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1.
Public Health ; 187: 157-160, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32980782

ABSTRACT

OBJECTIVES: The Japanese prime minister declared a state of emergency on April 7 2020 to combat the outbreak of coronavirus disease 2019 (COVID-19). This declaration was unique in the sense that it was essentially driven by the voluntary restraint of the residents. We examined the change of the infection route by investigating contact experiences with COVID-19-positive cases. STUDY DESIGN: This study is a population-level questionnaire-based study using a social networking service (SNS). METHODS: To assess the impact of the declaration, this study used population-level questionnaire data collected from an SNS with 121,375 respondents (between March 27 and May 5) to assess the change in transmission routes over the study period, which was measured by investigating the association between COVID-19-related symptoms and (self-reported) contact with COVID-19-infected individuals. RESULTS: The results of this study show that the declaration prevented infections in the workplace, but increased domestic infections as people stayed at home. However, after April 24, workplace infections started to increase again, driven by the increase in community-acquired infections. CONCLUSIONS: While careful interpretation is necessary because our data are self-reported from voluntary SNS users, these findings indicate the impact of the declaration on the change in transmission routes of COVID-19 over time in Japan.


Subject(s)
Coronavirus Infections/prevention & control , Coronavirus Infections/transmission , Disease Outbreaks/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19 , Community-Acquired Infections/epidemiology , Contact Tracing , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Female , Humans , Japan/epidemiology , Male , Middle Aged , Occupational Health/statistics & numerical data , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Self Report , Social Networking , Surveys and Questionnaires , Symptom Assessment , Young Adult
2.
BJOG ; 120(13): 1622-30; discussion 1630, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23924217

ABSTRACT

OBJECTIVE: To investigate the risk of adverse pregnancy outcomes and caesarean section among adolescents in low- and middle-income countries. DESIGN: Secondary analysis using facility-based cross-sectional data from the World Health Organization (WHO) Global Survey on Maternal and Perinatal Health. SETTING: Twenty-three countries in Africa, Latin America, and Asia. POPULATION: Women admitted for delivery in 363 health facilities during 2-3 months between 2004 and 2008. METHODS: We constructed multilevel logistic regression models to estimate the effect of young maternal age on risks of adverse pregnancy outcomes. MAIN OUTCOME MEASURES: Risk of adverse pregnancy outcomes among young mothers. RESULTS: A total of 78 646 nulliparous mothers aged ≤24 years and their singleton infants were included in the analysis. Compared with mothers aged 20-24 years, adolescents aged 16-19 years had a significantly lower risk of caesarean section (adjusted OR 0.75, 95% CI 0.71-0.79). When the analysis was restricted to caesarean section indicated for presumed cephalopelvic disproportion, the risk of caesarean section was significantly higher among mothers aged ≤15 years (aOR 1.27, 95% CI 1.07-1.49) than among those aged 20-24 years. Higher risks of low birthweight and preterm birth were found among adolescents aged 16-19 years (aOR 1.10, 95% CI 1.03-1.17; aOR 1.16, 95% CI 1.09-1.23, respectively) and ≤15 years (aOR 1.33, 95% CI 1.14-1.54; aOR 1.56, 95% CI 1.35-1.80, respectively). CONCLUSIONS: Adolescent girls experiencing pregnancy at a very young age (i.e. <16 years) have an increased risk of adverse pregnancy outcomes.


Subject(s)
Developing Countries , Pregnancy Outcome , Adolescent , Africa , Asia , Body Height , Body Mass Index , Cephalopelvic Disproportion/surgery , Cesarean Section/statistics & numerical data , Cross-Sectional Studies , Educational Status , Female , Health Surveys , Humans , Infant, Low Birth Weight , Infant, Newborn , Latin America , Maternal Age , Parity , Pregnancy , Pregnancy in Adolescence , Premature Birth/epidemiology , Prenatal Care/statistics & numerical data , Single Person , Young Adult
3.
Zhonghua Liu Xing Bing Xue Za Zhi ; 41(4): 476-479, 2020 Apr 10.
Article in Zh | MEDLINE | ID: mdl-32125128

ABSTRACT

Objective: The number of confirmed and suspected cases of the COVID-19 in Hubei province is still increasing. However, the estimations of the basic reproduction number of COVID-19 varied greatly across studies. The objectives of this study are 1) to estimate the basic reproduction number (R(0)) of COVID-19 reflecting the infectiousness of the virus and 2) to assess the effectiveness of a range of controlling intervention. Methods: The reported number of daily confirmed cases from January 17 to February 8, 2020 in Hubei province were collected and used for model fit. Four methods, the exponential growth (EG), maximum likelihood estimation (ML), sequential Bayesian method (SB) and time dependent reproduction numbers (TD), were applied to estimate the R(0). Results: Among the four methods, the EG method fitted the data best. The estimated R(0) was 3.49 (95%CI: 3.42-3.58) by using EG method. The R(0) was estimated to be 2.95 (95%CI: 2.86-3.03) after taking control measures. Conclusions: In the early stage of the epidemic, it is appropriate to estimate R(0) using the EG method. Meanwhile, timely and effective control measures were warranted to further reduce the spread of COVID-19.


Subject(s)
Basic Reproduction Number , Coronavirus Infections/epidemiology , Pneumonia, Viral/epidemiology , Bayes Theorem , Betacoronavirus , COVID-19 , China/epidemiology , Humans , Likelihood Functions , Models, Statistical , Pandemics , SARS-CoV-2
4.
Am J Physiol Endocrinol Metab ; 297(3): E629-37, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19509186

ABSTRACT

Placental human growth hormone-variant (hGH-V) and pituitary human growth hormone-N (hGH-N) are of identical size (22 kDa) but differ in 13 residues scattered throughout the protein. Several isoforms of GH are produced by the hGH-N and hGH-V genes including a 20-kDa hGH-V resulting from a 45-bp deletion caused by the use of an alternative acceptor site within exon 3. To date, the biological properties of the 20-kDa GH-V have not been characterized in vivo. Using young male Wistar rats fed either chow or a high-fat (HF) diet for 4 wk postweaning, we investigated the effect of 7 days treatment with either 22-kDa hGH-N, 20-kDa hGH-V (5 ug x g(-1) x day(-1) sc), or vehicle on body composition and endocrine and metabolic profiles. Total body growth (absolute weight gain and linear growth trajectory) in the 20-kDa hGH-V-treated animals was intermediary between that of control and hGH-N-treated animals. Both 22-kDa hGH-N and 20-kDa hGH-V significantly reduced total body fat mass compared with control animals, and there were no differences between the GH isoforms in anti-lipogenic activity in animals fed the HF diet. Fasting plasma insulin and C peptide were significantly increased in animals on the HF diet and further increased by hGH-N but were unchanged in 20-kDa hGH-V-treated animals compared with saline-treated controls. Plasma volume as assessed by hematocrit was increased in hGH-N-treated animals but was unchanged in 20-kDa hGH-V-treated animals compared with controls. Furthermore, 20-kDa hGH-V had reduced lactogenic (prolactin receptor mediated) activity characteristic of hGH-N as tested in vitro compared with the 20-kDa hGH-N and 22-kDa hGH-N variants. In summary, placental 20-kDa hGH-V retains some of the growth-promoting and all antilipogenic activities of pituitary 22-kDa hGH-N but has diminished diabetogenic and lactogenic properties compared with the native 22-kDa hGH-N.


Subject(s)
Diabetes Mellitus, Experimental/chemically induced , Growth Hormone/pharmacology , Human Growth Hormone/pharmacology , Lactation/drug effects , Lipogenesis/drug effects , Peptide Fragments/pharmacology , Placental Hormones/pharmacology , Animals , Body Weight/drug effects , Diet, Atherogenic , Drug Evaluation, Preclinical , Female , Growth Hormone/chemistry , Hypolipidemic Agents/pharmacology , Male , Molecular Weight , Placental Hormones/chemistry , Protein Isoforms/chemistry , Protein Isoforms/pharmacology , Rats , Rats, Wistar
5.
Am J Transplant ; 9(2): 294-300, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19067656

ABSTRACT

Outcomes research in pediatric liver transplant (LT) has focused on mortality and morbidity but there is a need to also evaluate functional outcomes. Standardized cognitive testing was administered to a cohort of children with infantile chronic liver disease who were transplanted at the University of Alberta during their preschool years. Thirty children had comprehensive assessments with the Bayley Scales of Infant Development or Wechsler testing. Patient variables potentially associated with cognitive delay were analyzed with multiple regression analysis. The mean DQ/IQ score (developmental quotient/intelligence quotient) was 81 +/- 17. Delay (DQ/IQ score < 70), and borderline delay (DQ/IQ 70-84) were each present in 27% of the cohort, with only 46% demonstrating normal cognition. Regression analysis demonstrated that the decreased IQ was associated with pretransplant growth retardation and elevated calcineurin inhibitor levels. Performance IQ had strong correlation with pretransplant growth retardation and elevated serum ammonia, R(2)= 45%, compared to verbal IQ that was associated was elevated calcineurin inhibitor levels, R(2)= 23%. Children post-LT are at high risk for cognitive delay or borderline delay. This is the first study to demonstrate the association calcineurin inhibitors with impaired IQ and also the unique finding of different variables predictive of impaired verbal intelligence quotient (VIQ) versus performance intelligence quotient (PIQ).


Subject(s)
Cognition Disorders/etiology , Developmental Disabilities/etiology , Liver Transplantation , Adaptation, Psychological , Adaptor Proteins, Signal Transducing , Alberta , Calcineurin/blood , Child , Child, Preschool , Chronic Disease , Cognition Disorders/diagnosis , Cohort Studies , Developmental Disabilities/diagnosis , Female , Humans , Infant , Liver Diseases/complications , Liver Diseases/surgery , Male , Neuropsychological Tests , Outcome Assessment, Health Care
6.
Science ; 280(5360): 104-6, 1998 Apr 03.
Article in English | MEDLINE | ID: mdl-9525853

ABSTRACT

Many plants, including Arabidopsis, show increased resistance to freezing after they have been exposed to low nonfreezing temperatures. This response, termed cold acclimation, is associated with the induction of COR (cold-regulated) genes mediated by the C-repeat/drought-responsive element (CRT/DRE) DNA regulatory element. Increased expression of Arabidopsis CBF1, a transcriptional activator that binds to the CRT/DRE sequence, induced COR gene expression and increased the freezing tolerance of nonacclimated Arabidopsis plants. We conclude that CBF1 is a likely regulator of the cold acclimation response, controlling the level of COR gene expression, which in turn promotes tolerance to freezing.


Subject(s)
Arabidopsis Proteins , Arabidopsis/genetics , DNA-Binding Proteins/genetics , Freezing , Gene Expression Regulation, Plant , Genes, Plant , Plant Proteins/genetics , Trans-Activators/genetics , Acclimatization , Arabidopsis/physiology , Cold Temperature , DNA-Binding Proteins/metabolism , Gene Transfer Techniques , Plant Leaves/physiology , Plant Proteins/metabolism , Plants, Genetically Modified , Promoter Regions, Genetic , Regulon , Trans-Activators/metabolism
7.
Science ; 276(5316): 1233-6, 1997 May 23.
Article in English | MEDLINE | ID: mdl-9157876

ABSTRACT

Garito and co-workers have suggested a mechanism to dramatically increase the second hyperpolarizability, gamma, in linear pi-electron-conjugated molecules. Polarization is introduced that leads to a difference between the dipole moments of the molecule's ground state and excited state. Here a series of carotenoids was examined that had increasing intramolecular charge transfer (ICT) from the polyenic chain to the acceptor moiety in the ground state, and gamma was measured for these compounds as a function of wavelength by third-harmonic generation. The compound with the greatest ICT exhibited a 35-fold enhancement of gammamax (the gamma measured at the peak of the three-photon resonance) relative to the symmetric molecule beta-carotene, which itself has one of the largest third-order nonlinearities known. Stark spectroscopic measurements revealed the existence of a large difference dipole moment, Delta mu, between the ground and excited state. Quantum-chemical calculations underline the importance of interactions involving states with large Delta mu.


Subject(s)
Carotenoids/chemistry , Molecular Structure , Optics and Photonics , Photochemistry , Spectrum Analysis
8.
Am J Transplant ; 8(7): 1567-9, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18513273

ABSTRACT

This is the first reported case of respiratory failure associated with human metapneumovirus (hMPV) infection in a liver transplant recipient or in a pediatric solid transplant recipient. A 9-month-old female developed respiratory distress 8 days following a liver transplant. hMPV was detected and she required intubation followed by extracorporeal membrane oxygenation for 26 days. Immunosuppressive medications were stopped during the acute infection except for methylprednisolone as treatment for acute respiratory distress. Serial Doppler ultrasounds were used to monitor for hepatic vessel thromboses and serum liver function tests to assess for hepatic dysfunction and there was no evidence of allograft rejection. The patient recovered from the nosocomial hMPV infection with satisfactory pulmonary function and possible mild developmental delay.


Subject(s)
Liver Transplantation , Metapneumovirus , Respiratory Insufficiency/virology , Female , Humans , Infant , Paramyxoviridae Infections
9.
Clin Nutr ESPEN ; 28: 41-51, 2018 12.
Article in English | MEDLINE | ID: mdl-30390892

ABSTRACT

BACKGROUND & AIMS: Malnutrition is highly prevalent in chronic liver disease (CLD) due to alterations in nutrient utilization, malabsorption and poor intake. Low serum concentrations of branched chain amino acids (BCAA) in the presence of elevated aromatic acid concentrations is commonly observed in adult and children with liver cirrhosis and is associated with malnutrition and other adverse patient outcomes. The efficacy of BCAA supplementation has not been well established in adults and children with CLD. The purpose of this review was to critically evaluate the literature regarding the impact of BCAA supplementation related to changes in body composition, muscle strength, liver biomarkers, medical and hepatic complications (hepatic encephalopathy (HE), ascites, edema) and patient care outcomes (event free survival, health related quality of life, length of hospitalization). METHODS: A total of 40 articles retrieved from PubMed or Web of Science databases (1989-2017) were included. RESULTS: BCAA supplementation may be beneficial in improving muscle strength, ascites and edema with potential clinically significant improvements in HE in adult liver patients. In children, limited data have shown that BCAA supplementation may exert favourable effects on weight, fat mass, fat free mass and serum albumin level. CONCLUSIONS: Heterogeneity of study findings attributed to variability in BCAA dose (total, relative proportions), duration, disease severity and lack of uniformity in tools used for assessing patient outcomes limit overall conclusions. Longitudinal studies examining the efficacy of BCAA supplementation as a therapeutic treatment of malnutrition in chronic liver disease is warranted.


Subject(s)
Amino Acids, Branched-Chain , Dietary Supplements , Liver Cirrhosis/diet therapy , Adult , Child , Humans , Liver Cirrhosis/mortality , Survival Analysis , Treatment Outcome
10.
Oncogene ; 25(10): 1543-53, 2006 Mar 09.
Article in English | MEDLINE | ID: mdl-16278677

ABSTRACT

Ornithine decarboxylase (ODC) overexpression coupled with activated Ras is fully sufficient to oncogenically transform primary keratinocytes. To determine the Ras effector pathways that represent the minimal essential contribution to full oncogenic transformation in this context, we evaluated the cooperativity of different Ras effector mutants with overexpressed ODC in an in vivo tracheal xenotransplantation assay for epithelial cell invasiveness. Primary keratinocytes, isolated from either K6/ODC transgenic mouse skin (expressing increased ODC) or from normal littermate skin were infected with retrovirus producing an activated RasV12 or partial loss-of-function effector mutants of RasV12 that selectively induce only the Raf/ERK, RalGDS, or the PI3-kinase signaling pathway. Whereas keratinocytes expressing a fully activated RasV12 are not invasive in tracheal xenotransplants, ODC-overexpressing keratinocytes acquire an invasive phenotype with additional expression of either RasV12 or activation of the Raf/ERK pathway. Independent of a mutated ras, elevated levels of ODC activate the Akt/mTOR signaling pathway as well as the Rho/Rac pathway in primary keratinocytes. Thus, Raf/ERK signaling is sufficient to cooperate with increased ODC activity in the conversion of normal keratinocytes to invasive cells. In order to promote invasiveness in keratinocytes, elevated levels of ODC may cooperate with Raf/ERK via activation of the Akt and Rho/Rac signaling pathway.


Subject(s)
Cell Transformation, Neoplastic/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Keratinocytes/pathology , Neoplasm Invasiveness/pathology , Ornithine Decarboxylase/biosynthesis , raf Kinases/metabolism , Animals , Cell Transformation, Neoplastic/pathology , Cells, Cultured , Enzyme Activation/physiology , Extracellular Signal-Regulated MAP Kinases/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , NIH 3T3 Cells , Ornithine Decarboxylase/blood , Ornithine Decarboxylase/genetics , Phosphatidylinositol 3-Kinases/physiology , Polyamines/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/physiology , rac GTP-Binding Proteins/metabolism , raf Kinases/physiology , ral Guanine Nucleotide Exchange Factor/metabolism , rho GTP-Binding Proteins/metabolism
11.
Int J STD AIDS ; 17(5): 319-23, 2006 May.
Article in English | MEDLINE | ID: mdl-16643682

ABSTRACT

The aim of this study was to determine sex work practices and predictors of condom use among female sex workers (SWs) in Sydney. SWs from two centres completed a self-administered questionnaire covering demographic and sexual characteristics and sex work practices. One hundred and forty-eight international (born in Asia) and 141 local SWs (born in Australia, New Zealand or the UK) were recruited. Local SWs saw more clients per shift than international SWs (P = 0.002), but international SWs worked more shifts per week than local SWs (P = 0.001). International SWs used condoms less consistently at work than local SWs (P = 0.001). About 37% of international SWs never used condoms with non-paying partners, compared with 14% of local SWs (P = 0.01). Speaking Thai (odds ratio [OR] 8.9, 95% confidence interval [CI]; 3.19-24.87) or Chinese (OR 17.4; 95% CI 4.98-60.89) (both P < 0.001) and previous sex work in Thailand (OR 10.0 95% CI 2.31-43.52; P = 0.02) were associated with inconsistent condom use. Strategies to improve condom use need to be evaluated.


Subject(s)
Condoms/statistics & numerical data , Health Behavior , Sex Work , Sexual Behavior , Sexually Transmitted Diseases/psychology , Adolescent , Adult , Asia , Female , Humans , New South Wales , New Zealand/ethnology , Surveys and Questionnaires , United Kingdom/ethnology
12.
Addict Behav ; 31(3): 371-87, 2006 Mar.
Article in English | MEDLINE | ID: mdl-15972245

ABSTRACT

This economic evaluation was part of the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD) project. Data from four trials of heroin detoxification methods, involving 365 participants, were pooled to enable a comprehensive comparison of the cost-effectiveness of five inpatient and outpatient detoxification methods. This study took the perspective of the treatment provider in assessing resource use and costs. Two short-term outcome measures were used-achievement of an initial 7-day period of abstinence, and entry into ongoing post-detoxification treatment. The mean costs of the various detoxification methods ranged widely, from AUD 491 dollars(buprenorphine-based outpatient); to AUD 605 dollars for conventional outpatient; AUD 1404 dollars for conventional inpatient; AUD 1990 dollars for rapid detoxification under sedation; and to AUD 2689 dollars for anaesthesia per episode. An incremental cost-effectiveness analysis was carried out using conventional outpatient detoxification as the base comparator. The buprenorphine-based outpatient detoxification method was found to be the most cost-effective method overall, and rapid opioid detoxification under sedation was the most cost-effective inpatient method.


Subject(s)
Analgesics, Opioid/economics , Heroin Dependence/economics , Narcotic Antagonists/economics , Adult , Analgesics, Opioid/therapeutic use , Analysis of Variance , Buprenorphine/economics , Buprenorphine/therapeutic use , Chi-Square Distribution , Cost-Benefit Analysis , Female , Heroin Dependence/drug therapy , Humans , Hypnotics and Sedatives/therapeutic use , Male , Methadone/economics , Methadone/therapeutic use , Naltrexone/economics , Naltrexone/therapeutic use , Narcotic Antagonists/therapeutic use
13.
Cancer Res ; 60(20): 5696-703, 2000 Oct 15.
Article in English | MEDLINE | ID: mdl-11059762

ABSTRACT

We have shown that ornithine decarboxylase (ODC) overexpression in the skin of TG.AC v-Ha-ras transgenic mice induces the formation of spontaneous skin carcinomas. Treatment of ODC/Ras double transgenic mice with alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC enzyme activity, causes a rapid regression of these spontaneous tumors. DFMO treatment led to dramatic decreases in ODC activity and putrescine levels, but v-Ha-ras expression was not affected in the regressed tumors. Moreover, cyclin D1 continued to be strongly expressed in the basal epithelial cells of regressed tumors, and there was no decrease in the proliferative index of these same tumor cells. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling analyses revealed increased DNA fragmentation in DFMO regressed tumors compared with similarly sized spontaneous tumors from ODC/Ras transgenic mice not treated with DFMO. Moreover, the blood vessel count was significantly decreased in regressed tumors within the first four days of DFMO treatment. The decreased vasculature in DFMO regressed tumors was not attributable to altered expression of murine vascular endothelial growth factor (VEGF) isoforms. Elevated levels of ODC activity in the skin of K6/ODC transgenic mice increased the dermal vascularization compared with that in nontransgenic normal littermates. Our results suggest that ODC stimulates an angiogenic factor(s) other than VEGF and/or may play a key role in a cell survival effector pathway of Ras that is independent of a Ras-induced proliferation pathway.


Subject(s)
Genes, ras/genetics , Neovascularization, Pathologic/enzymology , Ornithine Decarboxylase Inhibitors , Skin Neoplasms/blood supply , Skin Neoplasms/prevention & control , Animals , Antineoplastic Agents/pharmacology , Cell Differentiation/drug effects , Cell Division/drug effects , Crosses, Genetic , Eflornithine/pharmacology , Enzyme Inhibitors/pharmacology , Female , Gene Expression/drug effects , In Situ Hybridization , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/prevention & control , Ornithine Decarboxylase/biosynthesis , Ornithine Decarboxylase/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Skin Neoplasms/enzymology , Skin Neoplasms/pathology , Transgenes
14.
Cancer Res ; 55(8): 1680-6, 1995 Apr 15.
Article in English | MEDLINE | ID: mdl-7712475

ABSTRACT

Ornithine decarboxylase (ODC) plays a key role in the biosynthesis of polyamines, which are necessary for cell growth and differentiation. ODC expression is very tightly controlled in all normal cells; however, regulation of its expression is altered in many tumor cells resulting in much higher basal levels of ODC in tumors. To investigate the potential role of ODC overexpression in epidermal tumorigenesis, we constructed a replication-defective retroviral vector to overexpress a truncated ODC protein in epidermal cells. Stable viral infection of mouse epidermal cells dramatically increases not only the basal ODC activity but also the basal putrescine and spermidine levels. In all infected epidermal cells with high polyamine levels, DNA synthesis is increased as measured by [3H]thymidine incorporation into DNA as well as increased bromodeoxyuridine staining in the nuclei of ODC-infected epidermal cells. ODC viral infection of nontumorigenic BK-1 epidermal cells and primary cultures of mouse keratinocytes and fibroblasts from newborn mouse skin yields no tumors when injected s.c. into athymic nude mice or when transplanted as skin grafts onto nude mice. Epidermal cell lines SP-1 and 308 (which possess an activated rasHa gene) are not tumorigenic when injected s.c. into nude mice. However, following infection with the ODC virus, they form tumors filled with keratin and papilloma-like projections of hyperplastic epidermal cells displaying dysplasia and many mitotic figures. These data indicate that ODC overexpression by itself is not sufficient to induce tumors in normal cells but that increased expression of ODC enhances tumor development in initiated premalignant epidermal cells.


Subject(s)
Keratinocytes/enzymology , Ornithine Decarboxylase/metabolism , Skin Neoplasms/enzymology , Skin Neoplasms/pathology , 9,10-Dimethyl-1,2-benzanthracene , Animals , Animals, Newborn , Bromodeoxyuridine , Cell Line , Cells, Cultured , Fibroblasts/enzymology , Genetic Vectors , Mice , Mice, Inbred BALB C , Ornithine Decarboxylase/biosynthesis , Papilloma/enzymology , Papilloma/pathology , Polyamines/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/metabolism , Retroviridae , Skin Neoplasms/chemically induced , Skin Transplantation/physiology , Tetradecanoylphorbol Acetate , Transfection
15.
Cancer Res ; 47(5): 1221-5, 1987 Mar 01.
Article in English | MEDLINE | ID: mdl-3815331

ABSTRACT

Topical treatment of mouse skin with the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) results in an array of biochemical alterations, one of the earliest being a more than 200-fold transient induction of epidermal ornithine decarboxylase (ODC) activity. There is an excellent correlation between the induction of epidermal ODC activity and changes in the level of immunoreactive ODC protein following a single TPA treatment to skin. Both ODC activity and protein levels peak at 4.5 h after TPA treatment and rapidly fall to basal levels by 24 h. Cycloheximide treatment of mice in which ODC had been previously induced by TPA indicated a similar rapid turnover of both ODC catalytic activity and protein levels. Northern blot analysis of polyadenylated RNA isolated from mouse epidermis after a single TPA treatment revealed the stimulation of one species of ODC mRNA of 2.0 kilobases with a maximum at 3.5 h declining by 16 h. The same-sized species of ODC mRNA was detected 4.5 h after multiple biweekly treatments with TPA as well as in mouse papillomas and carcinomas not treated with TPA for at least 1 week. Southern blot analysis of EcoRI or BamHI digests of DNA derived from mouse liver, papillomas, or carcinomas revealed no ODC gene amplification or rearrangement during neoplastic progression. These observations indicate that the induction of epidermal ODC activity following TPA treatment results in a transient increase in the steady state levels of ODC mRNA and in the rate of synthesis of ODC protein, in contrast to epidermal tumors where the levels of ODC mRNA and protein are constitutively elevated.


Subject(s)
Epidermis/enzymology , Gene Expression Regulation , Ornithine Decarboxylase/genetics , Skin Neoplasms/enzymology , Animals , Female , Gene Amplification , Mice , Mice, Inbred Strains , Ornithine Decarboxylase/analysis , RNA, Messenger/analysis , Skin Neoplasms/chemically induced , Tetradecanoylphorbol Acetate
16.
Cancer Res ; 48(5): 1252-7, 1988 Mar 01.
Article in English | MEDLINE | ID: mdl-3342404

ABSTRACT

Previous studies have demonstrated the presence in mouse epidermal tumors of a structurally and functionally altered ornithine decarboxylase (ODC). In this report, the enzymatic properties of ODC from normal human skin and squamous cell carcinomas are examined. Some tumors contained a more heat stable ODC than the enzyme found in normal skin. GTP stimulated enzyme activity in four of seven tumor extracts tested but had no effect on normal skin ODC. Kinetic analyses indicated that GTP either lowered the apparent Km of tumor ODC for L-ornithine, increased the Vmax, or had both effects, depending on the tumor examined. Gel filtration chromatography of crude tumor extracts indicated the existence of multiple molecular weight forms of ODC, some of which can be activated by GTP and some of which are unaffected by GTP. Some tumors contain both a GTP-activatable and -nonactivatable form of the enzyme. Immunolocalization studies demonstrated the presence within squamous cell carcinomas of cells with a constitutively high level of immunoreactive ODC, a situation never observed in normal skin tissue. These results suggest that some human squamous cell carcinomas contain a functionally altered ODC that may be aberrantly regulated.


Subject(s)
Carcinoma, Squamous Cell/enzymology , Guanosine Triphosphate/pharmacology , Ornithine Decarboxylase/analysis , Skin Neoplasms/enzymology , Enzyme Activation/drug effects , Humans , Kinetics , Skin/enzymology
17.
Cancer Res ; 57(11): 2104-8, 1997 Jun 01.
Article in English | MEDLINE | ID: mdl-9187103

ABSTRACT

Ornithine decarboxylase (ODC) overexpression cooperates with genetic lesions such as an activated c-rasHa to enhance epithelial tumorigenesis. To assess the invasiveness of ODC-overexpressing cells, two noninvasive epidermal cell lines, nontumorigenic BK-1 cells, and the papilloma-derived cell line SP-1 were infected with a replication-defective retrovirus that overexpresses ODC, inoculated into deepithelialized rat tracheas, and transplanted into athymic nude mice. After 5 weeks, ODC-overexpressing BK-1 cells remained localized on the luminal surface of the tracheal xenotransplants, whereas the ODC-overexpressing SP-1 cells were extremely invasive, with the whole tracheal wall penetrated. This invasiveness of ODC-overexpressing SP-1 cells was accompanied by elevated proteinase expression, including increased urokinase plasminogen activator activity in ODC-overexpressing cells and elevated stromelysin-1 mRNA expression in the stromal cells of invaded tracheal transplants.


Subject(s)
Neoplasm Invasiveness , Ornithine Decarboxylase/biosynthesis , Papilloma/enzymology , Animals , Endopeptidases/metabolism , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Genes, ras , In Situ Hybridization , Matrix Metalloproteinase 3/metabolism , Mice , Mice, Nude , Neoplasm Transplantation , Ornithine Decarboxylase/genetics , Papilloma/genetics , Rats , Stromal Cells/metabolism , Trachea/transplantation , Trachea/virology , Tumor Cells, Cultured , Urokinase-Type Plasminogen Activator/metabolism
18.
Cancer Res ; 50(15): 4741-6, 1990 Aug 01.
Article in English | MEDLINE | ID: mdl-2369749

ABSTRACT

Ornithine decarboxylase (ODC), the initial enzyme in the polyamine biosynthetic pathway, has been used as a marker for the hyperplasia that occurs following exposure of mouse epidermis to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Using flow cytometry in combination with polyclonal antibodies to ODC, we examined the levels of ODC-associated immunoreactive protein present within mouse epidermal cells at 4 and 24 h after a single topical application of TPA, as well as following chronic exposure to TPA and in papillomas. Basal levels of ODC-specific antibody binding were detectable in acetone-treated CD-1 mouse epidermis and were increased 3-fold at 4 h after TPA treatment. The amount of ODC antibody binding detected after exposure to 17 nmol TPA twice weekly for 3 weeks was similar to that detected within cells isolated from papillomas and was 2.5-fold higher than in cells isolated at 4 h after a single topical treatment of mice with TPA. These observations support the hypothesis that specific subpopulations of keratinocytes constitutively express high levels of ODC following chronic exposure to TPA. The novel method for ODC detection described in these studies provides a means to identify, isolate, and further characterize epidermal cells that may give rise to papillomas and carcinomas.


Subject(s)
Epidermis/enzymology , Ornithine Decarboxylase/metabolism , Papilloma/enzymology , Skin Neoplasms/enzymology , Tetradecanoylphorbol Acetate/pharmacology , Animals , Cells, Cultured , Epidermal Cells , Epidermis/drug effects , Female , Flow Cytometry , Mice
19.
Cancer Res ; 55(19): 4205-9, 1995 Oct 01.
Article in English | MEDLINE | ID: mdl-7671221

ABSTRACT

Ornithine decarboxylase, a critical regulatory enzyme for polyamine biosynthesis, is highly inducible by growth-promoting stimuli in mouse epidermis but the enzyme level is only transiently elevated due to rapid turnover of the protein. Here we report that constitutive overexpression of the enzyme in the skin of transgenic mice causes several phenotypic abnormalities. Effects observed include development of dermal follicular cysts, excessive skin wrinkling, enhanced nail growth, alopecia, and spontaneous tumor development. These results indicate that up-regulation of polyamine biosynthesis can profoundly disturb skin homeostasis and alter susceptibility to neoplastic development.


Subject(s)
Ornithine Decarboxylase/physiology , Skin Neoplasms/etiology , Animals , Base Sequence , Female , Male , Mice , Mice, Transgenic , Molecular Sequence Data , Ornithine Decarboxylase/genetics , Skin/enzymology , Skin Neoplasms/genetics
20.
Cancer Res ; 50(7): 2088-94, 1990 Apr 01.
Article in English | MEDLINE | ID: mdl-2317797

ABSTRACT

Ornithine decarboxylase (ODC) activity was measured in colon adenocarcinomas and adjacent normal-appearing colon mucosa from a total of 40 patients undergoing surgical resections. The enzyme activity was measured in the presence and absence of GTP, since recent work has demonstrated a GTP-activatable form of ODC in some murine and human tumors. In general, ODC specific activity was higher in adenocarcinomas than in adjacent normal-appearing mucosa. Of greater interest, however, was the finding that 13 of 40 tumors and 3 of 40 mucosae contained a GTP-activatable form of ODC. These are minimal estimates of the proportion of tissues positive for this enzyme form, since a multiple sampling protocol indicated that expression of a GTP-activatable ODC was not uniform throughout a given tumor. Chromatographic analyses of tumor extracts revealed the presence in some tumors of multiple size forms of ODC, only some of which were activated by GTP. Enzyme kinetic data indicated that the multiple forms of ODC can have different affinities for L-ornithine and that GTP can "normalize" the aberrant kinetic properties of these forms. While there was no statistically significant correlation of the presence of a GTP-activatable ODC with stage of disease, analysis of our data revealed a positive association of a GTP-activatable ODC with tumor site; a much higher percentage of tumors of the cecum contained this ODC isoform than tumors of other colonic segments (64% versus less than or equal to 25% for other sites). These results demonstrate (a) the presence of a functionally distinct form of ODC in some human colon adenocarcinomas and (b) a distinct regional distribution of this ODC form within the colon. We suggest this alteration in a key enzyme in the growth-associated pathway of polyamine biosynthesis may play a role in colon tumor progression.


Subject(s)
Adenocarcinoma/enzymology , Colorectal Neoplasms/enzymology , Ornithine Decarboxylase/metabolism , Enzyme Activation , Guanosine Triphosphate/physiology , Humans , Intestinal Mucosa/enzymology , Kinetics
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