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BACKGROUND: Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. METHODS/DESIGN: PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. DISCUSSION: The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018.
Assuntos
Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/terapia , Implementação de Plano de Saúde , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Qualidade de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos do Sistema Biliar , Carcinoma Ductal Pancreático/epidemiologia , Criança , Pré-Escolar , Análise por Conglomerados , Drenagem , Terapia de Reposição de Enzimas , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Terapia Neoadjuvante , Países Baixos/epidemiologia , Cuidados Paliativos , Neoplasias Pancreáticas/epidemiologia , Pancreaticoduodenectomia , Cooperação do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Stents , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. METHODS: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). RESULTS: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8-2.3) and 5.4 months (95% CI, 4.0-6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0-1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. CONCLUSIONS: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. FUNDING: Johannes J.M. Kwakman received an unrestricted research grant from Servier.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Humanos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Países Baixos , Neutropenia/induzido quimicamente , Prognóstico , Pirrolidinas , Timina , Resultado do Tratamento , Trifluridina/efeitos adversos , Uracila/efeitos adversos , Uracila/uso terapêuticoRESUMO
Post-deposition annealing by ultra-short laser pulses can modify the optical properties of SnO2 thin films by means of thermal processing. Industrial grade SnO2 films exhibited improved optical properties after picosecond laser irradiation, at the expense of a slightly increased sheet resistance [Proc. SPIE 8826, 88260I (2013)]. The figure of merit Ï = T¹° / R(sh) was increased up to 59% after laser processing. In this paper we study and discuss the causes of this improvement at the atomic scale, which explain the observed decrease of conductivity as well as the observed changes in the refractive index n and extinction coefficient k. It was concluded that the absorbed laser energy affected the optoelectronic properties preferentially in the top 100-200 nm region of the films by several mechanisms, including the modification of the stoichiometry, a slight desorption of dopant atoms (F), adsorption of hydrogen atoms from the atmosphere and the introduction of laser-induced defects, which affect the strain of the film.
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The death of a newborn infant is an extremely emotional event for relatives. Many hospitals provide the parents with support, and in some cases a mourning protocol is available. Some hospitals offer parents photographs of infants which have died around birth. The photographs are often taken by a nurse or doctor on the maternity or paediatric ward. It is advisable to draw up a mourning protocol which allows professional studio photographs to be taken. As a photograph is often the only concrete memento that parents have of their baby, it is important for it to be of good quality. The parents decide what they would prefer, but it is important to point out to them that their wishes and needs immediately following the death may differ to those in the longer term.
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Luto , Morte Fetal , Pais/psicologia , Fotografação , Humanos , Recém-NascidoRESUMO
In this study, polycarbonate (PC) and polystyrene (PS) are subjected to plastic deformation by means of cold rolling and the resulting variation of the free volume and its subsequent time evolution after rolling is investigated by means of positron annihilation lifetime spectroscopy (PALS). The value of the long lifetime component that is attributed to the decay of ortho-positronium (tau(o-Ps)) and its intensity (I(o-Ps)) are used to characterize, respectively, the size and the concentration of the free-volume holes. In addition to the PALS experiments, the effect of plastic deformation on the dynamic tensile modulus is investigated. The PALS results show that both for well-aged PC and PS an increase of tau(o-Ps) and a decrease of I(o-Ps) occur upon plastic deformation. During the subsequent aging, tau(o-Ps) tends to return to the value assumed before plastic deformation, while I(o-Ps) remains constant with time. These results corroborate the idea of an amorphous-amorphous transition, rather than that of a "mechanical rejuvenation" as proposed in the past to explain the ability of plastic deformation to reinitiate physical aging. Finally, a linear relation between the size of the free-volume holes and the dynamic tensile modulus is found, which suggests that the stiffness of amorphous glassy polymers is fully determined by their nanoscopic structure.
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The contribution of CYP1A2 to the formation of DNA adducts of the cooked meat-derived heterocyclic amines (HCAs) 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was examined in CYP1A2-null (knock-out, KO) and wild-type (WT) mice. IQ (25 mg and 75 mg/kg) and PhIP (150 mg/kg) were administered by gavage to mice and DNA adduct levels in liver, kidney, mammary gland and colon were examined by the 32P-postlabeling assay. Three hours after either dose of IQ, adducts levels in liver and kidney of KO mice were 20-30% of the levels in WT mice, a difference that was statistically significant (Student's t-test, P < 0.05). In the colon, adduct levels in KO mice were significantly lower than in the WT mice only at the lowest dose of IQ (1.6+/-0.6 vs 4.6+/-0.7, respectively, relative adduct labeling (RAL) x 10(8), mean+/-S.E.M., n = 3-5 mice). In the mammary gland, however, there was no difference in IQ-DNA adduct levels in KO and WT mice at either dose of IQ. Three hours after dosing with PhIP, PhIP-DNA adduct levels were statistically significantly lower in KO mice than in WT mice in all tissues examined. PhIP-DNA adducts in liver and kidney of WT mice were 9.9+/-1.1 and 22.5+/-6.9, respectively, whereas no PhIP-DNA adducts were detected in either organ of KO mice (limit of detection, 1.4-2.8 x 10(9)). PhIP-DNA adduct levels in mammary gland and colon of WT mice were 47.1+/-9.5 and 58.0+/-21.7, respectively, but accordingly only 3.8+/-0.7 and 5.4+/-0.9 in KO mice. The findings indicate that CYP1A2, responsible for IQ and PhIP N-hydroxylation, the first step in the metabolic action, significantly effects DNA adduct formation in vivo. However, the data raise the possibility that other cytochromes P450 as well as other pathways of activation potentially contribute to DNA adduct formation in specific organs, depending on the HCA substrate.
Assuntos
Aminas/metabolismo , Citocromo P-450 CYP1A2/deficiência , Adutos de DNA/metabolismo , Compostos Heterocíclicos/metabolismo , Animais , Colo/metabolismo , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/fisiologia , Feminino , Imidazóis/administração & dosagem , Imidazóis/metabolismo , Rim/metabolismo , Fígado/metabolismo , Glândulas Mamárias Animais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Quinolinas/administração & dosagem , Quinolinas/metabolismoRESUMO
In our previous experiments, multiple injections with the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were used to induce intestinal tumors in C57BL/6J-multiple intestinal neoplasia (Min)/+ mice. To define the period of highest susceptibility to PhIP perinatally, we first determined the effect of a single s.c. injection. Ten or 50 mg/kg PhIP increased the number and diameter of small intestinal tumors dose-dependently in 3-day-old Min/+ mice. In the colon, only 50 mg/kg PhIP increased the incidence and number of tumors. The number of dysplastic aberrant crypt foci decreased from weeks 7 to 11. In the same period, an increase in the number of tumors was seen, indicating that over time the dysplastic aberrant crypt foci develop into tumors. Min/+ mice were then exposed in utero through their dams being given one s.c. injection of 50 mg/kg PhIP 3 days before giving birth or were exposed directly to the same dose on day 3, 12, or 36 after birth. Remarkably, the most susceptible period for tumorigenesis in the small intestine was between days 3-12 after birth, whereas in the colon it was from day 3 before to day 3 after birth. Furthermore, we examined whether the formation of DNA adducts determined after 24 h could explain the observed time-dependent and regional susceptibility to PhIP. A higher level of PhIP-DNA adducts was found after exposure on day 12 after birth, compared with day 36 after birth, in all parts of the small intestine but not in the colon, which was in close accordance with the numbers of tumors present. The levels of PhIP-DNA adducts along the intestines were highest in the middle and distal parts of the small intestine, where tumor numbers were also the highest. In conclusion, Min/+ mice are most susceptible to intestinal tumor induction by PhIP from day 3 before to day 12 after birth, and this susceptibility could at least partly be explained by the formation of PhIP-DNA adducts.
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Carcinógenos/toxicidade , Adutos de DNA/metabolismo , Imidazóis/toxicidade , Neoplasias Intestinais/induzido quimicamente , Neoplasias Intestinais/metabolismo , Administração Oral , Fatores Etários , Animais , Animais Recém-Nascidos , Carcinógenos/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Imidazóis/administração & dosagem , Injeções Subcutâneas , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Scientific opinion differs on whether pathological (or complicated, traumatic) grief is an entity distinct from post-traumatic stress disorder. Some argue that it is different, and for the creation of a new category of pathological grief for the DSM system, while others consider bereavement and associated grief reactions to fall within the category of traumatic life events, for which the existing system would offer adequate classification. Although investigators have begun to explore similarities and differences in the trauma and bereavement domains, there is still confusion and lack of consensus about definitions and basic concepts. A conceptual framework, suggested here, may help bring clarity to the area. Our analysis shows that the lack of consensus about the nature of reactions and disorders of bereavement is due to concentration on different parts of the framework. Furthermore, the lack of differentiation between traumatic and non-traumatic bereavement has caused neglect of the unique features of non-traumatic grief reactions. These components need further exploration, especially since extension of DSM classification is currently under consideration.
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Adaptação Psicológica , Pesar , Acontecimentos que Mudam a Vida , Transtornos de Estresse Pós-Traumáticos/psicologia , Violência , Luto , Humanos , Modelos Psicológicos , Psicopatologia , Índice de Gravidade de Doença , Transtornos de Estresse Pós-Traumáticos/etiologiaRESUMO
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mammary gland carcinogen in cooked meat. Using the HC11 mouse mammary epithelial cell line, a well-characterized model for hormone-mediated differentiation, we examined whether PhIP altered the expression of genes regulated by lactogenic hormones dexamethasone, insulin, and prolactin (DIP). When HC11-Lux cells (stably transfected with a beta-casein promoter luciferase construct) were cultured in DIP-containing medium, PhIP (100 microM) enhanced luciferase activity 11-fold over that observed in DIP medium alone. The effect of PhIP on augmenting luciferase activity was observed only when lactogenic hormones were included in the medium. Expression of the endogenous beta-casein gene was also higher in HC11 cells treated with PhIP in hormone-enriched medium. With the increased expression of beta-casein gene, the level of phospho-signal transducer and activator of transcription 5A (phospho-STAT5A), the transcription factor regulating beta-casein gene expression, was elevated in PhIP-exposed HC11 cells. AG490, a Janus kinase 2 (JAK2)-specific inhibitor, blocked the effect of PhIP on beta-casein gene expression. PhIP-treated cells also showed higher expression of Bcl-2 and lower expression of Bax, consistent with a possible antiapoptotic action of PhIP. The findings indicate that PhIP modulates lactogenic hormone-mediated gene expression in mammary epithelial cells, apparently via enhanced phosphorylation of STAT5A. The findings have implications for a novel mechanism of action of the mammary gland carcinogen PhIP.
Assuntos
Carcinógenos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imidazóis , Neoplasias Mamárias Animais/metabolismo , Proteínas do Leite , Prolactina/metabolismo , Animais , Northern Blotting , Western Blotting , Caseínas/metabolismo , Adutos de DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Imuno-Histoquímica , Janus Quinase 2 , Luciferases/metabolismo , Camundongos , Proteínas Quinases Ativadas por Mitógeno , Fosforilação , Regiões Promotoras Genéticas , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT5 , Transdução de Sinais , Fatores de Tempo , Transativadores/metabolismo , Transfecção , Células Tumorais Cultivadas , Tirfostinas/farmacologia , Proteína X Associada a bcl-2RESUMO
The use of DSM-IV based questionnaires in child psychopathology is on the increase. The internal construct validity of a DSM-IV based model of ADHD, CD, ODD, Generalised Anxiety, and Depression was investigated in 11 samples by confirmatory factor analysis. The factorial structure of these syndrome dimensions was supported by the data. However, the model did not meet absolute standards of good model fit. Two sources of error are discussed in detail: multidimensionality of syndrome scales, and the presence of many symptoms that are diagnostically ambiguous with regard to the targeted syndrome dimension. It is argued that measurement precision may be increased by more careful operationalisation of the symptoms in the questionnaire. Additional approaches towards improved conceptualisation of DSM-IV are briefly discussed. A sharper DSM-IV model may improve the accuracy of inferences based on scale scores and provide more precise research findings with regard to relations with variables external to the taxonomy.
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Transtornos Mentais/diagnóstico , Escalas de Graduação Psiquiátrica/normas , Adolescente , Criança , Psiquiatria Infantil/normas , Pré-Escolar , Análise Fatorial , Feminino , Humanos , Masculino , Transtornos Mentais/psicologia , Modelos Psicológicos , Psicopatologia , Reprodutibilidade dos Testes , Estudos de Amostragem , Inquéritos e QuestionáriosRESUMO
Helicobacter hepaticus infection is associated with chronic hepatitis and the development of liver tumours in mice. The underlying mechanism of this liver carcinogenesis is not clear but the oxidative stress associated with H. hepaticus infection may result in induction of lipid peroxidation and the generation of malondialdehyde. Malondialdehyde can react with deoxyguanosine in DNA resulting in the formation of the cyclic pyrimidopurinone N-1,N(2) malondialdehyde-deoxyguanosine (M1dG) adduct. This adduct has the potential to cause mutations that may ultimately lead to liver carcinogenesis. The objective of this study was to determine the control and infection-related levels of M1dG in the liver DNA of mice over time, using an immunoslot-blot procedure. The level of M1dG in control A/J mouse livers at 3, 6, 9 and 12 months averaged 37.5, 36.6, 24.8 and 30.1 adducts per 10(8) nucleotides, respectively. Higher levels of M1dG were detected in the liver DNA of H. hepaticus infected A/JCr mice, with levels averaging 40.7, 47.0, 42.5 and 52.5 adducts per 10(8) nucleotides at 3, 6, 9 and 12 months, respectively. There was a significant age dependent increase in the level of M1dG in the caudate and median lobes of the A/JCr mice relative to control mice. A lobe specific distribution of the M1dG adduct in both infected and control mice was noted, with the left lobe showing the lowest level of the adduct compared with the right and median lobes at all time points. In a separate series of mice experimentally infected with H. hepaticus, levels of 8-hydroxy-deoxyguanosine were significantly greater in the median compared with the left lobe at 12 weeks after treatment. In conclusion, these results suggest that M1dG occurs as a result of oxidative stress associated with H. hepaticus infection of mice, and may contribute to liver carcinogenesis in this model.
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Adutos de DNA/metabolismo , DNA/química , Infecções por Helicobacter/metabolismo , Fígado/química , Malondialdeído/química , Animais , Cromatografia Líquida de Alta Pressão , Infecções por Helicobacter/microbiologia , Masculino , CamundongosRESUMO
This study examined the natural course of psychological functioning in recently bereaved middle-aged women. 69 widows were assessed four times (T1-T4) between the period of 4 to 13 mo. after the loss and were compared to a matched nonwidowed group of 57. Of the SCL-90 feelings of depression, agoraphobic behavior, anxiety, hostility, somatization, feelings of insufficiency, and sleep disorders were heightened at 4 mo. after bereavement compared to the norm group. Significantly higher psychological dysfunctioning was found on all SCL-90 subscales than for non-widows. Over time, a decrease in psychological dysfunction was found for most widows; however, not every widow appeared to recover psychologically, and 17% of the widows showed severe psychological dysfunctioning at 13 mo. postbereavement (T4). With respect to the predictive value of the Total score on the SCL-90, at 13 mo., 27% of these widows had scores indicating severe psychological dysfunctioning; these were comparable to their scores at 4 mo. postbereavement.
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Adaptação Psicológica , Luto , Viuvez/psicologia , Idoso , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Inventário de PersonalidadeRESUMO
Helicobacter hepaticus causes chronic active hepatitis and liver tumors in mice, with associated increase in reactive oxygen species. Indigenous (I)-compounds are bulky DNA adducts present at low levels and detected by 32P-post-labeling. Some may be caused by reactive oxygen species; others occur normally and decrease during liver tumorigenesis. The identity of most is unknown. We investigated whether mouse liver infection by H. hepaticus and resulting progression of hepatic lesions would be associated with qualitative or quantitative changes in I-compounds. Mice were 3, 6, 9, and 12 months of age; liver disease ranged from minimal through marked. In control A/J mice, up to 20 I-compounds were detected, and the total level of these did not change with age, whereas 11 individual I-compounds showed marked age-related differences. These appeared to be coordinately regulated, as the total of these 11 adducts was constant at 6-12 months. In A/JNCr mice naturally infected with H. hepaticus, up to 12 hepatic I-compounds were found. Total levels varied markedly with age and were high at 6 and 12 months. Neither total adduct levels, nor the amount of any individual adduct, correlated positively with severity of hepatic lesions; in some cases, highest levels were found in livers with least disease. Thus, liver infection and tumorigenesis by H. hepaticus was not associated with an increase in any 32P-postlabeled DNA adduct. Marked, and distinct, age-related changes in total or individual adducts in control and infected mice suggest a role in the physiological alterations of aging and in host response to infection.
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Envelhecimento , Adutos de DNA/análise , Infecções por Helicobacter/microbiologia , Helicobacter , Fígado/metabolismo , Animais , Cromatografia em Camada Fina , DNA/genética , DNA/metabolismo , Infecções por Helicobacter/complicações , Fígado/química , Fígado/patologia , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/genética , Masculino , Camundongos , Camundongos Endogâmicos , Radioisótopos de FósforoRESUMO
The heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is formed during the cooking of proteinaceous animal foods (meat, chicken, and fish). PhIP is a carcinogen in the Fischer 344 (F-344) rat; it induces mammary tumors in female rats and lymphomas and colon and prostate tumors in male rats. In F-344 rats, PhIP forms DNA adducts in various organs, including the target organs. Inhibition of PhIP-DNA adduct formation is likely to lead to inhibition of PhIP tumorigenicity. We have examined the chemopreventive properties of green tea and black tea in PhIP carcinogenesis by evaluating their effects on PhIP-DNA adduct formation in the female F-344 rat. Young adult animals were maintained on powdered AIN-76A diet while receiving regular drinking water or 2% (wt/vol) infusions of green tea or black tea for a total of six weeks. During Weeks 3, 4, and 5, all animals received PhIP by gavage (1 mg/kg/day). Three rats per group were euthanized on Days 1 and 8 after termination of PhIP exposure. DNA was isolated from a number of organs and analyzed for PhIP-DNA adducts by 32P-postlabeling assays. Compared with animals on regular drinking water, PhIP-DNA adduct formation was inhibited in small intestine, colon, liver, and mammary epithelial cells (MECs) of animals receiving green tea or black tea as the sole source of drinking fluid. Green tea inhibited adduct formation in colon, liver, and MECs (33.3-80.0%) on both days, but only on Day 8 (54.4%) in small intestine. Black tea inhibited adduct formation on both days in liver (71.4-80.0%), on Day 1 in colon (40.0%), and on Day 8 in small intestine (81.8%); it had no effect on MEC adducts. Neither green tea nor black tea had an effect on adduct levels in pancreas, lungs, white blood cells, heart, kidneys, spleen, cecum, or stomach. Similarly, these teas did not affect the rate of adduct removal (percent change from Day 1 to Day 8) in any organ. It is concluded that green tea and black tea are potential chemopreventive agents in PhIP-induced tumorigenesis in the F-344 rat.
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Anticarcinógenos , Carcinógenos/metabolismo , Adutos de DNA/metabolismo , Imidazóis/metabolismo , Neoplasias Experimentais/induzido quimicamente , Chá , Animais , Feminino , Mucosa Intestinal/metabolismo , Rim/metabolismo , Cinética , Leucócitos/metabolismo , Pulmão/metabolismo , Miocárdio/metabolismo , Neoplasias Experimentais/prevenção & controle , Pâncreas/metabolismo , Ratos , Ratos Endogâmicos F344 , Baço/metabolismoRESUMO
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine (HCA) found in cooked meats, causes colon and prostate tumors in male rats. Polymorphic N-acetyltransferase metabolizes N-hydroxy-PhIP to a DNA-reactive form. Liver, colon, and prostate PhIP-DNA adduct levels were compared in male rapid-acetylator Fischer 344 (F344) and slow-acetylator Wistar-Kyoto (WKY) rats fed 0.01 or 0.04% PhIP. Liver PhIP-DNA adduct levels at both PhIP doses, and colon PhIP-DNA adduct levels at the 0.01% PhIP dose were unaffected by acetylator genotype. However, in rats fed 0.04% PhIP, colon PhIP-DNA adduct levels were higher in rapid acetylator F344 rats (P < 0.05). Similarly, prostate PhIP-DNA adduct levels were higher in rapid acetylator F344 rats at both PhIP doses (P < 0.05). The combination of the high-PhIP dose and rapid-acetylator genotype resulted in the highest level of PhIP-DNA adducts in rat colon and prostate.
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Carcinógenos/administração & dosagem , Colo/metabolismo , Adutos de DNA/metabolismo , Imidazóis/administração & dosagem , Próstata/metabolismo , Animais , Neoplasias do Colo/etiologia , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Adutos de DNA/genética , Predisposição Genética para Doença , Masculino , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos WKY , Especificidade da EspécieRESUMO
The chemopreventive properties of dietary indole-3-carbinol (I3C) were evaluated by assessing its effect on DNA adduct formation and metabolism of the dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and the induction of cytochromes P450 1A1 and -1A2 in female F344 rats. In experiment 1, animals on I3C diets (0, 0.02% or 0.1%, w/w) were treated by gavage with 1mg/kg/day of PhIP for 23 days. On days 2, 9, 16 and 23, their 24-hr urine was collected and unmetabolized PhIP was measured by GC/MS. On day 24, the animals were sacrificed, and DNA from pancreas, spleen, white blood cells (WBCs), lung, colon, kidney, mammary epithelial cells, caecum, heart, small intestine, liver and stomach was isolated for determination of PhIP-DNA adduct levels by (32)P-postlabelling assays. Except in the mammary gland, I3C diets significantly inhibited PhIP-DNA adduct formation in WBCs and in all organs, ranging from 34.7 to 67.7% with the 0.02% I3C diet to 68.4 to 95.3% with the 0.1% I3C diet. I3C diets also significantly decreased the concentration of urinary unmetabolized PhIP to 29.5-38.4% (0.02% I3C) and 12.8-17.8% (0.1% I3C) of values obtained with the I3C-free diet. In experiment 2, animals were either treated by intubation of I3C at 100 or 200mg/kg for 2 consecutive days or given an I3C-containing diet (0.02% or 0.1%, w/w) for 2 weeks. The expression and activity of cytochromes P450 1A1 and -1A2 were studied by Northern blots, Western blots, and in vitro enzyme determinations. Both the expression and activity of these cytochromes were induced by all of the I3C treatments. It is concluded that, in the female F344 rat, dietary I3C inhibits PhIP-DNA adduct formation and accelerates PhIP metabolism, probably through induction of cytochromes P450 1A1 and -1A2. The chemopreventive properties of I3C in PhIP-induced carcinogenesis are probably mediated through enhancement of PhIP detoxification pathways.
Assuntos
Anticarcinógenos/farmacologia , Transformação Celular Neoplásica , Sistema Enzimático do Citocromo P-450/metabolismo , Adutos de DNA/genética , Imidazóis/efeitos adversos , Indóis/farmacologia , Mutagênicos/efeitos adversos , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Indução Enzimática , Feminino , Contaminação de Alimentos , Imidazóis/metabolismo , Mutagênicos/metabolismo , Ratos , Ratos Endogâmicos F344RESUMO
It has been suggested that pathological grief should become either a separate category of mental disorder or be integrated within existing, extended classifications in systems such as the Diagnostic and Statistical Manual of Mental Disorders. Despite strong arguments for inclusion, and advancements by scientists toward development of diagnostic classification, there has been a lack of critical evaluation. Several issues need further scrutiny and clarification. These concern the definition of pathological grief, the distinction of pathological from normal grief, its relationship with other disorders, and the lack of agreement among scientists about criteria for pathological grief. Further research needs to focus on delineation of syndromes that comprise "pathological grief," and on derivation of acceptable, valid, diagnostic criteria. Evaluation of the ramifications--both positive and potentially negative--associated with the revision of the diagnostic status of pathological grief needs also to be undertaken.
Assuntos
Pesar , Transtornos Mentais/diagnóstico , Humanos , Transtornos Mentais/psicologia , Terminologia como AssuntoRESUMO
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mammary gland carcinogen present in the human diet in cooked meat. To examine if PhIP and its reactive metabolite N-hydroxy-PhIP inhibit apoptosis in human mammary epithelial MCF-10A cells, confluent cultures deprived of serum and growth factors were incubated for 24 h with either compound. The percentages of dead cells (mean +/- SEM, n = 3) as measured by trypan blue exclusion were 5.7 +/- 0.6, 3.4 +/- 0.3, 2.7 +/- 0.3, and 0.2 +/- 0.003%, in control, 1 microM N-hydroxy-PhIP-, 5 microM N-hydroxy-PhIP-, and 100 microM PhIP-treated dishes, respectively. The expression of Bcl-2 and Bcl-x(L) as quantitated by Western blotting was 1.2- to 1.9-fold higher in the treated groups. PhIP-DNA adducts induced by N-hydroxy-PhIP in MCF-10A cells measured by the (32)P-postlabeling assay were low (<1 x 10(7), relative adduct labeling). No adducts were detected after incubation with PhIP. Western blot analysis indicated that PhIP increased ERK2 phosphorylation concomitant with Bcl-2. The results suggest that the inhibition of cell death in mammary epithelial cells by PhIP occurs independently of PhIP-DNA adducts and may involve enhanced signaling through the MAP kinase pathways.
Assuntos
Apoptose/efeitos dos fármacos , Mama/citologia , Carcinógenos/farmacologia , Células Epiteliais/citologia , Temperatura Alta , Imidazóis/farmacologia , Carne , Mama/efeitos dos fármacos , Carcinógenos/metabolismo , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Meios de Cultura Livres de Soro , Adutos de DNA/análise , Adutos de DNA/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Imidazóis/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/análise , Piridinas/metabolismo , Piridinas/farmacologia , Fatores de Tempo , Proteína bcl-XRESUMO
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) are two important heterocyclic amines formed in proteinaceous foods during the cooking process. Both PhIP and IQ are carcinogenic in several strains of rats. PhIP induces mammary tumors in female F344 rats, while IQ induces principally mammary and liver tumors in female Sprague-Dawley rats. Both PhIP and IQ are activated enzymatically, first by N-hydroxylation, catalyzed by CYP1A1 and CYP1A2, and subsequently by esterification (O-acetylation or sulfation), to yield DNA adducts. Such DNA adduct formation, and persistence of adducts, is related to initiation of carcinogenesis, while inhibition of this process leads to prevention of carcinogenesis. Indole-3-carbinol (I3C), a constituent of cruciferous vegetables, has chemopreventive properties in various systems; it probably acts by induction of detoxification enzymes. We have examined the effect of dietary I3C on DNA adduct formation by PhIP in female F344 rats and on that by IQ in female Sprague-Dawley rats. In experiment 1, F344 rats were maintained on AIN-76A diet containing 0.1% (w/w) I3C and then given p.o. doses (10 or 50 mg/kg) of PhIP. These doses are known to induce CYP1A1 and CYP1A2. Groups of animals (4/time point) were euthanized 1, 2, 6, and 16 days later, and their blood (for isolation of white blood cells), mammary glands, liver, stomach, small intestine, cecum, colon, heart, lungs, kidneys, and spleen were removed for DNA isolation and quantitation of PhIP-DNA adducts by 32P-postlabeling. PhIP-DNA adduct formation was inhibited (40-100%) by I3C in virtually all organs, including the mammary gland (the target organ), at both doses of PhIP, and at almost all time points. In a second experiment, Sprague-Dawley rats were fed either control AIN-76A diet or this diet containing 0.02% I3C or 0.1% I3C for a total of 42 days. IQ was added to the diets (0.01%, w/w) from day 15 to day 42, after which all rats received diet free of IQ and I3C. Groups of animals (4/time point) were killed on days 43 and 57. In addition to the organs removed in experiment 1, the pancreas, uterus, and ovaries were also removed, and IQ-DNA adducts were quantitated by 32P-postlabeling. Both dietary concentrations of I3C inhibited IQ-DNA adduct formation in most organs (except in lungs, kidneys, and pancreas) on both days 43 and 57; in liver, stomach, mammary gland, and spleen, inhibition was evident only on day 43. Inhibitions ranged from 22.6 to 86.6% with the 0.02% I3C diet and from 32.2 to 89.6% with the 0.1% I3C diet. I3C diets did not affect rate of adduct removal in either experiment. It is concluded that dietary I3C inhibits PhIP- and IQ-DNA adduct formation in both target and nontarget organs of female rats, even with high doses of PhIP when CYP1A1 and CYP1A2, the enzymes responsible for the initial activation (N-hydroxylation) of PhIP, are expected to be induced.
Assuntos
Anticarcinógenos/farmacologia , Carcinógenos/toxicidade , Adutos de DNA/antagonistas & inibidores , Imidazóis/toxicidade , Indóis/farmacologia , Quinolinas/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Adutos de DNA/biossíntese , Adutos de DNA/metabolismo , Dieta , Feminino , Quinolinas/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Intact prostate epithelial cells prepared from benign prostatic hypertrophy tissues from two patients were incubated for 2 h with N-hydroxy derivatives of 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (N-OH-PhIP) or 2-amino-3,8-dimethylimidazo[4, 5-f]quinoxaline (N-OH-MeIQx). (32)P-post-labeling analysis detected PhIP and MeIQx adducts in the DNA of these cells but not in the untreated control. Adduct levels were approximately 100 times greater in N-OH-PhIP- than in N-OH-MeIQx-treated cells. Repair synthesis of DNA was observed in cells, prepared from two additional patients, treated for 24 h with these carcinogens and was greater for N-OH-PhIP than for N-OH-MeIQx. PhIP, MeIQx and their nitro derivatives did not produce repair synthesis of DNA in this system. The difference in the activity of N-OH-PhIP and N-OH-MeIQx may be due to their stability, since N-OH-MeIQx decomposed rapidly in neutral solution. Transcripts of NAT1 and NAT2 were detected by an in situ hybridization method in prostate epithelial cells, but were absent from stromal tissues. These results suggest that PhIP may be a potential carcinogen for human prostate, since cooked meats, which contain this heterocyclic amine, have been associated with human prostate cancer.