The aim of this study was to evaluate the association between overweight and severity, drug response, and clinical outcomes of novel coronavirus disease 2019 (COVID-19). In this retrospective cohort study, we reviewed medical records of 240 COVID-19 patients admitted to Union Hospital in Wuhan, China, between December 24, 2019, and March 25, 2020. Physical, clinical, laboratory, radiological characteristics, treatment, and outcome data were abstracted. Patients who were obese [body mass index (BMI) ≥28 kg/m 2 ], underweight (BMI < 18.5 kg/m 2 ), under 18 years old, pregnant, or still in hospital were excluded. Disease severity was classified as moderate or severe pneumonia based on the World Health Organization interim guidance. Overweight was defined as BMI ≥24 kg/m 2 and <28 kg/m 2 . Patients were followed for discharge or death through April 10, 2020. We used logistic regression models to identify risk factors for severe disease, Cox proportional hazard models to explore associations between medications and patient outcomes (discharge or in-hospital death), and Kaplan–Meier survival curves and Cox regression models to evaluate risk factors for in-hospital death. One-half of patients (120, 50.0%) had severe pneumonia, while nearly one-half (114, 47.5%) were overweight. Among patients over 45 years old, overweight patients had significantly lower rates of fatigue, higher rates of headache, and higher median C-reactive protein levels. Patients under 45 years old had higher rates of cough and myalgia and higher proportions of increased alanine aminotransferase and lactic dehydrogenase, as well as more pulmonary lobes involved in the pneumonia revealed by chest computed tomography scans. Overweight patients were at higher risk of developing severe pneumonia. Although weight was not a risk factor for in-hospital death, overweight patients showed different responses to medications compared with normal weight patients. Intravenous interferon-α, intravenous glucocorticoids, and antifungal drugs were associated with reduced mortality in overweight patients. Intravenous immunoglobulin, oseltamivir, and ribavirin were associated with reduced mortality in normal weight patients. Overweight is a worldwide health problem. We found overweight to be related to the COVID-19 severity but not to in-hospital death. Clinicians should be aware that overweight COVID-19 patients require increased attention for different clinical features and treatment response.
Background Programmed cell death protein 1 (PD-1) antibody has been approved for a variety of tumors, but its effective rate is unsatisfactory. New evidence suggests that mast cells are an important component of the tumor microenvironment and are associated with resistance to immunotherapy, but the underlying mechanism is not clear. Methods Bioinformatics analysis of patients with melanoma in TCGA-SKCM and GSE91061 was used to determine the prognostic value of mast cells and their association with anti-PD-1 immunotherapy. HMC-1 cells (mast cell line) and bone marrow-derived mast cells (BMMCs) were used to verify the effect of PD-1 antibody and cromolyn sodium in vitro. The mouse subcutaneous melanoma model was used to verify the effect of the PD-1 antibody on mast cells in vivo. Results Bioinformatics analysis showed that mast cells were a poor prognostic factor associated with resistance to anti-PD-1 immunotherapy. PD-1 was expressed on the mast cell membrane. The PD-1 antibody promoted the release of histamine and cytokines from mast cells via the PI3K/AKT pathway and calcium signaling pathway. The activation of mast cells induced by PD-1 antibody could be partially inhibited by cromolyn sodium. In vivo, cromolyn sodium increased the efficacy of PD-1 antibody and decreased the infiltration of mast cells and the density of microvessels. Conclusion PD-1+ mast cell activated by PD-1 antibody plays a negative role in the tumor microenvironment via the enhanced function of releasing histamine and cytokines. Inhibition of mast cell may provide a new solution to solve the low response rate of anti-PD-1 immunotherapy.
REV1 is the central member of the family of TLS polymerases, which participate in various DNA damage repair and tolerance pathways and play a significant role in maintaining genomic stability. However, the role of REV1 in tumors is rarely reported. In this study, we found that the expression of REV1 was significantly upregulated in lung cancer tissues compared with matched adjacent tissues and was associated with poor prognosis. Functional experiments demonstrated that REV1 silencing decreased the growth and proliferation capacity of lung cancer cells. Mechanistically, REV1 upregulated the expression of SERTAD2 in a Rad18-dependent manner, thereby promoting lung carcinogenesis. A novel REV1 inhibitor, JH-RE-06, suppressed lung tumorigenesis in vivo and in vitro and was shown to be safe and well tolerated. Our study confirmed that REV1 is a potential diagnostic marker and therapeutic target for lung cancer and that JH-RE-06 may be a safe and efficient therapeutic agent for NSCLC.
Background Chemoradiotherapy‐induced PD‐L1 upregulation leads to therapeutic resistance and treatment failure. The PD‐1/PD‐L1 blocking antibodies sensitize cancers to chemoradiotherapy by blocking extracellular PD‐1 and PD‐L1 binding without affecting the oncogenic function of intracellular PD‐L1. Reversing the chemoradiation‐induced PD‐L1 expression could provide a new strategy to achieve a greater anti‐tumour effect of chemoradiotherapy. Here, we aimed to identify candidate small molecular inhibitors that might boost the anti‐tumour immunity of chemoradiotherapy by decreasing treatment‐induced PD‐L1 expression in non‐small cell lung cancer (NSCLC). Methods A drug array was used to recognize compounds that can suppress the cisplatin‐induced and radiation‐induced PD‐L1 expression in NSCLC via the flow cytometry‐based assay. We examined whether and how targeting bromodomain containing 4 (BRD4) inhibits chemoradiation‐induced PD‐L1 expression and evaluated the effect of BRD4 inhibition and chemoradiation combination in vivo. Results BRD4 inhibitors JQ1 and ARV‐771 were identified as the most promising drugs both in the cisplatin and radiation screening projects in two NSCLC cell lines. Targeting BRD4 was supposed to block chemoradiotherapy inducible PD‐L1 expression by disrupting the recruitment of BRD4‐IRF1 complex to PD‐L1 promoter. A positive correlation between BRD4 and PD‐L1 expression was observed in human NSCLC tissues. Moreover, BRD4 inhibition synergized with chemoradiotherapy and PD‐1 blockade to show a robust anti‐tumour immunity dependent on CD8+ T cell through limiting chemoradiation‐induced tumour cell surface PD‐L1 upregulation in vivo. Notably, the BRD4‐targeted combinatory treatments did not show increased toxicities. Conclusion The data showed that BRD4‐targeted therapy synergized with chemoradiotherapy and anti‐PD‐1 antibody by boosting anti‐tumour immunity in NSCLC.
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