RESUMEN
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related death. The biologic response of CRC to standard of care adjuvant therapies such as chemotherapy and radiation are poorly understood. MicroRNAs (miRs) have been shown to affect CRC progression and metastasis. Therefore, we hypothesized that specific miRs modulate CRC response to chemoradiation. METHODS: In this study, we used miR expression profiling and discovered a set of microRNAs upregulated rapidly in response to either a single 2 Gy dose fraction or a 10 Gy dose of γ-radiation in mouse colorectal carcinoma models. We used gain and loss-of-function studies in 2D and 3Dcell proliferation assays and colony formation assays to understand the role of the top miR candidate from our profiling. We used Student's T-tests for simple comparisons and two-factor ANOVA for evaluating significance. RESULTS: The most upregulated candidate at early time points in our signature, miR-451a inhibited tumor cell proliferation and attenuated surviving fraction in longer-term cultures. Conversely, inhibition of miR-451a increased proliferation, tumorsphere formation, and surviving fraction of tumor cells. Using a bioinformatics approach, we identified four genes, CAB39, EMSY, MEX3C, and EREG, as targets of miR-451a. Transfection of miR-451a decreased both mRNA and protein levels of these targets. Importantly, we found miR-451a expression was high and CAB39, EMSY levels were low in a small subset of rectal cancer patients who had a partial response to chemoradiation when compared to patients that had no response. Finally, analysis of a TCGA colorectal cancer dataset revealed that CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients. Higher levels of CAB39 and EMSY correlated with poorer overall survival. CONCLUSIONS: Taken together, our data indicates miR-451a is induced by radiation and may influence colorectal carcinoma proliferation via CAB39 and EMSY pathways.
Asunto(s)
Proliferación Celular/efectos de la radiación , Neoplasias Colorrectales/terapia , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , MicroARNs/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Proliferación Celular/genética , Quimioradioterapia/métodos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Conjuntos de Datos como Asunto , Femenino , Perfilación de la Expresión Génica , Células HCT116 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transducción de Señal/genética , Análisis de Supervivencia , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Nitrosatable drugs react with nitrite in the stomach to form N-nitroso compounds, observed in animal models to result in adverse pregnancy outcomes, such as birth defects and reduced fetal weight. Previous studies examining prenatal exposure to medications classified as nitrosatable have reported an increased risk of preterm births (PTBs) and small-for-gestational-age (SGA) infants. METHODS: Using data from mothers (controls) of babies without major birth defects from the National Birth Defects Prevention Study, prenatal nitrosatable drug usage by trimester and month of gestation was examined in relation to PTBs and SGA infants. RESULTS: Positive associations were observed with nitrosatable drug use and PTBs, with the strongest relationship with second trimester exposure (adjusted hazard ratio [aHR] 1.37, [95% confidence interval (CI) 1.10, 1.70]). Of the nitrosatable functional groups, secondary amines were the most notable, with a higher association among women with second (aHR 1.37, [95% CI 1.05, 1.79]) and third (aHR 1.34, [95% CI 1.02, 1.76]) trimester exposure compared with women with no prenatal nitrosatable drug use. Among SGA infants, a borderline association was noted with amide exposure during the third trimester (adjusted odds ratio 1.43 [95% confidence interval [CI] 1.00, 2.05]). CONCLUSIONS: Prenatal exposure to nitrosatable drugs during the second and third trimester of pregnancy, particularly secondary amines, might increase the risk of PTBs. However, prenatal exposure to nitrosatable drugs was not associated with SGA infants, with the exception of amide drugs.
Asunto(s)
Amidas/efectos adversos , Aminas/efectos adversos , Recién Nacido Pequeño para la Edad Gestacional , Nacimiento Prematuro/inducido químicamente , Adolescente , Adulto , Amidas/administración & dosificación , Aminas/administración & dosificación , Ácido Ascórbico/administración & dosificación , Estudios de Casos y Controles , Suplementos Dietéticos , Femenino , Humanos , Recién Nacido , Masculino , Embarazo , Trimestres del Embarazo , Nacimiento Prematuro/epidemiología , Factores de Riesgo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
UNLABELLED: Nitrosatable drugs, such as secondary or tertiary amines and amides react with nitrite in an acidic environment to form N-nitroso compounds, teratogens in animal models. Vitamin C is a known nitrosation inhibitor. METHODS: Using data from the National Birth Defects Prevention Study, we assessed nitrosatable drug exposure and vitamin C intake during the first trimester among 11,606 case-mothers of infants with oral clefts, limb deficiencies (LDs), or congenital heart defects and 6807 control-mothers of infants without major birth defects during 1997-2005. Daily intake of vitamin C was estimated from maternal interviews that elicited information about supplement use and dietary intake. RESULTS: With no reported use of nitrosatable drugs as the referent group, a lower odds ratio (OR) was observed for transverse LDs among births to mothers exposed to secondary amine drugs and daily vitamin C supplementation (adjusted odds ratio [aOR] 1.2, 95% confidence interval [CI] 0.83-1.8) compared with women taking these drugs and no supplementation (aOR 2.7, 95% CI 1.5-4.6). The OR for longitudinal LDs associated with secondary amine exposure was lower with daily dietary vitamin C intake ≥85 mg (aOR 1.2, 95% CI 0.68-2.0) compared with <85 mg (aOR 1.9, 95% CI 1.2-3.1). Daily vitamin C supplementation in combination with higher dietary vitamin C intake reduced associations between nitrosatable drug exposures and limb deficiencies and atrial septal defects not otherwise specified. CONCLUSION: Prenatal dietary and vitamin C supplement intake may diminish the association between nitrosatable drug exposure during pregnancy and selected birth defects.
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Ácido Ascórbico/metabolismo , Exposición Materna/efectos adversos , Nitrosación/efectos de los fármacos , Compuestos Nitrosos/metabolismo , Encéfalo/anomalías , Estudios de Casos y Controles , Labio Leporino/inducido químicamente , Labio Leporino/etiología , Fisura del Paladar/inducido químicamente , Fisura del Paladar/etiología , Suplementos Dietéticos , Femenino , Cardiopatías Congénitas/inducido químicamente , Humanos , Deformidades Congénitas de las Extremidades/inducido químicamente , EmbarazoAsunto(s)
Suplementos Dietéticos/análisis , Exposición a Riesgos Ambientales , Excipientes/análisis , Preparaciones Farmacéuticas/análisis , Ácidos Ftálicos/análisis , Animales , Preparaciones de Acción Retardada/análisis , Excipientes/química , Excipientes/toxicidad , Humanos , Ácidos Ftálicos/química , Ácidos Ftálicos/toxicidad , Estados UnidosRESUMEN
BACKGROUND: In animal studies, some ortho-phthalates, including di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP), have been shown to be reproductive and developmental toxicants. Human studies show widespread population exposure to background levels of phthalates. Limited evidence suggests that particularly high exposure levels may result from orally ingested medicinal products containing phthalates as excipients (inactive ingredients). OBJECTIVE: In this study we aimed to identify and describe the scope of prescription (RX) and nonprescription (over-the-counter; OTC) medicinal products and dietary supplements marketed in the United States and Canada since 1995 that include phthalates as excipients. METHODS: We used lists of modified-release drug products to identify potential drug products. Inclusion of phthalates was verified using available electronic databases, print references, published package inserts, product packages, and direct communication from manufacturers. Additional products were identified using Internet searches utilizing keywords for phthalates. RESULTS: Based on labeling information, 6 RX drug products included DBP as an excipient, and 45 specified the use of diethyl phthalate (DEP). Phthalate polymers with no known toxicity--hypromellose phthalate (HMP), cellulose acetate phthalate (CAP), and polyvinyl acetate phthalate (PVAP)--were included in 75 RX products. Three OTC drug and dietary supplement products listed DBP, 64 listed DEP, and > 90 indicated inclusion of polymers. CONCLUSIONS: Numerous RX and OTC drug products and supplements from a wide range of therapeutic categories may use DBP or DEP as excipients in oral dosage forms. The potential effects of human exposure to these phthalates through medications are unknown and warrant further investigation.
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Suplementos Dietéticos/análisis , Exposición a Riesgos Ambientales , Excipientes/análisis , Medicamentos sin Prescripción/análisis , Ácidos Ftálicos/análisis , Medicamentos bajo Prescripción/análisis , Canadá , Preparaciones de Acción Retardada/análisis , Excipientes/clasificación , Preparaciones Farmacéuticas/análisis , Ácidos Ftálicos/química , Ácidos Ftálicos/toxicidad , Estados UnidosRESUMEN
Nitrosatable drugs, such as secondary or tertiary amines and amides, form N-nitroso compounds in the presence of nitrite. Various N-nitroso compounds have been associated with neural tube defects in animal models. Using data from the National Birth Defects Prevention Study, the authors examined nitrosatable drug exposure 1 month before and 1 month after conception in 1,223 case mothers with neural tube defect-affected pregnancies and 6,807 control mothers who delivered babies without major congenital anomalies from 1997 to 2005. Nitrite intakes were estimated from mothers' responses to a food frequency questionnaire. After adjustment for maternal race/ethnicity, educational level, and folic acid supplementation, case women were more likely than were control women to have taken tertiary amines (odds ratio = 1.60, 95% confidence interval (CI): 1.31, 1.95). This association was strongest with anencephalic births (odds ratio = 1.96, 95% CI: 1.40, 2.73); odds ratios associated with tertiary amines from the lowest tertile of nitrite intake to the highest tertile were 1.16 (95% CI: 0.59, 2.29), 2.19 (95% CI: 1.25, 3.86), and 2.51 (95% CI: 1.45, 4.37), respectively. Odds ratios for anencephaly with nitrosatable drug exposure were reduced among women who also took daily vitamin supplements that contained vitamin C. Prenatal exposure to nitrosatable drugs may increase the risk of neural tube defects, especially in conjunction with a mother's higher dietary intake of nitrites, but vitamin C might modulate this association.
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Amidas/efectos adversos , Aminas/efectos adversos , Defectos del Tubo Neural/inducido químicamente , Compuestos Nitrosos/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Amidas/metabolismo , Aminas/metabolismo , Ácido Ascórbico/administración & dosificación , Estudios de Casos y Controles , Suplementos Dietéticos , Femenino , Humanos , Defectos del Tubo Neural/prevención & control , Nitritos/metabolismo , Compuestos Nitrosos/metabolismo , EmbarazoRESUMEN
BACKGROUND: Experimental evidence indicates that certain drugs, that are secondary or tertiary amines or amides, form N-nitroso compounds in the presence of nitrite in an acidic environment. Nitrosatable drugs have been associated with birth defects in a few epidemiologic studies. This study describes the prevalence and patterns of nitrosatable drug use among U.S. women during early pregnancy and examines maternal factors associated with such use. METHODS: Data were analyzed from the National Birth Defects Prevention Study and included 6807 mothers who gave birth to babies without major congenital malformations during 1997 to 2005. Information was collected by telephone interview about medication use, demographic factors, and maternal health. Drugs taken during the first trimester were classified according to nitrosatability, amine and amide functional groups, and primary indication of use. RESULTS: Approximately 24% of the women took one or more nitrosatable drugs during the first trimester, including 12.4%, 12.2%, and 7.6% who respectively took secondary amines, tertiary amines, or amides. Five of the ten most commonly taken drugs were available over the counter. Women who were non-Hispanic white (29.5%), with 1 year or more college education (27.3%) or 40 years or older (28.8%) had the highest prevalence of use. Supplemental vitamin C, an inhibitor of nitrosation, was not taken by 41.6% and 19.3% of nitrosatable drug users during the first and second months of pregnancy, respectively. CONCLUSIONS: In this U.S. population, ingestion of drugs classified as nitrosatable was common during the first trimester of pregnancy, especially among non-Hispanic white, more educated, and older mothers.
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Aminas/administración & dosificación , Ácido Ascórbico/farmacología , Nitritos/administración & dosificación , Compuestos Nitrosos/administración & dosificación , Embarazo , Suplementos Dietéticos , Femenino , Humanos , Edad Materna , Nitrosación , Complicaciones del Embarazo/epidemiología , Primer Trimestre del Embarazo , Prevalencia , Estados Unidos/epidemiología , Población BlancaRESUMEN
OBJECTIVE: Interest in herbal treatments has increased without data on safety, efficacy, or rates of use in pregnancy. We examined antenatal herbal and natural product use among mothers of nonmalformed infants in 5 geographic centers. STUDY DESIGN: We used data on nonmalformed infants from the Slone Epidemiology Center's case-control surveillance program for birth defects to examine rates and predictors of herbal use. Exposures were identified through maternal interview. In addition to overall use, 5 categories based on traditional uses and 2 natural product categories were created; topical products and herbal-containing multivitamins were excluded. RESULTS: Among 4866 mothers of nonmalformed infants, 282 (5.8%) reported use of herbal or natural treatments. Use varied by study center and increased with increasing age. CONCLUSION: Although rates of use are low, there remains a need for investigation of the safety of these products. Given sparse data on efficacy, even small risks might well outweigh benefits.
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Fitoterapia/estadística & datos numéricos , Adulto , Femenino , Humanos , Modelos Logísticos , Embarazo , Estados Unidos , Adulto JovenRESUMEN
OBJECTIVES: The aim of this paper was to determine similarities and differences in the use of herbal/natural supplements among various racial/ethnic groups. DESIGN: A random-digit dial (RDD) telephone survey of medication use during the week before the interview was used. SETTINGS/LOCATION: Households in the 48 contiguous United States comprised our study. SUBJECTS: One (1) subject was selected by a random procedure from each contacted household, including interviews conducted from 1998 through September 2004. There were 13,436 subjects at least 18 years of age, including 10,372 non-Hispanic whites, 1174 African Americans, 1109 Hispanics, 335 Asian/Pacific Islanders, and 446 others. OUTCOME MEASURES: Use of any herbal/natural product during the prior week served as outcome measures. Prevalence of use was weighted according to household size; for comparisons among the three largest groups, estimates were also adjusted for age, gender, and education. RESULTS: The overall prevalence was lowest in African Americans (9.5%; 95% confidence interval [CI], 7.8%-11%), intermediate in Hispanics (12%; 10%-14%), and highest in non-Hispanic whites (19%; 18%-20%). Use was higher among women and generally higher for subjects 45-64 years of age, regardless of race/ethnicity; use increased with increasing years of education. The most commonly taken individual herbal/natural substances were similar among the groups. Hispanics used the largest number of products. Distribution of product type differed somewhat, with Hispanics taking more monopreparations and herbal mixtures than the other groups, and herbal mixture use particularly uncommon among African Americans. Use between 1998 and 2004 increased slightly for non-Hispanic whites, increased then declined for African Americans, and did not change for Hispanics. CONCLUSIONS: Based on nationally representative U.S. data, these results provide a comparative picture of contemporary use of herbal/natural supplements in the largest racial/ethnic groups in the United States. The prevalence of use was lowest among African Americans, with a possible decline in recent years, whereas Hispanics take the greatest number of products.
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Suplementos Dietéticos/estadística & datos numéricos , Etnicidad/estadística & datos numéricos , Conductas Relacionadas con la Salud/etnología , Fitoterapia/estadística & datos numéricos , Adulto , Negro o Afroamericano/estadística & datos numéricos , Anciano , Asiático/estadística & datos numéricos , Femenino , Estado de Salud , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Indígenas Norteamericanos/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Aceptación de la Atención de Salud/etnología , Encuestas y Cuestionarios , Estados Unidos/epidemiología , Población Blanca/estadística & datos numéricosRESUMEN
PURPOSE: To assess how use of postmenopausal hormone therapy (PHT) has changed since the Women's Health Initiative (WHI) trial was halted early due to an excess risk of stroke and other adverse outcomes. To estimate whether use of alternative drugs to treat menopausal symptoms (e.g., selective serotonin reuptake inhibitors [SSRIs], soy) has increased. METHODS: Women were interviewed in the Slone Survey, a random-digit-dial (RDD) survey of current medication use in a representative national sample. Information was obtained on PHT including dose, route, and reason for use, and on use of alternative drugs to treat menopausal symptoms. There were 3853 women aged >or=50 years, interviewed from 1/2001 to 6/2004. RESULTS: The average weekly prevalence of PHT declined 57%, from 28% in the first half of 2002 to 12% in the first half of 2004. Use declined for conjugated estrogens (CE) and for other estrogens, taken either alone or with progestin. The decrease exceeded 50% in most strata of age, race, education, and region. The proportion of PHT users taking 0.3 mg CE did not change. Comparing prevalence in 2004 with prevalence in 2002, there was no material increase in use of black cohosh (2.0% in 2004) or soy (2.0%) and use of SSRIs was somewhat lower (8.9%). CONCLUSIONS: These population-based usage data demonstrate a large decline in PHT use among women of postmenopausal age. The proportion of CE users taking lower doses has not increased. On a population basis, millions fewer women are using PHT in 2004 than before the WHI results were published, but there has been no appreciable increase in use of alternative therapies for menopausal symptoms over the same period.
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Terapia de Reemplazo de Estrógeno/tendencias , Posmenopausia , Terapias Complementarias/estadística & datos numéricos , Terapias Complementarias/tendencias , Recolección de Datos , Terapia de Reemplazo de Estrógeno/efectos adversos , Terapia de Reemplazo de Estrógeno/estadística & datos numéricos , Femenino , Medicina de Hierbas/estadística & datos numéricos , Medicina de Hierbas/tendencias , Humanos , Persona de Mediana Edad , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Alimentos de Soja/estadística & datos numéricos , Estados Unidos , Salud de la MujerRESUMEN
BACKGROUND: The benefits of herbal and other natural products (dietary supplements) are increasingly cited in the media. Dramatic increases in use reported during the last decade have led to growing concerns about efficacy and safety. METHODS: To determine which dietary supplements American adults use, whether the prevalence has continued to increase in recent years, and whether popularity of individual supplements has changed, demographic information and details of use of all medicines and dietary supplements in the preceding week were obtained by telephone interview from February 1998 through December 2002 from households in 48 contiguous states and the District of Columbia. Participants included randomly selected residents of households with telephones; compared with 2000 US Census data, participants were representative of the US population. The main outcome measure was the weekly prevalence of dietary supplement use, alone or in a multicomponent product. RESULTS: There were 8470 subjects 18 years or older. The annual prevalence of dietary supplement use increased from 14.2% in 1998-1999 to 18.8% in 2002. Although use did not change among younger subjects, it doubled for men and women 65 years or older. Use of Ginkgo biloba and Panax ginseng declined during the study, while lutein use increased dramatically, because of its addition to multivitamin products. The overall 2002 prevalence excluding lutein use was 13.9%. CONCLUSIONS: The popularity of specific supplements has varied over time and differs according to age and sex. The sharp increase in supplement use in the 1990s appears to have slowed. However, the addition of supplements, such as lutein and lycopene, to mainstream multivitamins has become an important source of exposure.