RESUMEN

The data presented in this article is related to the research article titled "Racial differences in dietary choices and their relationship to inflammatory potential in childbearing age women at risk for exposure to COVID-19". This data article provides details of dietary intake data from 509 women (African American, n = 327 and Caucasian American, n = 182) who are residents of Birmingham, AL. All women were characterized for demographic and lifestyle factors and indicators of excess body weight (EBW) that are likely to influence overall dietary habits. Dietary intake data was collected by administering the modified version of the NCI validated Block food frequency questionnaire (98.2-isoflav version) that includes 110 food items of the original version (98.2 version) and an additional 24 phytochemical rich food items. The data article describes our approach to derive the dietary inflammatory score using a validated empirical dietary inflammatory index based on the frequency and the amount of consumption of each food item with minor modifications. This data will allow researchers to understand the composition of a Southern-style diet consumed by women of childbearing age and its relationship to inflammatory potential, EBW, dietary guidelines, dietary reference intakes or diet quality indices.

RESUMEN

Since the ongoing coronavirus disease 2019 (COVID-19) pandemic is linked to chronic inflammation, people with initial lower inflammatory status could have better outcomes from exposure to this disease. Because dietary habits are one of the most important modifiable risk factors for inflammation, identification of dietary components associated with inflammation could play a significant role in controlling or reducing the risk of COVID-19. We investigated the inflammatory potential of diets consumed by African American (AA) and Caucasian American (CA) women of childbearing age (n = 509) who are at high risk for exposure to COVID-19 by being residents of Birmingham, Alabama, a city severely affected by this pandemic. The overall pro- and anti- inflammatory scores were calculated using dietary intake data gathered using Block food frequency questionnaire. The proinflammatory potential of diets consumed by AAs was significantly higher compared to CAs. Several anti- and proinflammatory nutrients and food groups consumed differed by race. With consumption of a greater number of antioxidants and B-vitamins, CAs switched toward an anti-inflammatory score more effectively than AAs while AAs performed better than CAs in improving the anti-inflammatory score with the consumption of a greater number of minerals and vitamin D. Effective race-specific dietary modifications or supplementation with nutrients identified will be useful to improve proinflammatory diets toward anti-inflammatory. This approach could aid in controlling the current COVID-19 pandemic and future pandemics of a similar nature in women at risk for exposure.

Asunto(s)

Negro o Afroamericano/estadística & datos numéricos , COVID-19/prevención & control , Dieta/métodos , Inflamación/fisiopatología , Población Blanca/estadística & datos numéricos , Adulto , Alabama , Dieta/efectos adversos , Dieta/estadística & datos numéricos , Femenino , Humanos , Persona de Mediana Edad , Pandemias , SARS-CoV-2 , Encuestas y Cuestionarios , Adulto Joven

RESUMEN

Residue-residue close contact (R2R-C) data procured from three-dimensional protein-protein interaction (PPI) experiments is currently used for predicting residue-residue interaction (R2R-I) in PPI. However, due to complex physiochemical environments, R2R-I incidences, facilitated by multiple factors, are usually entangled in the source environment and masked in the acquired data. Here we present a novel method, P2K (Pattern to Knowledge), to disentangle R2R-I patterns and render much succinct discriminative information expressed in different specific R2R-I statistical/functional spaces. Since such knowledge is not visible in the data acquired, we refer to it as deep knowledge. Leveraging the deep knowledge discovered to construct machine learning models for sequence-based R2R-I prediction, without trial-and-error combination of the features over external knowledge of sequences, our R2R-I predictor was validated for its effectiveness under stringent leave-one-complex-out-alone cross-validation in a benchmark dataset, and was surprisingly demonstrated to perform better than an existing sequence-based R2R-I predictor by 28% (p: 1.9E-08). P2K is accessible via our web server on https://p2k.uwaterloo.ca .

RESUMEN

Purpose: We investigated the role of the human endogenous retrovirus type K (HERV-K) envelope (env) gene in pancreatic cancer.Experimental Design: shRNA was employed to knockdown (KD) the expression of HERV-K in pancreatic cancer cells.Results: HERV-K env expression was detected in seven pancreatic cancer cell lines and in 80% of pancreatic cancer patient biopsies, but not in two normal pancreatic cell lines or uninvolved normal tissues. A new HERV-K splice variant was discovered in several pancreatic cancer cell lines. Reverse transcriptase activity and virus-like particles were observed in culture media supernatant obtained from Panc-1 and Panc-2 cells. HERV-K viral RNA levels and anti-HERV-K antibody titers were significantly higher in pancreatic cancer patient sera (N = 106) than in normal donor sera (N = 40). Importantly, the in vitro and in vivo growth rates of three pancreatic cancer cell lines were significantly reduced after HERV-K KD by shRNA targeting HERV-K env, and there was reduced metastasis to lung after treatment. RNA-Seq results revealed changes in gene expression after HERV-K env KD, including RAS and TP53. Furthermore, downregulation of HERV-K Env protein expression by shRNA also resulted in decreased expression of RAS, p-ERK, p-RSK, and p-AKT in several pancreatic cancer cells or tumors.Conclusions: These results demonstrate that HERV-K influences signal transduction via the RAS-ERK-RSK pathway in pancreatic cancer. Our data highlight the potentially important role of HERV-K in tumorigenesis and progression of pancreatic cancer, and indicate that HERV-K viral proteins may be attractive biomarkers and/or tumor-associated antigens, as well as potentially useful targets for detection, diagnosis, and immunotherapy of pancreatic cancer. Clin Cancer Res; 23(19); 5892-911. ©2017 AACR.

Asunto(s)

Carcinogénesis/genética , Retrovirus Endógenos/genética , Neoplasias Pancreáticas/genética , Proteínas del Envoltorio Viral/genética , Línea Celular Tumoral , Proliferación Celular/genética , Retrovirus Endógenos/patogenicidad , Regulación Neoplásica de la Expresión Génica , Regulación Viral de la Expresión Génica , Técnicas de Silenciamiento del Gen , Interacciones Huésped-Patógeno/genética , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/virología , ARN Interferente Pequeño/genética , Proteínas Recombinantes de Fusión/genética , Transducción de Señal/genética

RESUMEN

Human endogenous retroviruses (HERVs), which make up approximately 8% of the human genome, are overexpressed in some breast cancer cells and tissues but without regard to cancer subtype. We, therefore, analyzed TCGA RNA-Seq data to evaluate differences in expression of the HERV-K family in breast cancers of the various subtypes. Four HERV-K loci on different chromosomes were analyzed in basal, Her2E, LumA, and LumB breast cancer subtypes of 512 breast cancer patients with invasive ductal carcinoma (IDC). The results for all four loci showed higher HERV-K expression in the basal subtype, suggesting similar mechanisms of regulation regardless of locus. Expression of the HERV-K envelope gene (env) was highly significantly increased in basal tumors in comparison with the also-upregulated expression of other HERV-K genes. Analysis of reverse-phase protein array data indicated that increased expression of HERV-K is associated with decreased mutation of H-Ras (wild-type). Our results show elevation of HERV-K expression exclusively in the basal subtype of IDC breast cancer (as opposed to the other subtypes) and suggest HERV-K as a possible target for cancer vaccines or immunotherapy against this highly aggressive form of breast cancer.

Asunto(s)

Neoplasias de la Mama/patología , Carcinoma Basocelular/patología , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/patología , Retrovirus Endógenos/genética , Proteínas del Envoltorio Viral/genética , Neoplasias de la Mama/genética , Carcinoma Basocelular/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Bases de Datos Factuales , Femenino , Regulación Neoplásica de la Expresión Génica , Regulación Viral de la Expresión Génica , Genoma Humano , Humanos

RESUMEN

Human endogenous retrovirus type K (HERV-K) Env protein was previously demonstrated to be overexpressed in human breast cancer (BC) cells and tissues. However, the molecular pathways driving the specific alterations are unknown. We now show that knockdown of its expression with an shRNA (shRNAenv) blocked BC cell proliferation, migration, and invasion. shRNAenv transduction also attenuated the ability of BC cells to form tumors, and notably prevented metastasis. Mechanistically, downregulation of HERV-K blocked expression of tumor-associated genes that included Ras, p-RSK, and p-ERK. The major upstream regulators influenced by HERV-K knockdown were p53, TGF- ß1, and MYC. Of interest, when the HERV-K env gene was overexpressed in shRNAenv-transduced BC cells using an HERV-K env expression vector, Ras/Raf/MEK/ERK pathway signaling was restored. CDK5, which alters p53 phosphorylation in some cancers, was upregulated and p53 was downregulated when HERV-K was overexpressed. CDK5 is also a mediator of TGF-ß1-induced epithelial-mesenchymal transition and migration in cancer cells, and is involved in tumor formation. Importantly, reductions in migration, invasion, and transformation of BC cells stably transduced with shRNAenv was reversed after adding back a vector with a synonymous mutation of HERV-K env. Taken together, these results indicate that HERV-K Env protein plays an important role in tumorigenesis and metastasis of BC.

Asunto(s)

Neoplasias de la Mama/genética , Carcinogénesis/genética , Productos del Gen env/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Subunidad gamma Común de Receptores de Interleucina/genética , Células MCF-7 , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Metástasis de la Neoplasia , Interferencia de ARN , Tratamiento con ARN de Interferencia , Transducción de Señal/genética

RESUMEN

The primary aim of the study was to determine whether plasma concentrations of homocysteine (Hcy), a functional indicator of methyl donor nutrients, are associated with altered risk of higher grades of cervical intraepithelial neoplasia (CIN 2+) and the degree of methylation in long interspersed nucleotide elements (LINE-1s) of peripheral blood mononuclear cells, a potential biomarker of CIN 2+ in a population of women exposed to the United States folic acid fortification program. The secondary aim was to assess the determinants of plasma Hcy in the same population. The study included 457 women diagnosed with either CIN 2+ (cases, n = 132) or ≤ CIN 1 (non-cases, n = 325). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors of cervical cancer. Women with higher Hcy concentrations were at a greater risk of being diagnosed with CIN 2+ [odds ratio (OR) = 1.86, P = 0.005]. Higher plasma folate concentrations were a significant determinant of lower Hcy (OR = 0.40, P = 0.0002). Women with higher Hcy concentrations were more likely to have a lower degree of LINE-1 methylation (OR = 2.30, P = 0.0007). These results suggested that further improvement in folate status in this population may be beneficial for lowering Hcy and improving the degree of LINE-1 methylation.

Asunto(s)

Ácido Fólico/sangre , Hiperhomocisteinemia/genética , Elementos de Nucleótido Esparcido Largo/genética , Displasia del Cuello del Útero/etiología , Neoplasias del Cuello Uterino/etiología , Adulto , Índice de Masa Corporal , Anticonceptivos Hormonales Orales/administración & dosificación , Metilación de ADN , Femenino , Ácido Fólico/administración & dosificación , Ácido Fólico/genética , Homocisteína/sangre , Humanos , Hiperhomocisteinemia/complicaciones , Leucocitos Mononucleares/fisiología , Modelos Logísticos , Persona de Mediana Edad , Infecciones por Papillomavirus/sangre , Infecciones por Papillomavirus/genética , Factores de Riesgo , Neoplasias del Cuello Uterino/genética , Adulto Joven , Displasia del Cuello del Útero/genética

RESUMEN

Endogenous retroviral sequences are spread throughout the genome of all humans, and make up about 8% of the genome. Despite their prevalence, the function of human endogenous retroviruses (HERVs) in humans is largely unknown. In this review we focus on the brain, and evaluate studies in animal models that address mechanisms of endogenous retrovirus activation in the brain and central nervous system (CNS). One such study in mice found that TRIM28, a protein critical for mouse early development, regulates transcription and silencing of endogenous retroviruses in neural progenitor cells. Another intriguing finding in human brain cells and mouse models was that endogenous retrovirus HERV-K appears to be protective against neurotoxins. We also report on studies that associate HERVs with human diseases of the brain and CNS. There is little doubt of an association between HERVs and a number of CNS diseases. However, a cause and effect relationship between HERVs and these diseases has not yet been established.

Asunto(s)

Encefalopatías/virología , Encéfalo/fisiología , Encéfalo/virología , Retrovirus Endógenos/fisiología , Animales , Encéfalo/crecimiento & desarrollo , Encéfalo/fisiopatología , Encefalopatías/etiología , Encefalopatías/terapia , Sistema Nervioso Central/virología , Modelos Animales de Enfermedad , Retrovirus Endógenos/genética , Humanos , Ratones , Neurotoxinas/toxicidad , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Proteínas Represoras/genética , Proteínas Represoras/fisiología , Proteína 28 que Contiene Motivos Tripartito , Activación Viral/genética

RESUMEN

We have previously reported that human endogenous retrovirus-K (HERV-K) envelope (env) protein is a tumor-associated antigen (TAA) for cancer vaccines, and that its antibodies (mAbs) possess antitumor activity against cancer. In this study, a chimeric antigen receptor (CAR) specific for HERV-K env protein (K-CAR) was generated using anti-HERV-K mAb. K-CAR T cells from peripheral blood mononuclear cells (PBMCs) of 9 breast cancer (BC) patients and 12 normal donors were able to inhibit growth of, and to exhibit significant cytotoxicity toward, BC cells but not MCF-10A normal breast cells. The antitumor effects in cancer cells were significantly reduced when control T cells were used, or the expression of HERV-K was knocked down by an shRNA. Secretion of multiple cytokines, including IFNγ, TNF-α, and IL-2, was significantly enhanced in culture media of BC cells treated with K-CARs. Significantly reduced tumor growth and tumor weight was observed in xenograft models bearing MDA-MB-231 or MDA-MB-435.eB1 BC cells. Importantly, the K-CAR prevented tumor metastasis to other organs. Furthermore, downregulation of HERV-K expression in tumors of mice treated with K-CAR correlated with upregulation of p53 and downregulation of MDM2 and p-ERK. Importantly, the expression of HERV-K env protein in metastatic tumor tissues treated with K-CAR T cells correlated with the expression of Ras. Our results indicate that HERV-K env protein is an oncoprotein and may play an important role in tumorigenesis related to p53 and Ras signaling pathways. Anti-HERV-K treatment, including K-CAR treatment, shows potential for immunotherapy of BC.

RESUMEN

PURPOSE: To determine whether HERV-K envelope (ENV) protein could function as a tumor-associated antigen and elicit specific T-cell responses against autologous ovarian cancer cells. EXPERIMENTAL DESIGN: The expression of HERV-K transcripts and ENV protein, the presence of serum antibodies against HERV-K, reverse transcriptase (RT) activities, and cellular immune responses in primary ovarian cancer tissues and patient blood samples were analyzed and compared with samples from patients with benign ovarian diseases and normal female donors. RESULTS: Ovarian cancer cells in primary tumors and ascites expressed markers of cancer stem cells and markers of both mesenchymal and epithelial cells. Expression of HERV transcripts and HERV-K ENV protein and reverse transcriptase activities were higher in ovarian cancer compared with adjacent normal and benign tissues. The ovarian cancer patient plasma also had high reverse transcriptase activities and the ovarian cancer patient sera contained HERV-K immunoreactive antibodies. HERV-K-specific T cells generated from autologous dendritic cells pulsed with HERV-K ENV antigens exhibited phenotypes and functions consistent with a cellular immune response including T-cell proliferation, IFNγ production, and HERV-K-specific cytotoxic T lymphocyte (CTL) activity. Significantly higher CTL lysis of autologous tumor cells than of uninvolved normal cells was demonstrated in patients with ovarian cancer than patients with benign diseases and further enhanced lysis was observed if T regulatory cells were depleted. CONCLUSION: Endogenous retroviral gene products in ovarian cancer may represent a potentially valuable new pool of tumor-associated antigens for targeting of therapeutic vaccines to ovarian cancer. Clin Cancer Res; 21(2); 471-83. ©2014 AACR.

Asunto(s)

Retrovirus Endógenos/genética , Productos del Gen env/genética , Neoplasias Ováricas/sangre , Linfocitos T Citotóxicos/inmunología , Antígenos de Neoplasias/sangre , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Línea Celular Tumoral , Proliferación Celular , Citotoxicidad Inmunológica , Retrovirus Endógenos/metabolismo , Femenino , Productos del Gen env/sangre , Humanos , Activación de Linfocitos , Neoplasias Ováricas/virología , ADN Polimerasa Dirigida por ARN/sangre , ADN Polimerasa Dirigida por ARN/genética , Linfocitos T Citotóxicos/virología

RESUMEN

OBJECTIVE: We evaluated time to clearance of high risk (HR) HPV infection in relation to functional variants in three genes (CYP1A1, GSTT1, and GSTM1). METHODS: The study group consisted of 450 HR-HPV infected women from the Atypical squamous cells of undetermined significance-low-grade squamous intraepithelial Lesion Triage Study (ALTS) cohort followed up at the clinical center at Birmingham, Alabama. The Cox proportional hazard model with the Wei-Lin-Weisfeld (WLW) approach was used, controlling for relevant covariates. RESULTS: Women who were polymorphic for CYP1A1 experienced an HR-HPV clearance rate that was 20% (HR=0.80, p=0.04) lower than women without the polymorphism for CYP1A1, adjusting for all other cofactors. The GSTM1 null genotype was associated with higher HR-HPV clearance rate (HR=1.39, p=0.006). The polymorphism in GSTT1 was not significantly associated with time to clearance of HR-HPV. CONCLUSIONS: Xenobiotic metabolism genes may influence the natural history of HR-HPV infection and its progression to cervical cancer.

Asunto(s)

Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Infecciones por Papillomavirus/enzimología , Infecciones por Papillomavirus/virología , Adulto , Estudios de Cohortes , ADN Viral/genética , ADN Viral/aislamiento & purificación , Femenino , Genotipo , Humanos , Papillomaviridae/genética , Enfermedades del Cuello del Útero/enzimología , Enfermedades del Cuello del Útero/virología , Neoplasias del Cuello Uterino/enzimología , Neoplasias del Cuello Uterino/virología

RESUMEN

BACKGROUND: Studies in populations unexposed to folic acid (FA) fortification have demonstrated that MTHFR C677T polymorphism is associated with increased risk of higher grades of cervical intraepithelial neoplasia (CIN 2+). However, it is unknown whether exposure to higher folate as a result of the FA fortification program has altered the association between MTHFR C677T and risk of CIN, or the mechanisms involved with such alterations. The current study investigated the following in a FA fortified population: 1) The association between MTHFR C677T polymorphism and risk of CIN 2+; 2) The modifying effects of plasma folate concentrations on this association; and 3) The modifying effects of plasma folate on the association between the polymorphism and degree of methylation of long interspersed nucleotide elements (L1s), in peripheral blood mononuclear cell (PBMC) DNA, a documented biomarker of CIN risk. METHODS: The study included 457 US women diagnosed with either CIN 2+ (cases) or ≤ CIN 1 (non-cases). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors for CIN. RESULTS: The 677CT/TT MTHFR genotypes were not associated with the risk of CIN 2+. Women with CT/TT genotype with lower folate, however, were more likely to be diagnosed with CIN 2+ compared to women with CT/TT genotype with higher folate (OR = 2.41, P = 0.030). Women with CT/TT genotype with lower folate were less likely to have a higher degree of PBMC L1 methylation compared to women with CT/TT genotype with higher folate (OR = 0.28, P = 0.017). CONCLUSIONS: This study provides the first evidence that the MTHFR 677CT/TT genotype-associated lower degree of PBMC L1 methylation increases the risk of CIN 2+ in women in the US post-FA fortification era. Thus, even in the post-FA fortification era, not all women have adequate folate status to overcome MTHFR 677CT/TT genotype-associated lower degree of L1 methylation.

Asunto(s)

Metilación de ADN , Ácido Fólico/metabolismo , Elementos de Nucleótido Esparcido Largo , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple , Displasia del Cuello del Útero/genética , Displasia del Cuello del Útero/metabolismo , Adulto , Alelos , Biomarcadores , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Leucocitos Mononucleares/metabolismo , Persona de Mediana Edad , Factores de Riesgo , Estados Unidos/epidemiología , Adulto Joven , Displasia del Cuello del Útero/epidemiología , Displasia del Cuello del Útero/patología

RESUMEN

We previously reported that a higher degree of methylation of CpG sites in the promoter (positions 31, 37, 43, 52, and 58) and enhancer site 7862 of human papillomavirus (HPV) 16 was associated with a lower likelihood of being diagnosed with HPV 16-associated CIN 2+. The purpose of this study was to replicate our previous findings and, in addition, to evaluate the influence of plasma concentrations of folate and vitamin B12 on the degree of HPV 16 methylation (HPV 16m). The study included 315 HPV 16-positive women diagnosed with either CIN 2+ or ≤CIN 1. Pyrosequencing technology was used to quantify the degree of HPV 16m. We reproduced the previously reported inverse association between HPV 16m and risk of being diagnosed with CIN 2+. In addition, we observed that women with higher plasma folate and HPV 16m or those with higher plasma vitamin B12 and HPV 16m were 75% (P < 0.01) and 60% (P = 0.02) less likely to be diagnosed with CIN 2+, respectively. With a tertile increase in the plasma folate or vitamin B12, there was a 50% (P = 0.03) and 40% (P = 0.07) increase in the odds of having a higher degree of HPV 16m, respectively. This study provides initial evidence that methyl donor micronutrients, folate and vitamin B12, may play an important role in maintaining a desirably high degree of methylation at specific CpG sites in the HPV E6 promoter and enhancer that are associated with the likelihood of being diagnosed with CIN 2+.

Asunto(s)

Metilación de ADN , ADN Viral/química , Ácido Fólico/sangre , Infecciones por Papillomavirus/virología , Displasia del Cuello del Útero/virología , Vitamina B 12/sangre , Adulto , Biopsia , Islas de CpG , Elementos de Facilitación Genéticos , Femenino , Genotipo , Papillomavirus Humano 16 , Humanos , Masculino , Micronutrientes/sangre , Persona de Mediana Edad , Proteínas Oncogénicas Virales/química , Infecciones por Papillomavirus/sangre , Regiones Promotoras Genéticas , Proteínas Represoras/química , Factores de Riesgo , Análisis de Secuencia de ADN , Adulto Joven , Displasia del Cuello del Útero/sangre

RESUMEN

A simple and accurate test to detect early-stage breast cancer has not been developed. Previous studies indicate that the level of human endogenous retrovirus type K (group HERV-K(HML-2)) transcription may be increased in human breast tumors. We hypothesized that HERV-K(HML-2) reactivation can serve as a biomarker for early detection of breast cancer. Serum samples were collected from women without cancer (controls) and patients with ductal carcinoma in situ (DCIS) and invasive breast cancer. ELISA assays were used to detect serum anti-HERV-K(HML-2) antibody titers. RNA was extracted from sera and analyzed by real-time RT-PCR to quantitate the level of HERV-K(HML-2) mRNA. We measured significantly higher serum mRNA and serum antibody titers against HERV-K(HML-2) proteins in women with DCIS and stage I disease than in women without cancer. At optimized cutoffs for the antibody titers, the assay produced an area under the receiver operating characteristic curve (AUC) of 0.89 (95% confidence interval 0.77-1.00) for DCIS and of 0.95 (95% confidence interval 0.89-1.00) for invasive breast cancer. These AUCs are comparable to those observed for mammograms. We also found that serum HERV-K(HML-2) mRNA tended to be higher in breast cancer patients with a primary tumor who later on developed the metastatic disease than in patients who did not develop cancer metastasis. Our results show that HERV-K(HML-2) antibodies and mRNA are already elevated in the blood at an early stage of breast cancer, and further increase in patients who are at risk of developing a metastatic disease.

Asunto(s)

Anticuerpos Antivirales/sangre , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Carcinoma Intraductal no Infiltrante/sangre , Retrovirus Endógenos/inmunología , ARN Mensajero/sangre , ARN Viral/sangre , Neoplasias de la Mama/patología , Neoplasias de la Mama/virología , Carcinoma Intraductal no Infiltrante/patología , Carcinoma Intraductal no Infiltrante/virología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Metástasis de la Neoplasia , Reacción en Cadena en Tiempo Real de la Polimerasa

RESUMEN

We evaluated folate status of child-bearing age women diagnosed with abnormal pap smear in the US post-folic acid (FA) fortification era and assessed the determinants of NTD-protective and supra-physiologic (SP) concentrations of folate. The distribution of 843 women according to NTD-protective concentrations of RBC folate, plasma folate and SP concentrations of plasma folate were tested in relation to demographic and life-style factors. Logistic regression models specified NTD-protective concentrations of RBC and plasma folate or SP concentrations of plasma folate as dependent variables and demographic and life-style factors as independent predictors of interest. More than 82% reached NTD-protective concentrations of RBC and plasma folate and ~30% reached SP concentrations of plasma folate. FA supplement use was associated with having SP concentrations of plasma folate rather than NTD-protective concentrations of folate. African American (AA) women and smokers were significantly less likely to achieve NTD-protective concentrations of RBC and plasma folate. A large majority of women reached NTD-protective concentrations of folate with the current level of FA fortification without using supplementary FA. Therefore, the remaining disparities in AA women and in smokers should be addressed by targeted individual improvements in folate intake.

RESUMEN

BACKGROUND: Identification of associations between global DNA methylation and excess body weight (EBW) and related diseases and their modifying factors are an unmet research need that may lead to decreasing DNA methylation-associated disease risks in humans. The purpose of the current study was to evaluate the following; 1) Association between the degree of peripheral blood mononuclear cell (PBMC) L1 methylation and folate, and indicators of EBW, 2) Association between the degree of PBMC L1 methylation and folate, and insulin resistance (IR) as indicated by a higher homeostasis model assessment (HOMA-IR). METHODS: The study population consisted of 470 child-bearing age women diagnosed with abnormal pap. The degree of PBMC L1 methylation was assessed by pyrosequencing. Logistic regression models specified indicators of EBW (body mass index-BMI, body fat-BF and waist circumference-WC) or HOMA-IR as dependent variables and the degree of PBMC L1 methylation and circulating concentrations of folate as the independent predictor of primary interest. RESULTS: Women with a lower degree of PBMC L1 methylation and lower plasma folate concentrations were significantly more likely to have higher BMI, % BF or WC (OR = 2.49, 95% CI:1.41-4.47, P = 0.002; OR = 2.49, 95% CI:1.40-4.51, P = 0.002 and OR = 1.98, 95% = 1.14-3.48 P = 0.0145, respectively) and higher HOMA-IR (OR = 1.78, 95% CI:1.02-3.13, P = 0.041). CONCLUSION: Our results demonstrated that a lower degree of PBMC L1 methylation is associated with excess body weight and higher HOMA-IR, especially in the presence of lower concentrations of plasma folate.

Asunto(s)

Metilación de ADN , Ácido Fólico/sangre , Homeostasis , Modelos Biológicos , Monocitos/metabolismo , Sobrepeso , Adulto , Secuencia de Bases , Glucemia/análisis , Cartilla de ADN , Demografía , Femenino , Humanos , Insulina/sangre , Estilo de Vida , Reacción en Cadena de la Polimerasa , Adulto Joven

RESUMEN

BACKGROUND: The envelope (env) protein of the human endogenous retrovirus type K (HERV-K) family is commonly expressed on the surface of breast cancer cells. We assessed whether HERV-K env is a potential target for antibody-based immunotherapy of breast cancer. METHODS: We examined the expression of HERV-K env protein in various malignant (MDA-MB-231, MCF-7, SKBR3, MDA-MB-453, T47D, and ZR-75-1) and nonmalignant (MCF-10A and MCF-10AT) human breast cell lines by immunoblot, enzyme-linked immunosorbent assay, immunofluorescence staining, and flow cytometry. Anti-HERV-K env monoclonal antibodies (mAbs; 6H5, 4D1, 4E11, 6E11, and 4E6) were used to target expression of HERV-K, and antitumor effects were assessed by quantifying growth and apoptosis of breast cancer cells in vitro, and tumor growth in vivo in mice (n = 5 per group) bearing xenograft tumors. The mechanisms responsible for 6H5 mAb-mediated effects were investigated by microarray assays, flow cytometry, immunoblot, and immunofluorescence staining. The expression of HERV-K env protein was assessed in primary breast tumors (n = 223) by immunohistochemistry. All statistical tests were two-sided. RESULTS: The expression of HERV-K env protein in malignant breast cancer cell lines was substantially higher than nonmalignant breast cells. Anti-HERV-K-specific mAbs inhibited growth and induced apoptosis of breast cancer cells in vitro. Mice treated with 6H5 mAb showed statistically significantly reduced growth of xenograft tumors compared with mice treated with control immunoglobulin (control [mIgG] vs 6H5 mAb, for tumors originating from MDA-MB-231 cells, mean size = 1448.33 vs 475.44 mm(3); difference = 972.89 mm(3), 95% CI = 470.17 to 1475.61 mm(3); P < .001). Several proteins involved in the apoptotic signaling pathways were overexpressed in vitro in 6H5 mAb-treated malignant breast cells compared with mIgG-treated control. HERV-K expression was detected in 148 (66%) of 223 primary breast tumors, and a higher rate of lymph node metastasis was associated with HERV-K-positive compared with HERV-K-negative tumors (43% vs 23%, P = .003). CONCLUSION: Monoclonal antibodies against HERV-K env protein show potential as novel immunotherapeutic agents for breast cancer therapy.

Asunto(s)

Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/virología , Retrovirus Endógenos , Productos del Gen env/antagonistas & inhibidores , Inmunoterapia/métodos , Proteínas de los Retroviridae/antagonistas & inhibidores , Adulto , Anciano , Animales , Anticuerpos Antiidiotipos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Bromodesoxiuridina/metabolismo , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/virología , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática , Estudios de Factibilidad , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Regulación Neoplásica de la Expresión Génica , Regulación Viral de la Expresión Génica , Productos del Gen env/metabolismo , Humanos , Immunoblotting , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Antígeno Ki-67/análisis , Ratones , Ratones Desnudos , Persona de Mediana Edad , Terapia Molecular Dirigida , Clasificación del Tumor , Estadificación de Neoplasias , Proyectos Piloto , Análisis por Matrices de Proteínas , Distribución Aleatoria , Proteínas de los Retroviridae/metabolismo , Transducción de Señal , Trasplante Heterólogo , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba

RESUMEN

There is a paucity of research examining the relationships between dietary patterns and risk of developing precancerous lesions as well as biomarkers associated with such dietary patterns. The purpose of the current study was to identify dietary patterns that are associated with higher grades of cervical intraepithelial neoplasia (CIN 2+) and to determine whether these dietary patterns are associated with the degree of DNA methylation in the long interspersed nucleotide elements (L1s) of peripheral blood mononuclear cells (PBMCs), a biomarker associated with risk of developing CIN 2+. Study population consisted of 319 child-bearing age women. Dietary patterns were derived by factor analysis. The degree of PBMC L1 methylation was assessed by pyrosequencing. Logistic regression models were used to evaluate the associations between dietary patterns and CIN 2+. Similar models were used to evaluate the associations between dietary patterns and degree of PBMC L1 methylation in women free of CIN 2+. Women with the unhealthiest dietary pattern were 3.5 times more likely to be diagnosed with CIN 2+ than women with the healthiest dietary pattern [OR = 3.5; 95% confidence interval (CI), 1.2-10.1; P = 0.02]. Women at risk for developing CIN 2+ with the healthiest dietary pattern were 3.3 times more likely to have higher PBMC L1 methylation than women with the unhealthiest dietary pattern (OR = 3.3; 95% CI, 1.0-10.6; P = 0.04). Our findings suggest that human papilloma virus associated risk of developing CIN 2+ may be reduced by improving dietary patterns. The degree of PBMC L1 methylation may serve as a biomarker for monitoring the effectiveness of dietary modifications needed for reducing the risk of CIN 2+.

Asunto(s)

Metilación de ADN , Dieta , Variación Genética/genética , Infecciones por Papillomavirus/genética , Displasia del Cuello del Útero/genética , Neoplasias del Cuello Uterino/genética , Adulto , Estudios de Casos y Controles , ADN/genética , Femenino , Humanos , Leucocitos Mononucleares , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/dietoterapia , Reacción en Cadena de la Polimerasa , Factores de Riesgo , Neoplasias del Cuello Uterino/dietoterapia , Adulto Joven , Displasia del Cuello del Útero/dietoterapia

RESUMEN

OBJECTIVE: The objective of the study was to evaluate LINE-1 methylation as an intermediate biomarker for the effect of folate and vitamin B12 on the occurrence of higher grades of cervical intraepithelial neoplasia (CIN ≥ 2). METHODS: This study included 376 women who tested positive for high-risk human papillomaviruses and were diagnosed with CIN ≥ 2 (cases) or CIN ≤ 1 (non-cases). CIN ≥ 2 (yes/no) was the dependent variable in logistic regression models that specified the degree of LINE-1 methylation of peripheral blood mononuclear cells (PBMCs) and of exfoliated cervical cells (CCs) as the independent predictors of primary interest. In analyses restricted to non-cases, PBMC LINE-1 methylation (≥ 70% versus <70%) and CC LINE-1 methylation (≥ 54% versus <54%) were the dependent variables in logistic regression models that specified the circulating concentrations of folate and vitamin B12 as the primary independent predictors. RESULTS: Women in the highest tertile of PBMC LINE-1 methylation had 56% lower odds of being diagnosed with CIN ≥ 2 (odds ratio 0.44, 95% confidence interval 0.24-0.83, P = 0.011), whereas there was no significant association between degree of CC LINE-1 methylation and CIN ≥ 2 (odds ratio 0.86, 95% confidence interval 0.51-1.46, P = 0.578). Among non-cases, women with supraphysiologic concentrations of folate (>19.8 ng/mL) and sufficient concentrations of plasma vitamin B12 (≥ 200.6 ng/mL) were significantly more likely to have highly methylated PBMCs compared with women with lower folate and lower vitamin B12 (odds ratio 3.92, 95% confidence interval 1.06-14.52, P = 0.041). None of the variables including folate and vitamin B12 were significantly associated with CC LINE-1 methylation. CONCLUSION: These results suggest that a higher degree of LINE-1 methylation in PBMCs, a one-carbon nutrient-related epigenetic alteration, is associated with a lower risk of developing CIN.

Asunto(s)

Desoxirribonucleasa I/metabolismo , Epigenómica , Leucocitos Mononucleares/metabolismo , Metilación , Displasia del Cuello del Útero/diagnóstico , Adulto , Biomarcadores , Carbono , Estudios de Casos y Controles , Cuello del Útero/citología , Intervalos de Confianza , Metilación de ADN , Femenino , Ácido Fólico/sangre , Estudios de Seguimiento , Humanos , Leucocitos Mononucleares/citología , Modelos Logísticos , Persona de Mediana Edad , Oportunidad Relativa , Infecciones por Papillomavirus , Premenopausia , Regiones Promotoras Genéticas , Estudios Prospectivos , Factores de Riesgo , Encuestas y Cuestionarios , Vitamina B 12/sangre , Complejo Vitamínico B/sangre , Adulto Joven , Displasia del Cuello del Útero/virología