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1.
Public Health ; 190: 135-144, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33451823

ABSTRACT

OBJECTIVES: Diabetes mellitus is the most common cause of chronic kidney disease (CKD); however, the inter-relationships and pathogenetic mechanisms among risk factors are still largely unknown. Structural equation modelling (SEM) was applied to test a hypothesis of causal pathways related to CKD in patients with type 2 diabetes mellitus (T2DM). STUDY DESIGN: This is a prospective observational study. METHODS: A total of 3395 patients with T2DM were enrolled in this study. A hypothesised SEM was applied to assess associations among demographic data, diabetic self-management behaviours, diabetes control, lifestyle, psycho-social, chronic inflammation factors, anthropometric and metabolic variables simultaneously and the risk of CKD. RESULTS: Demographic data (including education, marital status and mini-mental state examination score) (-0.075), white blood cell count (0.084), high blood pressure (0.144), World Health Organisation (WHO) 5 well-being index (-0.082), diabetes control (0.099), triglyceride (0.091) and uric acid (0.282) levels had direct effects on the risk of CKD. The final model could explain 26% of the variability in baseline CKD status. In addition, the same direct and specific indirect factors at baseline CKD status analysis contributed to the risk of CKD at the 12-month follow-up. The final model could explain 31% of the variability in the risk of CKD at the 12-month follow-up. CONCLUSIONS: This study investigates associations between factors obtained from real-world daily practice and CKD status simultaneously and delineates the potential pathways and inter-relationships of the risk factors that contribute to the development of CKD in patients with T2DM.


Subject(s)
Diabetes Mellitus, Type 2/complications , Hypertension/complications , Hyperuricemia/diagnosis , Renal Insufficiency, Chronic/diagnosis , Triglycerides/blood , Uric Acid/blood , Adult , Aged , Biomarkers/blood , Blood Pressure/physiology , Diabetes Mellitus, Type 2/diagnosis , Female , Glomerular Filtration Rate , Humans , Hyperuricemia/blood , Hyperuricemia/etiology , Latent Class Analysis , Male , Middle Aged , Prospective Studies , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/etiology , Risk Factors
3.
Osteoporos Int ; 29(6): 1227-1242, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29460102

ABSTRACT

Fracture liaison services (FLS), implemented in different ways and countries, are reported to be a cost-effective or even a cost-saving secondary fracture prevention strategy. This presumed favorable cost-benefit relationship is encouraging and lends support to expanded implementation of FLS per International Osteoporosis Foundation Best Practice Standards. This study summarizes the economic impact and cost-effectiveness of FLS implemented to reduce subsequent fractures in individuals with osteoporosis. This systematic review identified studies reporting economic outcomes for FLS in osteoporotic patients aged 50 and older through a comprehensive search of MEDLINE, EMBASE, Cochrane Central, and PubMed of studies published January, 2000 to December, 2016. Grey literature (e.g., Google scholar, conference abstracts/posters) were also hand searched through February 2017. Two independent reviewers screened titles and abstracts and conducted full-text review on qualified articles. All disagreements were resolved by discussion between reviewers to reach consensus or by a third reviewer. In total, 23 qualified studies that evaluated the economic aspects of FLS were included: 16 cost-effectiveness studies, 2 cost-benefit analyses, and 5 studies of cost savings. Patient populations varied (prior fragility fracture, non-vertebral fracture, hip fracture, wrist fracture), and FLS strategies ranged from mail-based interventions to comprehensive nurse/physician-coordinated programs. Cost-effectiveness studies were conducted in Canada, Australia, USA, UK, Japan, Taiwan, and Sweden. FLS was cost-effective in comparisons with usual care or no treatment, regardless of the program intensity or the country in which the FLS was implemented (cost/QALY from $3023-$28,800 US dollars (USD) in Japan to $14,513-$112,877 USD in USA. Several studies documented cost savings. FLS, implemented in different ways and countries, are reported to be cost-effective or even cost-saving. This presumed favorable cost-benefit relationship is encouraging and lends support to expanded implementation of FLS per International Osteoporosis Foundation Best Practice Standards.


Subject(s)
Osteoporotic Fractures/prevention & control , Secondary Prevention/economics , Cost-Benefit Analysis , Delivery of Health Care/economics , Delivery of Health Care/organization & administration , Health Care Costs/statistics & numerical data , Humans , Osteoporosis/economics , Osteoporosis/therapy , Osteoporotic Fractures/economics , Secondary Prevention/organization & administration
4.
Oncogenesis ; 6(8): e369, 2017 Aug 07.
Article in English | MEDLINE | ID: mdl-28785073

ABSTRACT

The coupling between DNA methylation and histone modification contributes to aberrant expression of oncogenes or tumor suppressor genes that leads to tumor development. Our previous study demonstrated that lysine demethylase 2A (KDM2A) functions as an oncogene in breast cancer by promoting cancer stemness and angiogenesis via activation of the Notch signaling. Here, we demonstrate that knockdown of KDM2A significantly increases the 5'-hydroxymethylcytosine (5'-hmc) level in genomic DNA and expression of tet-eleven translocation 2 (TET2) in various breast cancer cell lines. Conversely, ectopic expression of KDM2A inhibits TET2 expression in KDM2A-depleted cells suggesting TET2 is a transcriptional repression target of KDM2A. Our results show that KDM2A interacts with RelA to co-occupy at the TET2 gene promoter to repress transcription and depletion of RelA or KDM2A restores TET2 expression. Upregulation of TET2 in the KDM2A-depleted cells induces the re-activation of two TET downstream tumor suppressor genes, epithelial cell adhesion molecule (EpCAM) and E-cadherin, and inhibits migration and invasion. On the contrary, knockdown of TET2 in these cells decreases EpCAM and E-cadherin and increases cell invasiveness. More importantly, TET2 expression is negatively associated KDM2A in triple-negative breast tumor tissues, and its expression predicts a better survival. Taken together, we demonstrate for the first time that TET2 is a direct repression target of KDM2A and reveal a novel mechanism by which KDM2A promotes DNA methylation and breast cancer progression via the inhibition of a DNA demethylase.

5.
Oncogene ; 36(39): 5532-5543, 2017 09 28.
Article in English | MEDLINE | ID: mdl-28581520

ABSTRACT

Krüppel-like transcription factor 10 (KLF10), also named as TIEG1, plays essential roles in mediating transforming growth factor beta (TGFß) signaling and has been shown to function as a tumor suppressor in multiple cancer types. However, its roles in mediating cancer progression in vivo have yet to be fully characterized. Here, we have employed two well-characterized Pdx-1CreLSL-KrasG12D and Pdx-1CreLSL-KrasG12Dp53L/L pancreatic cancer models to ablate KLF10 expression and determine the impact of KLF10 deletion on tumor development and progression. We show that loss of KLF10 cooperates with KrasG12D leading to an invasive and widely metastatic phenotype of pancreatic ductal adenocarcinoma (PDAC). Mechanistically, loss of KLF10 in PDAC is shown to increase distant metastases and cancer stemness through activation of SDF-1/CXCR4 and AP-1 pathways. Furthermore, we demonstrate that targeting the SDF-1/CXCR4 pathway in the context of KLF10 deletion substantially suppresses PDAC progression suggesting that inhibition of this pathway represents a novel therapeutic strategy for PDAC treatment.


Subject(s)
Carcinoma, Pancreatic Ductal/metabolism , Chemokine CXCL12/metabolism , Early Growth Response Transcription Factors/deficiency , Kruppel-Like Transcription Factors/deficiency , Pancreatic Neoplasms/metabolism , Animals , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Chemokine CXCL12/genetics , Early Growth Response Transcription Factors/genetics , Early Growth Response Transcription Factors/metabolism , Humans , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Mice , Mice, Inbred C57BL , Neoplasm Metastasis , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins p21(ras)/genetics , Signal Transduction , Survival Rate , Tumor Suppressor Protein p53/genetics
6.
New Microbes New Infect ; 13: 17-21, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27358743

ABSTRACT

The pathogenesis of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) pneumonia in influenza-infected elderly individuals has not yet been elucidated in detail. In the present study, a 92-year-old man infected with influenza developed CA-MRSA pneumonia. His CA-MRSA was an emerging type, originated in ST121/agr4 S. aureus, with diversities of Panton-Valentine leucocidin (PVL)(-)/spat5110/SCCmecV(+) versus PVL(+)/spat159((etc.))/SCCmec (-), but with common virulence potentials of strong adhesin and cytolytic activities. Resistance to erythromycin/clindamycin (inducible-type) and gentamicin was detected. Pneumonia improved with the administration of levofloxacin, but with the subsequent development of fatal aspiration pneumonia. Hence, characteristic CA-MRSA with strong adhesin and cytolytic activities triggered influenza-related sequential complications.

7.
Oncogene ; 35(17): 2223-34, 2016 04 28.
Article in English | MEDLINE | ID: mdl-26411367

ABSTRACT

Adenomatous polyposis coli (APC), a tumor-suppressor gene critically involved in familial adenomatous polyposis, is integral in Wnt/ß-catenin signaling and is implicated in the development of sporadic tumors of the distal gastrointestinal tract including pancreatic cancer (PC). Here we report for the first time that functional APC is required for the growth and maintenance of pancreatic islets and maturation. Subsequently, a non-Kras mutation-induced premalignancy mouse model was developed; in this model, APC haploinsufficiency coupled with p53 deletion resulted in the development of a distinct type of pancreatic premalignant precursors, mucinous cystic neoplasms (MCNs), exhibiting pathomechanisms identical to those observed in human MCNs, including accumulation of cystic fluid secreted by neoplastic and ovarian-like stromal cells, with 100% penetrance and the presence of hepatic and gastric metastases in >30% of the mice. The major clinical implications of this study suggest targeting the Wnt signaling pathway as a novel strategy for managing MCN.


Subject(s)
Adenomatous Polyposis Coli Protein/genetics , Neoplasms, Glandular and Epithelial/genetics , Pancreatic Neoplasms/genetics , Tumor Suppressor Protein p53/genetics , Animals , Disease Models, Animal , Female , Haploinsufficiency/genetics , Humans , Loss of Heterozygosity , Mice , Neoplasms, Glandular and Epithelial/pathology , Pancreatic Neoplasms/pathology , Wnt Signaling Pathway/genetics , Pancreatic Neoplasms
8.
Blood Cancer J ; 5: e313, 2015 May 15.
Article in English | MEDLINE | ID: mdl-25978433

ABSTRACT

Epigenetic modifying enzymes have a crucial role in the pathogenesis of acute myeloid leukemia (AML). Methylation of lysine 9 on histone H3 by the methyltransferase G9a and SUV39H1 is associated with inhibition of tumor suppressor genes. We studied the effect of G9a and SUV39H1 inhibitors on viability and differentiation of AML cells and tested the cytotoxicity induced by combination of G9a and SUV39H1 inhibitors and various epigenetic drugs. The SUV39H1 inhibitor (chaetocin) and the G9a inhibitor (UNC0638) caused cell death in AML cells at high concentrations. However, only chaetocin-induced CD11b expression and differentiation of AML cells at non-cytotoxic concentration. HL-60 and KG-1a cells were more sensitive to chaetocin than U937 cells. Long-term incubation of chaetocin led to downregulation of SUV39H1 and reduction of H3K9 tri-methylation in HL-60 and KG-1a cells. Combination of chaetocin with suberoylanilide hydroxamic acid (SAHA, a histone deacetylase inhibitor) or JQ (a BET (bromodomain extra terminal) bromodomain inhibitor) showed synergistic cytotoxicity. Conversely, no synergism was found by combining chaetocin and UNC0638. More importantly, chaetocin-induced differentiation and combined cytotoxicity were also found in the primary cells of AML patients. Collectively, the SUV39H1 inhibitor chaetocin alone or in combination with other epigenetic drugs may be effective for the treatment of AML.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Differentiation/drug effects , DNA Methylation/drug effects , Leukemia, Myeloid, Acute/drug therapy , Methyltransferases/antagonists & inhibitors , Repressor Proteins/antagonists & inhibitors , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cells, Cultured , Drug Synergism , Epigenesis, Genetic , Humans , Immunoblotting , Piperazines/pharmacology , Reverse Transcriptase Polymerase Chain Reaction
9.
Oncogene ; 34(35): 4558-69, 2015 Aug 27.
Article in English | MEDLINE | ID: mdl-25435370

ABSTRACT

Interstitial fluid flow in and around the tumor tissue is a physiologically relevant mechanical signal that regulates intracellular signaling pathways throughout the tumor. Yet, the effects of interstitial flow and associated fluid shear stress on the tumor cell function have been largely overlooked. Using in vitro bioengineering models in conjunction with molecular cell biology tools, we found that fluid shear (2 dyn/cm(2)) markedly upregulates matrix metalloproteinase 12 (MMP-12) expression and its activity in human chondrosarcoma cells. MMP-12 expression is induced in human chondrocytes during malignant transformation. However, the signaling pathway regulating MMP-12 expression and its potential role in human chondrosarcoma cell invasion and metastasis have yet to be delineated. We discovered that fluid shear stress induces the synthesis of insulin growth factor-2 (IGF-2) and vascular endothelial growth factor (VEGF) B and D, which in turn transactivate MMP-12 via PI3-K, p38 and JNK signaling pathways. IGF-2-, VEGF-B- or VEGF-D-stimulated chondrosarcoma cells display markedly higher migratory and invasive potentials in vitro, which are blocked by inhibiting MMP-12, PI3-K, p38 or JNK activity. Moreover, recombinant human MMP-12 or MMP-12 overexpression can potentiate chondrosarcoma cell invasion in vitro and the lung colonization in vivo. By reconstructing and delineating the signaling pathway regulating MMP-12 activation, potential therapeutic strategies that interfere with chondrosarcoma cell invasion may be identified.


Subject(s)
Bone Neoplasms/enzymology , Chondrosarcoma/enzymology , Insulin-Like Growth Factor II/physiology , Lung Neoplasms/enzymology , Matrix Metalloproteinase 12/metabolism , Vascular Endothelial Growth Factor B/metabolism , Vascular Endothelial Growth Factor D/metabolism , Animals , Biomechanical Phenomena , Bone Neoplasms/pathology , Cell Line, Tumor , Cell Movement , Chondrosarcoma/secondary , Enzyme Activation , Enzyme Induction , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/secondary , MAP Kinase Signaling System , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Neoplasm Invasiveness , Neoplasm Transplantation
10.
Br J Cancer ; 109(3): 731-8, 2013 Aug 06.
Article in English | MEDLINE | ID: mdl-23820254

ABSTRACT

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) activation is frequently found in human lung cancer and is associated with increased metastasis and reduced survival. How STAT3 enhances invasiveness is unclear. METHODS: The expression of microRNAs and target genes was measured by real-time RT-PCR. Protein level was studied by western blotting. Luciferase reporter assay was used to confirm the direct targeting of microRNAs. Gelatin zymography was used to study matrix metalloproteinase (MMP) activity. Transwell assay was used to investigate cell migration and invasion. RESULTS: Enforced expression of STAT3 decreases the endogenous MMP inhibitor RECK protein but not mRNA level in H460 cells. Conversely, STAT3 inhibitor S3I-201 increases RECK protein in STAT3-activating H1299 cells. We demonstrate that STAT3 upregulates miR-92a to repress RECK via post-transcriptional inhibition. The RECK 3'-untranslated region (3'UTR) reporter activity assay suggests that RECK is a direct repression target of miR-92a. Delivery of pre-miR-92a reduces RECK protein level whereas transfection of anti-miR-92a restores STAT3-induced downregulation of RECK. Anti-miR-92a attenuates MMP activity, migration and invasion of H1299 cells and STAT3-overexpressing H460 cells, suggesting miR-92a is critical for STAT3-induced invasiveness. CONCLUSION: The STAT3-induced miR-92a promotes cancer invasion by suppressing RECK and targeting of the STAT3/miR-92a axis may be helpful for cancer treatment.


Subject(s)
GPI-Linked Proteins/antagonists & inhibitors , MicroRNAs/genetics , STAT3 Transcription Factor/genetics , Cell Line, Tumor , Cell Movement/physiology , GPI-Linked Proteins/biosynthesis , GPI-Linked Proteins/genetics , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , MicroRNAs/metabolism , Neoplasm Invasiveness , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , STAT3 Transcription Factor/metabolism , Transcription, Genetic , Transfection , Up-Regulation
11.
Curr Pharm Biotechnol ; 12(5): 839-46, 2011 May.
Article in English | MEDLINE | ID: mdl-21446905

ABSTRACT

Three blending methods were introduced to combine a biodegradable cationic- polyurethane (PUg3) and polyethylenimine (PEI) together with DNA by different mixing sequences. Results of gel electrophoresis assays and particle size measurements show that complexes prepared by method 1 and 3 bear an ability to condense DNA into small nanoparticles. On the contrary, the use of method 2 in making complexes produces significantly large particles because of the weaker interaction with DNA and lack of DNA condensation. Moreover, cell proliferation assays show that no cytotoxicity of the DNA/blended-polymers complexes (exhibited by method 1) was found and due to a result of the outer coating of PUg3, reducing cytotoxic PEI exposure outside the complexes. With a new technique in pharmaceutics, the complexes prepared for DNA delivery by mixing of PEI and PUg3 with DNA in a sequence (method 1) could achieve an even better transfection efficiency (reaching 40% higher) than using PEI alone as well as reduce the cytotoxicity substantially. In conclusion, a new class of complexes (non-viral combo-system) made by a skillful blending sequence (method 1) has been designed and demonstrated to obtain the beneficial properties from two useful and individual polymers for gene delivery. This method can be used in greatly improving the transfection efficiency of polymer-based gene vectors. The blended polymers with DNA also have a better biocompatibility and no cytotoxicity, which are the requirements and critical points for great success in performing gene therapy in vivo.


Subject(s)
DNA/administration & dosage , Polyethyleneimine/chemistry , Polyurethanes/chemistry , Transfection/methods , Animals , COS Cells , Cations/administration & dosage , Cations/chemistry , Cell Proliferation/drug effects , Chlorocebus aethiops , DNA/chemistry , DNA/genetics , Genetic Therapy/methods , Genetic Vectors/administration & dosage , Genetic Vectors/genetics , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Particle Size , Polyethyleneimine/administration & dosage , Polyurethanes/administration & dosage , Tumor Cells, Cultured
12.
Exp Clin Endocrinol Diabetes ; 118(6): 346-52, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20140850

ABSTRACT

BACKGROUND: Cytochrome P450 (CYP) 2J2 is a regulatory enzyme in the biosynthesis of biologically active CIS-epoxyeicosatrienoic acids (EETs). EETs have been suggested to modulate PPAR-gamma and PPAR-alpha transcription activity and play a role in stimulus-secretion coupling in pancreatic beta cells. Genetic abnormalities in the expression of CYP2J enzymes may play a role in the pathogenesis of type 2 diabetes mellitus (T2DM). Our objective was to investigate CYP2J2 G-50T polymorphism (rs890293) in association with insulin resistance markers and T2DM in a Chinese population. METHODS: A total of 1 747 Chinese T2DM patients and 994 non-diabetic subjects were studied. The CYP2J2 G-50T polymorphism was determined by a restriction fragment-length polymorphism polymerase chain reaction. RESULTS: Neither the CYP2J2 genotype distribution nor allele frequency differed between the control subjects and the T2DM patients. However, among diabetics, subjects with a younger age at diagnosis (AAD; <40 years) had significantly higher T variant frequency than those with an AAD>/=40 years. When diabetic patients were stratified by their AAD in 10-year intervals, the trend was significantly linear among age grades. A significant interaction between the CYP2J2 T variant and younger onset diabetic subjects with positive family diabetes history, and BMI>/=27 kg/m (2) were observed to have the highest risk of diabetes and younger onset diabetics with the T variant had higher homeostasis model assessment estimate of insulin resistance (HOMA-IR) and HOMA-beta values than their GG genotype counterparts. Plasma concentrations of stable EET metabolites were significantly lower in individuals with the G-50T SNP in younger onset diabetics. CONCLUSION: These data suggest that age of onset, family history, and obesity may modify the association between the CYP2J2 G-50T polymorphism and T2DM risk. CYP2J2 G-50T polymorphism may contribute to the pathogenesis of T2DM, partially by effects on insulin resistance, in patients with younger onset T2DM.


Subject(s)
Cytochrome P-450 Enzyme System/genetics , Diabetes Mellitus, Type 2/genetics , Polymorphism, Single Nucleotide , Adolescent , Adult , Age of Onset , Asian People/genetics , Body Mass Index , China , Cytochrome P-450 CYP2J2 , Diabetes Mellitus, Type 2/enzymology , Genetic Predisposition to Disease , Humans , Insulin Resistance/genetics , Medical History Taking , Obesity/genetics , Oxygenases/genetics , Polymorphism, Genetic , Polymorphism, Restriction Fragment Length , Risk Assessment
13.
Lasers Surg Med ; 41(5): 391-7, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19533759

ABSTRACT

BACKGROUND AND OBJECTIVES: Multidrug-resistant (MDR) Pseudomonas aeruginosa infection is becoming a critical problem worldwide. Currently, only limited therapeutic options are available for the treatment of infections caused by MDR P. aeruginosa, therefore, the development of new alternative treatments is needed. Toluidine blue O (TBO) is an effective antibacterial photosensitizing agent against various bacteria. However, reports on antibacterial photosensitization of MDR bacteria are limited. This study aims to determine the in vitro photobactericidal activity of TBO against MDR P. aeruginosa. STUDY DESIGN/MATERIALS AND METHODS: The efficacy of antibacterial photodynamic inactivation, DNA fragmentation and protein carbonylation of three MDR P. aeruginosa strains and one susceptible strain was compared using TBO as the photosensitizer followed by red light irradiation (630 nm, 90 J/cm(2)) from a light-emitting diode light source. Subsequently, the efficacy of TBO photodynamic inactivation (TBO-PDI) on 60 MDR strains, including 11 with the efflux pump phenotype and 49 with no pump activity, was tested using the minimum lethal drug concentration (MLC) assay. RESULTS: TBO-PDI caused similar bactericidal effect (6-7 logs of killing effect), DNA fragmentation and protein carbonylation in three MDR and one susceptible P. aeruginosa strains. Although the TBO accumulation assay indicated that TBO is a substrate for the efflux pump, TBO-PDI produce similar photobactericidal activity against 60 MDR P. aeruginosa strains, either with or without efflux-pump phenotype, and 19 susceptible strains. CONCLUSION: MDR did not affect the susceptibility of P. aeruginosa strains to TBO-PDI. The efflux pump played an insignificant role in TBO-PDI of MDR P. aeruginosa.


Subject(s)
Drug Resistance, Multiple, Bacterial/drug effects , Drug Resistance, Multiple, Bacterial/radiation effects , Photochemotherapy , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/radiation effects , Tolonium Chloride/pharmacology , Humans , Microbial Sensitivity Tests
14.
Cancer Gene Ther ; 15(6): 393-401, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18369382

ABSTRACT

Increasing the specificity of chemotherapy may improve the efficacy of cancer treatment. Toward this aim, we developed a strain of bacteria to express enzymes for selective prodrug activation and non-invasive imaging in tumors. beta-glucuronidase and the luxCDABE gene cluster were expressed in the DH5alpha strain of Escherichia coli to generate DH5alpha-lux/betaG. These bacteria emitted light for imaging and hydrolyzed the glucuronide prodrug 9ACG to the topoisomerase I inhibitor 9-aminocamptothecin (9AC). By optical imaging, colony-forming units (CFUs) and staining for betaG activity, we found that DH5alpha-lux/betaG preferentially localized and replicated within CL1-5 human lung tumors in mice. The intensity of luminescence, CFU and betaG activity increased with time, indicating bacterial replication occurred in tumors. In comparison with DH5alpha-lux/betaG, 9AC or 9ACG treatment, combined systemic administration of DH5alpha-lux/betaG followed by 9ACG prodrug treatment significantly (P<0.005) delayed the growth of CL1-5 tumors. Our results demonstrate that prodrug-activating bacteria may be useful for selective cancer chemotherapy.


Subject(s)
Bacteria/metabolism , Neoplasms/therapy , Prodrugs/therapeutic use , Animals , Bacteria/genetics , Glucuronidase/genetics , Glucuronidase/metabolism , Glucuronides/metabolism , Humans , Models, Biological , Neoplasms/microbiology , Neoplasms/pathology , Prodrugs/metabolism
15.
J Clin Pathol ; 61(5): 658-64, 2008 May.
Article in English | MEDLINE | ID: mdl-17908805

ABSTRACT

BACKGROUND: Hypoxia inducible factor (HIF)-1alpha is a critical regulatory protein of cellular response to hypoxia and is closely related to angiogenic process. AIMS: To explore the potential role and the prognostic value of HIF-1alpha in urothelial carcinoma (UC). METHODS: Clinicopathological and follow-up data on 99 UC cases were reviewed and immunostained for HIF-1alpha, CD68, vascular endothelial growth factor (VEGF) and CD34 antigen. Tumour-associated macrophage (TAM) counts and HIF-1alpha expression were compared with clinicopathologic characteristics, overall survival (OS) and disease-free survival rates (DFS). RESULTS: High expression of HIF-1alpha was detected in 55 of 99 (55.6%) tumours. HIF-1alpha expression was correlated with tumour size, histological grade, tumour invasiveness and recurrence. VEGF and microvessel density (MVD) demonstrated their positive correlation with HIF-1alpha overexpression, supporting the correlation of HIF-1alpha up-regulation with tumour angiogenesis. Higher TAM infiltration was identified in high expression of HIF-1alpha cases rather than HIF-1alpha low expression cases (p = 0.002). Kaplan-Meier analysis found that HIF-1alpha overexpression and high TAM count was only associated with worse DFS (p = 0.009, p = 0.023) but was not associated with OS (p = 0.696, p = 0.141). Multivariate analyses indicated only tumour size (p = 0.038) to be an independently significant prognostic factor for OS, in addition, HIF-1alpha expression (p = 0.011), as well as histological grade (p = 0.038), and MVD (p = 0.004), to be independently significant prognostic factors for DFS. CONCLUSIONS: Our results indicate that HIF-1alpha is a key regulator of the angiogenic cascade. We show that HIF-1alpha is an independent prognostic factor for disease-free survival.


Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Transitional Cell/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Macrophages/pathology , Neovascularization, Pathologic/metabolism , Urinary Bladder Neoplasms/metabolism , Adult , Aged , Aged, 80 and over , Carcinoma, Transitional Cell/blood supply , Carcinoma, Transitional Cell/pathology , Disease Progression , Female , Follow-Up Studies , Humans , Immunoenzyme Techniques , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Proteins/metabolism , Prognosis , Survival Analysis , Urinary Bladder Neoplasms/blood supply , Urinary Bladder Neoplasms/pathology , Vascular Endothelial Growth Factor A/metabolism
16.
Histopathology ; 51(6): 785-92, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17953697

ABSTRACT

AIMS: The mechanisms of urothelial carcinogenesis in areas highly contaminated with arsenic remain unclear. The aim was to determine whether hypermethylation of death-associated protein kinase (DAPK) gene is associated with chronic arsenic exposure. METHODS AND RESULTS: The frequency of aberrant promoter methylation of DAPK in 17 urothelial carcinomas from an arsenic-contaminated area and 21 urothelial carcinomas from a non-arsenic-contaminated area was determined by methylation-specific polymerase chain reaction. DAPK hypermethylation status was significantly higher in urothelial cancers arising in arsenic-contaminated areas when compared with tumours from patients from non-contaminated areas (P = 0.018). In the subset of patients from living environments which were contaminated with arsenic, there was a statistically significant association between DAPK hypermethylation and patient's age, tumour invasiveness, histological grade and recurrence. This was not seen for urothelial carcinoma from patients from non-contaminated areas. A close correlation was also found between DAPK promoter methylation and low-intensity DAPK expression, as detected by immunohistochemistry (P = 0.037). CONCLUSION: Exposure to arsenic may induce DAPK promoter hypermethylation and inactivate the function of DAPK in urothelial carcinoma. This could prove to be a key molecular event contributing to the malignant phenotype of tumour arising in patients from arsenic-contaminated environments.


Subject(s)
Apoptosis Regulatory Proteins/genetics , Arsenic Poisoning/genetics , Calcium-Calmodulin-Dependent Protein Kinases/genetics , Carcinoma/genetics , DNA Methylation , Urinary Bladder Neoplasms/genetics , Aged , Biomarkers, Tumor/genetics , Carcinoma/chemically induced , Death-Associated Protein Kinases , Female , Humans , Immunohistochemistry , Male , Middle Aged , Polymerase Chain Reaction , Promoter Regions, Genetic , Taiwan/epidemiology , Urinary Bladder Neoplasms/chemically induced , Urothelium/drug effects , Urothelium/pathology
17.
Neurology ; 66(6): 804-8, 2006 Mar 28.
Article in English | MEDLINE | ID: mdl-16567695

ABSTRACT

BACKGROUND: Turbulent blood flow caused by arterial stenosis can induce platelet activation and aggregation, which subsequently participate in arterial thromboembolic events. OBJECTIVE: To test the hypothesis that platelet activation (expressed by CD62p) is enhanced in cerebral vs systemic circulation in patients with severe internal carotid artery (ICA) stenosis. METHODS: Platelet CD62p expression was prospectively measured using flow cytometry in 35 consecutive symptomatic patients with severe ICA stenosis and in 20 at-risk control subjects who underwent both coronary and cerebral angiographic studies due to angina pectoris and suspicious vertebral artery or intracranial artery stenosis. The CD62p expression was also evaluated in 20 healthy subjects. Blood samples were first drawn from the right internal jugular vein (cerebral circulation) and right femoral vein (systemic circulation) before extra- and intracerebral angiographic examination of both patients and at-risk control subjects and again at 40 minutes after ICA stenting. Clopidogrel was administered to the patients following the second blood sampling. RESULTS: Systemic CD62p expression was higher in patients than in both the healthy and at-risk control subjects (both p < 0.0001). Additionally, cerebral CD62p expression was higher in patients than in at-risk control subjects (p < 0.0001) prior to intervention. Moreover, CD62p expression was higher in cerebral circulation than in systemic circulation in the patients (p < 0.0001) before ICA stenting. However, CD62p expression was less enhanced in cerebral circulation than in systemic circulation after ICA stenting (p < 0.0001). Furthermore, CD62p expression was decreased after 3 months of follow-up (p < 0.0001). CONCLUSIONS: Compared to systemic CD62p expression, cerebral CD62p expression was more enhanced prior to ICA stenting and was less enhanced after ICA stenting in patients with severe ICA stenosis.


Subject(s)
Carotid Artery, Internal/metabolism , Carotid Stenosis/blood , Platelet Activation/physiology , Aged , Brain/diagnostic imaging , Brain/metabolism , Carotid Artery, Internal/diagnostic imaging , Carotid Stenosis/diagnostic imaging , Female , Humans , Male , Middle Aged , P-Selectin/biosynthesis , Prospective Studies , Radiography
18.
FEBS Lett ; 508(3): 365-8, 2001 Nov 23.
Article in English | MEDLINE | ID: mdl-11728453

ABSTRACT

Recent studies show that up-regulation of cyclooxygenase-2 (COX-2) in human cancer cells induces activation of matrix metalloproteinases (MMPs) and increase of metastatic potential. In this study, we investigate the effect of a COX-2 selective inhibitor, NS398, on the expression and enzymatic activity of MMPs in human lung cancer cells. We found that NS398 inhibited MMP-2, not MMP-9, mRNA expression. NS398 also reduced the amount of MMP-2, not MMP-9, released into the medium. Additionally, this COX-2 inhibitor attenuated the degrading activity of MMP-2 as demonstrated by gelatin zymography. Investigation of cellular MMP-2 by Western blotting indicated that synthesis and processing of MMP-2 was significantly suppressed by NS398. We performed promoter activity assay to address whether NS398 might affect MMP-2 gene transcription. Our results indicated that NS398 directly inhibited MMP-2 promoter activity. However, the inhibitory effect of NS398 is not fully dependent on inhibition of COX-2 because a high concentration of NS398 was needed to suppress MMP-2 expression and addition of prostaglandin E2 only partially reversed the action of NS398. Moreover, a non-selective COX inhibitor indomethacin also suppressed the expression of MMP-2. Taken together, these results indicate that non-steroidal anti-inflammatory drugs suppress MMP-2 expression via repression of transcription and support the notion that COX inhibitors may be useful in inhibition and/or prevention of metastasis.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Gene Expression Regulation, Enzymologic/drug effects , Lung Neoplasms/enzymology , Matrix Metalloproteinase 2/genetics , Nitrobenzenes/pharmacology , Sulfonamides/pharmacology , Transcription, Genetic/drug effects , Culture Media, Conditioned , Cyclooxygenase Inhibitors/pharmacology , Dinoprostone/pharmacology , Dose-Response Relationship, Drug , Humans , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/genetics , Promoter Regions, Genetic/drug effects , Reverse Transcriptase Polymerase Chain Reaction , Transfection , Tumor Cells, Cultured
19.
Jpn Heart J ; 42(4): 519-23, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11693287

ABSTRACT

A 23 year-old Taiwanese male presented with complete membranous obstruction of the inferior vena cava at its suprahepatic portion. After 3 angioplasty procedures using Inoue-balloon catheters, a Wall stent was deployed for restenosis 4 years after the first procedure. Venography at 6 months showed no significant restenosis. At 20 months transfemoral venography confirmed patency of the vena cava.


Subject(s)
Angioplasty, Balloon , Budd-Chiari Syndrome/therapy , Stents , Vena Cava, Inferior/pathology , Adult , Budd-Chiari Syndrome/pathology , Constriction, Pathologic , Humans , Male , Recurrence
20.
Am J Kidney Dis ; 38(5): 1096-104, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11684565

ABSTRACT

Advanced glycation end products (AGEs) are important in the pathogenesis of diabetic nephropathy, which leads to renal fibrosis. Previously, we found that the janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway is necessary for AGE-induced cellular proliferation in normal rat kidney interstitial fibroblast (NRK-49F) cells. However, a direct link between JAK/STAT and cell-cycle progression has not been well established. In this regard, STAT5 has been found to induce cyclin D1 and proliferation in hematopoietic cells. Therefore, we examined effects of AGE on STAT5 and cell-cycle-dependent mitogenesis in NRK-49F cells. We found that AGE increased cyclin D1 expression and cyclin-dependent kinase (cdk)4 activity while decreasing p21(WAF1/CIP1) expression. We also found that AGE (100 microg/mL) induced STAT5 tyrosine phosphorylation. Meanwhile, AGE induced STAT5 protein-DNA binding activity, which was reversed by AG-490 (a specific JAK2 inhibitor) and STAT5 decoy oligodeoxynucleotide (ODN). In addition, STAT5 decoy ODN reversed AGE-induced cell-cycle-dependent cellular proliferation and cyclin D1 protein expression. We concluded that AGE induced cell-cycle-dependent cellular proliferation by inducing the JAK2-STAT5-cyclin D1 and cdk4 pathways in NRK-49F cells.


Subject(s)
Cell Division/drug effects , Cyclin D1/drug effects , DNA-Binding Proteins/physiology , Glycation End Products, Advanced/pharmacology , Milk Proteins , Protein-Tyrosine Kinases/physiology , Proto-Oncogene Proteins , Trans-Activators/physiology , Animals , Cell Cycle/drug effects , Cell Cycle/physiology , Cell Cycle Proteins/drug effects , Cell Cycle Proteins/metabolism , Cell Division/physiology , Cell Line , Cyclin D1/metabolism , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinases/drug effects , Cyclin-Dependent Kinases/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Electrophoretic Mobility Shift Assay , Janus Kinase 2 , Oligonucleotides/genetics , Oligonucleotides/pharmacology , Phosphorylation/drug effects , Protein Binding/drug effects , STAT5 Transcription Factor , Signal Transduction/drug effects , Time Factors , Trans-Activators/genetics , Trans-Activators/metabolism , Tyrosine/metabolism
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