RESUMO
Rates of hospital-acquired infections, specifically methicillin-resistant Staphylococcus aureus (MRSA), are increasingly being used as indicators for quality of hospital hygiene. There has been much effort on understanding the transmission process at the hospital level; however, interhospital population-based transmission remains poorly defined. We evaluated whether the proportion of shared patients between hospitals was correlated with genetic similarity of MRSA strains from those hospitals. Using data collected from 30 of 32 hospitals in Orange County, California, multivariate linear regression showed that for each twofold increase in the proportion of patients shared between 2 hospitals, there was a 7.7% reduction in genetic heterogeneity between the hospitals' MRSA populations (permutation P value = 0.0356). Pairs of hospitals that both served adults had more similar MRSA populations than pairs including a pediatric hospital. These findings suggest that concerted efforts among hospitals that share large numbers of patients may be synergistic to prevent MRSA transmission.
Assuntos
Genética Populacional , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Infecções Estafilocócicas/genética , California , Humanos , Análise Multivariada , Infecções Estafilocócicas/transmissãoRESUMO
Cell senescence is a process of irreversible arrest of cell proliferation and plays an important role in tumor suppression. Recent studies showed that Wnt inhibition is a trigger of cellular senescence. Using methods of reverse genetics, we recently identified VentX, a human homolog of the vertebrate Xenopus Vent family of homeobox genes, as a novel Wnt repressor and a putative tumor suppressor in lymphocytic leukemia. Here, we show that VentX is a direct transcriptional activator of p53-p21 and p16ink4a-Rb tumor suppression pathways. Ectopic expression of VentX in cancer cells caused an irreversible cell cycle arrest with a typical senescence-like phenotype. Conversely, inhibition of VentX expression by RNA interference ameliorated chemotherapeutic agent-induced senescence in lymphocytic leukemia cells. The results of our study further reveal the mechanisms underlying tumor suppression function of VentX and suggest a role of VentX as a potential target in cancer prevention and treatment.
Assuntos
Senescência Celular/fisiologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proteínas de Homeodomínio/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Células Cultivadas , Senescência Celular/genética , Imunoprecipitação da Cromatina , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Citometria de Fluxo , Proteínas de Homeodomínio/genética , Humanos , Linfócitos/citologia , Linfócitos/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Proteína Supressora de Tumor p53/genéticaRESUMO
Disorders of iron metabolism are a significant problem primarily in young and old populations. In this study, We compared 1-year-old C57BL6/J mice on iron deficient, iron overload, or iron sufficient diets with two similarly aged genetic models of disturbed iron homeostasis, the sla (sex-linked anemia), and the ceruloplasmin knockout mice (Cp(-/-)) on iron sufficient diet. We found tissue specific changes in sla and nutritional iron deficiency including decreased liver Hamp1 expression and increased protein expression of the enterocyte basolateral iron transport components, hephaestin and ferroportin. In contrast, the Cp(-/-) mice did not show significantly increased Hamp1 expression despite increased liver iron suggesting that regulation is independent of liver iron levels. Together, these results suggest that older mice have a distinct response to alterations in iron metabolism and that age must be considered in future studies of iron metabolism.
Assuntos
Envelhecimento/fisiologia , Ceruloplasmina/genética , Homeostase , Ferro/metabolismo , Mutação/genética , Anemia Ferropriva/genética , Anemia Ferropriva/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/metabolismo , Northern Blotting , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Hepcidinas , Homeostase/efeitos dos fármacos , Immunoblotting , Técnicas In Vitro , Sobrecarga de Ferro/metabolismo , Ferro da Dieta/farmacologia , Fígado/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Macrophages are critical players in both innate and adaptive immunity. While the exogenous signaling events leading to the terminal differentiation of macrophages from monocytes have been studied extensively, the underlying intracellular transcriptional mechanisms remain poorly understood. Here we report that the homeobox transcription factor VentX plays a pivotal role in human macrophage terminal differentiation and proinflammatory function. Our study showed that VentX expression was upregulated upon human primary monocyte-to-macrophage differentiation induced by cytokines such as M-CSF, GM-CSF, and IL-3. Moreover, ablation of VentX expression in primary monocytes profoundly impaired their differentiation to macrophages, and ectopic expression of VentX in a myeloid progenitor cell line triggered its differentiation with prominent macrophage features. Further analysis revealed that VentX was pivotal for the proinflammatory response of terminally differentiated macrophages. Mechanistically, VentX was found to control expression of proteins key to macrophage differentiation and activation, including M-CSF receptor. Importantly, preliminary analysis of gene expression in leukocytes from patients with autoimmune diseases revealed a strong correlation between levels of VentX and those of proinflammatory cytokines. Our results provide mechanistic insight into the crucial roles of VentX in macrophage differentiation and proinflammatory activation and suggest that dysregulation of VentX may play a role in the pathogenesis of autoimmune diseases.