamous epithelium supports active viral replication and represents an important source of viral shedding that facilitates person-to-person transmission by both the fecal-oral or oral-oral routes. It may also be a portal for viral entry. A correlation between viral infection and SCARB2 expression appears to be more significant than for PSGL-1 expression.
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Subnuclear distribution of SSX regulates its function.
Mol. Cell. Biochem.
PUBLISHED: 05-02-2013
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SSX, a family of genes clustered on the X chromosome, has been identified as a cancer-testis antigen and also forms a part of the SYT-SSX fusion gene found in synovial sarcoma, implying that it has an important role in tumorigenesis. However, knowledge of the molecular regulation of SSX is still limited. In this study, we demonstrate that SSX or its SYT fusion protein is distributed as nuclear speckles, in which it is co-localized with B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi1), which is a core factor of polycomb repressor complex 1. The C-terminal residues of SSX are indispensable for the nuclear speckle distribution, while the N-terminal domain is necessary for the recruitment of Bmi1, indicating that intact SSX must be needed for interaction with Bmi1 both spatially and functionally. In addition, the N-terminus of SSX also proved to contain an intrinsic nucleolar localization signal, which mediates the nucleolar translocation of SSX in particular kinds of cell stress such as the oxidation of hydrogen peroxide or heat shock. This stress-induced translocation is reversible and accompanied by HSP 70 or p14ARF traffic, suggesting that SSX is a stress response gene. It is of note that nucleolar translocation of SSX can result in disassociation of SSX from Bmi1, with consequent down-regulation of Bmi1 activity. These novel findings regarding distinct domains of SSX and its interaction with Bmi1 may shed light on the mechanism by which synovial sarcoma develops and on the up-regulation of SSX in cancer cells.
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Neuron-derived IgG protects dopaminergic neurons from insult by 6-OHDA and activates microglia through the Fc?R I and TLR4 pathways.
Int. J. Biochem. Cell Biol.
PUBLISHED: 03-05-2013
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Oxidative and immune attacks from the environment or microglia have been implicated in the loss of dopaminergic neurons of Parkinsons disease. The role of IgG which is an important immunologic molecule in the process of Parkinsons disease has been unclear. Evidence suggests that IgG can be produced by neurons in addition to its traditionally recognized source B lymphocytes, but its function in neurons is poorly understood. In this study, extensive expression of neuron-derived IgG was demonstrated in dopaminergic neurons of human and rat mesencephalon. With an in vitro Parkinsons disease model, we found that neuron-derived IgG can improve the survival and reduce apoptosis of dopaminergic neurons induced by 6-hydroxydopamine toxicity, and also depress the release of NO from microglia triggered by 6-hydroxydopamine. Expression of TNF-? and IL-10 in microglia was elevated to protective levels by neuron-derived IgG at a physiologic level via the Fc?R I and TLR4 pathways and microglial activation could be attenuated by IgG blocking. All these data suggested that neuron-derived IgG may exert a self-protective function by activating microglia properly, and IgG may be involved in maintaining immunity homeostasis in the central nervous system and serve as an active factor under pathological conditions such as Parkinsons disease.
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Correlation of immunoglobulin G expression and histological subtype and stage in breast cancer.
PLoS ONE
PUBLISHED: 02-05-2013
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Recently, growing evidence indicates that immunoglobulins (Igs) are not only produced by mature B lymphocytes or plasma cells, but also by various normal cells types at immune privileged sites and neoplasm, including breast cancer. However, the association of breast cancer derived IgG with genesis and development of the disease has not yet been established.
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SATB1 expression is associated with biologic behavior in colorectal carcinoma in vitro and in vivo.
PLoS ONE
PUBLISHED: 01-11-2013
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There is increasing evidence that Special AT-rich sequence-binding protein 1 (SATB1) is aberrantly expressed in several cancers and is correlated with clinicopathologic parameters in these tumors. In this study, we showed over-expression of SATB1 in 80 cases of colorectal cancer and in 3 colorectal cancer cell lines and found expression levels were strongly associated with tumor differentiation and stage. Expression levels of SATB1 protein were higher in poorly-differentiated as compared with well-differentiated cell lines, and both quantity and distribution patterns of SATB1 were associated with tumor differentiation and pTNM stage. Strikingly, we further investigated the effect of down regulation of SATB1 expression on malignant phenotypic features in colorectal cancer cells in vitro, and showed that SABT1 down-regulation negatively affected growth potential, anchorage-independent colony formation and cancer cell invasion, and resulted in increased apoptosis. SATB1 expression was positively associated with the expression of various biological and genetic markers, including Cyclin D1, MMP-2, NF-?B, and PCNA, and was associated with loss of APC and BRAF(V600E). These findings suggest that SATB1 is involved in the carcinogenesis, development and progression of colorectal cancer.
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Correlation of LAPTM4B polymorphisms with hepatocellular carcinoma in Chinese patients.
Med. Oncol.
PUBLISHED: 12-05-2011
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Hepatocellular carcinoma (HCC) is the leading cause of cancer mortality in many countries. Evaluation of new susceptibility risk factors is therefore warranted in order to explore means to improve the survival rate. Here, we report on a novel HCC-related gene known as lysosomal protein transmembrane 4 beta (LAPTM4B) that has two alleles designated LAPTM4B*1 and LAPTM4B*2. Allele *1 differs from allele *2 in that it contains one copy of a 19-bp sequence, whereas this sequence is duplicated in allele *2 in exon 1 of LAPTM4B. In this study, we aimed to investigate the relationship between LAPTM4B allelic variation and HCC susceptibility. The LAPTM4B genotype was analyzed in the blood samples from 102 HCC patients and 135 healthy individuals by PCR. The genotypic distribution of LAPTM4B was analyzed using the chi-squared test. The frequencies of allele *2 were 38.24 and 24.07% in the HCC group and control group, respectively, representing a significant difference between these two groups (P<0.001). Thus, allele *2 of LAPTM4B appears to be associated with genetic susceptibility of HCC and may therefore be considered as a risk factor.
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Elevated serum alpha fetoprotein levels promote pathological progression of hepatocellular carcinoma.
World J. Gastroenterol.
PUBLISHED: 06-21-2011
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To investigate the biological role of alpha fetoprotein (AFP) and its clinical significance in carcinogenesis of hepatocellular carcinoma (HCC).
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Eosinophilic gastroenteritis: clinical manifestations and morphological characteristics, a retrospective study of 42 patients.
Scand. J. Gastroenterol.
PUBLISHED: 05-30-2011
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To evaluate the clinical manifestations, endoscopic, and radiological characteristics, histological features, and treatment of eosinophilic gastroenteritis in adult patients.
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Combined lysosomal protein transmembrane 4 beta-35 and argininosuccinate synthetase expression predicts clinical outcome in hepatocellular carcinoma patients.
Surg. Today
PUBLISHED: 05-28-2011
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The newly-identified lysosomal protein transmembrane 4 beta-35 (LAPTM4B-35) plays important roles in tumor progression and metastasis, while argininosuccinate synthetase (ASS) provides arginine as an indispensable nutrient for hepatocellular carcinoma (HCC). The present study investigated the clinical significance of the coexpression of LAPTM4B-35 and ASS in HCC patients on determining the prognosis.
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Autophagy process is associated with anti-neoplastic function.
Acta Biochim. Biophys. Sin. (Shanghai)
PUBLISHED: 04-26-2011
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Autophagy is a highly conserved process of cellular degradation, which is present in yeast, plants, and mammals. Under normal physiological conditions, autophagy acts to maintain cellular homeostasis and regulate the turnover of organelles. In response to cellular stresses, autophagy prevents the accumulation of impaired proteins and organelles, which serves to inhibit carcinogenesis. On this basis, it is widely accepted that most tumor suppressors, such as beclin 1 associated proteins, forkhead box class O (FoxO) family proteins, multiple mammalian target of Rapamycin (mTOR) inactivators, and nuclear p53 play a role in inducing autophagy. Here, we focus on how the process of autophagy is associated with anti-neoplastic function.
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Upregulation of LAPTM4B-35 promotes malignant transformation and tumorigenesis in L02 human liver cell line.
Anat Rec (Hoboken)
PUBLISHED: 04-09-2011
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Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide and is the second leading cause of cancer death in China. We have previously demonstrated that LAPTM4B-35, encoded by lysosomal protein transmembrane 4 beta gene, is overexpressed in over 80% of HCCs and is a novel-independent prognostic factor for metastasis, recurrence, and postoperative survival in HCC. In this study, we investigated the role of LAPTM4B-35 in malignant transformation and tumorigenesis using L02 cells, a cell line originated from human normal liver cells. Our data show that replication-deficient adenovirus vector-mediated upregulation of LAPTM4B-35 promotes anchorage-independent proliferation and resistance to adriamycin-induced apoptosis. Study of the underlying mechanisms demonstrated alterations of molecular events involved in these processes, which included the activation of phosphoinositide 3-kinases (PI3K)/serine/threonine protein kinase B (PKB/AKT)/bcl-xL/bcl-2-associated death promoter homolog (Bad) signaling pathway, inhibition of caspase-3 activation, upregulation of Bcl-2, and downregulation of Bax. In addition, upregulation of LAPTM4B-35 in L02 cells resulted in tumorigenesis in 100% (6/6) of inoculated nude mice and accelerated the death of mice with xenografts in vivo. In conclusion, LAPTM4B-35 promotes malignant transformation and tumorigenesis in human liver L02 cell line through promotion of deregulated proliferation and inhibition of apoptosis. These findings suggest that overexpression of LAPTM4B-35 may play a critical role in hepatocarcinogenesis and therefore, may be a therapeutic target for HCC.
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Impact of intracellular alpha fetoprotein on retinoic acid receptors-mediated expression of GADD153 in human hepatoma cell lines.
Int. J. Cancer
PUBLISHED: 02-17-2011
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The aim of our study was to gain a better understanding of the molecular mechanism underlying the previously unrecognized role of cytoplasmic alpha fetoprotein (AFP) in retinoic acid receptors (RAR) mediated expression and biological effects of GADD153. Using microarray analysis, the expression of the GADD153 gene showed the greatest fold change among apoptosis/growth related genes in response to ATRA. AFP was able to interact with RAR in HepG2 cells, which was undetectable in HLE cells owing to absence of AFP. ATRA promoted nuclei entrance of RAR, expression of GADD153 and apoptosis, and these changes were reversed after transfection with the afp gene or addition of AGN193109. The level of GADD153 was gradually elevated as the effect of AFP was counteracted by increasing dose or prolonging treatment time with ATRA in HepG2 cells. Knockdown of AFP in siRNA-transfected HepG2 cells or over-expression of AFP in afp gene-transfected HLE cells was synchronously associated with up-regulation or down-regulation, respectively, of GADD153 expression. Both ATRA administration and AFP knockdown were each able to promote greater binding of RAR to its response element with consequent elevation of the proportion of apoptotic cells. Conversely, transfection of HLE cells with pcDNA3.1-afp resulted in apparent reduction of RAR binding to DNA and change of biological effect. These data taken together demonstrate the involvement of AFP in RAR-mediated expression and biological effects of GADD153. These findings provide a novel insight into the mechanism underlying the impact of AFP on the RAR signal network.
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SIRT1 is regulated by a PPAR{?}-SIRT1 negative feedback loop associated with senescence.
Nucleic Acids Res.
PUBLISHED: 07-25-2010
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Human Silent Information Regulator Type 1 (SIRT1) is an NAD(+)-dependent deacetylase protein which is an intermediary of cellular metabolism in gene silencing and aging. SIRT1 has been extensively investigated and shown to delay senescence; however, less is known about the regulation of SIRT1 during aging. In this study, we show that the peroxisome proliferator-activated receptor-? (PPAR?), which is a ligand-regulated modular nuclear receptor that governs adipocyte differentiation and inhibits cellular proliferation, inhibits SIRT1 expression at the transcriptional level. Moreover, both PPAR? and SIRT1 can bind the SIRT1 promoter. PPAR? directly interacts with SIRT1 and inhibits SIRT1 activity, forming a negative feedback and self-regulation loop. In addition, our data show that acetylation of PPAR? increased with increasing cell passage number. We propose that PPAR? is subject to regulation by acetylation and deacetylation via p300 and SIRT1 in cellular senescence. These results demonstrate a mutual regulation between PPAR? and SIRT1 and identify a new posttranslational modification that affects cellular senescence.
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Endocrine cells of the adenohypophysis in severe acute respiratory syndrome (SARS).
Biochem. Cell Biol.
PUBLISHED: 07-24-2010
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It is known that severe acute respiratory syndrome (SARS), a severe infectious illness, which caused an epidemic in Asia in 2003, has extensive and complex effects on human organ systems. It has been reported that the serum levels of prolactin (PRL), follicle stimulating hormone (FSH), and luteinizing hormone (LH) of SARS patients are significantly higher than those of control groups, while estradiol (E2), pregnancy hormone (P), and thyroid stimulating hormone (TSH) are considerably lower than those of normal controls. This phenomenon suggests that the adenohypophyseal endocrine cells in SARS patients may be damaged. However, up to now there has been no direct histological investigation on the endocrine cells of patients pituitary. Here we investigated the endocrine cells in the adenohypophysis obtained from autopsies of 5 SARS patients. The immunohistochemistry and quantitative image results showed that compared with control cases, both the number of positive cells and the staining intensity of immunoreactivity for growth hormone, TSH, and adrenocorticotrophic hormone in these cells were remarkably decreased, while that of PRL, FSH, and LH were significantly increased in all SARS cases studied. These findings indicated that alterations occurred in the patients adenohypophyseal endocrine cells, and these changes were consistent with the serum levels of relevant endocrine hormones reported previously. It appears that changes in these endocrine cells and their hormones are affected by the severity of this new infectious disease.
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Overexpression of LAPTM4B-35 promotes growth and metastasis of hepatocellular carcinoma in vitro and in vivo.
Cancer Lett.
PUBLISHED: 02-05-2010
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LAPTM4B-35, encoded by Lysosomal protein transmembrane 4 beta (LAPTM4B) is over-expressed in more than 71% of hepatocellular carcinomas (HCCs) and associated with prognosis of the patients. But the exact role and molecular mechanism in HCC have not been determined. In this study, we explored the effects and mechanisms of LAPTM4B-35 on tumor growth and metastasis in vitro and in vivo by overexpression and depletion of LAPTM4B in HCC HepG2 and Bel7402 cells. These findings suggest that overexpression of LAPTM4B-35 plays a critical role in the growth and metastasis of HCC, and LAPTM4B-35 may therefore be a therapeutic target for HCC.
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Blockade of the Ras-extracellular signal-regulated kinase 1/2 pathway is involved in smooth muscle 22 alpha-mediated suppression of vascular smooth muscle cell proliferation and neointima hyperplasia.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 02-05-2010
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Vascular smooth muscle cells (VSMCs) can switch between differentiated and dedifferentiated phenotypes, and this phenotype switch is believed to be essential for repair of vascular injury. We studied the inhibitory effect of smooth muscle 22 alpha (SM22 alpha) on VSMC proliferation in vitro and in vivo and explored the potential molecular mechanisms of this effect.
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CD117-positive cells of the heart: progenitor cells or mast cells?
J. Histochem. Cytochem.
PUBLISHED: 12-21-2009
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Human cardiac stem/progenitor cells and their potential for repair of heart injury are a current hot topic of research. CD117 has been used frequently as a marker for identification of stem/progenitor cells in the heart. However, cardiac mast cells, which are also CD117(+), have not been excluded by credible means when selecting putative cardiac progenitors by using CD117 as a marker. We evaluated the relationship between CD117(+) cells and mast cells in the left ventricle of human hearts (n=5 patients, ages 1 week-75 years) with the well-established mast cell markers tryptase, toluidine blue, and thionine. A large number (85-100%) of CD117(+) cells in the human heart were specifically identified as mast cells. In addition, mast cells showed weak or moderate CD45 immunostaining signals. These results indicate that the majority of CD117(+) cells in the heart are mast cells and that these cells are distinctly positive for CD45, although staining was weak or moderate. These results strongly suggest that the newly reported CD117(+)/CD45(dim/moderate) putative cardiac progenitor cells are mast cells. The significance of this observation in stem cell research of the heart is discussed.
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Expression and distribution of cystic fibrosis transmembrane conductance regulator in neurons of the human brain.
J. Histochem. Cytochem.
PUBLISHED: 08-03-2009
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The importance of the molecule cystic fibrosis transmembrane conductance regulator (CFTR) is reflected in the many physiological functions it regulates. It is known to be present in epithelial cells of the lungs, pancreas, sweat glands, gut, and other tissues, and gene mutations of CFTR cause cystic fibrosis (CF). We studied the expression and distribution of CFTR in the human brain with reverse transcriptase polymerase chain reaction, in situ hybridization, and immunohistochemistry. This study demonstrates widespread and abundant expression of CFTR in neurons of the human brain. Techniques of double labeling and evaluation of consecutive tissue sections localized CFTR protein and mRNA signals to the cytoplasm of neurons in all regions of the brain studied, but not to glial cells. The presence of CFTR in central neurons not only provides a possible explanation for the neural symptoms observed in CF patients, but also may lead to a better understanding of the functions of CFTR in the human brain.
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Mechanisms involved in phosphatidylinositol 3-kinase pathway mediated up-regulation of the mu opioid receptor in lymphocytes.
Biochem. Pharmacol.
PUBLISHED: 07-23-2009
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Despite the substantial progress made in understanding initiation expression of the MOR gene in lymphocytes, the signal pathway associated with MOR gene transcription remains to be better defined. As the phosphatidylinositol 3-kinase (PI3K)/AKT pathway can mediate diverse biological responses and is crucial for optimal immune responses and lymphocyte development, this study was undertaken to delineate the role of PI3K/AKT signaling in expression of the MOR gene in CEM x174 cells. The data show that morphine treatment enhanced the level of phosphorylated, rather than un-phosphorylated, PI3K and AKT, which were synchronously recruited to membrane. The levels of PTEN and p53 which are negative regulators of these signal molecules were reduced, and as a result, the interaction between PTEN and p53 was completely interrupted. With morphine treatment, the levels of both cytoplasmic and nuclear E2F1 which is the downstream effecter of AKT were elevated and the interaction of E2F1 with YY1, rather than Sp1, was also increased. Subsequently, E2F1 triggered the transcription of the MOR gene through its enhanced ability to bind the element in promoter region of the MOR gene. All responses to morphine were abolished by naloxone, which is an antagonist of MOR, or by LY294002, an inhibitor of PI3K, implying specific involvement of PI3K/AKT. These results strongly suggest that the PI3K/AKT pathway plays a critical role in the transfer of signal from morphine stimuli to the machinery by which MOR gene transcription is initiated.
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Age-dependent down-regulation of mitochondrial 8-oxoguanine DNA glycosylase in SAM-P/8 mouse brain and its effect on brain aging.
Rejuvenation Res
PUBLISHED: 07-15-2009
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Mitochondrial DNA (mtDNA) damage has been hypothesized to be responsible for aging and various neurological diseases. Abnormalities in 8-oxoguanine DNA glycosylase (OGG1) function can promote DNA oxidative damage, especially in the mitochondria. Here we report changes in the expression of OGG1 targeting to the nucleus, cytosol, and mitochondria in both accelerated senescence mice (SAM-P/8) and normal counterpart SAM-R/1 mice during brain aging. Our results showed that mRNA and protein levels of OGG1, especially OGG1 targeting to mitochondria, and the expression level of cytochrome c oxidase subunit III (COX III) in the brain of both SAM-P/8 mice and SAM-R/1 mice, decreased with age. However, such an age-dependent decrease in SAM-P/8 mice was larger than that in normal SAM-R/1 mice. These findings support the concept that down-regulation of OGG1, especially mitochondrial OGG1(mtOGG1) in SAM-P/8 mice, may promote brain aging by its effect on imbalance in the mtDNA damage repair systems, which leads to accumulation of mtDNA damage and oxidative phosphorylation-related protein dysfunction. Overall, our results provide novel insight into underlying the molecular mechanisms during brain aging.
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Expression and distribution of cystic fibrosis transmembrane conductance regulator in neurons of the spinal cord.
J. Neurosci. Res.
PUBLISHED: 06-18-2009
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To verify the hypothesis that cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in neurons of the human spinal cord, we investigated the presence and distribution of CFTR protein and mRNA in different segments of the human spinal cord obtained from autopsies. The techniques employed included reverse transcriptase-polymerase chain reaction (RT-PCR) to detect CFTR gene expression, in situ hybridization to detect mRNA distribution, and immunohistochemistry to detect protein distribution. The specificity of these experiments was established with extensive controls. We found widespread and abundant expression of CFTR in neurons of the human spinal cord. CFTR protein and mRNA are localized to the cytoplasm of neurons in all segments of the spinal cord but not to glial fibrillary acidic protein (GFAP)-positive cells. CFTR is a very important molecule, acting as a chloride channel and regulating many physiological functions, including salt transport, fluid flow, and intracellular ion concentrations. Its mutation causes cystic fibrosis. Our finding of abundant CFTR in the spinal cord suggests that this molecule may be significant in the normal function and pathology of the spinal cord.
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Enhanced atherothrombotic formation after oxidative injury by FeCl3 to the common carotid artery in severe combined hyperlipidemic mice.
Biochem. Biophys. Res. Commun.
PUBLISHED: 05-12-2009
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Enhanced susceptibility to atherosclerosis from severe hypertriglyceridemia (HTG) resulting from lipoprotein lipase (LPL) deficiency has been demonstrated in our recent findings which employed a unique mouse model. In the present study we provide further evidence that severe HTG due to LPL deficiency also promotes an atherothrombotic response to arterial injury induced by ferric chloride in a severe combined hyperlipidemic mouse model. Methods and results: A mouse model (LPL(-/-)XApoE(-/-) double knockout, DKO) with severe combined hyperlipidemia was established by crossing ApoE and LPL-deficient mice. The common carotid arteries of ApoE knockout (EKO) and DKO mice were subjected to injury by ferric chloride, and the formation of arterial thrombosis together with various markers were compared in these lesions. DKO mice demonstrated significantly enhanced thrombus formation overlying atherosclerotic plaque after injury, which contained smooth muscle cells, macrophages, and neutral lipid. The area of neointima, mean intima/media ratios, and the percentage of luminal stenosis were significantly greater (P<0.01) in DKO mice. Compared with EKO mice, the expression of von Willebrand factor (vWF) and plasminogen activator inhibitor type 1 (PAI-1) were increased in DKO mice. Conclusions: Severe combined hyperlipidemia promotes thrombosis after ferric chloride injury to atherosclerotic vessels and HTG plays a major role in the process.
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Proliferating cell nuclear antigen is protected from degradation by forming a complex with MutT Homolog2.
J. Biol. Chem.
PUBLISHED: 05-06-2009
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Proliferating cell nuclear antigen (PCNA) has been demonstrated to interact with multiple proteins involved in several metabolic pathways such as DNA replication and repair. However, there have been fewer reports about whether these PCNA-binding proteins influence stability of PCNA. Here, we observed a physical interaction between PCNA and MutT homolog2 (MTH2), a new member of the MutT-related proteins that hydrolyzes 8-oxo-7,8-dihydrodeoxyguanosine triphosphate (8-oxo-dGTP). In several unstressed human cancer cell lines and in normal human fibroblast cells, PCNA and MTH2 formed a complex and their mutual binding fragments were confirmed. It was intriguing that PCNA and MTH2 were dissociated dependent on acetylation of PCNA, which in turn induced degradation of PCNA in response to UV irradiation, but not in response to other forms of DNA-damaging stress. To further explore the link between dissociation of PCNA-MTH2 and degradation of PCNA, RNAi against MTH2 was performed to mimic the dissociated status of PCNA to evaluate changes in the half-life of PCNA. Knockdown of MTH2 significantly promoted degradation of PCNA, suggesting that the physiological interaction of PCNA-MTH2 may confer protection from degradation for PCNA, whereas UV irradiation accelerates PCNA degradation by inducing dissociation of PCNA-MTH2. Moreover, secondary to degradation of PCNA, UV-induced inhibition of DNA synthesis or cell cycle progression was enhanced. Collectively, our data demonstrate for the first time that PCNA is protected by this newly identified partner molecule MTH2, which is related to DNA synthesis and cell cycle progression.
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Cytoplasmic alpha-fetoprotein functions as a co-repressor in RA-RAR signaling to promote the growth of human hepatoma Bel 7402 cells.
Cancer Lett.
PUBLISHED: 04-17-2009
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The role of AFP in the retinoic acid-RAR signaling pathway was investigated in human hepatoma Bel 7402 cells. The results showed that AFP and RAR-beta were co-localized and interacted in cytoplasm. AFP may inhibit translocation of RAR-beta into the nucleus via competitive binding to RAR-beta with ATRA, which was reversed by AFP-siRNA transfection. Our data suggest that the ATRA resistance of Bel 7402 cells is at least in part attributable to their high level of cytoplasmic AFP. Thus, by counteracting the effect of AFP, it may be possible to increase the sensitivity of tumor cells to ATRA.
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Pyrimidone derivative inhibits simian immunodeficiency virus-induced apoptosis of CEM x174 cells.
Cell Biol. Int.
PUBLISHED: 03-31-2009
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The biochemical effects of 2-(ethoxymethylthio)-9-phenyl-cyclohepta[d]pyrimidone (EPCP), a novel non-nucleoside reverse transcriptase inhibitor, have been investigated. Treatment with EPCP (EC(50) of 0.88 nM in CEM x174 cells) significantly inhibited the activity of SIV reverse transcriptase and elevated the percentage of viable cells in an SIV-infected sample in a dose-dependent manner. The percentage of cells accumulated in G1 phase increased significantly from 34.5 to 62.4%, with a concomitant reduction in S-phase from 50.7% in the control to 22.6% in the infected group. This cell cycle profile was restored by treatment with EPCP. SIV upregulated the levels of the caspase-3, p53 and bax proteins, and downregulated the level of bcl-2 in infected cells. The apoptotic effect of SIV was also blocked by treatment with EPCP. The pharmacological effects of EPCP paralleled those of AZT, suggesting the possibility that EPCP might be a novel antiviral agent for SIV.
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Carcinoid tumour in a lumbar teratoma associated with tethered cord syndrome in an adult.
Br J Neurosurg
PUBLISHED: 03-24-2009
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An unusual case of a carcinoid tumour in a lumbar extradural teratoma presenting as tethered cord syndrome and spina bifida without carcinoid syndrome in a 51-year-old woman is reported. These entities existing simultaneously in the same region are extremely rare and this suggests they have a common origin.
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Quantitative morphometry by image analysis of normal, hyperplastic and cancerous ductal breasts.
Anal. Quant. Cytol. Histol.
PUBLISHED: 03-10-2009
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To analyze a number of quantitative variables in ductal epithelial breast proliferations and test them against diagnoses established by standard histologic and cytologic criteria in order to determine which variables are useful in discriminating between histologic diagnoses.
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Alpha fetoprotein is a novel protein-binding partner for caspase-3 and blocks the apoptotic signaling pathway in human hepatoma cells.
Int. J. Cancer
PUBLISHED: 03-10-2009
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Although there is increasing evidence that alpha fetoprotein (AFP) may function as regulatory factor in the growth of tumor cells, the precise mechanism is still unclear. In the current study, we investigated the role of the cytoplasmic AFP in caspase-3-mediated signaling of apoptosis. Our results showed that low doses of TNF-related apoptosis-inducing ligand (TRAIL) elevated the activity of caspase-8, but not caspase-3. Caspase-3 colocalized and interacted with AFP in the cytoplasm of Bel 7402 cells, and translocated into nuclei in association with the occurrence of apoptosis while cells were under cotreatment with all-trans retinoic acid (ATRA) or TRAIL. AFP was able to form complexes with caspase-3 and block onward transmission of signaling from caspase-8. Knockdown of AFP increased the sensitivity of Bel 7402 cells to TRAIL, and thereby, triggered caspase-3 signaling. No intermolecule interaction occurred between AFP and caspase-8, nor was caspase-8 activity altered after AFP knockdown, demonstrating the selectivity of AFP in interfering with the apoptotic signaling pathway. The effect of AFP on caspase-3 was further confirmed by transfection of the AFP gene into HLE cells (AFP negative). We conclude that ATRA or TRAIL resistance in AFP producing hepatoma is at least, in part, attributable to the high level of the cytoplasmic AFP. Therefore, it is possible that the combination of AFP gene silencing together with ATRA/TRAIL cotreatment will benefit the enhancement of the chemotherapeutic efficiency of these agents on tumors.
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NAT10, a nucleolar protein, localizes to the midbody and regulates cytokinesis and acetylation of microtubules.
Exp. Cell Res.
PUBLISHED: 03-03-2009
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The midbody is a structural organelle formed in late phase mitosis which is responsible for completion of cytokinesis. Although various kinds of proteins have been found to distribute or immigrate to this organelle, their functions have still not been completely worked out. In this study, we demonstrated that NAT10 (N-acetyltransferase 10, NAT10) is not only predominantly distributed in the nucleolus in interphase, but is also concentrated in the mitotic midbody during telophase. The domain in N-terminal residues 549-834 of NAT10 specifically mediated its subcellular localization. Treatment with genotoxic agents or irradiation increased concentration of NAT10 in both the nucleolus and midbody. Moreover, DNA damage induced increase of NAT10 in the midbody apparently accompanied by in situ elevation of the level of acetylated alpha-tubulin, suggesting that it plays a role in maintaining or enhancing stability of alpha-tubulin. The depletion of NAT10 induced defects in nucleolar assembly, cytokinesis and decreased acetylated alpha-tubulin, leading to G2/M cell cycle arrest or delay of mitotic exit. In addition, over-expression of NAT10 was found in a variety of soft tissue sarcomas, and correlated with tumor histological grading. These results indicate that NAT10 may play an important role in cell division through facilitating reformation of the nucleolus and midbody in the late phase of cell mitosis, and stabilization of microtubules.
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The comet assay: a sensitive method for detecting DNA damage in individual cells.
Methods
PUBLISHED: 02-18-2009
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The comet assay is a sensitive and rapid method for DNA strand break detection in individual cells, and the year 2009 represents the 25th anniversary of the first description of this methodology in 1984. Over time this method has been improved, but is still not completely standardized, and variations are currently in widespread use with emphasis on applications in research and genetic toxicology. Here we review the principles of the comet assay and cite key studies that have focused on this assay in the past 25 years. In addition, we present an example of how the comet assay was used in our laboratory for studying the induction of DNA damage in human lung cancer cells after differing doses of the cytosine analog 5-aza-2-deoxycytidine (5-aza-CdR). Finally, some insights into the potential of this assay in cancer research and work in related fields are offered.
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Involvement of STAT5a signaling in morphine-induced up-regulation of the cyclin D1.
Biochem. Pharmacol.
PUBLISHED: 02-11-2009
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Opioid receptors and cytokine receptor have been verified to have a functional link and interaction. However, the pathway by which opioid receptor in lymphocytes is linked to cytokine signaling is not well defined. Using confocal microscopy and Western blotting this study showed that morphine treatment was able to activate cytoplasmic STAT5a in CEM x174 cells, which then translocated into the nucleus and bound to elements of the cyclin D1 promoter. As a consequence the expression of the cyclin D1 was apparently up-regulated. The data from EMSA-superEMSA and ChIP-qPCR further confirmed that morphine was capable of promoting the binding of STAT5a to its elements (proximal and distal), and this was abolished by the antagonist naloxone. As shown by transient transfection assay, activity of the cyclin D1 promoter was significantly reduced by 82% (distal) and 65% (proximal) after two STAT5a elements were mutated in comparison with wild type STAT5a elements. Moreover, knockdown of STAT5a was associated with a concurrent silencing of morphine-induced expression of cyclin D1, demonstrating involvement of STAT5a in morphine-triggered signaling in the regulation of cyclin D1 expression. The finding provides evidence which demonstrates that there is cross-talk between the mu opioid receptor and cytokine signaling in lymphocytes. Thus, we conclude that morphine may modulate cyclin D1 gene expression via signal transducers and activators of transcription (STATs) signaling, which will be beneficial for further understanding of the pharmacological effect of morphine on immune regulation.
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Neuropathology in 2 cases of fatal enterovirus type 71 infection from a recent epidemic in the Peoples Republic of China: a histopathologic, immunohistochemical, and reverse transcription polymerase chain reaction study.
Hum. Pathol.
PUBLISHED: 01-30-2009
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Between late March and June of 2008, an outbreak of hand, foot, and mouth disease caused by enterovirus 71 occurred in China. In this outbreak, more than 176,000 cases occurred, and at least 40 people died. However, there has been no description of the neuropathologic features of fatal enterovirus 71 infection cases during this outbreak. We report postmortem studies in 2 fatal cases of enterovirus 71 infection with examination of the central nervous system using histopathology, immunohistochemistry, and reverse transcription polymerase chain reaction. Characteristic features of acute encephalitis were found predominantly in the brain stem and spinal cord. Abundant numbers of inflammatory cells with unusual irregularly rod-shaped and lobulated nuclei, which mimicked neutrophil morphology, were found both in abscess-like clusters associated with necrosis, as well as in inflammatory infiltrates. Immunohistochemistry showed that most of these cells were CD68 positive and CD15 negative. Viral antigens were found in the cytoplasm of neurons, neuronal processes, and inflammatory cells, most often associated with glial nodules. The presence of enterovirus 71 was confirmed by reverse transcription polymerase chain reaction and sequencing. Results indicate that immunohistochemistry with CD68 and CD15 may offer some help in the differential diagnosis of brain stem encephalitis caused by enterovirus 71. Postmortem reverse transcription polymerase chain reaction from brain stem tissues, which have already undergone fixation and histologic processing, can be an important diagnostic tool, which may be of particular value in patients who may have been misdiagnosed clinically.
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A cluster of polypyrimidine tracts is involved in the transcription regulation of telomerase transcriptional elements-interacting factor.
Mol. Cell. Biochem.
PUBLISHED: 01-28-2009
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In a previous study, we demonstrated that telomerase transcriptional elements-interacting factor (TEIF) could up-regulate the expression of telomerase and DNA polymerase beta, increasing resistance to genotoxic agents. Here, we further report that TEIF can be stimulated by DNA damage and we have identified a cluster of repeated polypyrimidine tracts in the promoter of TEIF, which mediate both its basal transcription and its response to genotoxic agents. These polypyrimidine tracts are arranged in three types of repeating units and in each of these units there are 14 bp length tandem sequences, which are repeated three times. These sequences are also characteristically separated by an 11 bp interval sequence. Among these units, one type (5-CCCCCCCATCCCCG-3) has been found to be involved in the transcriptional regulation of TEIF. At the same time, PTB1 (polypyrimidine tract-binding protein 1) has been shown to repress TEIF expression through interaction with this element. Up-regulation of TEIF may be achieved by PTB1 suppression that is induced by DNA damage, or by an olignucleotide decoy, which mediates reversal of suppression. This study provides new insight into the mechanism through which TEIF is involved in DNA damage response, together with insight into the role of polypyrimidine tracts in transcription regulation.
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The mechanism involved in the repression of the mu opioid receptor gene expression in CEM x174 cells infected by simian immunodeficiency virus.
J. Leukoc. Biol.
PUBLISHED: 01-21-2009
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Morphine can promote the pathogenesis of human acquired immunodeficiency syndrome through binding to the mu opioid receptor (MOR) in immune cells. Previous investigation has suggested that expression of the MOR gene in lymphocytes is triggered by cooperative interaction between transcription factors, specificity protein 1 (Sp1) and Ying Yang 1 (YY1), in the promoter region. However, the specific molecular mechanism by which immunodeficiency virus infection impacts regulation of the MOR gene expression in lymphocytes is still unclear. In this study, it was demonstrated that SIV (SIVmac239) infection may result in gradual reduction of the MOR gene expression and Sp1 during a period of 48 h postinfection by analysis of quantitative real-time RT-PCR and Western blotting. The results of methylation-specific PCR showed that two of 14 CpG islands adjacent to the Sp1 and YY1 elements in the promoter region were methylated, which together with reduced Sp1, contributed to the failure of interaction of Sp1 with YY1 and their binding to the elements, as determined by coimmunoprecipitation, chromatin immunoprecipitation-real-time PCR, and EMSAs. The repression of the MOR gene secondary to SIVmac239 infection could be abolished by the demethylating agent 5-aza-2-deoxycytidine. Transfection with Sp1-expressing vector (PN3-Sp1) was also able to enhance the activity of the promoter in SIVmac239-infected cells. We therefore concluded that aberrant methylation of the promoter and reduction of Sp1 resulting from SIVmac239 infection led to the silencing of the MOR gene. This finding will be helpful in understanding the synergistic mechanism of HIV infection and morphine addiction in the pathogenesis of AIDS.
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Changing pattern of adenocarcinoma of the esophagogastric junction in recent 10 years: experience at a large tertiary medical center in China.
Tumori
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To investigate the changing pattern of adenocarcinoma of the esophagogastric junction subtypes and its time trend relationship with that of reflux esophagitis over 10 years at a tertiary medical center in China.
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LAPTM4B allele *2 is a marker of poor prognosis for gallbladder carcinoma.
PLoS ONE
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Lysosomal protein transmembrane 4 beta (LAPTM4B) is a novel cancer-related gene which has two alleles designated LAPTM4B*1 and LAPTM4B*2. In this study we investigated the correlation of LAPTM4B genotype with prognosis and clinicopathologic features in patients who had undergone curative resection for gallbladder carcinoma (GBC).
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Pseudomonas aeruginosa syntrophy in chronically colonized airways of cystic fibrosis patients.
Antimicrob. Agents Chemother.
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Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients undergo remarkable phenotypic divergence over time, including loss of pigmentation, hemolysis, motility, and quorum sensing and emergence of antibiotic hypersusceptibility and/or auxotrophism. With prolonged antibiotic treatment and steady decline in lung function in chronically infected patients, the divergent characteristics associated with CF isolates have traditionally been regarded as "adapted/unusual virulence," despite the degenerative nature of these adaptations. We examined the phenotypic and genotypic diversity in clonally related isogenic strains of P. aeruginosa from individual CF patients. Our observations support a novel model of intra-airway pseudomonal syntrophy and accompanying loss of virulence. A 2007 calendar year collection of CF P. aeruginosa isolates (n = 525) from 103 CF patients yielded in vitro MICs of sulfamethoxazole-trimethoprim (SMX-TMP, which typically has no activity against P. aeruginosa) ranging from 0.02 to >32 ?g/ml (median, 1.5). Coisolation of clonally related SMX-TMP-susceptible and -resistant P. aeruginosa strains from the same host was common (57%), as were isogenic coisolates with mutations in efflux gene determinants (mexR, mexAB-oprM, and mexZ) and genes governing DNA mismatch repair (mutL and mutS). In this cohort, complete in vitro growth complementation between auxotrophic and prototrophic P. aeruginosa isogenic strains was evident and concurrent with the coding sequence mosaicism in resistance determinants. These observations suggest that syntrophic clonal strains evolve in situ in an organized colonial structure. We propose that P. aeruginosa adopts a multicellular lifestyle in CF patients due to host selection of an energetically favorable, less-virulent microbe restricted within and symbiotic with the airway over the hosts lifetime.
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Alpha-fetoprotein acts as a novel signal molecule and mediates transcription of Fn14 in human hepatocellular carcinoma.
J. Hepatol.
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The function of cytoplasmic AFP as a regulatory factor in the growth of tumor cells has been well defined. However, its precise mechanism of action and its clinical significance remain to be worked out.
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LAPTM4B allele *2 is a marker of poor prognosis following hepatic tumor resection for hepatocellular carcinoma.
PLoS ONE
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Lysosomal protein transmembrane 4 beta (LAPTM4B) is a gene related to hepatocellular carcinoma that has two alleles designated LAPTM4B*1 and LAPTM4B*2. This study aimed to investigate the correlation of LAPTM4B genotype with prognosis and clinicopathologic features in patients who have undergone resection for hepatocellular carcinoma (HCC).
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Correlation of LAPTM4B polymorphisms with gallbladder carcinoma susceptibility in Chinese patients.
Med. Oncol.
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Gallbladder carcinoma (GBC) is a malignancy with an extremely poor prognosis. In order to improve the survival rate, identification of new susceptibility risk factors is of importance. Here, we report findings on the novel cancer-related gene lysosomal protein transmembrane 4 beta (LAPTM4B) that has two alleles designated LAPTM4B*1 and LAPTM4B*2. Allele *1 differs from allele *2 in that it contains one copy of a 19-bp sequence, whereas this sequence is duplicated in exon 1 of allele *2. This study aimed to investigate the relationship of LAPTM4B allelic variation and GBC susceptibility. LAPTM4B genotype was analyzed in 155 healthy individuals and 91 GBC patients by PCR, and the genotypic distribution of LAPTM4B was analyzed with the chi-squared test. The frequency of allele *2 was 37.9 and 24.8% in the GBC and the control groups, respectively, representing a significant difference between these two groups (P<0.001). LAPTM4B allele *2 may be a risk factor associated with genetic susceptibility to GBC.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.