RESUMO
Advanced prostate cancer (PCa) patients with bone metastases are treated with androgen pathway directed therapy (APDT). However, this treatment invariably fails and the cancer becomes castration resistant. To elucidate resistance mechanisms and to provide a more predictive pre-clinical research platform reflecting tumor heterogeneity, we established organoids from a patient-derived xenograft (PDX) model of bone metastatic prostate cancer, PCSD1. APDT-resistant PDX-derived organoids (PDOs) emerged when cultured without androgen or with the anti-androgen, enzalutamide. Transcriptomics revealed up-regulation of neurogenic and steroidogenic genes and down-regulation of DNA repair, cell cycle, circadian pathways and the severe acute respiratory syndrome (SARS)-CoV-2 host viral entry factors, ACE2 and TMPRSS2. Time course analysis of the cell cycle in live cells revealed that enzalutamide induced a gradual transition into a reversible dormant state as shown here for the first time at the single cell level in the context of multi-cellular, 3D living organoids using the Fucci2BL fluorescent live cell cycle tracker system. We show here a new mechanism of castration resistance in which enzalutamide induced dormancy and novel basal-luminal-like cells in bone metastatic prostate cancer organoids. These PDX organoids can be used to develop therapies targeting dormant APDT-resistant cells and host factors required for SARS-CoV-2 viral entry.
Assuntos
Neoplasias Ósseas/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Organoides/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Androgênios/farmacologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Benzamidas/farmacologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , COVID-19/genética , COVID-19/metabolismo , COVID-19/virologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Virais/genética , Receptores Virais/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Transplante Heterólogo , Internalização do VírusRESUMO
BACKGROUND: House dust is considered an important source of aeroallergens, and the mites living there, are the main cause of allergy to it. In México, there have been few about house dust fauna, and mostly limited to México City. OBJECTIVE: To describe the house dust fauna from mattresses of allergic patients from different cities in México. METHODS: Sixty dust samples were collected from mattresses in 6 Mexican states: Oaxaca, Tamaulipas, Veracruz, Puebla, Chiapas and Campeche. Mites were isolated under a stereomicroscope using lactic acid -0.9% NaCI solution. Identification was performed on fixed slides prepared with Hoyer solution. Skin Tests were already performed with allergen extracts of different house dust mites species in the 60 mattress' owners, whom had previously been diagnosed with respiratory allergy. RESULTS: The Pyroglyphidae family was found in 100% of dust samples. Dermatophagoides pteronyssinus (Dp) and Dermatophagoides farinae (Df) were the species most frequently found (>90%). These findings were in agreement with the skin tests results, where 100% of patients were positive to Dp, whereas 70% was positive to Df. It was evidenced for the first time the presence of Blomia tropicalis in Tamaulipas, Veracruz and Campeche states, and Dermatophagoides siboney in Campeche. Both species are important allergenic sources in tropical/subtropical climates. CONCLUSIONS: These results confirm the importance of Pyroglyphid house dust mites, as indoor sensitizers in different climatic and geographical regions in México, as well as, the relevance of tropical species, particularly Blomia tropicalis and D. Siboney, in certain areas.
Assuntos
Leitos/parasitologia , Hipersensibilidade/imunologia , Pyroglyphidae , Adolescente , Adulto , Idoso , Animais , Criança , Pré-Escolar , Poeira , Humanos , México , Pessoa de Meia-Idade , Adulto JovemRESUMO
Se hicieron pruebas cutáneas a 201 pacientes (niños) con evidencias clínicas de alergia al polvo, con la utilización de 2 extractos acuosos del ácaro Dermatophagoides siboney (1:10 000 y 1:1 000), el extracto comercial de D farinae (1:10 000), 5 de hongos (Aspergillus, Penicillium, Rhizopus, Cladosporium y Alternaria), uno de polvo doméstico (1:50 000) y un control. Mostraron reacciones positivas 137 pacientes al extracto 1:1 000 y 113 al 1:10 000 de D. Siboney; 165 lo hicieron al extracto de D. farinae y 164 al polvo doméstico. Las reacciones por hongos fueron escasas. Tanto la prueba de X a la 2, para la positividad, como la prueba de la t de Student, para la reacción, no mostraron diferencias significativas para p < 0,95, entre los resultados obtenidos en los extractos de D. siboney 1:10 000, D. farinae 1:10 000, por lo que pudieran ser utilizados indistintamente, al tener en cuenta la diferencia de concentración