RESUMEN
Most women diagnosed with breast cancer (BC) have estrogen receptor alpha-positive (ER+) disease. The current mouse models of ER+ BC often rely on exogenous estrogen to encourage metastasis, which modifies the immune system and the function of some tissues like bone. Other studies use genetically modified or immunocompromised mouse strains, which do not accurately replicate the clinical disease. To create a model of antiestrogen responsive BC with spontaneous metastasis, we developed a mouse model of 4T1.2 triple-negative (TN) breast cancer with virally transduced ER expression that metastasizes spontaneously without exogenous estrogen stimulation and is responsive to antiestrogen drugs. Our mouse model exhibited upregulated ER-responsive genes and multi-organ metastasis without exogenous estrogen administration. Additionally, we developed a second TN BC cell line, E0771/bone, to express ER, and while it expressed ER-responsive genes, it lacked spontaneous metastasis to clinically important tissues. Following antiestrogen treatment (tamoxifen, ICI 182,780, or vehicle control), 4T1.2- and E0771/bone-derived tumor volumes and weights were significantly decreased, exemplifying antiestrogen responsivity in both cell lines. This 4T1.2 tumor model, which expresses the estrogen receptor, metastasizes spontaneously, and responds to antiestrogen treatment, will allow for further investigation into the biology and potential treatment of metastasis.
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Apolipoproteína L1 , Negro o Afroamericano , Enfermedades Renales/complicaciones , Adulto , Negro o Afroamericano/genética , Apolipoproteína L1/genética , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Enfermedades Renales/genética , Fallo Renal Crónico/genética , Masculino , Persona de Mediana EdadRESUMEN
N95 respirator masks are recommended for protection against respiratory viruses. Despite passing fit-testing 10% of N95 respirator users encountered breakthroughs with exposure to influenza virus compared to full protection provided by a powered air purifying respirator. The current recommendation of N95 respirators should be evaluated for endemic and emerging scenarios.
RESUMEN
Background: Viral infections can trigger chronic kidney disease (CKD) and the urine virome may inform risk. The Natural History of APOL1-Associated Nephropathy Study (NHAANS) reported that urine JC polyomavirus (JCPyV) associated with a lower risk of APOL1-associated nephropathy in African Americans. Herein, association was assessed between urine JCPyV with CKD in African Americans independent from the APOL1 genotype. Methods: Quantitative polymerase chain reaction was performed for urinary detection of JCPyV and BK polyoma virus (BKPyV) in 200 newly recruited nondiabetic African Americans. A combined analysis was performed in these individuals plus 300 NHAANS participants. Results: In the 200 new participants, urine JCPyV was present in 8.8% of CKD cases and 45.8% of nonnephropathy controls (P = 3.0 × 10-8). In those with APOL1 renal-risk genotypes, JCPyV was detected in 5.1% of cases and 40.0% of controls (P = 0.0002). In those lacking APOL1 renal-risk genotypes, JCPyV was detected in 12.2% of cases and 48.8% of controls (P = 8.5 × 10-5). BKPyV was detected in 1.3% of cases and 0.8% of controls (P = 0.77). In a combined analysis with 300 NHAANS participants (n = 500), individuals with urine JCPyV had a 63% lower risk of CKD compared with those without urine JCPyV (odds ratio 0.37; P = 4.6 × 10-6). RNA fluorescence in situ hybridization confirmed the presence of JCPyV genomic DNA and JCPyV messenger RNA (mRNA) in nondiseased kidney. Conclusions: Inverse relationships exist between JCPyV viruria and non-diabetic CKD. Future studies should determine whether renal inflammation associated with CKD is less permissive for JCPyV reactivation/replication or whether JCPyV is a marker of reduced host immune responsiveness that diminishes immune pathologic contributions to CKD.
Asunto(s)
Apolipoproteína L1/genética , Negro o Afroamericano/genética , Infecciones por Polyomavirus/virología , Insuficiencia Renal Crónica/prevención & control , Infecciones Tumorales por Virus/virología , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Virus JC/genética , Virus JC/aislamiento & purificación , Masculino , Persona de Mediana Edad , Infecciones por Polyomavirus/etnología , Infecciones por Polyomavirus/orina , Insuficiencia Renal Crónica/etnología , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/virología , Infecciones Tumorales por Virus/etnologíaRESUMEN
Measles virus (MeV) is known to be highly contagious, with an infectious period lasting from 4 days before to 4 days after rash onset. An unvaccinated, young, female patient with measles confirmed by direct epidemiologic link was hospitalized on day 5 after rash onset. Environmental samples were collected over the 4-day period of hospitalization in a single room. MeV RNA was detectable in air specimens, on surface specimens, and on respirators on days 5-8 after rash onset. This is the first report of environmental surveillance for MeV, and the results suggest that MeV-infected fomites may be present in healthcare settings.
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Microbiología Ambiental , Fómites/virología , Virus del Sarampión/aislamiento & purificación , ARN Viral/análisis , Femenino , Hospitales , Humanos , Virus del Sarampión/genética , ARN Viral/genética , Adulto JovenRESUMEN
OBJECTIVE: To determine peroxisome proliferator activated receptor α and γ mRNA expression in liver tissue of hepatitis C virus-infected patients with and without human immunodeficiency virus and its possible contribution to an acceleration of liver disease progression. METHODS: We measured peroxisome proliferator-activated receptor α and γ mRNA expression by real-time polymerase chain reaction in liver tissues from 40 subjects infected only with hepatitis C virus, 36 subjects co-infected with hepatitis C virus and human immunodeficiency virus and 11 normal adults. RESULTS: Hepatic mRNA expression of both peroxisome proliferator-activated receptors was significantly lower in hepatitis C virus-infected subjects with and without human immunodeficiency virus co-infection compared to the controls. Non-black race was also identified as a predictor of lower peroxisome receptor α and γ mRNA expression. Compared to subjects infected only with hepatitis C virus, liver peroxisome receptor γ mRNA expression was significantly lower in hepatitis C virus/human immunodeficiency virus-co-infected subjects (0.0092 in hepatitis C virus/human immunodeficiency virus-co-infection vs. 0.0120 in hepatitis C virus-only; p=0.004). Hepatic peroxisome receptor α mRNA expression in the hepatitis C virus-infected patients was lower in the presence of human immunodeficiency virus co-infection in non-black subjects (0.0769 vs. 0.1061; p=0.02), whereas the levels did not vary based on human immunodeficiency virus status among black subjects. CONCLUSION: mRNA expression of both peroxisome proliferator-activated receptors is impaired in hepatitis C virus-infected liver and further reduced by human immunodeficiency virus co-infection, although the suppressive effects of the viruses are substantially mitigated in black patients.
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Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Coinfección/patología , Infecciones por VIH/patología , Hepatitis C Crónica/patología , PPAR alfa/análisis , PPAR gamma/análisis , ARN Mensajero/análisis , Análisis de Varianza , Biopsia , Estudios Transversales , Coinfección/complicaciones , Coinfección/etnología , Infecciones por VIH/complicaciones , Infecciones por VIH/etnología , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/etnología , Modelos Lineales , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Hígado/patología , PPAR alfa/genética , PPAR gamma/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Valores de Referencia , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To determine peroxisome proliferator activated receptor α and γ mRNA expression in liver tissue of hepatitis C virus-infected patients with and without human immunodeficiency virus and its possible contribution to an acceleration of liver disease progression. METHODS: We measured peroxisome proliferator-activated receptor α and γ mRNA expression by real-time polymerase chain reaction in liver tissues from 40 subjects infected only with hepatitis C virus, 36 subjects co-infected with hepatitis C virus and human immunodeficiency virus and 11 normal adults. RESULTS: Hepatic mRNA expression of both peroxisome proliferator-activated receptors was significantly lower in hepatitis C virus-infected subjects with and without human immunodeficiency virus co-infection compared to the controls. Non-black race was also identified as a predictor of lower peroxisome receptor α and γ mRNA expression. Compared to subjects infected only with hepatitis C virus, liver peroxisome receptor γ mRNA expression was significantly lower in hepatitis C virus/human immunodeficiency virus-co-infected subjects (0.0092 in hepatitis C virus/human immunodeficiency virus-co-infection vs. 0.0120 in hepatitis C virus-only; p=0.004). Hepatic peroxisome receptor α mRNA expression in the hepatitis C virus-infected patients was lower in the presence of human immunodeficiency virus co-infection in non-black subjects (0.0769 vs. 0.1061; p=0.02), whereas the levels did not vary based on human immunodeficiency virus status among black subjects. CONCLUSION: mRNA expression of both peroxisome proliferator-activated receptors is impaired in hepatitis C virus-infected liver and further reduced by human immunodeficiency virus co-infection, although the suppressive effects of the viruses are substantially mitigated in black patients.
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Coinfección/patología , Infecciones por VIH/patología , Hepatitis C Crónica/patología , PPAR alfa/análisis , PPAR gamma/análisis , ARN Mensajero/análisis , Adulto , Anciano , Análisis de Varianza , Biopsia , Coinfección/complicaciones , Coinfección/etnología , Estudios Transversales , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/etnología , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/etnología , Humanos , Modelos Lineales , Hígado/patología , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , PPAR alfa/genética , PPAR gamma/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Valores de Referencia , Índice de Severidad de la EnfermedadRESUMEN
Individuals with HIV infection and two apolipoprotein L1 gene (APOL1) risk variants frequently develop nephropathy. Here we tested whether non-HIV viral infections influence nephropathy risk via interactions with APOL1 by assessing APOL1 genotypes and presence of urine JC and BK polyoma virus and plasma HHV6 and CMV by quantitative polymerase chain reaction. We analyzed 300 samples from unrelated and related first-degree relatives of African Americans with nondiabetic nephropathy using linear and nonlinear mixed models to account for familial relationships. The four groups evaluated were APOL1 zero/one versus two risk alleles, with or without nephropathy. Urine JCV and BKV were detected in 90 and 29 patients, respectively, whereas HHV6 and CMV were rare. Adjusting for family age at nephropathy, gender, and ancestry, presence of JCV genomic DNA in urine and APOL1 risk alleles were significantly negatively associated with elevated serum cystatin C, albuminuria (albumin-to-creatinine ratio over 30 mg/g), and kidney disease defined as an eGFR under 60 ml/min per 1.73 m(2) and/or albuminuria in an additive (APOL1 plus JCV) model. BK viruria was not associated with kidney disease. Thus, African Americans at increased risk for APOL1-associated nephropathy (two APOL1 risk variants) with JC viruria had a lower prevalence of kidney disease, suggesting that JCV interaction with APOL1 genotype may influence kidney disease risk.
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Apolipoproteínas/genética , Negro o Afroamericano/genética , Virus JC/aislamiento & purificación , Enfermedades Renales/genética , Enfermedades Renales/virología , Lipoproteínas HDL/genética , Infecciones por Polyomavirus/virología , Infecciones Tumorales por Virus/virología , Adulto , Anciano , Albuminuria/etnología , Albuminuria/genética , Albuminuria/virología , Apolipoproteína L1 , Distribución de Chi-Cuadrado , Cistatina C/sangre , ADN Viral/orina , Femenino , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Tasa de Filtración Glomerular , Humanos , Virus JC/genética , Enfermedades Renales/sangre , Enfermedades Renales/etnología , Enfermedades Renales/fisiopatología , Enfermedades Renales/prevención & control , Modelos Lineales , Masculino , Persona de Mediana Edad , Dinámicas no Lineales , North Carolina/epidemiología , Fenotipo , Infecciones por Polyomavirus/etnología , Prevalencia , Factores de Riesgo , Infecciones Tumorales por Virus/etnologíaRESUMEN
Familial aggregation of non-diabetic end-stage renal disease (ESRD) is found in African Americans and variants in the apolipoprotein L1 gene (APOL1) contribute to this risk. To detect genetic associations with milder forms of nephropathy in the high-risk families, analyses were performed using generalized estimating equations to assess relationships between kidney disease phenotypes and APOL1 variants in 786 relatives of 470 families. Adjusting for familial correlations, 23.1, 46.7, and 30.2% of genotyped relatives possessed two, one, or no APOL1 risk variants, respectively. Relatives with two compared with one or no risk variants had statistically indistinguishable median systolic blood pressure, urine albumin to creatinine ratio, estimated glomerular filtration rate (GFR; MDRD equation), and serum cystatin C levels. After adjusting for age, gender, age at ESRD in families, and African ancestry, significant associations were detected between APOL1 with overt proteinuria and estimated GFR (CKD-EPI equation), with a trend toward significance for quantitative albuminuria. Thus, relatives of African Americans with non-diabetic ESRD are enriched for APOL1 risk variants. After adjustment, two APOL1 risk variants weakly predict mild forms of kidney disease. Second hits appear necessary for the initiation of APOL1-associated nephropathy.
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Apolipoproteínas/genética , Población Negra/genética , Variación Genética , Enfermedades Renales/genética , Fallo Renal Crónico/genética , Lipoproteínas HDL/genética , Adulto , Anciano , Albuminuria/etnología , Albuminuria/genética , Apolipoproteína L1 , Distribución de Chi-Cuadrado , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Tasa de Filtración Glomerular/genética , Herencia , Humanos , Riñón/fisiopatología , Enfermedades Renales/diagnóstico , Enfermedades Renales/etnología , Enfermedades Renales/fisiopatología , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/etnología , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Linaje , Fenotipo , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: Coding variants in the apolipoprotein L1 gene (APOL1) are strongly associated with non-diabetic nephropathy in African Americans. ApoL1 proteins associate with high-density lipoprotein (HDL) particles in the circulation. Plasma HDL particle subclass concentrations were compared in 73 African Americans based on APOL1 genotypes to detect differences potentially contributing to renal disease. METHODS: HDL subclass concentrations were measured using nuclear magnetic resonance spectroscopy in African American first-degree relatives of patients with non-diabetic end-stage renal disease. Participants had estimated glomerular filtration rates (GFRs) > 80 mL/min and lacked albuminuria. Additive effects of the number of APOL1 risk variants on natural logarithm-transformed HDL subclass concentrations were computed. RESULTS: Participants were 58.9% female with mean ± SD age 47.2 ± 13.3 years and GFR 92.4 ± 18.8 mL/min. The numbers with 2, 1 and 0 APOL1 nephropathy risk variants, respectively, were 36, 17 and 20. Mean ± SD medium-sized HDL concentrations were significantly lower for each additional APOL1 risk variant (2 versus 1 versus 0 risk variants: 9.0 ± 5.6 versus 10.1 ± 5.5 versus 13.1 ± 8.2 µmol/L, respectively; P = 0.0222 unadjusted; P = 0.0162 triglyceride- and ancestry adjusted). CONCLUSIONS: Lower medium-sized HDL subclass concentrations are present in African Americans based on increasing numbers of APOL1 nephropathy risk variants. Potential mechanistic roles of altered medium HDL concentrations on APOL1-associated renal microvascular diseases should be evaluated.
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Apolipoproteínas/genética , Negro o Afroamericano/genética , Rechazo de Injerto/etiología , Enfermedades Renales/etnología , Enfermedades Renales/genética , Lipoproteínas HDL/sangre , Polimorfismo de Nucleótido Simple/genética , Adulto , Apolipoproteína L1 , Femenino , Estudios de Seguimiento , Genotipo , Tasa de Filtración Glomerular , Humanos , Enfermedades Renales/sangre , Pruebas de Función Renal , Lipoproteínas HDL/genética , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Pronóstico , Factores de RiesgoRESUMEN
Liver disease in patients with chronic hepatitis C virus (HCV) infection has an accelerated course in the presence of human immunodeficiency virus (HIV) coinfection. Some data suggest that HIV suppression achieved with highly active antiretroviral therapy (HAART) ameliorates HCV-related liver disease progression. The aim of this study was to test if there is overexpression of serum markers of liver inflammation and fibrosis in HIV-HCV-coinfected patients and if the effect is counteracted by HAART. In a pilot, cross-sectional, and comparative study serum markers of liver inflammation (CK-18 and HGF) and fibrosis (HGF, MMP-2, and TIMP-1) were measured via ELISA in HIV-infected patients off and on HAART, HCV monoinfected, HIV-HCV coinfected off and on HAART, and controls (10 per group). HIV-HCV-coinfected off HAART patients with low CD4 counts had higher levels of M30, HGF, and MMP-2 than HIV-HCV-coinfected on HAART. HCV coinfection predicted higher levels of MMP-2 [B 65.82 (95% CI 3.86-127.78); p = 0.04], HGF [B 520.22 (95% CI 123.65-916.78); p = 0.01] and M30 [B 128.02 (95%CI 16.39-239.64); p = 0.03]. HAART use was a predictor of lower levels of MMP2 [B -83.18 (95%CI (-146.8) - (-19.52)); p = 0.01] and M30 [B -112.9 (95% CI (-221.3) - (-4.52)); p = 0.04]. Other factors analyzed including alcohol intake ware not associated with the studied markers. In conclusion, serum markers of hepatic inflammation and fibrosis are overexpressed in HIV-HCV-coinfected patients with advanced immunosuppression, while HAART has a "protective" effect.
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Fármacos Anti-VIH/administración & dosificación , Biomarcadores , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/patología , Cirrosis Hepática/patología , Adulto , Anciano , Estudios Transversales , Femenino , Hepatitis C Crónica/diagnóstico , Humanos , Cirrosis Hepática/diagnóstico , Masculino , Persona de Mediana Edad , Proyectos PilotoRESUMEN
Iron is critical for cell growth and proliferation. Iron chelators are being explored for a number of clinical applications, including the treatment of neurodegenerative disorders, heart disease, and cancer. To uncover mechanisms of action of tachpyridine, a chelator currently undergoing preclinical evaluation as an anticancer agent, cell-cycle analysis was performed. Tachpyridine arrested cells at G2, a radiosensitive phase of the cell cycle, and enhanced the sensitivity of cancer cells but not nontransformed cells to ionizing radiation. G2 arrest was p53 independent and was accompanied by activation of the checkpoint kinases CHK1 and CHK2. G2 arrest was blocked by UCN-01, a CHK1 inhibitor, but proceeded in CHK2 knock-out cells, indicating a critical role for CHK1 in G2 arrest. Tachpyridine-induced cell-cycle arrest was abrogated in cells treated with caffeine, an inhibitor of the ataxia-telangiectasia mutated/ataxia-telangiectasia-mutated and Rad3-related (ATM/ATR) kinases. Further, G2 arrest proceeded in ATM-deficient cells but was blocked in ATR-deficient cells, implicating ATR as the proximal kinase in tachpyridine-mediated G2 arrest. Collectively, our results suggest that iron chelators may function as antitumor and radioenhancing agents and uncover a previously unexplored activity of iron chelators in activation of ATR and checkpoint kinases.
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Quelantes/farmacología , Ciclohexilaminas/farmacología , Fase G2/efectos de los fármacos , Fase G2/efectos de la radiación , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Piridinas/farmacología , Radiación Ionizante , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/metabolismo , División Celular/efectos de los fármacos , División Celular/efectos de la radiación , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Quinasa de Punto de Control 2 , Proteínas de Unión al ADN/metabolismo , Activación Enzimática/efectos de los fármacos , Activación Enzimática/efectos de la radiación , Humanos , Metales/antagonistas & inhibidores , Metales/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Fosforilación/efectos de los fármacos , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Iron chelators may be of value as therapeutic agents in the treatment of cancer. They may act by depleting iron, a necessary nutrient, and limiting tumor growth. Alternatively or additionally, they may form redox-active metal complexes that cause oxidative stress via production of reactive oxygen species, damaging critical intracellular targets and thereby eliciting a cytotoxic response. Studies in vitro have evaluated the structure-activity relationships and mechanism of action of many classes of iron chelators, including desferrioxamine (DFO), pyridoxal isonicotinoyl hydrazone (PIH) analogs, desferrithiocin (DFT) analogs, tachpyridine, the heterocyclic carboxaldehyde thiosemicarbazones, and O-Trensox. Animal studies have confirmed the antitumor activity of several chelators. Dexrazoxane has been approved for use in combination with doxorubicin, and its effectiveness in allowing higher doses of doxorubicin to be administered is, in part, based on the interactions of both drugs with iron. Clinical trials of the antitumor activity of chelators have been largely limited to DFO, which has been extensively studied as a consequence of its approved use for treatment of secondary iron overload. While the modest antitumor effects of DFO are encouraging, it is likely that more effective iron chelators may be identified.