RESUMO
Although tobacco use is declining in several countries including India (dropping from 35% in 2009-10 to 29% 2016-17 among adults)-it still poses a huge burden on India, as the world's second largest consumer of tobacco products. In Bihar state, with a prevalence of 25%, the Bihar School Teachers Study (BSTS) successfully enlisted teachers as role models for encouraging quitting and changing social norms pertaining to tobacco. The study used a mixed-methods approach to identify factors associated with teachers' quitting. Qualitative data were collected through focus groups with teachers and school principals. Quantitative data were collected through a written survey administered to school personnel post-intervention. Key findings from focus groups were that teachers and principals quit using tobacco and promoted cessation because they wanted to model positive behaviors; specific information about tobacco's harms aided cessation; and the BSTS intervention facilitated a school environment that supported quitting. Survey results indicated teachers who reported knowing people who quit using tobacco in the prior year were far more likely to quit as were teachers who reported that their school's tobacco policy was completely enforced. The combination of qualitative and quantitative data yielded important insights with strong implications for future interventions.
Assuntos
Docentes/estatística & dados numéricos , Papel Profissional , Instituições Acadêmicas/organização & administração , Abandono do Uso de Tabaco/estatística & dados numéricos , Logro , Adulto , Feminino , Grupos Focais , Humanos , Índia/epidemiologia , Masculino , Prevalência , Instituições Acadêmicas/normas , Normas Sociais , Adulto JovemRESUMO
Anti-angiogenic therapies for cancer such as VEGF neutralizing antibody bevacizumab have limited durability. While mechanisms of resistance remain undefined, it is likely that acquired resistance to anti-angiogenic therapy will involve alterations of the tumor microenvironment. We confirmed increased tumor-associated macrophages in bevacizumab-resistant glioblastoma patient specimens and two novel glioblastoma xenograft models of bevacizumab resistance. Microarray analysis suggested downregulated macrophage migration inhibitory factor (MIF) to be the most pertinent mediator of increased macrophages. Bevacizumab-resistant patient glioblastomas and both novel xenograft models of resistance had less MIF than bevacizumab-naive tumors, and harbored more M2/protumoral macrophages that specifically localized to the tumor edge. Xenografts expressing MIF-shRNA grew more rapidly with greater angiogenesis and had macrophages localizing to the tumor edge which were more prevalent and proliferative, and displayed M2 polarization, whereas bevacizumab-resistant xenografts transduced to upregulate MIF exhibited the opposite changes. Bone marrow-derived macrophage were polarized to an M2 phenotype in the presence of condition-media derived from bevacizumab-resistant xenograft-derived cells, while recombinant MIF drove M1 polarization. Media from macrophages exposed to bevacizumab-resistant tumor cell conditioned media increased glioma cell proliferation compared with media from macrophages exposed to bevacizumab-responsive tumor cell media, suggesting that macrophage polarization in bevacizumab-resistant xenografts is the source of their aggressive biology and results from a secreted factor. Two mechanisms of bevacizumab-induced MIF reduction were identified: (1) bevacizumab bound MIF and blocked MIF-induced M1 polarization of macrophages; and (2) VEGF increased glioma MIF production in a VEGFR2-dependent manner, suggesting that bevacizumab-induced VEGF depletion would downregulate MIF. Site-directed biopsies revealed enriched MIF and VEGF at the enhancing edge in bevacizumab-naive patients. This MIF enrichment was lost in bevacizumab-resistant glioblastomas, driving a tumor edge M1-to-M2 transition. Thus, bevacizumab resistance is driven by reduced MIF at the tumor edge causing proliferative expansion of M2 macrophages, which in turn promotes tumor growth.
Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/irrigação sanguínea , Glioblastoma/tratamento farmacológico , Fatores Inibidores da Migração de Macrófagos/metabolismo , Animais , Bevacizumab/farmacologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Feminino , Glioblastoma/metabolismo , Humanos , Macrófagos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In health education and behavior change interventions, process tracking monitors the delivery of an intervention and its receipt to the intended audience. A randomized controlled trial in the state of Bihar, India was conducted to help school teachers become tobacco free through appropriately designed intervention program and delivery system. We describe the results from process tracking of this intervention delivery. The intervention program was centred on six topics delivered in each school through 12 sessions over 6 successive months. The program deliverers recorded the process measures as total number of sessions and program-components implemented (fidelity); time spent conducting sessions (dose) and proportion of teachers attending at least one session (reach). The outcome measures (teachers' exposure to intervention messages and tobacco policy adoption) were assessed post-intervention. All 12 sessions were delivered in 33 out of 36 schools. Thirty-one schools implemented all six program components. In 18 schools, ≥95% of the teachers participated in one or more sessions. Thirty-three schools received 12 or more hours of dose. In 29 schools, 100% teachers reported exposure to all program messages. Tobacco policy was adopted by all schools. Thus, the intervention was generally delivered as planned and it had a positive impact on teachers and schools.
Assuntos
Docentes , Educação em Saúde/organização & administração , Tabagismo/prevenção & controle , Adulto , Estudos de Viabilidade , Feminino , Humanos , Índia , MasculinoRESUMO
CONTEXT: A high prevalence of tobacco use, even among educated professionals like teachers, has been reported from Bihar. After passing of the Cigarette and Other Tobacco Products Act (COTPA) in 2003, there have been major improvements in tobacco control nationwide. AIMS: To compare tobacco use prevalence among school teachers in Bihar reported in 2000 with a survey in 2008 and investigate correlates of current and past tobacco-use. METHODS: Data from the baseline survey of a cluster random sample of 72 government schools conducted during the beginning of two consecutive school years was analyzed. RESULTS: The prevalence of current tobacco use was 35.5% and past use, 11.3%. Likelihood of current use compared with no use increased with age (odds ratio [OR] =3.27 for > 50 years compared to < 30, 95% confidence interval [CI]: [1.50, 7.13]); whereas that of past use compared to current use decreased (OR = 0.25, 95% CI: [0.09-0.68] for age > 50 years compared to < 30 years). DISCUSSION: Compared to the tobacco use prevalence among Bihar school teachers reported from a survey in the year 2000 (77.4%), the prevalence in this survey in 2008 was much lower and past use, much higher. In the earlier survey, lal dantmajan was counted as a tobacco product. If we do the same in the current survey, and consider ever use, the prevalence even then was 53.9%, lower than the earlier figure. Although the tobacco use among teachers in Bihar is still high, it has decreased after the implementation of COTPA and the cessation has increased.
Assuntos
Docentes , Fumar/epidemiologia , Tabagismo/epidemiologia , Uso de Tabaco/efeitos adversos , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto , Instituições AcadêmicasRESUMO
Hypoxia is linked to epithelial-mesenchymal transition (EMT) and tumor progression in numerous carcinomas. Responses to hypoxia are thought to operate via hypoxia-inducible factors (HIFs), but the importance of co-factors that regulate HIF signaling within tumors is not well understood. Here, we elucidate a signaling pathway that physically and functionally couples tyrosine phosphorylation of ß-catenin to HIF1α signaling and HIF1α-mediated tumor EMT. Primary human lung adenocarcinomas accumulate pY654-ß-catenin and HIF1α. All pY654-ß-catenin, and only the tyrosine phosphorylated form, was found complexed with HIF1α and active Src, both within the human tumors and in lung tumor cell lines exposed to hypoxia. Phosphorylation of Y654, generated by hypoxia mediated, reactive oxygen species (ROS)-dependent Src kinase activation, was required for ß-catenin to interact with HIF1α and Src, to promote HIF1α transcriptional activity, and for hypoxia-induced EMT. Mice bearing hypoxic pancreatic islet adenomas, generated by treatment with anti-vascular endothelial growth factor antibodies, accumulate HIF1α/pY654-ß-catenin complexes and develop an invasive phenotype. Concurrent administration of the ROS inhibitor N-acetylcysteine abrogated ß-catenin/HIF pathway activity and restored adenoma architecture. Collectively, the findings implicate accumulation of pY654-ß-catenin specifically complexed to HIF1α and Src kinase as critically involved in HIF1α signaling and tumor invasion. The findings also suggest that targeting ROS-dependent aspects of the pY654-ß-catenin/ HIF1α pathway may attenuate untoward biological effects of anti-angiogenic agents and tumor hypoxia.
Assuntos
Adenocarcinoma/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/metabolismo , beta Catenina/metabolismo , Adenocarcinoma/patologia , Adenoma/metabolismo , Adenoma/patologia , Adenoma de Células das Ilhotas Pancreáticas , Animais , Anticorpos Neutralizantes/farmacologia , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Proteína Smad2/metabolismo , Tirosina/metabolismo , Fator A de Crescimento do Endotélio Vascular/imunologia , beta Catenina/genética , Quinases da Família src/metabolismoRESUMO
To formulate Functional Assessment of Cancer Therapy-Meningioma (FACT-MNG), a web-based tumor site-specific outcome instrument for assessing intracranial meningioma patients following surgical resection or stereotactic radiosurgery. We surveyed the relevant literature available on intracranial meningioma surgery and subsequent outcomes (38 papers), making note of which, if any, QOL/outcome instruments were utilized. None of the surgveyed papers included QOL assessment specific to tumor site. We subsequently developed questions that were relevant to the signs and symptoms that characterize each of 11 intracranial meningioma sites, and incorporated them into a modified combination of the Functional Assessment of Cancer Therapy-Brain (FACT-BR) and SF36 outcome instruments, thereby creating a new tumor site-specific outcome instrument, FACT-MNG. With outcomes analysis of surgical and radiosurgical treatments becoming more important, measures of the adequacy and success of treatment are needed. FACT-MNG represents a first effort to formalize such an instrument for meningioma patients. Questions specific to tumor site will allow surgeons to better assess specific quality of life issues not addressed in the past by more general questionnaires.
Assuntos
Internet , Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Avaliação de Resultados em Cuidados de Saúde , Qualidade de Vida , Radiocirurgia , HumanosRESUMO
Oncolytic herpes simplex viruses (HSVs), in clinical trials for the treatment of malignant gliomas, are assumed to be selective for tumor cells because their replication is strongly attenuated in quiescent cells, but not in cycling cells. Oncolytic selectivity is thought to occur because mutations in viral ICP6 (encoding a viral ribonucleotide reductase function) and/or gamma34.5 function are respectively complemented by mammalian ribonucleotide reductase and GADD34, whose genes are expressed in cycling cells. However, it is estimated that only 5-15% of malignant glioma cells are in mitosis at any one time. Therefore, effective replication of HSV oncolytic viruses might be limited to a subpopulation of tumor cells, since at any one time the majority of tumor cells would not be cycling. However, we report that an HSV with defective ICP6 function replicates in quiescent cultured murine embryonic fibroblasts obtained from mice with homozygous p16 deletions. Furthermore, intracranial inoculation of this virus into the brains of p16-/- mice provides evidence of viral replication that does not occur when the virus is injected into the brains of wild-type mice. These approaches provide in vitro and in vivo evidence that ICP6-negative HSVs are 'molecularly targeted,' because they replicate in quiescent tumor cells carrying specific oncogene deletions, independent of cell cycle status.
Assuntos
Ciclo Celular/fisiologia , Genes p16 , Vírus Oncolíticos/genética , Simplexvirus/genética , Simplexvirus/fisiologia , Proteínas Virais/genética , Replicação Viral/genética , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Ciclo Celular/genética , Células Cultivadas , Glioma/genética , Glioma/terapia , Homozigoto , Humanos , Camundongos , Camundongos Knockout , Mutação/fisiologia , Terapia Viral OncolíticaRESUMO
Among the broad array of genes that have been evaluated for tumor therapy, those encoding prodrug activation enzymes are especially appealing as they directly complement ongoing clinical chemotherapeutic regimes. These enzymes can activate prodrugs that have low inherent toxicity using both bacterial and yeast enzymes, or enhance prodrug activation by mammalian enzymes. The general advantage of the former is the large therapeutic index that can be achieved, and of the latter, the non-immunogenicity (supporting longer periods of prodrug activation) and the fact that the prodrugs will continue to have some efficacy after transgene expression is extinguished. This review article describes 13 different prodrug activation schemes developed over the last 15 years, two of which - activation of ganciclovir by viral thymidine kinase and activation of 5-fluorocytosine to 5-fluorouracil - are currently being evaluated in clinical trials. Essentially all of these prodrug activation enzymes mediate toxicity through disruption of DNA replication, which occurs at differentially high rates in tumor cells compared with most normal cells. In cancer gene therapy, vectors target delivery of therapeutic genes to tumor cells, in contrast to the use of antibodies in antibody-directed prodrug therapy. Vector targeting is usually effected by direct injection into the tumor mass or surrounding tissues, but the efficiency of gene delivery is usually low. Thus it is important that the activated drug is able to act on non-transduced tumor cells. This bystander effect may require cell-to-cell contact or be mediated by facilitated diffusion or extracellular activation to target neighboring tumor cells. Effects at distant sites are believed to be mediated by the immune system, which can be mobilized to recognize tumor antigens by prodrug-activated gene therapy. Prodrug activation schemes can be combined with each other and with other treatments, such as radiation, in a synergistic manner. Use of prodrug wafers for intratumoral drug activation and selective permeabilization of the tumor vasculature to prodrugs and vectors should further increase the value of this new therapeutic modality.
Assuntos
Antineoplásicos/uso terapêutico , Terapia Genética , Neoplasias/terapia , Pró-Fármacos/farmacocinética , Antineoplásicos/farmacocinética , Enzimas/genética , Enzimas/metabolismo , Humanos , Neoplasias/enzimologia , TransgenesRESUMO
Gliomas account for about 60% of all primary CNS tumors; two-thirds of all gliomas comprise the most malignant form, glioblastoma multiforme, or glioma grade IV. Although much progress has been achieved in the treatment of other solid tumors over the last few decades, the median survival of patients with glioblastoma remains at around 12 mo after standard treatment, which includes bulk resection and irradiation, as well as chemotherapy in some cases (1). Essentially, no patient can expect to survive 5 yr. New treatment modalities like immunotherapy have been applied so far with only limited success (2). With the improvement of methods for in vivo and ex vivo gene delivery, gene therapy became a new, promising approach to glioma therapy. Gliomas appear to be a particularly good target for a gene therapy approach using locally applied vectors, as the growth of gliomas is restricted to the brain. Clinical trials are under way using retrovirus and adenovirus vectors which carry the herpes simplex virus type-1 (HSV-1) thymidine kinase gene (HSV-tk). This gene encodes a prodrug-activating enzyme, which in infected cells converts the nontoxic prodrug, ganciclovir (GCV), to its cytotoxic phosphorylated form (3-5). There is an ever-increasing list of other prodrug-activation systems that showed efficacy in culture and in preclinical studies using rodent glioma models. These include, for example, cytosine deaminase converting 5-fluorocytosine to 5-fluoro-uracil (6), cytochrome P450-2B1 converting cyclophosphamide to phosphoramide mustard (7), deoxycytidine kinase phosphorylating cytosine arabinoside (8), and the Escherichia coli guanine phosphoribosyl transferase (gpt) metabolizing 6-thioxanthine and 6-thioguanine to toxic nucleoside analogs (9). Moreover, gene therapy approaches to brain tumors include the viral transfer of immune-enhancing cytokines, particularly granulocyte/macrophage colony-stimulating factor (10), or antisense to TGF-ß to glioma cells (11) used for vaccination purposes. Other approaches use the transfer of genes that modulate angiogenesis (12,13) or are involved in apoptosis like p53 (14). All aforementioned gene-transfer methods use nonreplicative viral vectors.
RESUMO
Multimodal therapy is generally more effective than single-agent treatment for cancer. rRp450 is an engineered herpes simplex viral mutant that replicates in and kills tumor cells in a relatively selective fashion. It also expresses, in infected cells, the cyclophosphamide (CPA)-sensitive rat cytochrome P450 2B1 (CYP2B1) and the ganciclovir (GCV)-sensitive herpes simplex virus thymidine kinase (HSV-TK) transgenes. We show that cultured rat 9L and human U87deltaEGFR glioma cells, infected and lysed by rRp450, also exhibit supra-additive sensitivity to both CPA and GCV, as determined by Chou-Talalay synergy analysis. DNA cross-linking, assayed by ethidium bromide fluorescence, was significantly inhibited in the presence of GCV, suggesting that interactions between the CPA/CYP2B1 and GCV/HSV-TK gene therapies occurred at the level of DNA repair. In vivo, regression of 9L s.c. tumor volumes in athymic mice was achieved only by the multimodal treatment allowed by rRp450 viral oncolysis combined with CPA/CYP2B1 and GCV/HSV-TK gene therapies, whereas all other treatment combinations produced only tumor growth retardation.
Assuntos
Antineoplásicos/uso terapêutico , Ciclofosfamida/uso terapêutico , Ganciclovir/uso terapêutico , Terapia Genética , Glioma/genética , Glioma/terapia , Vírus/genética , Animais , Terapia Combinada , Ciclofosfamida/análogos & derivados , Citocromo P-450 CYP2B1/genética , Técnicas de Transferência de Genes , Humanos , Camundongos , Camundongos Nus , Ratos , Timidina Quinase/genética , Células Tumorais Cultivadas , Replicação ViralRESUMO
BACKGROUND: Although antifolates are popular agents for use in chemotherapy, they display minimal toxicity against slow-growing tumors and are toxic to actively replicating cells in normal tissues. These drugs are converted intracellularly into polyglutamate derivatives by the enzyme folylpolyglutamyl synthetase (FPGS). Because tumors with high expression of FPGS often respond to nontoxic antifolate doses, we investigated whether augmenting tumoral FPGS activity by gene delivery would enhance tumoral antifolate sensitivity. METHODS: 9L rat gliosarcoma cells were stably transfected with a human FPGS complementary DNA (cDNA), producing 9L/FPGS cells. The sensitivity of these cells to the antifolates methotrexate and edatrexate was measured in culture and in subcutaneous tumors, as was their ability to increase the chemosensitivity of nearby nontransfected cells, i.e., a bystander effect. The antifolate sensitivity of nonselected cells transduced with a hybrid amplicon vector that expressed FPGS was also ascertained. RESULTS: In comparison with 9L cells, 9L/FPGS cells displayed enhanced sensitivity to 4-hour pulses of antifolate. Subcutaneous 9L/FPGS tumors responded as well to methotrexate given every third day as 9L tumors did to daily treatment. A modest bystander effect was observed with edatrexate treatment in culture and in vivo. The observed bystander effect appeared to result from the release of antifolates by transfected cells after the removal of extracellular drug. In culture, enhanced antifolate sensitivity was also seen in other stably transfected rodent and human glioma cell lines, including one with high pre-existing FPGS activity, and in canine and human glioblastoma cell lines transduced with a vector bearing FPGS cDNA. CONCLUSIONS: FPGS gene delivery enhances the antifolate sensitivity of several glioma cell lines and merits further evaluation as a therapeutic strategy.
Assuntos
Aminopterina/análogos & derivados , Antimetabólitos Antineoplásicos/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Técnicas de Transferência de Genes , Terapia Genética/métodos , Metotrexato/farmacologia , Neoplasias/terapia , Peptídeo Sintases/genética , Aminopterina/farmacologia , Animais , Cromatografia em Camada Fina , Cães , Relação Dose-Resposta a Droga , Glioma , Humanos , Neoplasias/enzimologia , Neoplasias/genética , Peptídeo Sintases/metabolismo , Ratos , Transdução Genética , Transfecção , Células Tumorais CultivadasRESUMO
BACKGROUND: The versatility of HSV-1 vectors includes large transgene capacity, selective replication of mutants in dividing cells, and availability of recombinant virus (RV) and plasmid-derived (amplicon) vectors, which can be propagated in a co-dependent, 'piggyback', manner. METHODS: A replication-defective piggyback vector system was generated in which the amplicon carries either of two genes essential for virus replication, IE2 (ICP27) or IE3 (ICP4), as well as lacZ; the RV is deleted in both these genes, and vector stocks are propagated in cells transfected with one of the complementary genes. In the replication-competent system, the amplicon carries the IE2 and lacZ; the RV had a large deletion in the IE2; and stocks are propagated in untransfected cells. Titers over successive passages, recombination between amplicon and RV, and the structural integrity of vector genomes were evaluated. The replication-competent system was tested for therapeutic efficacy in subcutaneous 9L gliosarcoma tumors in nude mice with activation of ganciclovir via the viral HSV-thymidine kinase gene. RESULTS: Both systems generated high titer amplicon vectors (about 10(7) tu/ml) and amplicon:RV ratios (0.6-3.0). No replication-competent RV was generated in either system. The replication-defective system showed low toxicity and increased packaging efficiency of amplicon vectors, as compared to single mutant RV helper virus. The replication-competent system allowed co-propagation of amplicon and RV; injection into tumors followed by ganciclovir treatment inhibited tumor growth without systemic toxicity. CONCLUSION: New replication-defective and replication-competent piggyback HSV, vector systems allow gene delivery via amplicon vectors with reduced toxicity and co-propagation of both RV and amplicon vectors in target cells, with effective tumor therapy via focal virus replication and pro-drug activation.
Assuntos
Terapia Genética , Vetores Genéticos , Gliossarcoma/terapia , Herpesvirus Humano 1/genética , Animais , Sequência de Bases , Linhagem Celular , Chlorocebus aethiops , Cricetinae , Vírus Defeituosos/genética , Vírus Defeituosos/fisiologia , Genes Precoces , Vírus Auxiliares/genética , Vírus Auxiliares/fisiologia , Herpesvirus Humano 1/fisiologia , Óperon Lac , Masculino , Camundongos , Camundongos Nus , Plasmídeos/genética , Ratos , Recombinação Genética , Células Vero , Replicação ViralRESUMO
BACKGROUND: A bacterial enzyme, Escherichia coli cytosine deaminase, which converts the prodrug 5-fluorocytosine into the toxic drug 5-fluorouracil, and a viral enzyme, herpes simplex virus thymidine kinase, which converts ganciclovir from an inactive prodrug to a cytotoxic agent by phosphorylation, are being actively investigated for use in gene therapy for cancer. The purpose of this study was to determine whether combining these prodrug-activating gene therapies might result in enhanced anticancer effects. METHODS: Rat 9L gliosarcoma cells were transfected with plasmids containing the E. coli cytosine deaminase gene (9L/CD cells), with plasmids containing the herpes simplex virus thymidine kinase gene (9L/TK cells), or with both expression plasmids (9L/CD-TK cells). The drug sensitivities of the cell lines were evaluated; in addition, the sensitivities of 9L and 9L/CD-TK cells mixed in varied proportions were measured. The effects of prodrug treatment on 9L/CD-TK tumor growth (i.e., size and volume) in nude mice were monitored. The isobologram method of Loewe and the multiple drug-effect analysis method of Chou-Talalay were used to measure the interaction between the two prodrug-activating gene therapies. To elucidate the mechanism of interaction, the phosphorylation of ganciclovir in 9L/CD-TK cells after varying prodrug treatments was studied. RESULTS AND CONCLUSIONS: The presence of transfected cytosine deaminase and thymidine kinase genes in 9L gliosarcoma cells reduced cell survival, both in vitro and in vivo, following treatment with the relevant prodrugs; the effects of the two components appeared to be synergistic and related mechanistically to the enhancement of ganciclovir phosphorylation by thymidine kinase following 5-fluorouracil treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Flucitosina/química , Ganciclovir/química , Terapia Genética , Gliossarcoma/terapia , Nucleosídeo Desaminases/farmacologia , Timidina Quinase/farmacologia , Animais , Sobrevivência Celular , Citosina Desaminase , Fluoruracila/administração & dosagem , Gliossarcoma/tratamento farmacológico , Gliossarcoma/genética , Humanos , Camundongos , Camundongos Nus , Mitose , Fosforilação/efeitos dos fármacos , Pró-Fármacos , Ratos , Células Tumorais CultivadasRESUMO
OBJECTIVE: To develop and test a food frequency questionnaire (FFQ) for use in rural areas of Kerala, India. DESIGN: Based on food use and market surveys of the study area, a quantitative 81-item interviewer-administered FFQ was developed. A validation study was conducted consisting of 24-h diet recalls (24HR) administered on 8 days randomly selected over an entire year and two administrations of the FFQ, one at the beginning of the 1-year period and the other at the end. FFQ and 24HR-derived nutrient scores were compared using correlation and regression analyses and by examining differences in the nutrient scores. SETTING: Rural villages in Ernakulum district, Kerala, South India. SUBJECTS: In each of 30 households, the male head of household and female food preparer were enrolled. RESULTS: Pearson (parametric) correlation coefficients (r(p)) averaged about 0.50 in comparing nutrient scores derived from the 24HR with those from the first FFQ and about 0.55 in comparing the second FFQ. On average, Spearman correlation coefficients (r(s)) were slightly lower than the r(p) in comparing the scores derived from the first FFQ, but virtually identical for the second FFQ. Regression analyses indicated better agreement in the comparison of the 24HR-derived scores with the first FFQ than the second FFQ. Difference scores, however, tended to be larger in comparing the first FFQ scores with the 24HR. CONCLUSIONS: This FFQ produces results broadly comparable to those used in Europe and North America, indicating its suitability for comparing exposures within a study population in reference to health-related endpoints.
Assuntos
Registros de Dieta , Inquéritos sobre Dietas , Inquéritos e Questionários/normas , Feminino , Humanos , Índia , Entrevistas como Assunto , Modelos Lineares , Masculino , Rememoração Mental , Reprodutibilidade dos Testes , Saúde da População Rural/estatística & dados numéricosRESUMO
A second-generation replication-conditional herpes simplex virus type 1 (HSV) vector defective for both ribonucleotide reductase (RR) and the neurovirulence factor gamma34.5 was generated and tested for therapeutic safety and efficiency in two different experimental brain tumor models. In culture, cytotoxic activity of this double mutant HSV vector, MGH-1, for 9L gliosarcoma cells was similar to that of the HSV mutant, R3616, which is defective only for gamma34.5, but was significantly weaker than that of the HSV mutant hrR3, which is defective only for RR. The diminished tumoricidal effect of the gamma34.5 mutants could be accounted for by their reduced ability to replicate in 9L cells. The MGH-1 vector did not achieve significant prolongation of survival in vivo in the syngeneic 9L rat gliosarcoma model for either single brain tumor focus or multiple intracerebral and leptomeningeal tumors, when the vector was applied intratumorally or intrathecally, respectively, and with or without subsequent ganciclovir (GCV) treatment. In identical 9L brain tumor models with single and multiple foci, application of hrR3 with or without GCV was previously shown to result in marked long-term survival. Contrary to the findings with intrathecal injection of hrR3, no vector-related mortality was observed in any animals treated with MGH-1. Thus, in these rat brain tumor models, the double mutant, replication-conditional HSV vector MGH-1 showed a higher therapeutic safety than the RR-minus vector, hrR3, but had clearly decreased therapeutic efficiency compared to hrR3. The development of new HSV vectors for brain tumor gene therapy will require a balance between maximizing therapeutic efficacy and minimizing toxicity to the brain. Standardized application in brain tumor models as presented here will help to screen new HSV vectors for these requirements.
Assuntos
Neoplasias Encefálicas/terapia , Terapia Genética , Vetores Genéticos , Gliossarcoma/terapia , Herpesvirus Humano 1/genética , Ribonucleotídeo Redutases/genética , Proteínas Virais/genética , Animais , Chlorocebus aethiops , Terapia Combinada , Modelos Animais de Doenças , Ganciclovir/uso terapêutico , Deleção de Genes , Vetores Genéticos/toxicidade , Gliossarcoma/secundário , Humanos , Masculino , Neoplasias Meníngeas/secundário , Ratos , Ratos Endogâmicos F344 , Ribonucleotídeo Redutases/metabolismo , Células Tumorais Cultivadas , Células Vero , Proteínas Virais/metabolismo , Replicação ViralRESUMO
The governments of South Asia designed the 1990's as the Decade of the Girl Child, in order to confront the extreme discrimination faced by girls in the region. A range of research studies undertaken by UNICEF and other agencies leading up to the Decade had documented the aspects and degrees of discrimination against girls in the region-with the most severe conditions in India, Bangladesh, Nepal and Pakistan.
Assuntos
Preconceito , Materiais de Ensino , Direitos da Mulher , Adolescente , Adulto , Ásia Ocidental , Recursos Audiovisuais , Desenhos Animados como Assunto , Criança , Feminino , Pesquisa sobre Serviços de Saúde , HumanosRESUMO
Oral cancer is caused by chewing and smoking of tobacco. To assess the feasibility of primary prevention of oral cancer, two cohorts were studied in base-line surveys and then followed up annually for 10-yr in Ernakulam district of Kerala state. The intervention cohort consisted of 12212 tobacco users aged 15 yr and over, who were exposed to a concentrated program of education against tobacco use. The control cohort was a non-concurrent cohort of 6075 tobacco users studied using similar methods but with a minimal amount of advice against tobacco use. The stoppage of tobacco use increased and the incidence rate of leukoplakia decreased significantly and substantially in the intervention cohort compared to the control cohort. The decrease in the incidence of leukoplakia was indicative of the decrease in the risk of oral cancer since the two were intimately related. This study demonstrated feasibility of primary prevention of oral cancer.
Assuntos
Neoplasias Bucais/prevenção & controle , Plantas Tóxicas , Prevenção do Hábito de Fumar , Tabaco sem Fumaça , Adulto , Estudos de Coortes , Feminino , Seguimentos , Educação em Saúde Bucal , Humanos , Incidência , Índia , Leucoplasia Oral/prevenção & controle , Masculino , Recidiva , Fatores de Risco , Abandono do Hábito de Fumar , Ensino/métodosRESUMO
Animals pretreated with cromakalim (1 mg/kg,po) along with isoproterenol (85 mg/kg,sc) showed less myocardial degenerative changes on histopathological examinations when compared with those treated with isoproterenol alone. Cromakalim's beneficial effects on myocardium were in dose-dependent manner. Administration of cromakalim (po) lowered significantly the serum LDH and SGOT and depleted intracytoplasmic glycogen as demonstrated by periodic schiff staining procedure. Increase in blood clotting time was highly significant (P less than 0.001). The results suggest cardioprotective effect of cromakalim in isoproterenol induced myocardial infarction.