RESUMO
BACKGROUND: Current clinical guidelines suggest that breast cancers with low hormone receptor expression (LowHR) in 1-10% of tumor cells should be regarded as hormone receptor positive. However, clinical data show that these patients have worse outcome compared to patients with hormone receptor expression above 10%. We performed DNA methylation profiling on 23 LowHR breast cancer specimens, including 13 samples with HER2 amplification and compared our results with a reference breast cancer cohort from The Cancer Genome Atlas to clarify the status for this infrequent but important patient subgroup. RESULTS: In unsupervised clustering and dimensionality reduction, breast cancers with low hormone receptor expression that lacked HER2 amplification usually clustered with triple negative breast cancer (TNBC) reference samples (8/10; "LowHR TNBC-like"). In contrast, most specimens with low hormone receptor expression and HER2 amplification grouped with hormone receptor positive cancers (11/13; "LowHR HRpos-like"). We observed highly similar DNA methylation patterns of LowHR TNBC-like samples and true TNBCs. Furthermore, the Ki67 proliferation index of LowHR TNBC-like samples and clinical outcome parameters were more similar to TNBCs and differed from LowHR HRpos-like cases. CONCLUSIONS: We here demonstrate that LowHR breast cancer comprises two epigenetically distinct groups. Our data strongly suggest that LowHR TNBC-like samples are molecularly, histologically and clinically closely related to TNBC, while LowHR HRpos-like specimens are closely related to hormone receptor positive tumors.
Assuntos
Neoplasias da Mama/genética , Receptor ErbB-2/metabolismo , Adulto , Neoplasias da Mama/classificação , Metilação de DNA/genética , Metilação de DNA/fisiologia , Feminino , Expressão Gênica/genética , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/análiseRESUMO
AIM: To evaluate HER2-negative breast cancer (BC) with a low hormone receptor (HR) expression, with regard to pathological complete response (pCR) and survival, in comparison to triple-negative BC (TNBC) and strong HR-positive BC. METHODS: We compared negative [oestrogen (ER) and progesterone receptor (PR) <1%], low-positive (ER and/or PR 1-9%) and strong-positive (ER or PR 10-100%) HR-expression in neoadjuvant clinical trial cohorts (n = 2765) of BC patients. End-points were disease-free survival (DFS), distant-disease free survival (DDFS) and overall survival (OS). We performed RNA sequencing on available tumour tissue samples from patients with low-HR expression (n = 38). RESULTS: Ninety-four (3.4%) patients had low HR-positive tumours, 1769 (64.0%) had strong HR-positive tumours, and 902 (32.6%) had TNBC. There were no significant differences in pCR rates between women with low HR-positive tumours (27.7%) and women with TNBC (35.5%). DFS and DDFS were also not different [for DFS, hazard ratio 1.26, 95%-CI (confidence interval) : 0.87-1.83, log-rank test p = 0.951; for DDFS, hazard ratio 1.17, 95%-CI: 0.78-1.76, log-rank test p = 0.774]. Patients with strong HR-positive tumours had a significantly lower pCR rate (pCR 9.4%; odds ratio 0.38, 95%-CI: 0.23-0.63), but better DFS (hazard ratio 0.48, 95%-CI: 0.33-0.70) and DDFS (hazard ratio 0.49, 95%-CI: 0.33-0.74) than patients with low HR-positive tumours. Molecular subtyping (RNA sequencing) of low HR-positive tumours classified these predominantly into a basal subtype (86.8%). CONCLUSION: Low HR-positive, HER2-negative tumours have a similar clinical behaviour to TNBC showing high pCR rates and poor survival and also a basal-like gene expression signature. Patients with low HR-positive tumours should be regarded as candidates for therapy strategies targeting TNBC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Quimioterapia Adjuvante/mortalidade , Terapia Neoadjuvante/mortalidade , Neoplasias de Mama Triplo Negativas/mortalidade , Adulto , Idoso , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Indução de Remissão , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
INTRODUCTION: Disparities observed in colorectal cancer (CRC) incidence and mortality among blacks and Hispanics compared with whites may be in part due to lower screening rates. The New York City (NYC) Department of Health and Mental Hygiene (DOHMH) has implemented a patient navigator (PN) program at NYC hospitals serving lower-income patients to promote high adherence by patients referred for screening colonoscopy. A prior study showed this PN program increased adherence at 3 public hospitals. The aim of this study was to determine the feasibility of expanding the PN program to 10 hospital sites by assessing the impact of the PN program on adherence to screening colonoscopy in a large, urban, lower-income population. METHODS: Data were collected from 2007 through the first quarter of 2012 from PN sites. One site also contributed data from the pilot phase of the project, from 2005 to 2006. Adherence to scheduled screening colonoscopy among those ≥ 50 years was assessed among 10 hospital sites in NYC participating in the colonoscopy PN program. RESULTS: Among the 37,077 asymptomatic adults ≥ 50 years who were scheduled for a screening colonoscopy from 2005 to the first quarter of 2012, 84.2% (83.2% of black, 84.9% of Hispanic, and 87.5% of white adults) were adherent to scheduled colonoscopy. CONCLUSIONS: Expansion of PN programs to navigate all patients referred for a colonoscopy was feasible in a large, urban setting. This can be implemented resulting in high overall adherence rates to screening colonoscopies. The program likely did not result in large ethnic disparities.
Assuntos
Colonoscopia/estatística & dados numéricos , Diversidade Cultural , Detecção Precoce de Câncer/estatística & dados numéricos , Cooperação do Paciente/etnologia , Navegação de Pacientes/organização & administração , População Urbana/estatística & dados numéricos , Idoso , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etnologia , Estudos de Viabilidade , Feminino , Disparidades nos Níveis de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Cooperação do Paciente/estatística & dados numéricos , Pobreza , Avaliação de Programas e Projetos de SaúdeRESUMO
Chromophobe renal cell carcinoma (chRCC) accounts for approximately 5% of all renal cancers and around 30% of chRCC cases have mutations in TP53. chRCC is poorly supported by microvessels and has markably lower glucose uptake than clear cell RCC and papillary RCC. Currently, the metabolic status and mechanisms by which this tumor adapts to nutrient-poor microenvironments remain to be investigated. In this study, we performed proteome and metabolome profiling of chRCC tumors and adjacent kidney tissues and identified major metabolic alterations in chRCC tumors, including the classical Warburg effect, the downregulation of gluconeogenesis and amino acid metabolism, and the upregulation of protein degradation and endocytosis. chRCC cells depended on extracellular macromolecules as an amino acid source by activating endocytosis to sustain cell proliferation and survival. Inhibition of the phospholipase C gamma 2 (PLCG2)/inositol 1,4,5-trisphosphate (IP3)/Ca2+/protein kinase C (PKC) pathway significantly impaired the activation of endocytosis for amino acid uptakes into chRCC cells. In chRCC, whole-exome sequencing revealed that TP53 mutations were not related to expression of PLCG2 and activation of endocytosis. Our study provides novel perspectives on metabolic rewiring in chRCC and identifies the PLCG2/IP3/Ca2+/PKC axis as a potential therapeutic target in patients with chRCC. SIGNIFICANCE: This study reveals macropinocytosis as an important process utilized by chRCC to gain extracellular nutrients in a p53-independent manner.
Assuntos
Aminoácidos/metabolismo , Carcinoma de Células Renais/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Neoplasias Renais/metabolismo , Amilorida/análogos & derivados , Amilorida/farmacologia , Compostos de Boro/farmacologia , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Estrenos/farmacologia , Gluconeogênese , Humanos , Indóis/farmacologia , Inositol 1,4,5-Trifosfato/antagonistas & inibidores , Inositol 1,4,5-Trifosfato/metabolismo , Neoplasias Renais/patologia , Maleimidas/farmacologia , Metaboloma , Fosfolipase C gama/antagonistas & inibidores , Fosfolipase C gama/metabolismo , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Proteoma , Pirrolidinonas/farmacologiaRESUMO
Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma are closely related, rare kidney tumors. Mutations in complex I (CI)-encoding genes play an important role in dysfunction of the oxidative phosphorylation (OXPHOS) system in renal oncocytoma, but are less frequently observed in chRCC. As such, the relevance of OXPHOS status and role of CI mutations in chRCC remain unknown. To address this issue, we performed proteome and metabolome profiling as well as mitochondrial whole-exome sequencing to detect mitochondrial alterations in chRCC tissue specimens. Multiomic analysis revealed downregulation of electron transport chain (ETC) components in chRCC that differed from the expression profile in renal oncocytoma. A decrease in mitochondrial (mt)DNA content, rather than CI mutations, was the main cause for reduced OXPHOS in chRCC. There was a negative correlation between protein and transcript levels of nuclear DNA- but not mtDNA-encoded ETC complex subunits in chRCC. In addition, the reactive oxygen species scavenger glutathione (GSH) was upregulated in chRCC due to decreased expression of proteins involved in GSH degradation. These results demonstrate that distinct mechanisms of OXPHOS exist in chRCC and renal oncocytoma and that expression levels of ETC complex subunits can serve as a diagnostic marker for this rare malignancy. SIGNIFICANCE: These findings establish potential diagnostic markers to distinguish malignant chRCC from its highly similar but benign counterpart, renal oncocytoma.
Assuntos
Adenoma Oxífilo/metabolismo , Carcinoma de Células Renais/metabolismo , DNA Mitocondrial/metabolismo , Neoplasias Renais/metabolismo , Fosforilação Oxidativa , Adenoma Oxífilo/diagnóstico , Carcinoma de Células Renais/diagnóstico , DNA Mitocondrial/genética , Diagnóstico Diferencial , Regulação para Baixo , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Glutationa/sangue , Glutationa/urina , Humanos , Neoplasias Renais/diagnóstico , Metaboloma , Mutação , Análise Serial de Proteínas/métodos , Proteoma/análise , Regulação para CimaRESUMO
Abstract Aim: To assess the risk of tuberculosis (infection and disease) in children less than 15 years' old who are household contacts of pulmonary tuberculosis patients in three Colombian cities (Medellín, Cali, and Popayán). Methods: A cohort of 1,040 children household contacts of 380 adults with smear-positive pulmonary tuberculosis was followed up for 24 months. Study period 2005-2009. Results: Tuberculin skin test was positive (≥10 mm) in 43.7% (95% CI: 39.2-48.2). Tuberculin skin test positivity was associated with age 10-14 years (Prevalence Ratio -PR= 1.43, 95% CI: 1.1-1.9), having a BCG vaccine scar (PR= 1.52, 95% CI: 1.1-2.1), underweight, closer proximity to the index case and exposure time >3 months. The annual risk of infection (tuberculin skin test induration increase of 6 mm or more per year) was 17% (95% CI: 11.8-22.2) and was associated with a bacillary load of the adult index case (Relative Risk -RR= 2.12, 95% CI: 1.0-4.3). The incidence rate of active tuberculosis was 12.4 cases per 1,000 persons-year. Children <5 years without BCG vaccine scar had a greater risk of developing active disease (Hazard Ratio -HR= 6.00, 95% CI: 1.3-28.3) than those with scar (HR= 1.33, 95% CI: 0.5-3.4). The risk of developing active tuberculosis augmented along with the increase from initial tuberculin skin test (tuberculin skin test 5-9 mm HR= 8.55, 95% CI: 2.5-29.2; tuberculin skin test ≥10 mm HR= 8.16, 95% CI: 2.0-32.9). Conclusions: There is a need for prompt interruption of adult-to-children tuberculosis transmission within households. Conducting proper contact investigation and offering chemoprophylaxis to infected children could reduce tuberculosis transmission.
Resumen Objetivo: Evaluar el riesgo de tuberculosis (infección y enfermedad) en niños menores de 15 años de edad convivientes de pacientes con tuberculosis pulmonar en tres ciudades colombianas (Medellín, Cali y Popayán). Métodos: Se siguió durante 24 meses una cohorte de 1,040 niños convivientes de 380 adultos con tuberculosis pulmonar bacilífera. Periodo de estudio 2005-2009. Resultados: La prueba de tuberculina fue positiva (≥10 mm) en el 43.7% (IC 95%: 39.2-48.2), y estuvo asociada con la edad de 10-14 años (Razón de Prevalencia-RP= 1.43, IC 95%: 1.1-1.9), tener cicatriz de la vacuna BCG (RP= 1.52, IC 95%: 1.1-2.1). El riesgo anual de infección (aumento de la induración en la prueba de tuberculina de 6 mm o más al año) fue 17% (IC 95%: 11.8-22.2), y estuvo asociado con mayor carga bacilar en el adulto con tuberculosis pulmonar (Riesgo Relativo-RR= 2.12, IC 95%: 1.0-4.3). La tasa de incidencia de tuberculosis activa fue de 12.4 casos por 1,000 años-persona de seguimiento. Los niños menores de 5 años sin cicatriz de vacuna BCG tuvieron un mayor riesgo de desarrollar tuberculosis activa (Razón de Peligro -HR= 6.00, IC 95%: 1.3-28.3), que quienes tenían cicatriz (HR= 1.33, IC 95%: 0.5-3.4). El riesgo de desarrollar tuberculosis activa aumentó conforme el aumento de la prueba de tuberculina inicial (prueba de tuberculina 5-9 mm HR= 8.55, IC 95%: 2.5-29.2; prueba de tuberculina ≥10 mm HR= 8.16, IC 95%: 2.0-32.9). Conclusión: Es necesario interrumpir rápidamente la transmisión de tuberculosis de adultos a niños en los hogares. Realizar investigaciones de contacto apropiadas y ofrecer quimioprofilaxis a los niños infectados podría reducir la transmisión de la tuberculosis.
Assuntos
Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Tuberculose/epidemiologia , Tuberculose Pulmonar/epidemiologia , Vacina BCG/administração & dosagem , Tuberculose/prevenção & controle , Tuberculose/transmissão , Tuberculose Pulmonar/prevenção & controle , Tuberculose Pulmonar/transmissão , Teste Tuberculínico , Incidência , Prevalência , Estudos de Coortes , Busca de Comunicante , Colômbia/epidemiologia , Progressão da DoençaRESUMO
Papillary renal cell carcinoma (pRCC) is a malignant kidney cancer with a prevalence of 7-20% of all renal tumors. Proteome and metabolome profiles of 19 pRCC and patient-matched healthy kidney controls were used to elucidate the regulation of metabolic pathways and the underlying molecular mechanisms. Glutathione (GSH), a main reactive oxygen species (ROS) scavenger, was highly increased and can be regarded as a new hallmark in this malignancy. Isotope tracing of pRCC derived cell lines revealed an increased de novo synthesis rate of GSH, based on glutamine consumption. Furthermore, profound downregulation of gluconeogenesis and oxidative phosphorylation was observed at the protein level. In contrast, analysis of the The Cancer Genome Atlas (TCGA) papillary RCC cohort revealed no significant change in transcripts encoding oxidative phosphorylation compared to normal kidney tissue, highlighting the importance of proteomic profiling. The molecular characteristics of pRCC are increased GSH synthesis to cope with ROS stress, deficient anabolic glucose synthesis, and compromised oxidative phosphorylation, which could potentially be exploited in innovative anti-cancer strategies.
RESUMO
AIM: To assess the risk of tuberculosis (infection and disease) in children less than 15 years' old who are household contacts of pulmonary tuberculosis patients in three Colombian cities (Medellín, Cali, and Popayán). METHODS: A cohort of 1,040 children household contacts of 380 adults with smear-positive pulmonary tuberculosis was followed up for 24 months. Study period 2005-2009. RESULTS: Tuberculin skin test was positive (≥10 mm) in 43.7% (95% CI: 39.2-48.2). Tuberculin skin test positivity was associated with age 10-14 years (Prevalence Ratio -PR= 1.43, 95% CI: 1.1-1.9), having a BCG vaccine scar (PR= 1.52, 95% CI: 1.1-2.1), underweight, closer proximity to the index case and exposure time >3 months. The annual risk of infection (tuberculin skin test induration increase of 6 mm or more per year) was 17% (95% CI: 11.8-22.2) and was associated with a bacillary load of the adult index case (Relative Risk -RR= 2.12, 95% CI: 1.0-4.3). The incidence rate of active tuberculosis was 12.4 cases per 1,000 persons-year. Children <5 years without BCG vaccine scar had a greater risk of developing active disease (Hazard Ratio -HR= 6.00, 95% CI: 1.3-28.3) than those with scar (HR= 1.33, 95% CI: 0.5-3.4). The risk of developing active tuberculosis augmented along with the increase from initial tuberculin skin test (tuberculin skin test 5-9 mm HR= 8.55, 95% CI: 2.5-29.2; tuberculin skin test ≥10 mm HR= 8.16, 95% CI: 2.0-32.9). CONCLUSIONS: There is a need for prompt interruption of adult-to-children tuberculosis transmission within households. Conducting proper contact investigation and offering chemoprophylaxis to infected children could reduce tuberculosis transmission.
OBJETIVO: Evaluar el riesgo de tuberculosis (infección y enfermedad) en niños menores de 15 años de edad convivientes de pacientes con tuberculosis pulmonar en tres ciudades colombianas (Medellín, Cali y Popayán). MÉTODOS: Se siguió durante 24 meses una cohorte de 1,040 niños convivientes de 380 adultos con tuberculosis pulmonar bacilífera. Periodo de estudio 2005-2009. Resultados: La prueba de tuberculina fue positiva (≥10 mm) en el 43.7% (IC 95%: 39.2-48.2), y estuvo asociada con la edad de 10-14 años (Razón de Prevalencia-RP= 1.43, IC 95%: 1.1-1.9), tener cicatriz de la vacuna BCG (RP= 1.52, IC 95%: 1.1-2.1). El riesgo anual de infección (aumento de la induración en la prueba de tuberculina de 6 mm o más al año) fue 17% (IC 95%: 11.8-22.2), y estuvo asociado con mayor carga bacilar en el adulto con tuberculosis pulmonar (Riesgo Relativo-RR= 2.12, IC 95%: 1.0-4.3). La tasa de incidencia de tuberculosis activa fue de 12.4 casos por 1,000 años-persona de seguimiento. Los niños menores de 5 años sin cicatriz de vacuna BCG tuvieron un mayor riesgo de desarrollar tuberculosis activa (Razón de Peligro -HR= 6.00, IC 95%: 1.3-28.3), que quienes tenían cicatriz (HR= 1.33, IC 95%: 0.5-3.4). El riesgo de desarrollar tuberculosis activa aumentó conforme el aumento de la prueba de tuberculina inicial (prueba de tuberculina 5-9 mm HR= 8.55, IC 95%: 2.5-29.2; prueba de tuberculina ≥10 mm HR= 8.16, IC 95%: 2.0-32.9). CONCLUSIÓN: Es necesario interrumpir rápidamente la transmisión de tuberculosis de adultos a niños en los hogares. Realizar investigaciones de contacto apropiadas y ofrecer quimioprofilaxis a los niños infectados podría reducir la transmisión de la tuberculosis.
Assuntos
Vacina BCG/administração & dosagem , Tuberculose Pulmonar/epidemiologia , Tuberculose/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Colômbia/epidemiologia , Busca de Comunicante , Progressão da Doença , Feminino , Humanos , Incidência , Lactente , Masculino , Prevalência , Teste Tuberculínico , Tuberculose/prevenção & controle , Tuberculose/transmissão , Tuberculose Pulmonar/prevenção & controle , Tuberculose Pulmonar/transmissãoAssuntos
Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/uso terapêutico , Criança , Pré-Escolar , Colômbia , Controle de Doenças Transmissíveis/métodos , Feminino , Humanos , Infectologia/métodos , Isoniazida/farmacologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/metabolismo , Setor Privado , Saúde Pública , Setor Público , Rifampina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/diagnósticoAssuntos
Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Tuberculose Extensivamente Resistente a Medicamentos/patologia , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/isolamento & purificação , Adolescente , Adulto , Proteínas de Bactérias/genética , Análise por Conglomerados , Colômbia/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Tipagem Molecular , Proteínas Mutantes/genética , Mutação de Sentido Incorreto , Mycobacterium tuberculosis/genética , Adulto JovemRESUMO
17α-ethynyl-5α-androstane-3α, 17ß-diol (HE3235, Apoptone) is an orally bioavailable synthetic analogue of 3ß-androstanediol, that is active in rodent models of prostate and breast cancer, and is in Phase IIa clinical trials for the treatment of early- and late-stage prostate cancer. In preparation for clinical studies, nuclear hormone receptor and P450 interactions for HE3235 and major metabolites were characterized in vitro, and pharmacokinetics and metabolite profiles were studied in rodents, dogs, and monkeys. Four-week safety studies conducted in rats and dogs indicated a substantial margin of safety for clinical use, and no evidence of electrocardiographic or neurological effects, although anorexia, thrombocytopenia, and hypokalemia were identified as potentially dose-limiting toxicities at superpharmacological exposures. Pharmacokinetics and drug metabolism have been studied in prostate cancer patients.
Assuntos
Androstanóis/farmacocinética , Antineoplásicos Hormonais/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Administração Oral , Androstanóis/administração & dosagem , Androstanóis/sangue , Androstanóis/toxicidade , Androstenodiona/sangue , Animais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/toxicidade , Biotransformação , Linhagem Celular Tumoral , Cromatografia Líquida , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/biossíntese , Desidroepiandrosterona/sangue , Cães , Esquema de Medicação , Indução Enzimática , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Macaca fascicularis , Masculino , Metabolômica , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Especificidade da Espécie , Espectrometria de Massas em Tandem , Testosterona/sangue , Ativação Transcricional/efeitos dos fármacos , TransfecçãoRESUMO
Two natural 5-androstene steroid tetrols, androst-5-ene-3ß,7ß,16α,17ß-tetrol (HE3177) and androst-5-ene-3α,7ß,16α,17ß-tetrol (HE3413), were discovered in human plasma and urine. These compounds had significant aqueous solubility, did not bind or transactivate steroid-binding nuclear hormone receptors, and were not immunosuppressive in murine mixed-lymphocyte studies. Both compounds appear to be metabolic end products, as they were resistant to primary and secondary metabolism. Both were orally bioavailable, and were very well tolerated in a two-week dose-intensive toxicity study in mice. Anti-inflammatory properties were found with exogenous administration of these compounds in rodent disease models of multiple sclerosis, lung injury, chronic prostatitis, and colitis.
Assuntos
Androstenóis/farmacologia , Anti-Inflamatórios/farmacologia , Colite/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Prostatite/tratamento farmacológico , Adolescente , Adulto , Idoso , Androstenóis/química , Androstenóis/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Colite/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Pessoa de Meia-Idade , Conformação Molecular , Esclerose Múltipla/metabolismo , Prostatite/metabolismo , Ratos , Solubilidade , Estereoisomerismo , Adulto JovemRESUMO
BACKGROUND AND GOALS: To increase colorectal cancer screening among urban minorities, New York Presbyterian Hospital/Columbia University, with support from the New York City Department of Health and the Citywide Colon Cancer Control Coalition (C5), instituted a patient navigation and direct endoscopic referral system. We assessed the effect of this program on the volume of colonoscopy in this institution, which caters to a socioeconomically diverse patient population. STUDY: We compared colonoscopy volume during the first year of the navigator program with the volume during the year before this program. We stratified on Medicaid status to assess the secular trend of screening rates. To assess quality during this period, we measured cecal intubation rates, preparation quality, and adenoma detection rates. RESULTS: Of the 749 patients assessed by the patient navigators, 678 (91%) underwent colonoscopy. Colonoscopy volume among the Medicaid outpatients increased by 56% (957 to 1489). Adenoma detection was 27% and the cecal intubation rate was 97%. Comparing navigated patients with the nonnavigated Medicaid outpatients, preparation quality was superior (34% vs. 40% suboptimal, P=0.0282), although preparation quality remained inferior to that of private patients (20% suboptimal, P<0.0001). CONCLUSIONS: Volume of the colonoscopy increased, coinciding with the onset of the patient navigation program. This increase was nearly entirely owing to a rise in the colonoscopies among Medicaid outpatients, the principal focus of the navigator program. This increase in quantity was accomplished while maintaining an overall high level of quality as measured by cecal intubation rates and adenoma detection, although preparation quality requires further efforts at improvement.
Assuntos
Colonoscopia/estatística & dados numéricos , Neoplasias Colorretais/diagnóstico , Avaliação de Programas e Projetos de Saúde , Qualidade da Assistência à Saúde , Encaminhamento e Consulta , Adenoma/diagnóstico , Adenoma/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/prevenção & controle , Agentes Comunitários de Saúde , Detecção Precoce de Câncer , Feminino , Hispânico ou Latino , Hospitais Municipais , Humanos , Masculino , Programas de Rastreamento/estatística & dados numéricos , Medicaid , Pessoa de Meia-Idade , Cidade de Nova Iorque , Estados UnidosRESUMO
Resultados: se encontró un 80% de los estetoscopios contaminados, con una mediana de colonización de 2.58 Unidades Formadoras de Colonias (UFC)/cm2 y un 100% de los teléfonos móviles contaminados con una mediana de 0.401 UFC/cm2. En estetoscopios se aislaron SAMR (n=3) y Enterobacterias resistentes a cefalosporinas de tercera generación (n=2). En teléfonos móviles se aislaron SAMR(n=1), Candida spp (n=1) y Enterobacterias (n=5). La encuesta permitió establecer una tendencia de hábitos de higiene inapropiados sobre el uso de los fómites. Conclusiones: el hallazgo de bacterias resistentes en estos fómites los convierte en fuentes potenciales de transmisión cruzada y de brotes de infección intrahospitalaria. Estos resultados deben orientar el desarrollo de protocolos para el uso racional de dispositivos médicos y tecnología portátil dentro de ambientes hospitalarios.
Results: 80% of the stethoscopes (n=40) were found contaminated with a median count of 2,58 CFU/cm2 meanwhile 100% of cellular phones where found contaminated with a median count of 0,401 CFU/cm2. MRSA (n=3) and third generation cephalosporin-resistant Enterobacteriaceae (n=2) were isolated from stethoscopes, whereas in cellular phones MRSA (n=1), Candida (n=1) and third generation cephalosporin-sensitive Enterobacteriaceae (n=5) where found. Survey results indicated a trend towards inappropriate hygiene habits with fomites; however no statistical correlation could be established between these habits and colonization. Conclusion: The finding of nosocomial pathogens in these fomites transforms them in potential sources of crosscontamination and hospital-acquired infections outbreaks. Present results must steer development of protocols for rational use of medical devices and portable technology gadgets within hospital controlled environments.
Assuntos
Humanos , Masculino , Feminino , Enterobacteriaceae , Infecção Hospitalar , Controle de Infecções , Staphylococcus aureus , Unidades de Terapia Intensiva NeonatalRESUMO
Androstenediol (androst-5-ene-3ß,17ß-diol; 5-AED), a natural adrenal steroid, has been shown to suppress experimental autoimmune encephalomyelitis (EAE) in female SJL/J mice. We here report that 5-AED limits inflammation and proinflammatory cytokines including TNFα in murine models of carrageenan-induced pleurisy and lippopolysaccaride- (LPS) induced septic shock. 5-AED binds to and transactivates sex steroid receptors with the same general rank order of potency (ERß > ERα â« AR). 5-AED provides benefit in EAE in a dose-dependent fashion, even when treatment is delayed until onset of disease. The minimally effective dose may be as low as 4 mg/kg in mice. However, benefit was not observed when 5-AED was given in soluble formulation, leading to a short half-life and rapid clearance. These observations suggest that treatment with 5-AED limits the production of pro-inflammatory cytokines in these animal models and, ultimately, when formulated and administered properly, may be beneficial for patients with multiple sclerosis and other Th1-driven autoimmune diseases.
RESUMO
Introducción. El tratamiento acortado estrictamente supervisado hace parte de una estrategia multifactorial adoptada por la Organización Mundial de la Salud para controlar la tuberculosis y en Colombia alcanza una cobertura de 70%. Objetivo. Establecer las características clínicas, epidemiológicas y microbiológicas y el desenlace de la terapia antituberculosa, en una cohorte de pacientes nuevos con diagnóstico de tuberculosis pulmonar con baciloscopia positiva en Cali, Colombia.Materiales y métodos. Se llevó a cabo un estudio descriptivo, anidado en un ensayo clínico de multicéntrico, en el que se incluyeron 106 pacientes con tuberculosis pulmonar con baciloscopia positiva entre abril de 2005 y junio de 2006, a través de instituciones de salud de la red pública de Cali que administraron el tratamiento antituberculoso. Se practicó baciloscopia seriada, cultivo para micobacterias, prueba de sensibilidad a medicamentos antituberculosos de primera línea, radiografía de tórax postero-anterior y lateral y prueba ELISA para VIH. Se recolectó información clínica y epidemiológica, y se hizo seguimiento por 30 meses, haciendo uso de incentivos de transporte y alimentación.Resultados. La mayoría de los pacientes fueron hombres jóvenes, con diagnóstico hecho más de nueve semanas después del inicio de los síntomas y con baciloscopia muy positiva (2+ o 3+). La resistencia a cualquier medicamento fue de 7,5% y la resistencia inicial a los medicamentos de primera línea fue de 1,9%. La incidencia de efectos secundarios asociados al tratamiento fue de 8,5%. La infección concomitante con VIH fue de 5,7%. El 86,8% de los pacientes completó la terapia con diagnóstico de curación.
Introduction. The World Health Organization recommended strategy for global tuberculosis control is a short-course, clinically administered treatment, This approach has approximately 70% coverage in Colombia. Objective. The clinical, epidemiological and microbiological characteristics along with drug therapy outcomes were described in newly diagnosed, pulmonary tuberculosis patients. Materials and methods. This was a descriptive study, conducted as part of a multicenter clinical trial of tuberculosis treatment. A cohort of 106 patients with pulmonary tuberculosis were recruited from several public health facilities in Cali between April 2005 and June 2006. Sputum smear microscopy, culture, drug susceptibility tests to first-line anti-tuberculosis drugs, chest X- ray and HIV-ELISA were performed. Clinical and epidemiological information was collected for each participant. Treatment was administered by the local tuberculosis health facility. Food and transportation incentives were provided during a 30 month follow-up period.Results. The majority of patients were young males with a diagnostic delay longer than 9 weeks and a high sputum smear grade (2+ or 3+). The initial drug resistance was 7.5% for single drug treatment and 1.9% for multidrug treatments. The incidence of adverse events associated with treatment was 8.5%. HIV co-infection was present in 5.7% of the cases. Eighty-six percent of the patients completed the treatment and were considered cured. The radiographic presentation varied within a broad range and differed from the classic progression to cavity formation. Conclusion. Delay in tuberculosis diagnosis was identified as a risk factor for treatment compliance failure. The study population had similar baseline epidemiologic characteristics to those described in other cohort studies.
Assuntos
Humanos , Resultado do Tratamento , Tuberculose PulmonarRESUMO
Insulin resistance, the major metabolic abnormality underlying type 2 diabetes, is associated with chronic inflammation and heavy macrophage infiltration in white adipose tissue (WAT). The therapeutic properties of the synthetic adrenal steroid Delta(5)-androstene-17alpha-ethynyl-3beta,7beta,17beta-triol (HE3286) were characterized in metabolic disease models. Treatment of diabetic db/db mice with HE3286 suppressed progression to hyperglycemia and markedly improved glucose clearance. Similar effects were also observed in insulin-resistant, diet-induced obese C57BL/6J mice and genetically obese ob/ob mice. This effect appeared to be a consequence of reduced insulin resistance because HE3286 lowered blood insulin levels in db/db and ob/ob mice. Treatment with HE3286 was accompanied by suppressed expression of the prototype macrophage-attracting chemokine monocyte chemoattractant protein-1 in WAT, along with its cognate receptor C-C motif chemokine receptor-2. Exposure of mouse macrophages to HE3286 in vitro caused partial suppression of endotoxin (lipopolysaccharide)-induced nuclear factor kappa-B (NF-kappaB)-sensitive reporter gene expression, NF-kappaB nuclear translocation, and NF-kappaB/p65 serine phosphorylation. Proinflammatory kinases, including IkappaB kinase, c-Jun NH2-terminal kinase, and p38, were also inhibited by HE3286. In ligand competition experiments HE3286 did not bind to classical sex steroid or corticosteroid receptors, including androgen receptor (AR), progesterone receptor, estrogen receptor (ER) alpha or ERbeta, and glucocorticoid receptor (GR). Likewise, in cells expressing nuclear receptor-sensitive reporter genes HE3286 did not substantially stimulate transactivation of AR, ER, GR, or peroxisome proliferator-activated receptor (PPAR) alpha, PPARdelta, and PPARgamma. These findings indicate that HE3286 improves glucose homeostasis in diabetic and insulin-resistant mice and suggest that the observed therapeutic effects result from attenuation of proinflammatory pathways, independent of classic sex steroid receptors, corticosteroid receptors, or PPARs.
Assuntos
Anti-Inflamatórios/farmacologia , Desidroepiandrosterona/análogos & derivados , Hipoglicemiantes/farmacologia , Animais , Anti-Inflamatórios/farmacocinética , Linhagem Celular , Desidroepiandrosterona/farmacocinética , Desidroepiandrosterona/farmacologia , Perfilação da Expressão Gênica , Intolerância à Glucose/metabolismo , Intolerância à Glucose/prevenção & controle , Hiperglicemia/metabolismo , Hiperglicemia/prevenção & controle , Hipoglicemiantes/farmacocinética , Resistência à Insulina , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , NF-kappa B/metabolismo , Fosforilação , Receptores de Esteroides/biossíntese , Receptores de Esteroides/genéticaRESUMO
INTRODUCTION: The World Health Organization recommended strategy for global tuberculosis control is a short-course, clinically administered treatment, This approach has approximately 70% coverage in Colombia. OBJECTIVE: The clinical, epidemiological and microbiological characteristics along with drug therapy outcomes were described in newly diagnosed, pulmonary tuberculosis patients. MATERIALS AND METHODS: This was a descriptive study, conducted as part of a multicenter clinical trial of tuberculosis treatment. A cohort of 106 patients with pulmonary tuberculosis were recruited from several public health facilities in Cali between April 2005 and June 2006. Sputum smear microscopy, culture, drug susceptibility tests to first-line anti-tuberculosis drugs, chest X- ray and HIV-ELISA were performed. Clinical and epidemiological information was collected for each participant. Treatment was administered by the local tuberculosis health facility. Food and transportation incentives were provided during a 30 month follow-up period. RESULTS: The majority of patients were young males with a diagnostic delay longer than 9 weeks and a high sputum smear grade (2+ or 3+). The initial drug resistance was 7.5% for single drug treatment and 1.9% for multidrug treatments. The incidence of adverse events associated with treatment was 8.5%. HIV co-infection was present in 5.7% of the cases. Eighty-six percent of the patients completed the treatment and were considered cured. The radiographic presentation varied within a broad range and differed from the classic progression to cavity formation. CONCLUSION: Delay in tuberculosis diagnosis was identified as a risk factor for treatment compliance failure. The study population had similar baseline epidemiologic characteristics to those described in other cohort studies.
Assuntos
Antituberculosos/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/microbiologia , Adolescente , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Colômbia/epidemiologia , Comorbidade , Feminino , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Escarro/microbiologia , Resultado do Tratamento , Tuberculose Pulmonar/fisiopatologia , Organização Mundial da Saúde , Adulto JovemRESUMO
Late blight caused by Phytophthora infestans is one of the most limiting diseases in solanaceous crops in the world. This pathogen is a main constraint in the highland Andes, where these plants are grown under high humidity conditions and continuous cropping. The aim of this research was to increase the available information on the biology of P. infestans, specifically on its level of genetic variation in south-western Colombia, an area where various solanaceous crops susceptible to this pathogen converge. The study was carried out by using AFLP molecular markers with the restriction enzymes EcoRI and MseI and different primer combinations. Results indicated a low level of genetic variation among the 26 isolates evaluated, with only 18 polymorphic bands out of 135 amplicons obtained (13.43%), a Nei's genetic diversity index of 0.04, and a Shannon's information index of 0.06.
Assuntos
Variação Genética , Phytophthora infestans/genética , Colômbia , Phytophthora infestans/isolamento & purificação , Solanum/microbiologiaRESUMO
El mildeo velloso de la rosa es la enfermedad más limitante de este cultivo en Colombia . Aunque algunos trabajos de investigación se han adelantado recientemente sobre la epidemiología de esta enfermedad, uno de los campos menos estudiados es el nivel de variabilidad de su agente causal. El conocimiento de este aspecto es fundamental para definir las estrategias de manejo, especialmente aquellas relacionadas con la resistencia genética y el control químico. Los objetivos de esta investigación fueron confirmar la identidad taxonómica del agente causal del mildeo velloso de la rosa y profundizar en el conocimiento de su estructura poblacional en Colombia . Para esto se colectaron 34 aislamientos del pseudohongo en cultivos de rosas ubicados en Antioquia y la sabana de Bogotá y se extrajo su ADN, para proceder a la amplificación mediante PCR de la región ITS del ADNr utilizando los primers especieespecíficos PS3 y PS1. Dichos productos se emplearon tanto para su secuenciación directa como para la evaluación de variabilidad genética mediante la técnica PCRRFLP, resultados que se complementaron con la utilización de los marcadores RAPD y RAMS. La presencia de un amplicón de aproximadamente 700 pb que compartió un porcentaje de identidad del 100% con secuencias depositadas en el GenBank, permitió confirmar a los aislamientos como pertenecientes a Peronospora sparsa, mientras que el análisis de RFLP, RAPD y RAMS indicó un muy bajo nivel de variabilidad entre todos los aislamientos, concluyéndose que la población de P. sparsa en Colombia es predominantemente clonal.
Downy mildew of roses is the most restrictive disease of this crop in Colombia . Although some studies have been carried out on the epidemiology of this disease, one of the fields less studied is the level of variability of its causal agent. The knowledge of this aspect is fundamental to define management strategies, especially those related with the genetic resistance and the chemical control. The objectives of this research were to confirm the taxonomic identity of the causal agent of downy mildew of rose and to deepen in the knowledge of their population structure in Colombia. Thirtyfour isolates of the pseudofungi were collected in rose crops located in Antioquia and the Savanna of Bogota and their DNA was extracted to amplify by PCR the ITS region of the DNAr using the species-specific primers PS3 and PS1. The products were used for their direct sequencing and to evaluate genetic variability by PCR-RFLP. Additionally the study was complemented throught RAPD and RAMS markers. Presence of a band of approximately 700 pb that shared a percentage of identity of 100% with sequences deposited in the GenBank, allowed to confirm the identity of the isolates as belonging to Peronospora sparsa, while the analysis of RFLP, RAPD and RAMS indicated a very low level of variability among all the isolates, concluding that the population of P. sparsa in Colombia is predominantly clonal.