RESUMEN
BACKGROUND: Familial Colorectal Cancer Type X (FCCTX) is defined as individuals with colorectal cancer (CRC) who families meet Amsterdam Criteria-1 (AC1), but whose tumours are DNA-mismatch-repair-proficient, unlike Lynch syndrome (LS). FCCTX does not have an increased risk of extra-colonic cancers. This analysis compares epidemiologic and clinicopathologic features among FCCTX, LS, and 'non-familial' (non-AC1) CRC cases. METHODS: From the Colon Cancer Family Registry, FCCTX (n=173), LS (n=303), and non-AC1 (n=9603) CRC cases were identified. Questionnaire-based epidemiologic information and CRC pathologic features were compared across case groups using polytomous logistic regression. RESULTS: Compared with LS, FCCTX cases were less likely to be current (vs never) smokers; have a proximal subsite (vs rectal) tumour; or have mucinous histology, poor differentiation, or tumour-infiltrating lymphocytes. There were no observed differences in co-morbidities or medication usage. CONCLUSIONS: FCCTX were less likely to be current tobacco users; other exposures were similar between these groups. Histopathologic differences highly suggestive of LS CRCs do not appear to be shared by FCCTX.
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Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Quísticas, Mucinosas y Serosas/epidemiología , Anciano , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Comorbilidad , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Neoplasias Quísticas, Mucinosas y Serosas/patología , Oportunidad Relativa , Sistema de Registros , Encuestas y CuestionariosRESUMEN
BACKGROUND: Mutations in the Kirsten Ras (KRAS) oncogene are common in colorectal cancer (CRC). The role of KRAS-mutation status as a prognostic factor, however, is unclear. We evaluated the relationship between KRAS-mutation status and CRC survival, considering heterogeneity in this association by tumour and patient characteristics. METHODS: The population-based study included individuals diagnosed with CRC between 1998-2007 in Western Washington State. Tumour specimens were tested for KRAS exon 2 mutations, the BRAF p.V600E mutation, and microsatellite instability (MSI). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between KRAS-mutation status and disease-specific and overall survival. Stratified analyses were conducted by age, sex, tumour site, stage, and MSI. We conducted additional analyses combining KRAS-mutation, BRAF-mutation, and MSI status. RESULTS: Among 1989 cases, 31% had KRAS-mutated CRC. Kirsten Ras (KRAS)-mutated CRC was associated with poorer disease-specific survival (HR=1.37, 95% CI: 1.13-1.66). This association was not evident in cases who presented with distant-stage CRC. Cases with KRAS-wild-type/BRAF-wild-type/MSI-high CRC had the most favourable prognosis; those with CRC exhibiting a KRAS- or BRAF-mutation and no MSI had the poorest prognosis. Patterns were similar for overall survival. CONCLUSION: Kirsten Ras (KRAS)-mutated CRC was associated with statistically significantly poorer survival after diagnosis than KRAS-wild-type CRC.
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Neoplasias Colorrectales/genética , Genes ras , Mutación , Adulto , Anciano , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Programa de VERF , Tasa de Supervivencia , Washingtón/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Excess body weight and a sedentary lifestyle are associated with the development of several diseases, including cardiovascular disease, diabetes and cancer in women. One proposed mechanism linking obesity to chronic diseases is an alteration in adipose-derived adiponectin and leptin levels. We investigated the effects of 12-month reduced calorie, weight loss and exercise interventions on adiponectin and leptin concentrations. METHODS: Overweight/obese postmenopausal women (n = 439) were randomized as follows: (i) a reduced calorie, weight-loss diet (diet; N = 118), (ii) moderate-to-vigorous intensity aerobic exercise (exercise; N = 117), (iii) a combination of a reduced calorie, weight-loss diet and moderate-to-vigorous intensity aerobic exercise (diet + exercise; N = 117), and (iv) control (N = 87). The reduced calorie diet had a 10% weight-loss goal. The exercise intervention consisted of 45 min of moderate-to-vigorous aerobic activity 5 days per week. Adiponectin and leptin levels were measured at baseline and after 12 months of intervention using a radioimmunoassay. RESULTS: Adiponectin increased by 9.5% in the diet group and 6.6% in the diet + exercise group (both P ≤ 0.0001 vs. control). Compared with controls, leptin decreased with all interventions (diet + exercise, -40.1%, P < 0.0001; diet, -27.1%, P < 0.0001; exercise, -12.7%, P = 0.005). The results were not influenced by the baseline body mass index (BMI). The degree of weight loss was inversely associated with concentrations of adiponectin (diet, P-trend = 0.0002; diet + exercise, P-trend = 0.0005) and directly associated with leptin (diet, P-trend < 0.0001; diet + exercise, P-trend < 0.0001). CONCLUSION: Weight loss through diet or diet + exercise increased adiponectin concentrations. Leptin concentrations decreased in all of the intervention groups, but the greatest reduction occurred with diet + exercise. Weight loss and exercise exerted some beneficial effects on chronic diseases via effects on adiponectin and leptin.
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Adiponectina/metabolismo , Dieta Reductora/métodos , Ejercicio Físico/fisiología , Leptina/metabolismo , Obesidad/terapia , Adiponectina/análisis , Anciano , Índice de Masa Corporal , Femenino , Estudios de Seguimiento , Humanos , Leptina/análisis , Persona de Mediana Edad , Obesidad/diagnóstico , Sobrepeso/diagnóstico , Sobrepeso/terapia , Posmenopausia , Valores de Referencia , Medición de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Pérdida de PesoRESUMEN
BACKGROUND: The evidence for a role of tobacco smoking, alcohol drinking, and body mass index (BMI) in the etiology of small intestine cancer is based mainly on case-control studies from Europe and United States. SUBJECTS AND METHODS: We harmonized the data across 12 cohort studies from mainland China, Japan, Korea, Singapore, and Taiwan, comprising over 500,000 subjects followed for an average of 10.6 years. We calculated hazard ratios (HRs) for BMI and (only among men) tobacco smoking and alcohol drinking. RESULTS: A total of 134 incident cases were observed (49 adenocarcinoma, 11 carcinoid, 46 other histologic types, and 28 of unknown histology). There was a statistically non-significant trend toward increased HR in subjects with high BMI [HR for BMI>27.5 kg/m2, compared with 22.6-25.0, 1.50; 95% confidence interval (CI) 0.76-2.96]. No association was suggested for tobacco smoking; men drinking>400 g of ethanol per week had an HR of 1.57 (95% CI 0.66-3.70), compared with abstainers. CONCLUSIONS: Our study supports the hypothesis that elevated BMI may be a risk factor for small intestine cancer. An etiologic role of alcohol drinking was suggested. Our results reinforce the existing evidence that the epidemiology of small intestine cancer resembles that of colorectal cancer.
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Adenocarcinoma/etiología , Consumo de Bebidas Alcohólicas/efectos adversos , Índice de Masa Corporal , Neoplasias Intestinales/etiología , Fumar/efectos adversos , Adenocarcinoma/epidemiología , Anciano , Asia/epidemiología , Estudios de Cohortes , Femenino , Humanos , Neoplasias Intestinales/epidemiología , Masculino , Persona de Mediana Edad , Modelos de Riesgos ProporcionalesRESUMEN
Distribution of orientations of myosin was examined in ex-vivo myofibrils from hearts of transgenic (Tg) mice expressing Familial Hypertrophic Cardiomyopathy (FHC) troponin T (TnT) mutations I79N, F110I and R278C. Humans are heterozygous for sarcomeric FHC mutations and so hypertrophic myocardium contains a mixture of the wild-type (WT) and mutated (MUT) TnT. If mutations are expressed at a low level there may not be a significant change in the global properties of heart muscle. In contrast, measurements from a few molecules avoid averaging inherent in the global measurements. It is thus important to examine the properties of only a few molecules of muscle. To this end, the lever arm of one out of every 60,000 myosin molecules was labeled with a fluorescent dye and a small volume within the A-band (~1 fL) was observed by confocal microscopy. This volume contained on average 5 fluorescent myosin molecules. The lever arm assumes different orientations reflecting different stages of acto-myosin enzymatic cycle. We measured the distribution of these orientations by recording polarization of fluorescent light emitted by myosin-bound fluorophore during rigor and contraction. The distribution of orientations of rigor WT and MUT myofibrils was significantly different. There was a large difference in the width and of skewness and kurtosis of rigor distributions. These findings suggest that the hypertrophic phenotype associated with the TnT mutations can be characterized by a significant increase in disorder of rigor cross-bridges.
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Cardiomiopatía Hipertrófica Familiar/genética , Mutación/genética , Miocardio/metabolismo , Miocardio/patología , Miosinas/metabolismo , Troponina T/genética , Animales , Cardiomiopatía Hipertrófica Familiar/patología , Cardiomiopatía Hipertrófica Familiar/fisiopatología , Humanos , Ratones , Ratones Transgénicos , Tono Muscular/genética , Miofibrillas/genética , Miofibrillas/metabolismo , Miofibrillas/patologíaRESUMEN
BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) and hormone therapy (HT) independently decrease the risk of colorectal cancer. However, their role in altering survival after a colorectal cancer diagnosis is not well established. METHODS: We examined the association between the use of these common medications before diagnosis and colorectal cancer survival among women in western Washington State diagnosed with incident colorectal cancer from 1997 to 2002. Cases were ascertained using the Surveillance, Epidemiology and End Results cancer registry; mortality follow-up was completed through linkages to the National Death Index. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We observed no overall association between colorectal cancer survival and pre-diagnostic NSAID use. However, when stratified by tumour sub-site, NSAID use was associated with a reduced risk of colorectal cancer mortality for women diagnosed with proximal (HR=0.55; 95% CI: 0.32-0.92), but not distal or rectal (HR=1.32; 95% CI: 0.83-2.10) tumours. The usage of HT was not associated with colorectal cancer survival overall or by tumour sub-site. CONCLUSION: Usage of NSAIDs before diagnosis may be associated with improved colorectal cancer survival among women diagnosed with proximal tumours. The usage of HT does not appear to have a function in altering colorectal cancer mortality.
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Antiinflamatorios no Esteroideos/uso terapéutico , Neoplasias Colorrectales/mortalidad , Hormonas Esteroides Gonadales/uso terapéutico , Adulto , Anciano , Neoplasias Colorrectales/diagnóstico , Femenino , Humanos , Persona de Mediana Edad , Factores de TiempoRESUMEN
BACKGROUND: Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers. METHODS: A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry. RESULTS: During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56). CONCLUSION: Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers.
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Proteínas Adaptadoras Transductoras de Señales/genética , Adenosina Trifosfatasas/genética , Índice de Masa Corporal , Neoplasias Colorrectales/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Mutación de Línea Germinal/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Adulto , Reparación de la Incompatibilidad de ADN , Femenino , Estudios de Seguimiento , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , Pronóstico , Factores de Riesgo , Adulto JovenRESUMEN
Rapid increases in nitrogen (N) loading are occurring in many tropical watersheds, but the fate of N in tropical streams is not well documented. Rates of nitrate uptake and denitrification were measured in nine tropical low-order streams with contrasting land use as part of the Lotic Intersite Nitrogen eXperiment II (LINX II) in Puerto Rico using short term (24-hour) additions of K(15)NO3 and NaBr. Background nitrate concentrations ranged from 105 to 997 microg N/L, and stream nitrate uptake lengths were long, varying from 315 to 8480 m (median of 1200 m). Other indices of nitrate uptake (mass transfer coefficient, V(f) [cm/s], and whole-stream nitrate uptake rate, U [microg N m(-2) s(-1)]) were low in comparison to other regions and were related to chemical, biological, and physical parameters. Denitrification rates were highly variable (0-133 microg N m(-2) min(-1); median = 15 microg N m(-2) min(-1)), were dominated by the end product N2 (rather than N2O), and were best predicted by whole-stream respiration rates and stream NO3 concentration. Denitrification accounted for 1-97% of nitrate uptake with five of nine streams having 35% or more of nitrate uptake via denitrification, showing that denitrification is a substantial sink for nitrate in tropical streams. Whole-stream nitrate uptake and denitrification in our study streams closely followed first-order uptake kinetics, indicating that NO3 uptake is limited by delivery of substrate (NO3) to the organisms involved in uptake or denitrification. In the context of whole-catchment nitrogen budgets, our finding that in-stream denitrification results in lower proportional production of N2O than terrestrial denitrification suggests that small streams can be viewed as the preferred site of denitrification in a watershed in order to minimize greenhouse gas N2O emissions. Conservation of small streams is thus critical in tropical ecosystem management.
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Desnitrificación , Nitratos/química , Nitratos/metabolismo , Ríos/química , Clima Tropical , Ecosistema , Monitoreo del Ambiente , Puerto RicoRESUMEN
BACKGROUND: Germline mutations in DNA mismatch repair (MMR) genes cause Lynch syndrome colon cancers. Less understood is the risk of colon cancer associated with common polymorphisms in MMR genes and the potential interacting role of lifestyle factors known to damage DNA. METHODS: A study was conducted to examine whether MLH1 (-93G>A and Ile219Val) and MSH6 (Gly39Glu) polymorphisms were associated with risk of colon cancer in data from 1609 colon cancer cases and 1972 controls. Genotype data were further stratified by microsatellite instability status, smoking, alcohol, Western diet, alcohol and obesity, to investigate potential heterogeneity. RESULTS: The MSH6 39Glu allele was associated with increased risk of colon cancer among men (Gly/Glu or Glu/Glu vs Gly/Gly, OR 1.27; 95% CI 1.04 to 1.54). Neither MLH1 polymorphism was associated with colon cancer risk overall. When stratified by microsatellite stability status, however, the MLH1 -93A allele was associated with a more than doubling in microsatellite instability (MSI)-positive colon cancer risk (AA vs GG, OR 2.47; 95% CI 1.48 to 4.11); no associations were observed between the MMR polymorphisms examined and MSI-negative colon cancer. Statistically significant interactions were observed between: MLH1 -93G>A and smoking (MSI-negative colon cancer only, p value interaction: 0.005); and MLH1 Ile219Val and Western diet (p value interaction: 0.03). CONCLUSIONS: The MSH6 Gly39Glu and MLH1 -93G>A polymorphisms were associated with risk of overall colon and MSI-positive colon cancers, respectively. Risk for colon cancer, stratified by MMR genotype, was further modified by smoking and Western diet.
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Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias del Colon/genética , Reparación de la Incompatibilidad de ADN/genética , Proteínas de Unión al ADN/genética , Estilo de Vida , Proteínas Nucleares/genética , Polimorfismo Genético/genética , Adulto , Anciano , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Dieta/efectos adversos , Femenino , Frecuencia de los Genes , Genotipo , Mutación de Línea Germinal/genética , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Mutación Missense/genética , Medición de Riesgo , Factores de Riesgo , Estados UnidosRESUMEN
PURPOSE: To determine whether cytomegalovirus is causally associated with breast cancer and whether cytomegalovirus should be categorised as an oncogenic virus. METHODS: We undertook a review of published epidemiological and laboratory studies, using established causal criteria: Bradford Hill criteria to determine whether cytomegalovirus is associated with breast cancer; and Evans/Mueller criteria to determine whether cytomegalovirus should be categorised as an oncogenic virus. RESULTS: Although there are inconsistencies in the findings of published epidemiological and laboratory studies, these may be explained by factors such as: differences in timing of blood samples, differences in selection of cases and controls, or high cytomegalovirus seroprevalence among participants in the epidemiological studies; and, in the laboratory studies, differences in sample preparations, age of sample, whether or not paired breast cancer and normal breast tissue samples were used, differences in the tests, primers and/or antibodies used, differences in histological types of breast cancer studied, and/or features of the virus. CONCLUSIONS: Overall, the results of published studies of cytomegalovirus and breast cancer suggest cytomegalovirus is a causal factor for at least some types of breast cancer. If the evidence for a link between cytomegalovirus and breast cancer continues to strengthen, further research could lead to: targeted screening; therapy using antiviral drugs; and, perhaps, primary prevention of a significant proportion of breast cancer. Vaccination against viruses has already been shown to be effective in preventing cervix and liver cancer; cytomegalovirus vaccines are already under development.
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Neoplasias de la Mama/virología , Citomegalovirus/aislamiento & purificación , Animales , Neoplasias de la Mama/etiología , Citomegalovirus/genética , Citomegalovirus/inmunología , Femenino , Humanos , RatonesRESUMEN
Pathway analysis of microarray data evaluates gene expression profiles of a priori defined biological pathways in association with a phenotype of interest. We propose a unified pathway-analysis method that can be used for diverse phenotypes including binary, multiclass, continuous, count, rate, and censored survival phenotypes. The proposed method also allows covariate adjustments and correlation in the phenotype variable that is encountered in longitudinal, cluster-sampled, and paired designs. These are accomplished by combining the regression-based test statistic for each individual gene in a pathway of interest into a pathway-level test statistic. Applications of the proposed method are illustrated with two real pathway-analysis examples: one evaluating relapse-associated gene expression involving a matched-pair binary phenotype in children with acute lymphoblastic leukemia; and the other investigating gene expression in breast cancer tissues in relation to patients' survival (a censored survival phenotype). Implementations for various phenotypes are available in R. Additionally, an Excel Add-in for a user-friendly interface is currently being developed.
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Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Neoplasias de la Mama/genética , Niño , Demografía , Femenino , Humanos , Fenotipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Modelos de Riesgos Proporcionales , Recurrencia , Análisis de Supervivencia , Resultado del TratamientoAsunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Adenosina Trifosfatasas/genética , Neoplasias Colorrectales/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Mutación , Proteínas Nucleares/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenosina Trifosfatasas/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Estudios de Cohortes , Neoplasias Colorrectales/metabolismo , Análisis Mutacional de ADN/métodos , Enzimas Reparadoras del ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Humanos , Inmunohistoquímica , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , Proteínas Nucleares/metabolismo , Polimorfismo Genético , Sistema de RegistrosRESUMEN
Methotrexate (MTX) is used as an immunosuppressive agent for acute graft-versus-host disease (GVHD) prophylaxis following hematopoietic cell transplantation (HCT). Concerns that folate intake may impair MTX effectiveness or selectively rescue leukemic cells have led to variations in clinical practice regarding supplemental folic acid during MTX administration. A retrospective, observational study was undertaken to determine the association between folic acid intake (days 0-18 post transplant) and MTX toxicity and efficacy following HCT. The study population consisted of 311 adult patients who received a myeloablative HCT for chronic myelogenous leukemia, all four scheduled doses of MTX, and did not require leucovorin rescue. Multiple linear regression models were used to assess the relationships between folic acid intake (days 0-18 post-HCT) and oral mucositis index (OMI) scores, time to engraftment and risk of detectable acute GVHD. No statistically significant differences in mean OMI scores, time to engraftment, risk of acute GVHD, days to acute GVHD, risk of relapse or survival were observed when comparing patients taking, on average, <400 (14%), 400 (58%) or >400 microg (28%) folic acid per day. Our results suggest that concurrent folic acid supplementation does not change MTX effectiveness or toxicity in this patient population.
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Ácido Fólico/administración & dosificación , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Metotrexato/uso terapéutico , Enfermedad Aguda , Adolescente , Adulto , Anciano , Estudios de Cohortes , Suplementos Dietéticos , Femenino , Ácido Fólico/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Terapia de Inmunosupresión , Masculino , Metotrexato/efectos adversos , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del TratamientoRESUMEN
OBJECTIVE: Test the hypothesis that soy isoflavone supplementation preserves bone mineral density (BMD) in men and women. METHODS: We conducted a controlled, parallel-arm, double-blinded trial with 145 participants, 50-80 years, with random assignment to soy beverage daily for 12 months. Active treatment (+ISO) received soy protein containing 83 mg isoflavones (45.6 mg genistein, 31.7 mg daidzein), aglycone units; the comparison group (-ISO) received soy protein containing 3mg isoflavones. We measured BMD using dual-energy X-ray absorptiometry at the total hip and posterior-anterior spine (L1-L4) at baseline in 22 women and 123 men, and at 12 months in 13 women and 98 men. We used linear mixed models to test for an isoflavone effect on percentage BMD change from baseline in spine and hip. RESULTS: Among all participants, mean percent change in spine BMD (+/-S.E.) was 0.16+/-0.44 in -ISO (P=0.10) at 12 months. Treatment effects on spine BMD were significantly greater in women than men (P=0.01). At 12 months, in women, mean percent change was 0.58+/-0.70 in +ISO and -1.84+/-0.86 in -ISO (P=0.05); among men it was 1.32+/-0.53 in +ISO and 0.31+/-0.48 in -ISO (P=0.16). By comparison, percent change in hip BMD was similar in the treatment groups, and was not different between men and women. Mean percent change in hip BMD from baseline to 12 months was 0.54+/-0.38 in +ISO and -0.13+/-0.36 in -ISO (P=0.20) among all participants. CONCLUSIONS: Soy protein containing isoflavones showed a modest benefit in preserving spine, but not hip BMD in older women.
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Densidad Ósea/efectos de los fármacos , Osteoporosis/prevención & control , Proteínas de Soja/uso terapéutico , Absorciometría de Fotón , Anciano , Método Doble Ciego , Femenino , Cadera , Humanos , Vértebras Lumbares , Masculino , Persona de Mediana Edad , Osteoporosis/diagnóstico por imagen , Resultado del TratamientoRESUMEN
BACKGROUND: The EF-hand family is a large set of Ca(2+)-binding proteins that contain characteristic helix-loop-helix binding motifs that are highly conserved in sequence. Members of this family include parvalbumin and many prominent regulatory proteins such as calmodulin and troponin C. EF-hand proteins are involved in a variety of physiological processes including cell-cycle regulation, second messenger production, muscle contraction, microtubule organization and vision. RESULTS: We have determined the structures of parvalbumin mutants designed to explore the role of the last coordinating residue of the Ca(2+)-binding loop. An E101D substitution has been made in the parvalbumin EF site. The substitution decreases the Ca(2+)-binding affinity 100-fold and increases the Mg(2+)-binding affinity 10-fold. Both the Ca(2+)- and Mg(2+)-bound structures have been determined, and a structural basis has been proposed for the metal-ion-binding properties. CONCLUSIONS: The E101D mutation does not affect the Mg(2+) coordination geometry of the binding loop, but it does pull the F helix 1.1 A towards the loop. The E101D-Ca(2+) structure reveals that this mutant cannot obtain the sevenfold coordination preferred by Ca(2+), presumably because of strain limits imposed by tertiary structure. Analysis of these results relative to previously reported structural information supports a model wherein the characteristics of the last coordinating residue and the plasticity of the Ca(2+)-binding loop delimit the allowable geometries for the coordinating sphere.
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Motivos EF Hand , Parvalbúminas/química , Animales , Sitios de Unión , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Parvalbúminas/genética , Conformación Proteica , Estructura Terciaria de ProteínaRESUMEN
The epidemiology and molecular biology of colorectal cancer are reviewed with a view to understanding their interrelationship. Risk factors for colorectal neoplasia include a positive family history, meat consumption, smoking, and alcohol consumption. Important inverse associations exist with vegetables, nonsteroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy, and physical activity. There are several molecular pathways to colorectal cancer, especially the APC (adenomatous polyposis coli)-beta-catenin-Tcf (T-cell factor; a transcriptional activator) pathway and the pathway involving abnormalities of DNA mismatch repair. These are important, both in inherited syndromes (familial adenomatous polyposis [FAP] and hereditary nonpolyposis colorectal cancer [HNPCC], respectively) and in sporadic cancers. Other less well defined pathways exist. Expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. The roles of several of the environmental exposures in the molecular pathways either are established (e.g., inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat and tobacco smoke as sources of specific blood-borne carcinogens; vegetables as a source of folate, antioxidants, and inducers of detoxifying enzymes). The roles of other factors (e.g., physical activity) remain obscure even when the epidemiology is quite consistent. There is also evidence that some metabolic pathways, e.g., those involving folate and heterocyclic amines, may be modified by polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least some evidence that the general host metabolic state can provide a milieu that enhances or reduces the likelihood of cancer progression. Understanding the roles of environmental exposures and host susceptibilities in molecular pathways has implications for screening, treatment, surveillance, and prevention.
Asunto(s)
Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/etiología , Estilo de Vida , Poliposis Adenomatosa del Colon/genética , Consumo de Bebidas Alcohólicas/efectos adversos , Antiinflamatorios no Esteroideos/administración & dosificación , Neoplasias del Colon/epidemiología , Neoplasias del Colon/etiología , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/prevención & control , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Diagnóstico Diferencial , Exposición a Riesgos Ambientales/efectos adversos , Ejercicio Físico , Conducta Alimentaria , Femenino , Hormonas Esteroides Gonadales/administración & dosificación , Humanos , Masculino , Esfuerzo Físico , Polimorfismo Genético , Neoplasias del Recto/epidemiología , Neoplasias del Recto/etiología , Reproducción , Factores Sexuales , Fumar/efectos adversos , Estados Unidos/epidemiologíaRESUMEN
In 1979-81, 419 patients with incident cases of colon and rectal cancer and 732 controls were questioned regarding diet and alcohol. Cancer cases were a population-based series reported to the South Australian Central Cancer Registry, were 30-74 years of age, and were residing in Metropolitan Adelaide. Controls were selected from the electoral roll and individually age- and sex-matched to cancer cases. The most consistent risk factor for colorectal cancer was dietary protein, which was associated with a twofold-to-threefold relative risk for colon cancer and for rectal cancer in women for all levels of consumption above the base line (i.e., the lowest consumption quintile). For male colon cancer the corresponding relative risk was similar; but for male rectal cancer, risk was elevated only at old ages. Total energy intake and, less clearly, meal frequency were also positively associated with increased risk. Total alcohol intake (but not specifically beer) was associated with increased risk of both colon and rectal cancer in women; in both sexes, there was an increased risk of colon and rectal cancer associated with spirits consumption. A reduced risk of rectal cancer was associated with vitamin C but not with vitamin A. The increased risk associated with high protein and total energy was confined to those consuming a low fiber diet, particularly among women; but some other aspects of the relationship between fiber consumption and risk of colorectal cancer were more complex. Some modifications and extensions of the current fat-to-bile acid-to-fiber theory of bowel carcinogenesis were suggested.
Asunto(s)
Neoplasias del Colon/etiología , Dieta , Neoplasias del Recto/etiología , Adulto , Factores de Edad , Anciano , Consumo de Bebidas Alcohólicas , Animales , Ácido Ascórbico/administración & dosificación , Cerveza , Ácidos y Sales Biliares/biosíntesis , Grasas de la Dieta/administración & dosificación , Fibras de la Dieta/administración & dosificación , Proteínas en la Dieta/administración & dosificación , Ingestión de Energía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ratas , Riesgo , Factores Sexuales , Vitamina A/administración & dosificaciónRESUMEN
A community-based case-control study of the effect of reproductive factors on risk of large bowel cancer in Australia is described. The study involved 155 cases (99 colon cancer, 56 rectal cancer) and 311 controls who were interviewed with regard to pregnancies and their outcomes, lactation, menstrual history, and oral contraceptive (OC) use. Increasing parity was associated with a decreasing risk of colon cancer; para 0, relative risk (RR)=1; para 1-2, RR=0.9, 95% confidence interval (CI)=0.4-1.8; para greater than or equal to 3, RR=0.4, 95% CI=0.2-0.8; later age at first live birth (AFLB) was associated with increasing risk (AFLB less than or equal to 21 yr, RR=1; 22-25 yr, RR=2.3, 95% CI=1.0-5.5; greater than or equal to 26 yr, RR=2.7, 95% CI=1.2-6.2). These effects were independent of each other. Parity appeared to exert its predominant effect on risk of cancer of the right colon. OC use was more common among controls than cases (RR=0.5; 95% CI=0.3-1.2 for ever vs. never users) and showed a dose-response effect in multiple logistic analysis. The pattern of point-estimate RR for rectal cancer was largely congruent with those for colon cancer but was not significantly different from 1.0.
Asunto(s)
Neoplasias del Colon/epidemiología , Métodos Epidemiológicos , Paridad , Neoplasias del Recto/epidemiología , Adulto , Factores de Edad , Anciano , Australia , Femenino , Humanos , Lactancia , Masculino , Edad Materna , Menstruación , Persona de Mediana Edad , Embarazo , Sistema de Registros , Factores SexualesRESUMEN
BACKGROUND: Colorectal cancer is the third most common cancer in the world, arising mostly from pre-existing adenomatous polyps (adenomas) of the large bowel. Patients with colorectal adenomas are at increased risk of colorectal cancer because of a high recurrence rate for adenomas. We followed a cohort of 1490 patients with rectal adenomas to determine whether recurrence might be related to pathologic characteristics of the initial adenomas. METHODS: The patients were identified in Haining County, China, from 1977 through 1978 by means of examination with a 15-cm rigid sigmoidoscope. They were followed by endoscopic examination at years 2, 4, 6, 11, and 16 after their initial polypectomy. New adenomas in the rectum were identified in 280 patients in these follow-up examinations. RESULTS: Statistically significant twofold to threefold elevated risks of metachronous (recurrent) adenomas were observed for patients who had more than two initial adenomas or whose most advanced initial adenoma was more than 1.0 cm in size, was of villous/tubulovillous type, or showed moderate to severe dysplasia. Much stronger associations were observed for advanced metachronous neoplasms, which are defined as cancers or adenomas with severe dysplasia, with multivariate adjusted relative risks (95% confidence interval) of 4.2 (1.8-9.9) for a large initial adenoma (>1.0 cm), 8.1 (4.2-15.6) for villous/tubulovillous architecture, and 14.4 (5.0-41.3) for severe dysplasia. In particular, patients who had a large (>1.0 cm) adenoma with severe dysplasia at baseline had a relative risk of 37 (7.8-174.7) of developing advanced metachronous neoplasms compared with patients who had small adenoma(s) with mild dysplasia. CONCLUSIONS: The risk of metachronous adenomas is closely related to the pathology of initial adenomas, thus allowing identification of a high-risk group of adenoma patients for close surveillance after their initial polypectomy.
Asunto(s)
Adenoma/patología , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias del Recto/patología , Adulto , China , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Riesgo , Índice de Severidad de la Enfermedad , SigmoidoscopíaRESUMEN
In the past decade, significant progress has been made in understanding the genetic component of familial cancers. Genes associated with familial colon and breast cancers have recently been isolated and molecular diagnostic tests are expected to become available in the near future. Clinicians now have the opportunity to recognize and counsel individuals with elevated risk of cancer by identifying risk factors and genes associated with cancer predisposition. The rapid advances in molecular technology are a direct challenge to the medical community and cancer centers to supply specialized clinical services for familial cancers. We sought to ascertain the activities of cancer centers in the development of programs and the provision of genetic services for familial cancer. We surveyed 41 centers with National Cancer Institute (NCI) cancer center support grants. One half of the centers responding (17 of 34) reported that they provide some genetic services for familial cancer. About one half of these 17 centers (eight [57%] of 14; the three remaining clinics that responded had incomplete information on this indicator) see a variety of patient types on a small scale (fewer than 100 patients per year), and most provide four basic clinical evaluations: medical evaluation, cancer risk assessment, genetic counseling, and pedigree analysis. Staffing of each center varied widely, as did the types of screening services offered (including molecular diagnostic testing). Several centers (six [35%] of 17) indicated that they were in the developmental stages for serving familial cancer patients, and many seem to be increasing their activities in this area. The remaining 17 NCI-supported centers that responded, however, currently provide no genetic services for familial cancers. The results of this survey suggest that there is interest in developing clinical programs for familial cancers by NCI-supported cancer centers, but most of these programs are in developmental stages. A base line has been established to monitor future progress for the provision of cancer genetic services.