RESUMEN
Dysregulation of iron metabolism in cancer is well documented and it has been suggested that there is interdependence between excess iron and increased cancer incidence and progression. In an effort to better understand the linkages between iron metabolism and breast cancer, a predictive mathematical model of an expanded iron homeostasis pathway was constructed that includes species involved in iron utilization, oxidative stress response and oncogenic pathways. The model leads to three predictions. The first is that overexpression of iron regulatory protein 2 (IRP2) recapitulates many aspects of the alterations in free iron and iron-related proteins in cancer cells without affecting the oxidative stress response or the oncogenic pathways included in the model. This prediction was validated by experimentation. The second prediction is that iron-related proteins are dramatically affected by mitochondrial ferritin overexpression. This prediction was validated by results in the pertinent literature not used for model construction. The third prediction is that oncogenic Ras pathways contribute to altered iron homeostasis in cancer cells. This prediction was validated by a combination of simulation experiments of Ras overexpression and catalase knockout in conjunction with the literature. The model successfully captures key aspects of iron metabolism in breast cancer cells and provides a framework upon which more detailed models can be built.
Asunto(s)
Mama/metabolismo , Transformación Celular Neoplásica/metabolismo , Células Epiteliales/metabolismo , Hierro/metabolismo , Modelos Biológicos , Transducción de Señal , Adaptación Fisiológica , Animales , Mama/patología , Simulación por Computador , Células Epiteliales/patología , Femenino , Humanos , Proteína 2 Reguladora de Hierro/metabolismo , Células Tumorales Cultivadas , Proteínas ras/metabolismoRESUMEN
BACKGROUND: Babesiosis is an important cause of thrombocytopenia and hemolytic anemia in dogs. Babesia vulpes, reported in European dogs and North American foxes, rarely has been reported in domestic North American dogs. Newly optimized polymerase chain reaction (PCR) primers facilitate more sensitive amplification of B. vulpes DNA. OBJECTIVES: To determine the prevalence of Babesia sp. infections in dogs being tested for Babesia infection, and to describe co-infections and clinicopathologic abnormalities in B. vulpes positive dogs. ANIMALS: Dog blood or tissue samples (n = 9367) submitted to a diagnostic laboratory between June 2015 and June 2018 were tested using an optimized Babesia PCR assay. METHODS: Comprehensive canine vector-borne disease diagnostic testing was performed on convenience samples. RESULTS: Babesia sp. DNA was amplified from 269/9367 (2.9%) North American dogs. Babesia sp. infections included B. gibsoni monoinfection (157; 1.7%), B. vulpes monoinfection (19; 0.20%), and B. gibsoni and B. vulpes coinfection (29; 0.31%). Forty-three of the 48 total B. vulpes-infected dogs were American Pit Bull Terrier-type breeds, of which 36 historically were involved with dog fights. Coinfections with Mycoplasma, Dirofilaria immitis, or Wolbachia and coexposures to Bartonella, Ehrlichia, and Rickettsia spp. were documented in B. vulpes-infected dogs. Clinicopathologic data in B. vulpes-infected dogs both with and without coinfections included anemia, thrombocytopenia, hyperglobulinemia, hypoalbuminemia, and proteinuria. CONCLUSIONS AND CLINICAL IMPORTANCE: Babesia vulpes infection in domestic North American dogs is commonly found in conjunction with other coinfections, including B. gibsoni and hemotropic Mycoplasma. Similar to B. gibsoni, dog-to-dog transmission of B. vulpes may be a frequent mode of transmission.