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1.
Med Oncol ; 41(11): 289, 2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-39417935

RESUMO

Complex decongestive therapy is the current gold standard for non-surgical clinical lymphedema management and consists of manual therapy, compression exercise, skincare, and education. Complex decongestive therapy involves an intensive volume reduction phase (Phase I) followed by a maintenance phase (Phase II). The aim of the maintenance phase is to promote life-long control of lymphedema through use of self-management strategies and the provision of ongoing reduction therapies as needed. Compression therapies are the mainstay of lymphedema self-management. Poor adherence to self-management practices has been associated with increased volume and progression of lymphedema to more advanced stages, supporting the importance of education and regular monitoring to promote adherence to the Phase II maintenance recommendations. In this editorial, we provide consensus recommendations on the essential components of the maintenance phase, including education, skin care practices, managing infection/cellulitis, compression therapies, health and weight management, exercise, and ongoing follow-up care.


Assuntos
Linfedema , Humanos , Linfedema/terapia , Bandagens Compressivas , Higiene da Pele/métodos , Terapia por Exercício/métodos , Educação de Pacientes como Assunto
2.
Malar J ; 18(1): 85, 2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890179

RESUMO

BACKGROUND: Large-scale surveillance of mosquito populations is crucial to assess the intensity of vector-borne disease transmission and the impact of control interventions. However, there is a lack of accurate, cost-effective and high-throughput tools for mass-screening of vectors. METHODS: A total of 750 Anopheles gambiae (Keele strain) mosquitoes were fed Plasmodium falciparum NF54 gametocytes through standard membrane feeding assay (SMFA) and afterwards maintained in insectary conditions to allow for oocyst (8 days) and sporozoite development (14 days). Thereupon, each mosquito was scanned using near infra-red spectroscopy (NIRS) and processed by quantitative polymerase chain reaction (qPCR) to determine the presence of infection and infection load. The spectra collected were randomly assigned to either a training dataset, used to develop calibrations for predicting oocyst- or sporozoite-infection through partial least square regressions (PLS); or to a test dataset, used for validating the calibration's prediction accuracy. RESULTS: NIRS detected oocyst- and sporozoite-stage P. falciparum infections with 88% and 95% accuracy, respectively. This study demonstrates proof-of-concept that NIRS is capable of rapidly identifying laboratory strains of human malaria infection in African mosquito vectors. CONCLUSIONS: Accurate, low-cost, reagent-free screening of mosquito populations enabled by NIRS could revolutionize surveillance and elimination strategies for the most important human malaria parasite in its primary African vector species. Further research is needed to evaluate how the method performs in the field following adjustments in the training datasets to include data from wild-caught infected and uninfected mosquitoes.


Assuntos
Anopheles/parasitologia , Entomologia/métodos , Plasmodium falciparum/crescimento & desenvolvimento , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Feminino , Programas de Rastreamento/métodos , Carga Parasitária , Reação em Cadeia da Polimerase em Tempo Real
3.
Clin Rehabil ; 31(4): 500-507, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27121862

RESUMO

OBJECTIVE: To investigate whether caloric vestibular stimulation, a non-invasive form of neuro-modulation, alters the level of awareness in people residing in a minimally conscious state. DESIGN: Single-case ( n = 2), prospective, controlled (ABAB) efficacy study. SETTING: Tertiary, neuro-rehabilitation inpatient ward within a university hospital. PARTICIPANTS: Two individuals in a minimally conscious state. INTERVENTION: Left ear caloric vestibular stimulation was performed in two four/five-week blocks interleaved with two four/five-week blocks of sham stimulation. Session duration and frequency gradually increased within each block from once per day for 10 minutes (Week 1) to once per day for 20 minutes (Week 2) to 20 minutes twice per day in the remaining weeks. MEASURES: Wessex Head Injury Matrix, JFK Coma Recovery Scale - Revised. RESULTS: Both participants' Wessex Head Injury Matrix scores indicated a transition from involuntary (i.e. mechanical vocalization) to voluntary (i.e. gesture making, selective responses to family members) behaviour that was time-locked to the onset of active stimulation. In one participant, this improvement persisted for at least four weeks after active stimulation, while in the other it diminished two weeks after stimulation. Allied, although less dramatic, changes were seen on the arousal and auditory subscales of the JFK Coma Recovery Scale - Revised. CONCLUSION: The data provide the first evidence that vestibular stimulation may help improve outcome in a low awareness state, although further studies are needed to replicate effect and determine longer-term benefit.


Assuntos
Testes Calóricos/métodos , Infarto Cerebral/complicações , Parada Cardíaca/complicações , Meningioma/cirurgia , Estado Vegetativo Persistente/reabilitação , Tálamo/cirurgia , Idoso , Testes Calóricos/instrumentação , Infarto Cerebral/etiologia , Estudos Cross-Over , Escala de Coma de Glasgow , Parada Cardíaca/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estado Vegetativo Persistente/etiologia , Complicações Pós-Operatórias , Tálamo/patologia , Resultado do Tratamento , Fibrilação Ventricular/complicações
4.
Soc Cogn Affect Neurosci ; 10(6): 848-55, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25326041

RESUMO

Interpreting others' actions relies on an understanding of their current mental state. Emerging research has begun to identify a number of factors that give rise to individual differences in this ability. We report an event-related brain potential study where participants (N = 28) read contexts that described a character having a true belief (TB) or false belief (FB) about an object's location. A second sentence described where that character would look for the object. Critically, this sentence included a sentence-final noun that was either consistent or inconsistent with the character's belief. Participants also completed the Empathy Quotient questionnaire. Analysis of the N400 revealed that when the character held a TB about the object's location, the N400 waveform was more negative-going for belief inconsistent vs belief consistent critical words. However, when the character held an FB about the object's location the opposite pattern was found. Intriguingly, correlations between the N400 inconsistency effect and individuals' empathy scores showed a significant correlation for FB but not TB. This suggests that people who are high in empathy can successfully interpret events according to the character's FB, while low empathizers bias their interpretation of events to their own egocentric view.


Assuntos
Encéfalo/fisiologia , Formação de Conceito/fisiologia , Empatia/fisiologia , Potenciais Evocados/fisiologia , Pensamento/fisiologia , Adolescente , Compreensão/fisiologia , Eletroencefalografia , Feminino , Humanos , Masculino , Adulto Jovem
6.
J Nutr ; 140(10): 1757-63, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20702746

RESUMO

The role of antioxidants in the pathogenesis of reflux esophagitis (RE), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC) remains unknown. We evaluated the associations among dietary antioxidant intake and these diseases. We performed an assessment of dietary antioxidant intake in a case control study of RE (n = 219), BE (n = 220), EAC (n = 224), and matched population controls (n = 256) (the Factors Influencing the Barrett's Adenocarcinoma Relationship study) using a modification of a validated FFQ. We found that overall antioxidant index, a measure of the combined intake of vitamin C, vitamin E, total carotenoids, and selenium, was associated with a reduced risk of EAC [odds ratio (OR) = 0.57; 95% CI = 0.33-0.98], but not BE (OR = 0.95; 95% CI = 0.53-1.71) or RE (OR = 1.60; 95% CI = 0.86-2.98), for those in the highest compared with lowest category of intake. Those in the highest category of vitamin C intake had a lower risk of EAC (OR = 0.37; 95% CI = 0.21-0.66; P-trend = 0.001) and RE (OR = 0.46; 95% CI = 0.24-0.90; P-trend = 0.03) compared with those in the lowest category. Vitamin C intake was not associated with BE, and intake of vitamin E, total carotenoids, zinc, copper, or selenium was not associated with EAC, BE, or RE. In conclusion, the overall antioxidant index was associated with a reduced risk of EAC. Higher dietary intake of vitamin C was associated with a reduced risk of EAC and RE. These results suggest that antioxidants may play a role in the pathogenesis of RE and EAC and may be more important in terms of progression rather than initiation of the disease process.


Assuntos
Adenocarcinoma/prevenção & controle , Antioxidantes/administração & dosagem , Esôfago de Barrett/prevenção & controle , Dieta , Refluxo Gastroesofágico/prevenção & controle , Minerais/administração & dosagem , Idoso , Ácido Ascórbico/administração & dosagem , Carotenoides/administração & dosagem , Estudos de Casos e Controles , Cobre/administração & dosagem , Neoplasias Esofágicas/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Selênio/administração & dosagem , Vitamina E/administração & dosagem , Zinco/administração & dosagem
7.
Am J Physiol Lung Cell Mol Physiol ; 297(5): L912-9, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19734319

RESUMO

Oxidative stress plays an important role in the pathogenesis of pulmonary fibrosis. Heme oxygenase-1 (HO-1) is a key antioxidant enzyme, and overexpression of HO-1 significantly decreases lung inflammation and fibrosis in animal models. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that the PPARgamma ligands 15d-PGJ2 and 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), which have potent antifibrotic effects in vitro, also strongly induce HO-1 expression in primary human lung fibroblasts. Pharmacological and genetic approaches are used to demonstrate that induction of HO-1 is PPARgamma independent. Upregulation of HO-1 coincides with decreased intracellular glutathione (GSH) levels and can be inhibited by N-acetyl cysteine (NAC), a thiol antioxidant and GSH precursor. Upregulation of HO-1 is not inhibited by Trolox, a non-thiol antioxidant, and does not involve the transcription factors AP-1 or Nrf2. CDDO and 15d-PGJ2 contain an alpha/beta unsaturated ketone that acts as an electrophilic center that can form covalent bonds with free reduced thiols. Rosiglitazone, a PPARgamma ligand that lacks an electrophilic center, does not induce HO-1. These data suggest that in human lung fibroblasts, 15d-PGJ2 and CDDO induce HO-1 via a GSH-dependent mechanism involving the formation of covalent bonds between 15d-PGJ2 or CDDO and GSH. Inhibiting HO-1 upregulation with NAC has only a small effect on the antifibrotic properties of 15d-PGJ2 and CDDO in vitro. These results suggest that CDDO and similar electrophilic PPARgamma ligands may have great clinical potential as antifibrotic agents, not only through direct effects on fibroblast differentiation and function, but indirectly by bolstering antioxidant defenses.


Assuntos
Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Glutationa/metabolismo , Heme Oxigenase-1/biossíntese , Pulmão/citologia , Ácido Oleanólico/análogos & derivados , Prostaglandina D2/análogos & derivados , Acetilcisteína/farmacologia , Diferenciação Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Cromanos/farmacologia , Relação Dose-Resposta a Droga , Indução Enzimática/efeitos dos fármacos , Fibroblastos/citologia , Glutationa/química , Humanos , Ligantes , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , PPAR gama/metabolismo , Prostaglandina D2/farmacologia , Transporte Proteico/efeitos dos fármacos , Rosiglitazona , Tiazolidinedionas/farmacologia , Fator de Transcrição AP-1/metabolismo , Regulação para Cima/efeitos dos fármacos
8.
J Phys Chem A ; 113(37): 10013-23, 2009 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-19702256

RESUMO

The unimolecular reactions of 1-propanol, 3,3,3-propan-1-ol-d3, 3,3,3-trifluoropropan-1-ol, and 3-chloropropan-1-ol have been studied by the chemical activation technique. The recombination of CH3, CD3, CF3, and CH2Cl radicals with CH2CH2OH radicals at room temperature was used to generate vibrationally excited CH3CH2CH2OH, CD3CH2CH2OH, CF3CH2CH2OH, and CH2ClCH2CH2OH molecules. The principal unimolecular reaction for propanol and propanol-d3 with 90 kcal mol(-1) of vibrational energy is 1,2-H2O elimination with rate constants of 3.4 x 10(5) and 1.4 x 10(5) s(-1), respectively. For CH2ClCH2CH2OH also with 90 kcal mol(-1) of energy, 2,3-HCl elimination with a rate constant of 3.0 x 10(7) s(-1) is more important than 1,2-H2O elimination; the branching fractions are 0.95 and 0.05. For CF3CH2CH2OH with an energy of 102 kcal mol(-1), 1,2-H2O elimination has a rate constant of 7.9 x 10(5) and 2,3-HF elimination has a rate constant of 2.6 x 10(5) s(-1). Density functional theory was used to obtain models for the molecules and their transition states. The frequencies and moments of inertia from these models were used to calculate RRKM rate constants, which were used to assign threshold energies by comparing calculated and experimental rate constants. This comparison gives the threshold energy for H2O elimination from 1-propanol as 64 kcal mol(-1). The threshold energies for 1,2-H2O and 2,3-HCl elimination from CH2ClCH2CH2OH were 59 and 54 kcal mol(-1), respectively. The threshold energies for H2O and HF elimination from CF3CH2CH2OH are 62 and 70 kcal mol(-1), respectively. The structures of the transition states for elimination of HF, HCl, and H2O are compared.

9.
Gastroenterology ; 136(3): 799-805, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19162028

RESUMO

BACKGROUND & AIMS: Alcohol consumption may increase gastroesophageal reflux symptoms, cause damage to the esophageal mucosa, and/or promote carcinogenesis. However, reports about the association between alcohol and reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma are conflicting. METHODS: Information relating to alcohol consumption, at age 21 and 5 years before the interview date, was collected from 230 reflux esophagitis, 224 Barrett's esophagus, and 227 esophageal adenocarcinoma patients and 260 frequency-matched population controls. Logistic regression analyses were used to compare alcohol consumption in the 3 case groups to controls with adjustment for potential confounders. RESULTS: Population controls reporting gastroesophageal reflux symptoms were less likely than controls without symptoms to drink alcohol 5 years before the interview date (odds ratio [OR], 0.44, 0.20-0.99). No associations were observed between total alcohol consumption 5 years before the interview date and reflux esophagitis, Barrett's esophagus, or esophageal adenocarcinoma (OR, 1.26, 0.78-2.05; OR, 0.72, 0.43-1.21; and OR, 0.75, 0.46-1.22, respectively). Wine was inversely associated with reflux esophagitis (OR, 0.45, 0.27-0.75). Total alcohol consumption at age 21 years was significantly associated with reflux esophagitis (OR, 2.24, 1.35-3.74) but not with Barrett's esophagus or esophageal adenocarcinoma (OR, 1.06, 0.63-1.79 and OR, 1.27, 0.77-2.10, respectively). CONCLUSIONS: Alcohol consumption in early adulthood may lead to the development of reflux esophagitis. More recent alcohol consumption does not appear to confer any increased risk of reflux esophagitis, Barrett's esophagus, or esophageal adenocarcinoma. In fact, wine consumption may reduce the risk of these 3 esophageal disorders.


Assuntos
Adenocarcinoma/epidemiologia , Consumo de Bebidas Alcoólicas/epidemiologia , Esôfago de Barrett/epidemiologia , Neoplasias Esofágicas/epidemiologia , Esofagite Péptica/epidemiologia , Adulto , Feminino , Humanos , Irlanda/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Irlanda do Norte/epidemiologia , Adulto Jovem
10.
Cancer Causes Control ; 20(3): 279-88, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18839322

RESUMO

OBJECTIVE: To examine the association between dietary glycemic index (GI), glycemic load (GL), total carbohydrate, sugars, starch, and fiber intakes and the risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. METHODS: In an all-Ireland study, dietary information was collected from patients with esophageal adenocarcinoma (n = 224), long-segment Barrett's esophagus (n = 220), reflux esophagitis (n = 219), and population-based controls (n = 256). Multiple logistic regression analysis examined the association between dietary variables and disease risk by tertiles of intake and as continuous variables, while adjusting for potential confounders. RESULTS: Reflux esophagitis risk was positively associated with starch intake and negatively associated with sugar intake. Barrett's esophagus risk was significantly reduced in people in the highest versus the lowest tertile of fiber intake (OR 0.44 95%CI 0.25-0.80). Fiber intake was also associated with a reduced risk of esophageal adenocarcinoma, as was total carbohydrate intake (OR 0.45 95%CI 0.33-0.61 per 50 g/d increase). However, an increased esophageal adenocarcinoma risk was detected per 10 unit increase in GI intake (OR 1.42 95%CI 1.07-1.89). CONCLUSIONS: Our findings suggest that fiber intake is inversely associated with Barrett's esophagus and esophageal adenocarcinoma risk. Esophageal adenocarcinoma risk is inversely associated with total carbohydrate consumption but positively associated with high GI intakes.


Assuntos
Adenocarcinoma/epidemiologia , Esôfago de Barrett/epidemiologia , Neoplasias Esofágicas/epidemiologia , Esofagite Péptica/epidemiologia , Índice Glicêmico , Adenocarcinoma/patologia , Idoso , Índice de Massa Corporal , Intervalos de Confiança , Bases de Dados Factuais , Carboidratos da Dieta/metabolismo , Fibras na Dieta/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Humanos , Entrevistas como Assunto , Irlanda/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , População Rural , Fatores Sexuais , Inquéritos e Questionários , População Urbana , Relação Cintura-Quadril
11.
J Biol Chem ; 283(42): 28265-73, 2008 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-18697743

RESUMO

Significant discoveries have recently contributed to our knowledge of intracellular growth factor and nutrient signaling via mTOR (mammalian target of rapamycin). This signaling pathway is essential in cellular metabolism and cell survival by enhancing protein translation through phosphorylation of 4EBP-1 and p70S6K. Growth factors like insulin-like growth factor-I induce mTOR to prevent cell death during cellular stress. Agents targeting mTOR are of major interest as anticancer agents. We show here, using human breast cancer cells, that certain types of stress activate mTOR leading to 4E-BP1 and p70S6K phosphorylation. UV treatment increased phosphorylation of the translation inhibitor eIF2alpha, suggesting a potential mechanism for UV activation of Akt and mTOR. c-Myc, a survival protein regulated by cap-dependent protein translation, increased with IGF-I treatment, but this response was not inhibited by rapamycin. Additionally, UV treatment potently increased c-Myc degradation, which was reduced by co-treatment with the proteasomal inhibitor, MG-132. Together, these data suggest that protein translation does not strongly mediate cell survival in these models. In contrast, the phosphorylation status of retinoblastoma protein (pRB) was mediated by mTOR through its inhibitory effects on phosphatase activity. This effect was most notable during DNA damage and rapamycin treatment. Hypophosphorylated pRB was susceptible to inactivation by caspase-mediated cleavage, resulting in cell death. Reduction of pRB expression inhibited IGF-I survival effects. Our data support an important role of phosphatases and pRB in IGF-I/mTOR-mediated cell survival. These studies provide new directions in optimizing anticancer efficacy of mTOR inhibitors when used in combination with DNA-damaging agents.


Assuntos
Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Quinases/metabolismo , Proteína do Retinoblastoma/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Inibidores Enzimáticos/farmacologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Humanos , Leupeptinas/farmacologia , Modelos Biológicos , Fosforilação , Inibidores de Proteassoma , Proteínas Proto-Oncogênicas c-myc/metabolismo , Estresse Fisiológico , Serina-Treonina Quinases TOR , Raios Ultravioleta
12.
Cancer Epidemiol Biomarkers Prev ; 17(3): 727-31, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18349295

RESUMO

The incidence of esophageal adenocarcinoma has increased in recent years, and Barrett's esophagus is a recognized risk factor. Gastroesophageal reflux of acid and/or bile is linked to these conditions and to reflux esophagitis. Inflammatory disorders can lead to carcinogenesis through activation of "prosurvival genes," including cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Increased expression of these enzymes has been found in esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Polymorphic variants in COX-2 and iNOS genes may be modifiers of risk of these conditions. In a population-based case-control study, we examined associations of the COX-2 8473 T>C and iNOS Ser(608) Leu (C>T) polymorphisms with risk of esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Genomic DNA was extracted from blood samples collected from cases of esophageal adenocarcinoma (n = 210), Barrett's esophagus (n = 212), and reflux esophagitis (n = 230) and normal population controls frequency matched for age and sex (n = 248). Polymorphisms were genotyped using TaqMan allelic discrimination assays. Odds ratios and 95% confidence intervals were obtained from logistic regression models adjusted for potential confounding factors. The presence of at least one COX-2 8473 C allele was associated with a significantly increased risk of esophageal adenocarcinoma (adjusted odds ratio, 1.58; 95% confidence interval, 1.04-2.40). There was no significant association between this polymorphism and risk of Barrett's esophagus or reflux esophagitis or between the iNOS Ser 608 Leu polymorphism and risk of these esophageal conditions. Our study suggests that the COX-2 8473 C allele is a potential genetic marker for susceptibility to esophageal adenocarcinoma.


Assuntos
Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Esôfago de Barrett/enzimologia , Esôfago de Barrett/genética , Ciclo-Oxigenase 2/genética , Neoplasias Esofágicas/enzimologia , Neoplasias Esofágicas/genética , Esofagite Péptica/enzimologia , Esofagite Péptica/genética , Óxido Nítrico Sintase Tipo II/genética , Polimorfismo Genético , Alelos , Estudos de Casos e Controles , Feminino , Marcadores Genéticos , Variação Genética , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade
13.
Cancer Epidemiol Biomarkers Prev ; 17(3): 736-9, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18349297

RESUMO

Reflux of gastric contents can lead to development of reflux esophagitis and Barrett's esophagus. Barrett's esophagus is a risk factor for esophageal adenocarcinoma. Damage to DNA may lead to carcinogenesis but is repaired through activation of pathways involving polymorphic enzymes, including human 8-oxoguanine glycosylase 1 (hOGG1), X-ray repair cross-complementing 1 (XRCC1), and xeroderma pigmentosum group D (XPD). Of the single nucleotide polymorphisms identified in these genes, hOGG1 Ser 326 Cys, XRCC1 Arg 399 Gln, and XPD Lys 751 Gln are particularly common in Caucasians and have been associated with lower DNA repair capacity. Small studies have reported associations with XPD Lys 751 Gln and esophageal adenocarcinoma. XRCC1 Arg 399 Gln has been linked to Barrett's esophagus and reflux esophagitis. In a population-based case-control study, we examined associations of the hOGG1 Ser 326 Cys, XRCC1 Arg 399 Gln, and XPD Lys 751 Gln polymorphisms with risk of esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Genomic DNA was extracted from blood samples collected from cases of esophageal adenocarcinoma (n = 210), Barrett's esophagus (n = 212), reflux esophagitis (n = 230), and normal population controls frequency matched for age and sex (n = 248). Polymorphisms were genotyped using TaqMan allelic discrimination assays. Odds ratios and 95% confidence intervals were obtained from logistic regression models adjusted for potential confounding factors. There were no statistically significant associations between these polymorphisms and risk of esophageal adenocarcinoma, Barrett's esophagus, or reflux esophagitis.


Assuntos
Adenocarcinoma/genética , Esôfago de Barrett/genética , Neoplasias Esofágicas/genética , Esofagite Péptica/genética , Polimorfismo Genético , Estudos de Casos e Controles , Reparo do DNA , Feminino , Genótipo , Humanos , Irlanda , Masculino , Pessoa de Meia-Idade , Fatores de Risco
14.
Cancer Res ; 66(9): 4975-82, 2006 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-16651456

RESUMO

Observational studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of esophageal adenocarcinoma, but it is not known at what stage they may act in the esophageal inflammation-metaplasia-adenocarcinoma sequence. In an all-Ireland case-control study, we investigated the relationship between the use of NSAIDs and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Patients with esophageal adenocarcinoma, long-segment Barrett's esophagus and population controls were recruited from throughout Ireland. Esophagitis patients were recruited from Northern Ireland only. Data were collected on known and potential risk factors for esophageal adenocarcinoma and on the use of NSAIDs, including aspirin, at least 1 year before interview. Associations between use of NSAIDs and the stages of the esophageal inflammation-metaplasia-adenocarcinoma sequence were estimated by multiple logistic regression. In total, 230 reflux esophagitis, 224 Barrett's esophagus, and 227 esophageal adenocarcinoma and 260 population controls were recruited. Use of aspirin and NSAIDs was associated with a reduced risk of Barrett's esophagus [odds ratio [OR; 95% confidence interval (95% CI)], 0.53 (0.31-0.90) and 0.40 (0.19-0.81), respectively] and esophageal adenocarcinoma [OR (95% CI), 0.57 (0.36-0.93) and 0.58 (0.31-1.08), respectively]. Barrett's esophagus and esophageal adenocarcinoma patients were less likely than controls to have used NSAIDs. Selection or recall bias may explain these results and the results of previous observational studies indicating a protective effect of NSAIDs against esophageal adenocarcinoma. If NSAIDs have a true protective effect on the esophageal inflammation-metaplasia-adenocarcinoma sequence, they may act early in the sequence.


Assuntos
Adenocarcinoma/prevenção & controle , Anti-Inflamatórios não Esteroides/administração & dosagem , Esôfago de Barrett/prevenção & controle , Neoplasias Esofágicas/prevenção & controle , Esofagite Péptica/prevenção & controle , Acetaminofen/administração & dosagem , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Aspirina/administração & dosagem , Esôfago de Barrett/tratamento farmacológico , Esôfago de Barrett/patologia , Estudos de Casos e Controles , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Esofagite Péptica/tratamento farmacológico , Esofagite Péptica/patologia , Esôfago/efeitos dos fármacos , Esôfago/patologia , Feminino , Humanos , Masculino , Metaplasia , Pessoa de Meia-Idade
15.
Breast Cancer Res Treat ; 91(3): 259-69, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15952059

RESUMO

IRS-1 (Insulin Receptor Substrate-1) is an adaptor protein important for insulin and IGF-I receptor (Insulin-like Growth Factor-IR) transduction to downstream targets. One mechanism recently identified to downregulate IGF-I or insulin receptor signaling in diabetic models is IRS-1 Ser(312) phosphorylation. To date, the importance of this residue in cancer is unknown. This paper identifies mechanisms leading to Ser(312) regulation in MCF-7 breast cancer cells. Whereas IGF-I phosphorylation of IRS(312) is PI (phosphatidylinositol) 3-kinase dependent, anisomycin stress treatment requires JNK activation to induce phosphorylation of IRS(312). We show that both IGF-I and anisomycin stress treatment converge downstream onto mTOR (Mammalian Target of Rapamycin) and PKCdelta (Protein Kinase C-delta) to induce IRS-1 Ser(312) phosphorylation. mTOR associates with IRS-1 and is primarily required for Ser(312) phosphorylation in response to stress or IGF-I treatment. PKCdelta binds to mTOR and its activity is also important for stress or IGF-I mediated Ser(312) phosphorylation. Thus, mTOR and PKCdelta convey diverse signals to regulate IRS-1 function.


Assuntos
Neoplasias da Mama/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Fosfoproteínas/metabolismo , Proteína Quinase C/metabolismo , Proteínas Quinases/metabolismo , Anisomicina/farmacologia , Neoplasias da Mama/patologia , Ativação Enzimática , Feminino , Humanos , Proteínas Substratos do Receptor de Insulina , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , MAP Quinase Quinase 4 , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Fosforilação , Proteína Quinase C-delta , Proteínas Quinases/química , Proteínas Quinases/genética , Inibidores da Síntese de Proteínas/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina/química , Transdução de Sinais , Serina-Treonina Quinases TOR , Células Tumorais Cultivadas , Tirosina/metabolismo
16.
Am J Hum Genet ; 76(2): 340-8, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15593017

RESUMO

Although somatic mutations in a number of genes have been associated with development of human tumors, such as lipomas, relatively few examples exist of germline mutations in these genes. Here we describe an 8-year-old boy who has a de novo pericentric inversion of chromosome 12, with breakpoints at p11.22 and q14.3, and a phenotype including extreme somatic overgrowth, advanced endochondral bone and dental ages, a cerebellar tumor, and multiple lipomas. His chromosomal inversion was found to truncate HMGA2, a gene that encodes an architectural factor involved in the etiology of many benign mesenchymal tumors and that maps to the 12q14.3 breakpoint. Similar truncations of murine Hmga2 in transgenic mice result in somatic overgrowth and, in particular, increased abundance of fat and lipomas, features strikingly similar to those observed in the child. This represents the first report of a constitutional rearrangement affecting HMGA2 and demonstrates the role of this gene in human growth and development. Systematic genetic analysis and clinical studies of this child may offer unique insights into the role of HMGA2 in adipogenesis, osteogenesis, and general growth control.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Cerebelares/genética , Cromossomos Humanos Par 12/genética , Proteína HMGA2/genética , Lipoma/genética , Anormalidades Múltiplas/genética , Criança , Face/anormalidades , Transtornos do Crescimento/genética , Humanos , Masculino , Fenótipo
17.
J Biol Chem ; 278(46): 45793-800, 2003 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-12954616

RESUMO

The importance of the mitochondria in UV-induced apoptosis has become increasingly apparent. Following DNA damage cytochrome c and other pro-apoptotic factors are released from the mitochondria, allowing for formation of the apoptosome and subsequent cleavage and activation of caspase-9. Active caspase-9 then activates downstream caspases-3 and/or -7, which in turn cleave poly(ADP)-ribose polymerase (PARP) and other down-stream targets, resulting in apoptosis. In an effort to understand the mechanisms of Akt-mediated cell survival in breast cancer, we studied the effects of insulin-like growth factor (IGF)-I treatment on UV-treated MCF-7 human breast cancer cells. Apoptosis was induced in MCF-7 cells after UV treatment, as measured by caspase-7 and PARP cleavage, and IGF-I co-treatment protected against this response. Surprisingly caspase-9 cleavage was unchanged with UV and/or IGF-I treatment. Using MCF-7 cells overexpressing caspase-3 we have shown that resistance of caspase-9 to cleavage was not altered by the expression of caspase-3. Furthermore, overexpression of caspase-9 did not enhance PARP or caspase-7 cleavage after UV treatment. Because caspase-8 was activated with UV treatment alone, we believe that UV-induced apoptosis in MCF-7 cells occurs independently of cytochrome c and caspase-9, supporting the existence of a cytoplasmic inhibitor of cytochrome c in MCF-7 cells. We anticipate that such inhibitors may be overexpressed in cancer cells, allowing for treatment resistance.


Assuntos
Apoptose , Caspases/fisiologia , Citocromos c/metabolismo , Western Blotting , Neoplasias da Mama/metabolismo , Caspase 3 , Caspase 7 , Caspase 9 , Caspases/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Ativação Enzimática , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Microscopia de Fluorescência , Fosfatidilinositol 3-Quinases/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Testes de Precipitina , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA/metabolismo , Fatores de Tempo , Transfecção , Raios Ultravioleta , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X
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