Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 173
Filter
1.
Psychol Med ; 51(14): 2347-2356, 2021 10.
Article in English | MEDLINE | ID: mdl-32317043

ABSTRACT

BACKGROUND: Cognitive disturbances are common and disabling features of major depressive disorder (MDD). Previous studies provide limited insight into the co-occurrence of hot (emotion-dependent) and cold (emotion-independent) cognitive disturbances in MDD. Therefore, we here map both hot and cold cognition in depressed patients compared to healthy individuals. METHODS: We collected neuropsychological data from 92 antidepressant-free MDD patients and 103 healthy controls. All participants completed a comprehensive neuropsychological test battery assessing hot cognition including emotion processing, affective verbal memory and social cognition as well as cold cognition including verbal and working memory and reaction time. RESULTS: The depressed patients showed small to moderate negative affective biases on emotion processing outcomes, moderate increases in ratings of guilt and shame and moderate deficits in verbal and working memory as well as moderately slowed reaction time compared to healthy controls. We observed no correlations between individual cognitive tasks and depression severity in the depressed patients. Lastly, an exploratory cluster analysis suggested the presence of three cognitive profiles in MDD: one characterised predominantly by disturbed hot cognitive functions, one characterised predominantly by disturbed cold cognitive functions and one characterised by global impairment across all cognitive domains. Notably, the three cognitive profiles differed in depression severity. CONCLUSION: We identified a pattern of small to moderate disturbances in both hot and cold cognition in MDD. While none of the individual cognitive outcomes mapped onto depression severity, cognitive profile clusters did. Overall cognition-based stratification tools may be useful in precision medicine approaches to MDD.


Subject(s)
Cluster Analysis , Cognitive Dysfunction , Depressive Disorder, Major/therapy , Neuropsychological Tests/statistics & numerical data , Adult , Emotions/physiology , Female , Guilt , Humans , Male , Memory, Short-Term/physiology , Social Cognition
2.
AJNR Am J Neuroradiol ; 39(6): 1177-1184, 2018 06.
Article in English | MEDLINE | ID: mdl-29674416

ABSTRACT

BACKGROUND AND PURPOSE: Neural system was one of the important contributors to the etiopathogenesis of adolescent idiopathic scoliosis; additionally, the morphology of corpus callosum interconnecting both hemispheres of the brain was found to be altered morphologically. Our aim was to evaluate and compare the microstructural changes of the corpus callosum and its interhemispheric white matter fiber tracts interconnecting both cerebral hemispheres in patients with adolescent idiopathic scoliosis and matched controls using diffusion tensor imaging. MATERIALS AND METHODS: Brain DTI was performed in 69 patients with adolescent idiopathic scoliosis (female, right thoracic/thoracolumbar curve) and 40 age-matched controls without adolescent idiopathic scoliosis (female). 2D and 3D segmentation of the corpus callosum were performed using a region-growing method, and the corpus callosum was further divided into 6 regions, including the rostrum, genu, anterior and posterior midbodies, isthmus, and splenium. The laterality index was calculated to quantify the asymmetry of the corpus callosum. Interhemispheric fiber tractography were performed using the Brodmann atlas. RESULTS: 2D ROI analysis revealed reduced fractional anisotropy in the genu and splenium (P = .075 and P = .024, respectively). Consistently reduced fractional anisotropy on the left sides of the genu and splenium was also found in 3D ROI analysis (P = .03 and P = .012, respectively). The laterality index analysis revealed a pseudo-right lateralization of the corpus callosum in adolescent idiopathic scoliosis. Interhemispheric fibers via the splenium interconnecting Brodmann 3, 1, and 2; Brodmann 17; and Brodmann 18 (corresponding to the primary somatosensory cortex and primary and secondary visual cortices) were also found to have reduced fractional anisotropy (P ≤ .05). CONCLUSIONS: Reduced fractional anisotropy was found in the genu and splenium of the corpus callosum and corresponding interhemispheric fiber tracts interconnecting the somatosensory and visual cortices via the splenium. Our results are suggestive of altered white matter microstructure within the brain of those with adolescent idiopathic scoliosis, which could be related to abnormal brain maturation during adolescence in adolescent idiopathic scoliosis and could possibly explain the previously documented somatosensory function impairment and visuo-oculomotor dysfunction in this condition.


Subject(s)
Cerebral Cortex/pathology , Corpus Callosum/pathology , Scoliosis/pathology , White Matter/pathology , Adolescent , Cerebral Cortex/diagnostic imaging , Corpus Callosum/diagnostic imaging , Diffusion Tensor Imaging , Female , Humans , Male , White Matter/diagnostic imaging
3.
J Neuroendocrinol ; 29(10)2017 10.
Article in English | MEDLINE | ID: mdl-28485050

ABSTRACT

Peptide YY 3-36 (PYY3-36) is known as a critical satiety factor that reduces food intake both in rodents and humans. Although the anorexic effect of PYY3-36 is assumed to be mediated mainly by the Y2 receptor, the involvement of other Y-receptors in this process has never been conclusively resolved. Amongst them, the Y5 receptor (Y5R) is the most likely candidate to also be a target for PYY3-36, which is considered to counteract the anorectic effects of Y2R activation. In the present study, we show that short-term treatment of diet-induced obese wild-type (WT) and Y5R knockout mice (Y5KO) with PYY3-36 leads to a significantly reduced food intake in both genotypes, which is more pronounced in Y5R KO mice. Interestingly, chronic PYY3-36 infusion via minipumps to WT mice causes an increased cumulative food intake, which is associated with increased body weight gain. By contrast, lack of Y5R reversed this effect. Consistent with the observed increased body weight and fat mass in WT-treated mice, glucose tolerance was also impaired by chronic PYY3-36 treatment. Again, this was less affected in Y5KO mice, suggestive of a role of Y5R in the regulation of glucose homeostasis. Taken together, our data suggest that PYY3-36 mediated signalling via Y5 receptors may counteract the anorectic effects that it mediates via the Y2 receptor (Y2R), consequently lowering bodyweight in the absence of Y5 signalling. These findings open the potential of combination therapy using PYY3-36 and Y5R antagonists to enhance the food intake reducing effects of PYY3-36.


Subject(s)
Anorexia/metabolism , Obesity/metabolism , Peptide Fragments/metabolism , Peptide YY/metabolism , Receptors, Neuropeptide Y/metabolism , Animals , Body Weight , Bone and Bones/metabolism , Diet, High-Fat , Eating , Glucose/metabolism , Homeostasis , Mice, Knockout , Receptors, Neuropeptide Y/genetics
4.
Oncogene ; 36(12): 1607-1618, 2017 03 23.
Article in English | MEDLINE | ID: mdl-27841866

ABSTRACT

Oncogenesis is a pathologic process driven by genomic aberrations, including changes in nucleotide sequences. The majority of these mutational events fall into two broad categories: inactivation of tumor suppressor genes (hypomorph, antimorph or amorph) or activation of oncogenes (hypermorph). The recent surge in genome sequence data and functional genomics research has ushered in the discovery of aberrations in a third category: gain-of-novel-function mutation (neomorph). These neomorphic mutations, which can be found in both tumor suppressor genes and oncogenes, produce proteins with entirely different functions from their respective wild-type (WT) proteins and the other morphs. The unanticipated phenotypic outcomes elicited by neomorphic mutations imply that tumors with the neomorphic mutations may not respond to therapies designed to target the WT protein. Therefore, understanding the functional activities of each genomic aberration to be targeted is crucial in devising effective treatment strategies that will benefit specific cancer patients.


Subject(s)
Mutation , Neoplasms/genetics , Neoplasms/metabolism , Oncogenes , Animals , Biomarkers, Tumor , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Humans , Molecular Targeted Therapy , Neoplasms/drug therapy
5.
Exp Gerontol ; 69: 221-5, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26122132

ABSTRACT

The prevalence of vitamin B12 deficiency increases with age and is suggested to be even higher in the elderly living in institutions. This retrospective study evaluated the vitamin B12 and folate status of 1996 institutionalized elderly residents aged over 65years. Among them, 34.9% had vitamin B12 deficiency (serum vitamin B12 <150pmol/L), 11.8% had folate deficiency (serum folate <6.8nmol/L), and 4.9% had both. The majority of vitamin B12 deficient residents (68%) had serum vitamin B12 between 100pmol/L and 149pmol/L. Macrocytosis was found in 24.2% of vitamin B12 deficient residents. A significant increase in macrocytosis was associated with a decrease in serum vitamin B12 below 100pmol/L. Macrocytosis was most common in those with vitamin B12 ≦69pmol/L (50.9%). Overall, vitamin B12 deficiency is common in the institutionalized elderly, however macrocytosis cannot predict deficiency. More liberal testing for vitamin B12 status in the institutionalized elderly may be warranted.


Subject(s)
Folic Acid Deficiency , Folic Acid/blood , Institutionalization/statistics & numerical data , Vitamin B 12 Deficiency , Vitamin B 12/blood , Aged , Aged, 80 and over , China/epidemiology , Erythrocyte Indices , Female , Folic Acid Deficiency/blood , Folic Acid Deficiency/diagnosis , Folic Acid Deficiency/epidemiology , Folic Acid Deficiency/etiology , Humans , Male , Prevalence , Residential Facilities/statistics & numerical data , Retrospective Studies , Vitamin B 12 Deficiency/blood , Vitamin B 12 Deficiency/diagnosis , Vitamin B 12 Deficiency/epidemiology , Vitamin B 12 Deficiency/etiology
6.
J Photochem Photobiol B ; 148: 82-87, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25900553

ABSTRACT

Multidrug resistance (MDR) refers to the ability of cancer cells to develop cross resistance to a range of anticancer drugs which are structurally and functionally unrelated. P-glycoprotein (P-gp) is the best studied MDR phenotype in photodynamic therapy (PDT) treated cells. Our pervious study demonstrated that FosPeg® mediated PDT is effective to NPC cell line models. In this in vitro study, the expression of MDR1 gene and its product P-gp in undifferentiated, poorly differentiated and well differentiated human nasopharyngeal carcinoma (NPC) cells were investigated. The influence of P-gp efflux activities on photosensitizer FosPeg® was also examined. Regardless of the differentiation status, PDT tested NPC cell lines all expressed P-gp protein. Results indicated that FosPeg® photoactivation could heighten the expression of MDR1 gene and P-gp transporter protein in a dose dependent manner. Up to 2-fold increase of P-gp protein expression were seen in NPC cells after FosPeg® mediated PDT. Interestingly, our finding demonstrated that FosPeg® mediated PDT efficiency is independent to the MDR1 gene and P-gp protein expression in NPC cells. FosPeg® itself is not the substrate of P-gp transporter protein and no efflux of FosPeg® were observed in NPC cells. Therefore, the PDT efficiency would not be affected even though FosPeg® mediated PDT could induce MDR1 gene and P-gp protein expression in NPC cells. FosPeg® mediated PDT could be a potential therapeutic approach for MDR cancer patients.


Subject(s)
Gene Expression Regulation/drug effects , Liposomes/pharmacology , Mesoporphyrins/pharmacology , Photosensitizing Agents/pharmacology , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , Carcinoma , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Gene Expression Regulation/radiation effects , Humans , Light , Liposomes/chemistry , Liposomes/therapeutic use , Mesoporphyrins/chemistry , Mesoporphyrins/therapeutic use , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/pathology , Photochemotherapy , Photosensitizing Agents/chemistry , Photosensitizing Agents/therapeutic use , RNA, Messenger/metabolism
7.
J Hosp Infect ; 86(2): 83-9, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24433924

ABSTRACT

BACKGROUND: New strains of meticillin-resistant Staphylococcus aureus (MRSA) may be associated with changes in rates of disease or clinical presentation. Conventional typing techniques may not detect new clonal variants that underlie changes in epidemiology or clinical phenotype. AIM: To investigate the role of clonal variants of MRSA in an outbreak of MRSA bacteraemia at a hospital in England. METHODS: Bacteraemia isolates of the major UK lineages (EMRSA-15 and -16) from before and after the outbreak were analysed by whole-genome sequencing in the context of epidemiological and clinical data. For comparison, EMRSA-15 and -16 isolates from another hospital in England were sequenced. A clonal variant of EMRSA-16 was identified at the outbreak hospital and a molecular signature test designed to distinguish variant isolates among further EMRSA-16 strains. FINDINGS: By whole-genome sequencing, EMRSA-16 isolates during the outbreak showed strikingly low genetic diversity (P < 1 × 10(-6), Monte Carlo test), compared with EMRSA-15 and EMRSA-16 isolates from before the outbreak or the comparator hospital, demonstrating the emergence of a clonal variant. The variant was indistinguishable from the ancestral strain by conventional typing. This clonal variant accounted for 64/72 (89%) of EMRSA-16 bacteraemia isolates at the outbreak hospital from 2006. CONCLUSIONS: Evolutionary changes in epidemic MRSA strains not detected by conventional typing may be associated with changes in disease epidemiology. Rapid and affordable technologies for whole-genome sequencing are becoming available with the potential to identify and track the emergence of variants of highly clonal organisms.


Subject(s)
Bacteremia/epidemiology , Bacterial Typing Techniques , Cross Infection/epidemiology , Disease Outbreaks , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Staphylococcal Infections/epidemiology , Bacteremia/microbiology , Cluster Analysis , Cross Infection/microbiology , England , Genetic Variation , Genome, Bacterial , Genotype , High-Throughput Nucleotide Sequencing , Hospitals , Humans , Methicillin-Resistant Staphylococcus aureus/classification , Methicillin-Resistant Staphylococcus aureus/genetics , Staphylococcal Infections/microbiology , United Kingdom/epidemiology
8.
J Photochem Photobiol B ; 127: 114-22, 2013 Oct 05.
Article in English | MEDLINE | ID: mdl-24013466

ABSTRACT

Nasopharyngeal carcinoma (NPC) is one of the top ten cancers highly prevalent in Hong Kong and South China. Epstein-Barr virus (EBV) infection contributes to the tumorigenesis of NPC through the expression of different viral proteins. Among these, Latent Membrane Protein 1(LMP1) is the major oncoprotein expressed by EBV. Foscan® (Biolitec AG), m-tetrahydroxyphenylchlorin (mTHPC)-based photosensitizing drug, has been used in the photodynamic therapy (PDT) for head and neck cancers. FosPeg® (Biolitec AG) is a new formulation of mTHPC contained in PEGylated liposomes with optimized distribution properties. In this in vitro study, the potential of FosPeg®-PDT on human EBV positive NPC cell (c666-1) and EBV negative cells (HK1 and CNE2) were investigated. Effects of FosPeg®-PDT on the expression of EBV BART miRNAs (EBV miRNA BART 1-5p, BART 16, and BART 17-5p), LMP1 mRNA and proteins on c666-1 cells were also elucidated. The killing efficacy of FosPeg®-PDT on NPC cells were determined by MTT assay after LED activation. Effects of FosPeg®-PDT on the expression of LMP1 mRNA and protein were examined by real time PCR and western blot analysis. FosPeg®-PDT demonstrated its antitumor effect on c666-1 cells in a drug and light dose dependent manner. LD30, LD50 and LD70 were achieved by applying LED activation (3J/cm(2)) at 4h post incubated cells with 0.05µg/ml, 0.07µg/ml and 0.3µg/ml FosPeg®, respectively. Up-regulation of both LMP1 mRNA and protein were observed after FosPeg®-PDT in a dose dependent manner. FosPeg®-PDT exerted antitumor effect on c666-1 cells through up-regulation of LMP1 protein. Understanding the mechanism of FosPeg®-PDT may help to develop better strategies for the treatment of NPC.


Subject(s)
Gene Expression Regulation, Neoplastic/drug effects , Herpesvirus 4, Human/genetics , Mesoporphyrins/pharmacology , MicroRNAs/genetics , Nasopharyngeal Neoplasms/pathology , Photochemotherapy , Viral Matrix Proteins/metabolism , Cell Cycle/drug effects , Cell Cycle/radiation effects , Cell Line, Tumor , Chemistry, Pharmaceutical , Dose-Response Relationship, Drug , Gene Expression Regulation, Neoplastic/radiation effects , Herpesvirus 4, Human/physiology , Humans , Intracellular Space/drug effects , Intracellular Space/metabolism , Intracellular Space/radiation effects , Liposomes , Mesoporphyrins/administration & dosage , Mesoporphyrins/chemistry , Mesoporphyrins/metabolism , Mesoporphyrins/therapeutic use , Nasopharyngeal Neoplasms/virology , Polyethylene Glycols/chemistry , RNA, Viral/genetics , Viral Matrix Proteins/genetics
9.
Oncogene ; 32(22): 2767-81, 2013 May 30.
Article in English | MEDLINE | ID: mdl-22797058

ABSTRACT

Cisplatin and paclitaxel are standard chemotherapy for metastatic ovarian cancer, but with limited efficacy. Cancer stem/progenitor cells (or tumor-initiating cells, TICs) are hypothesized to be chemoresistant, and the existence of TICs in ovarian cancer has been previously demonstrated. However, the key signals and molecular events regulating the formation and expansion of ovarian tumor-initiating cells (OTICs) remain elusive. Here, we show that c-Kit is not just a marker of OTICs, but also a critical mediator of the phenotype that can be a viable target for the treatment of ovarian cancer. In contrast to non-OICs, c-Kit was overexpressed in OTICs. Moreover, the use of small interfering RNA to inhibit c-Kit expression markedly attenuated the number and size of OTIC subpopulations, inhibited the expression of stem cell markers and decreased the tumorigenic capabilities of OTICs. Imatinib (Gleevec), a clinical drug that blocks c-Kit kinase activity, also demonstrated its inhibition potency on OTICs. In addition, cisplatin/paclitaxel, which killed non-OTICs, with c-Kit knockdown or imatinib revealed that this was critically required for intervening ovarian cancer progression and recurrence in vitro and in xenograft tumors in vivo. Similar results were obtained with OTICs derived from ovarian carcinoma patients. Studies into the mechanisms suggest an important role for the activation of Wnt/ß-catenin and ATP-binding cassette G2 downstream of c-Kit. The tumor-promoting microenvironment, such as hypoxia, could promote OTICs via upregulation of c-Kit expression. These results unravel an integral role for c-Kit in ovarian neoplastic processes and shed light on its mechanisms of action.


Subject(s)
Benzamides/pharmacology , Drug Resistance, Neoplasm/genetics , Ovarian Neoplasms , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-kit/metabolism , Pyrimidines/pharmacology , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/metabolism , Animals , Antineoplastic Agents/pharmacology , Cell Hypoxia , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cisplatin/pharmacology , Female , Gene Expression Regulation, Neoplastic , Humans , Imatinib Mesylate , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Proteins/metabolism , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Paclitaxel/pharmacology , Proto-Oncogene Proteins c-kit/genetics , RNA Interference , RNA, Small Interfering , Tumor Microenvironment , Wnt Proteins/metabolism , Wnt Signaling Pathway/drug effects , Xenograft Model Antitumor Assays , beta Catenin/metabolism
10.
Oncogene ; 30(21): 2420-32, 2011 May 26.
Article in English | MEDLINE | ID: mdl-21258406

ABSTRACT

Ovarian cancer is highly metastatic with a poor prognosis. The serine/threonine kinase, p70 S6 kinase (p70(S6K)), which is a downstream effector of phosphatidylinositol 3-kinase/Akt pathway, is frequently activated in ovarian cancer. Here, we show that p70(S6K) is a critical regulator of the actin cytoskeleton in the acquisition of the metastatic phenotype. This regulation is through two important activities: p70(S6K) acts as an actin filament cross-linking protein and as a Rho family GTPase-activating protein. Ectopic expression of constitutively active p70(S6K) in ovarian cancer cells induced a marked reorganization of the actin cytoskeleton and promoted directional cell migration. Using cosedimentation and differential sedimentation assays, p70(S6K) was found to directly bind to and cross-link actin filaments. Immunofluorescence studies showed p70(S6K) colocalized with cytochalasin D-sensitive actin at the leading edge of motile cells. The p70(S6K) did not affect the kinetics of spontaneous actin polymerization, but could stabilize actin filaments by the inhibition of cofilin-induced actin depolymerization. In addition, we showed that p70(S6K) stimulated the rapid activation of both Rac1 and Cdc42, and their downstream effector p21-activated kinase (PAK1), but not RhoA. Depletion of p70(S6K) expression or inhibition of its activity resulted in significant inhibition of actin cytoskeleton reorganization and reduced migration, with a concomitant reduction in Rac1, Cdc42 and PAK1 activation, confirming that the effect was p70(S6K) specific. Similarly, the actin cytoskeleton reorganization/migratory phenotype could be reversed by expression of dominant negative Rac1 and Cdc42, or inhibition of PAK1. These results reveal a new direction for understanding the oncogenic roles of p70(S6K) in tumor progression.


Subject(s)
Actins/metabolism , Cell Movement , Cytoskeleton/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Actins/ultrastructure , Blotting, Western , Cell Line, Tumor , Cytoskeleton/ultrastructure , Enzyme Activation/drug effects , Female , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Hep G2 Cells , Hepatocyte Growth Factor/pharmacology , Humans , Microscopy, Electron , Microscopy, Fluorescence , Protein Binding , RNA Interference , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Transfection , Tumor Cells, Cultured , cdc42 GTP-Binding Protein/genetics , cdc42 GTP-Binding Protein/metabolism , p21-Activated Kinases/genetics , p21-Activated Kinases/metabolism , rac1 GTP-Binding Protein/genetics , rac1 GTP-Binding Protein/metabolism
11.
Mol Cell Neurosci ; 36(3): 416-24, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17889554

ABSTRACT

Tissue damage in the CNS is critically influenced by the adaptive immune system. Primary oligodendrocyte damage (by overexpression of PLP) leads to low-grade inflammation of high pathological impact, which is mediated by CD8+ T cells. To yield further insight into pathogenesis and nature of immune responses in myelin mutated mice, we here apply a detailed immunological characterization of CD8+ T cells in PLP-transgenic and aged wild type mice. We provide evidence that T effector cells accumulate in the CNS of PLP-transgenic and wild-type mice and show a higher level of activation in mutant mice, indicated by surface markers and clonal expansions, as demonstrated by T cell receptor CDR3-spectratype analysis. Vbeta-Jbeta similarities suggest specificity against a common antigen, albeit we could not find specific responses against myelin-antigen-derived peptides. The association of primary oligodendrocyte damage with secondary expansions of pathogenic cells underlines the role of adaptive immune reactions in neurodegenerative and neuroinflammatory diseases.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Central Nervous System/immunology , Demyelinating Diseases/immunology , Immune System/immunology , Myelin Sheath/immunology , Animals , Autoimmunity/genetics , Autoimmunity/immunology , CD8 Antigens/immunology , Cell Proliferation , Central Nervous System/metabolism , Central Nervous System/physiopathology , Clone Cells/immunology , Demyelinating Diseases/genetics , Demyelinating Diseases/physiopathology , Immune System/physiopathology , Immunity, Innate/genetics , Immunity, Innate/immunology , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Neurologic Mutants , Mice, Transgenic , Myelin Sheath/genetics , Myelin Sheath/metabolism , Oligodendroglia/immunology , Oligodendroglia/metabolism , Oligodendroglia/pathology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
12.
Toxicol Pathol ; 34(6): 776-84, 2006.
Article in English | MEDLINE | ID: mdl-17162535

ABSTRACT

This article describes the toxicity of alpha-naphthylisothiocyanate (ANIT), a compound known to induce dose-dependent hepatobiliary toxicity in vivo, using the slice model. Liver slices (200 microm thick) from male Sprague-Dawley rats and male beagle dogs were cultured for 7 days while exposed to a range of ANIT concentrations (1- 100 microM for rat and 4-320 microM for dog). Tissues (and medium for dog) were evaluated using a panel of clinically relevant biomarkers for liver and histological endpoints to assess viability and proliferation. ANIT increased slice levels of enzyme biomarkers corresponding to biliary markers. At high concentrations (80-100 microM for rat, 320 microM for dog) a diminution of tissue enzyme levels was observed, corresponding to severe hepatobiliary injury. By days 5 and 7, biochemical markers in the medium of dog slices indicated an elevation of hepatocellular and biliary markers. Histologically for both species, minimal hepatocellular injury was noted, but proliferation of biliary epithelial cells (BEC) was observed using 5-bromo-2-deoxyuridine (BrdU) immunostaining. In rat slices, ANIT increased the expression of inducible nitrous oxide synthase (iNOS) within 12 hrs of exposure. In summary, additional experimentation using slice culture may further demonstrate its value in screening compounds that cause hepatobiliary toxicity.


Subject(s)
1-Naphthylisothiocyanate/toxicity , Biomarkers/metabolism , Liver/drug effects , Liver/pathology , Tissue Culture Techniques/methods , Toxicity Tests , Alanine Transaminase/metabolism , Alkaline Phosphatase/metabolism , Animals , Aspartate Aminotransferases/metabolism , Bile Ducts, Intrahepatic/drug effects , Bile Ducts, Intrahepatic/pathology , Cell Proliferation/drug effects , Dogs , Dose-Response Relationship, Drug , Glycogen/metabolism , Liver/metabolism , Male , Rats , Rats, Sprague-Dawley , Species Specificity , Time Factors , gamma-Glutamyltransferase/metabolism
13.
Eur J Dent Educ ; 10(4): 210-6, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17038013

ABSTRACT

AIMS: To identify the subjects of interest and to examine the modes as well as means of study for continuing professional dental education amongst general dental practitioners who attended the 26th Asia Pacific Dental Congress, 28 May-1 June 2004, Hong Kong. METHODS: A total of 381 general dental practitioners as the registered conference delegates from Hong Kong, Mainland China and other Asia-Pacific regions were randomly selected for the present survey. The survey was conducted through face-to-face interviews by a group of practising dentists in Hong Kong. RESULTS: Overall, orthodontics and prosthodontics were the most popular subjects for clinical degree programmes, whilst oral implantology and cosmetic dentistry were the highly preferred subjects for continuing education courses. Concerning the preferred mode of study for degree programmes, the part-time study mode was chosen by 68.3% of the participating dentists. A didactic teaching approach was preferred by most of the participants (81.7%) for postgraduate study. The majority of the interviewees (76.5%) were interested in a proposed clinical degree programme to be offered jointly by The University of Hong Kong and a leading university in the Mainland. Overall, there was no marked difference in the preference for continuing dental education amongst the respondents from Hong Kong, Mainland China and other Asia-Pacific regions. CONCLUSIONS: The present survey shows the currently preferred specialty areas and subjects for continuing professional dental education amongst the general dental practitioners who attended the 26th Asia Pacific Dental Congress, with didactic teaching as the most preferred mode of study on a part-time basis.


Subject(s)
Education, Dental, Continuing/statistics & numerical data , Education, Dental, Graduate/statistics & numerical data , General Practice, Dental , Asia , China , Choice Behavior , Curriculum/statistics & numerical data , Education, Dental/methods , Female , Hong Kong , Humans , Male , Oceania , Specialties, Dental/education , Surveys and Questionnaires , Teaching/methods
14.
Oncogene ; 25(4): 546-54, 2006 Jan 26.
Article in English | MEDLINE | ID: mdl-16205645

ABSTRACT

Redox modification of thiol/disulfide interchange in proteins by selenium could lead to protein unfolding. When this occurs in the endoplasmic reticulum (ER), a process known as unfolded protein response (UPR) is orchestrated for survival through activation of PERK-eIF2alpha (PERK: double-stranded RNA-activated protein kinase-like ER kinase; eIF2alpha: eucaryotic initiation factor 2alpha), ATFalpha (ATFalpha: activating transcription factor 6) and inositol requiring 1 (IRE1)-x-box-binding protein 1 (XBP1) signalings. All three UPR transducer pathways were upregulated very rapidly when PC-3 cells were exposed to selenium. These changes were accompanied by increased expression of UPR target genes, including immunoglobulin heavy chain-binding protein/glucose-regulated protein, 78 kDa and CCAAT/enhancer binding protein-homologous protein/growth arrest- and DNA damage-inducible gene (CHOP/GADD153). Induction of BiP/GRP78, an ER-resident chaperone, is part of the damage control mechanism, while CHOP/GADD153 is a transcription factor associated with growth arrest and apoptosis in the event of prolonged ER stress. Knocking down BiP/GRP78 induction by small interference RNA produced a differential response of the three transducers to selenium, suggesting that the signaling intensity of each transducer could be fine-tuned depending on BiP/GRP78 availability. In the presence of selenium, CHOP/GADD153 expression was raised even higher by BiP/GRP78 knockdown. Under this condition, the selenium effect on wild-type p53-activated fragment p21 (p21(WAF)), cyclin-dependent kinase (CDK)1 and CDK2 was also magnified in a manner consistent with enhanced cell growth arrest. Additional experiments with CHOP/GADD153 siRNA knockdown strongly suggested that CHOP/GADD153 may play a positive role in upregulating the expression of p21(WAF) in a p53-independent manner (PC-3 cells are p53 null). Collectively, the above findings support the idea that UPR could be an important mechanism in mediating the anticancer activity of selenium.


Subject(s)
Heat-Shock Proteins/physiology , Molecular Chaperones/physiology , Organoselenium Compounds/pharmacology , Prostatic Neoplasms/drug therapy , Tumor Suppressor Protein p53/physiology , CDC2 Protein Kinase/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase Inhibitor p21/genetics , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Chaperone BiP , Humans , Male , Prostatic Neoplasms/pathology , Protein Folding , Signal Transduction , Transcription Factor CHOP/physiology , eIF-2 Kinase/metabolism
15.
Toxicol In Vitro ; 19(8): 1079-88, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16081239

ABSTRACT

The differential toxicity of two anticancer agents is described using the in vitro rat liver slice culture model. Liver slices from F-344 rats were cultured for 5 days in Waymouth's-based medium with exposure to a range of geldanamycin (GEL) or 17-allylaminogeldanamycin (17-AAG) concentrations. GEL induced concentration-dependent reduction of alkaline phosphatase and of gamma-glutamyl transferase levels, which are indicators of biliary epithelial cell(s) (BEC) viability, and exhibited hepatocellular toxicity at higher concentrations. Histologically, BEC cell injury was evident at the lowest GEL concentration (0.1 microM) and progressed to overt bile duct necrosis at 5 microM, a level at which hepatocellular damage was also more prominent. Slices exposed to the same concentrations were more sensitive to toxic effects of GEL than of 17-AAG. 17-AAG at the lowest concentration had more slice biomarker retention than GEL, and histological analysis revealed minimal toxic effect on BEC. With increasing concentration, BEC were progressively lost, and BEC proliferation was completely inhibited at 5 microM 17-AAG. Hepatocellular injury was evident only at high dose exposures. This is believed to be the first use of an in vitro liver tissue model to accurately predict the differential and concentration-dependent toxicities of these compounds.


Subject(s)
Liver/drug effects , Quinones/toxicity , Rifabutin/analogs & derivatives , Toxicity Tests/methods , Alanine Transaminase/metabolism , Alkaline Phosphatase/metabolism , Animals , Antibiotics, Antineoplastic/toxicity , Aspartate Aminotransferases/metabolism , Benzoquinones , Bile Ducts/drug effects , Bile Ducts/pathology , Cell Survival/drug effects , Drug Evaluation, Preclinical/methods , Epithelial Cells/drug effects , Epithelial Cells/pathology , Hepatocytes/drug effects , Hepatocytes/pathology , In Vitro Techniques , L-Lactate Dehydrogenase/metabolism , Lactams, Macrocyclic , Liver/metabolism , Liver/pathology , Male , Rats , Rats, Inbred F344 , Rifabutin/toxicity , gamma-Glutamyltransferase/metabolism
16.
Environ Pollut ; 138(3): 494-504, 2005 Dec.
Article in English | MEDLINE | ID: mdl-15970366

ABSTRACT

The accumulation of trace metals in aquatic organisms may lead to serious health problems through the food chain. The present research project aims to study the accumulation and potential sources of trace metals in aquatic organisms of the Pearl River Estuary (PRE). Four groups of aquatic organisms, including fish, crab, shrimp, and shellfish, were collected in the PRE for trace metal and Pb isotopic analyses. The trace metal concentrations in the aquatic organism samples ranged from 0.01 to 2.10 mg/kg Cd, 0.02 to 4.33 mg/kg Co, 0.08 to 4.27 mg/kg Cr, 0.15 to 77.8 mg/kg Cu, 0.17 to 31.0 mg/kg Ni, 0.04 to 30.7 mg/kg Pb, and 8.78 to 86.3 mg/kg Zn (wet weight). High concentrations of Cd were found in crab, shrimp and shellfish samples, while high concentration of Pb was found in fish. In comparison with the baseline reference values in other parts of the world, fish in the PRE had the highest elevated trace metals. The results of Pb isotopic compositions indicated that the bioaccumulation of Pb in fish come from a wide variety of food sources and/or exposure pathways, particularly the anthropogenic inputs.


Subject(s)
Lead/analysis , Metals, Heavy/analysis , Rivers , Water Pollutants, Chemical/analysis , Animals , Brachyura/chemistry , Cadmium/analysis , China , Chromium/analysis , Cobalt/analysis , Copper/analysis , Environmental Exposure/adverse effects , Fishes/metabolism , Isotopes/analysis , Nickel/analysis , Penaeidae/chemistry , Shellfish/analysis , Trace Elements/analysis , Vanadium/analysis , Zinc/analysis
17.
Environ Pollut ; 132(1): 157-72, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15276283

ABSTRACT

The rapid economic development in the Pearl River Delta (PRD) region in South China in the last three decades has had a significant impact on the local environment. Estuarine sediment is a major sink for contaminants and nutrients in the surrounding ecosystem. The accumulation of trace metals in sediments may cause serious environmental problems in the aquatic system. Thirty sediment cores were collected in the Pearl River Estuary (PRE) in 2000 for a study on trace metal pollution in this region. Heavy metal concentrations and Pb isotopic compositions in the four 210Pb-dated sediment cores were determined to assess the fluxes in metal deposits over the last one hundred years. The concentrations of Cu, Pb and Zn in the surface sediment layers were generally elevated when compared with the sub-surface layers. There has been a significant increase in inputs of Cu, Pb and Zn in the PRE since the 1970s. The results also showed that different sampling locations in the estuary received slightly different types of inputs. Pb isotopic composition data indicated that the increased Pb in the recent sediments was of anthropogenic origin. The results of trace metal influxes showed that about 30% of total Pb and 15% of total Zn in the sediments in the 1990s were from anthropogenic sources. The combination of trace metal analysis, Pb isotopic composition and 210Pb dating in an estuary can provide vital information on the long-term accumulation of metals in sediments.


Subject(s)
Geologic Sediments/chemistry , Rivers/chemistry , Trace Elements/analysis , Water Pollutants/analysis , China , Copper/analysis , Environmental Pollution/adverse effects , Isotopes/analysis , Lead/analysis , Lead Radioisotopes/analysis , Zinc/analysis
18.
Anticancer Res ; 24(3a): 1401-8, 2004.
Article in English | MEDLINE | ID: mdl-15274301

ABSTRACT

Selenium compounds show much promise in the prevention of prostate and other human cancers. Various selenium chemical forms have been shown to differ widely in their anticancer properties. The main dietary form is selenomethionine, which we showed modulated p53 activity by causing redox regulation of key p53 cysteine residues. In the current study we included other selenium chemical forms, sodium selenite and methyl-seleninic acid. All three forms are relevant selenium sources in human populations. All three forms can affect p53 activity defined as trans-activation of a p53-dependent reporter gene. In addition to the reduction of cysteine sulfhydryl groups, p53 phosphorylation was also affected in cells treated with selenium compounds. Methyl-seleninic acid caused phosphorylation of one or more p53 threonine residues, but did not affect any known serine phosphorylation sites. By contrast sodium selenite caused phosphorylation of p53 serines 20, 37 and 46 known to mediate apoptosis. Selenomethionine did not cause detectable phosphorylation of p53 serines or threonines. Our data show that, although p53 modulation may be a common denominator of selenium compounds, specific mechanisms of p53 activation differ among selenium chemical forms. Post-translational modifications of p53 are determinants of p53 activity and probably affect the threshold for p53-mediated functions. Different selenium chemical forms may differentially modify p53 for DNA repair or apoptosis in conjunction with a given level of endogenous or exogenous DNA damage.


Subject(s)
Organoselenium Compounds/pharmacology , Protein Processing, Post-Translational/drug effects , Selenomethionine/pharmacology , Sodium Selenite/pharmacology , Tumor Suppressor Protein p53/metabolism , Apoptosis/drug effects , Apoptosis/physiology , Cysteine/metabolism , DNA Repair , DNA-(Apurinic or Apyrimidinic Site) Lyase/antagonists & inhibitors , DNA-(Apurinic or Apyrimidinic Site) Lyase/physiology , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Phosphorylation/drug effects , Serine/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology , Threonine/metabolism , Transcriptional Activation/drug effects
19.
J Lipid Res ; 42(7): 1056-61, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11441132

ABSTRACT

Conjugated linoleic acid (CLA) is known to provide certain health benefits in experimental animal models. The major CLA isomer in food is c 9,t11-CLA. A primary objective of this study was to investigate the uptake of c 9,t11-CLA and its downstream metabolites into various lipid fractions in the liver of rats fed either a high or low CLA diet (containing 0.1 or 0.8 g CLA/100 g diet, respectively). As expected, the levels of all conjugated diene (CD) fatty acids (CD 18:2 + CD 18:3 + CD 20:3 + CD 20:4) were elevated about 8-fold in the high CLA diet group. However, there was no change in the distribution of CLA and CLA metabolites into various lipid fractions due to CLA intake. Unlike linoleic acid or gamma-linolenic acid, which were distributed mainly in phospholipids, CD 18:2, CD 18:3, and CD 20:3 were incorporated primarily in neutral lipid. Furthermore, the incorporation of all nonconjugated unsaturated fatty acids was not perturbed by CLA. Regardless of the level of CLA in the diet, CD 20:4 was predominantly enriched in phosphatidylserine and phosphatidylinositol. In contrast, arachidonic acid was primarily enriched in phosphatidylcholine and less so in phosphatidylethanolamine. The above findings may have potential implication regarding the role of CLA in modulating eicosanoid metabolism.


Subject(s)
Linoleic Acid/metabolism , Lipid Metabolism , Liver/metabolism , Phosphatidylcholines/metabolism , Phosphatidylinositols/metabolism , Phosphatidylserines/metabolism , Animal Feed , Animals , Chemical Fractionation/methods , Female , Linoleic Acid/analysis , Linoleic Acid/chemistry , Lipids/chemistry , Lipids/classification , Liver/chemistry , Phosphatidylcholines/chemistry , Phosphatidylethanolamines/chemistry , Phosphatidylethanolamines/metabolism , Phosphatidylinositols/chemistry , Phosphatidylserines/chemistry , Rats , Rats, Sprague-Dawley
20.
Anticancer Res ; 21(2A): 863-7, 2001.
Article in English | MEDLINE | ID: mdl-11396176

ABSTRACT

In the rat mammary carcinogenesis model, premalignant lesions known as intraductal proliferations (IDPs) are detectable within a few weeks after carcinogen treatment. These early transformed colonies are the precursors for the eventual formation of carcinomas. Our past research indicated that methylselenocysteine added to the diet of rats reduced the development of IDPs of all sizes (the size of each IDP was estimated operationally by the number of 5-micron serial sections showing the same pathology). The appearance of an IDP lesion represents a balance between cell proliferation and cell death. The modulation of these two cellular events by methylselenocysteine was investigated. The abdominal-inguinal mammary gland was excised 6 weeks after MNU administration. Proliferation and apoptosis were evaluated by BrdU labeling and the TUNEL assay, respectively. The expression levels of several cell cycle and apoptosis regulatory proteins, including cyclin D1, cyclin A, p27, p16, bcl-2, box and bak, were also assessed. All of the above endpoints were quantified by immunohistochemistry in paraffin-embedded sections. The results showed that the magnitude of the response to methylselenocysteine intervention seemed to depend on the size of the IDP lesion. For the purpose of this study, the small and large lesions were classified as those containing < or = 30 or > 30 serial sections, respectively. With the small lesions, methylselenocysteine significantly inhibited BrdU labeling and the expression of cyclin D1 and cyclin A, but increased the expression of p27. Interesting, only p27 was upregulated in the larger IDP lesions, while BrdU labeling and the cyclins were not affected. It is possible that the transformed phenotype becomes less sensitive to selenium-mediated arrest of proliferation once it progresses to a more advanced pathological stage. In contrast, methylselenocysteine stimulated apoptosis (TUNEL assay) by 3 to 4 fold, and this increase was evident in both the small and large IDP lesions. Consistent with the induction of apoptosis, a reduced expression of bcl-2 was also observed in the methylselenocysteine group. In summary, our data suggest that exposure to methylselenocysteine blocks clonal expansion of premalignant lesions at an early stage. This is achieved by simultaneously modulating certain molecular pathways that are responsible for inhibiting cell proliferation and enhancing apoptosis.


Subject(s)
Anticarcinogenic Agents/pharmacology , Apoptosis , Breast/pathology , Carcinoma, Ductal, Breast/pathology , Cysteine/analogs & derivatives , Cysteine/pharmacology , Mammary Neoplasms, Experimental/pathology , Organoselenium Compounds/pharmacology , Animals , Biomarkers , Breast/drug effects , Breast/metabolism , Carcinogens/adverse effects , Carcinoma, Ductal, Breast/chemically induced , Carcinoma, Ductal, Breast/drug therapy , Cell Division , Cyclin A/metabolism , Cyclin D1/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Female , Mammary Neoplasms, Experimental/chemically induced , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Methylnitrosourea/adverse effects , Proliferating Cell Nuclear Antigen/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Rats, Sprague-Dawley , Selenocysteine/analogs & derivatives , bcl-2 Homologous Antagonist-Killer Protein , bcl-2-Associated X Protein
SELECTION OF CITATIONS
SEARCH DETAIL
...