RESUMEN
BACKGROUND: Anosmia and ageusia are symptoms commonly associated with COVID-19, but the relationship with disease severity, onset and recovery are unclear. OBJECTIVE: To examine factors associated with anosmia and ageusia and the recovery from these symptoms in an ethnically diverse cohort. METHODS: Individuals tested for SARS-CoV-2 between March and April 2020 were eligible for the study. Randomly selected participants answered a telephone questionnaire on COVID-19 symptoms with a focus on anosmia and ageusia. Additionally, relevant past medical history and data on the COVID-19 clinical course were obtained from electronic medical records. 486 patients were in the COVID-19 group and 103 were COVID-19-negative. RESULTS: Patients who were younger were more likely to report anosmia and/or ageusia (odds ratio (OR) for anosmia per 1-year increase in age: 0·98, 95%CI:0-97-0·99, p = 0·003; for ageusia: 0·98, 95%CI:0·97-0·99, p = 0·005) as were patients with lower eosinophil counts (OR for anosmia per 0.1-K/µL increase in eosinophils: 0·02, 95%CI:0·001-0·46, p = 0·01, for ageusia 0·10, 95%CI:0·01-0·97, p = 0·047). Male gender was independently associated with a lower probability of ageusia (OR:0·56, 95%CI:0·38-0·82, p = 0·003) and earlier sense of taste recovery (HR:1·44, 95%CI:1·05-1·98, p = 0·02). Latinos showed earlier sense of taste recovery than white patients (HR:1·82, 95%CI:1·05-3·18, p = 0·03). CONCLUSION: Anosmia and ageusia were more common among younger patients and those with lower blood eosinophil counts. Ageusia was less commonly reported among men, and time to taste recovery was earlier among both men and Latinos.
Asunto(s)
Ageusia , COVID-19 , Trastornos del Olfato , Ageusia/epidemiología , Anosmia , Eosinófilos , Humanos , Lactante , Masculino , Trastornos del Olfato/inducido químicamente , Trastornos del Olfato/epidemiología , SARS-CoV-2RESUMEN
Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.
Asunto(s)
Ácido Aspártico/deficiencia , Carcinoma Ductal Pancreático , Cloroquina/farmacología , Lisosomas/metabolismo , Mitocondrias , Neoplasias Pancreáticas , Animales , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Femenino , Humanos , Lisosomas/patología , Masculino , Ratones , Mitocondrias/metabolismo , Mitocondrias/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Estrés Fisiológico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Although histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs, thus far, they have been unsuccessful in early phase clinical trials for pancreatic ductal adenocarcinoma (PDAC). One potential reason for their poor efficacy is the tumor stroma, where cancer-associated fibroblasts (CAFs) are a prominent cell type and a source of resistance to cancer therapies. Here, we demonstrate that stromal fibroblasts contribute to the poor efficacy of HDACi's in PDAC. HDACi-treated fibroblasts show increased biological aggressiveness and are characterized by increased secretion of pro-inflammatory tumor-supportive cytokines and chemokines. We find that HDAC2 binds to the enhancer and promoter regions of pro-inflammatory genes specifically in CAFs and in silico analysis identified AP-1 to be the most frequently associated transcription factor bound in these regions. Pharmacologic inhibition of pathways upstream of AP-1 suppresses the HDACi-induced inflammatory gene expression and tumor-supportive responses in fibroblasts. Our findings demonstrate that the combination of HDACi's with chemical inhibitors of the AP-1 signaling pathway attenuate the inflammatory phenotype of fibroblasts and may improve the efficacy of HDACi in PDAC and, potentially, in other solid tumors rich in stroma.