Proteomic and phosphoproteomic characteristics of the cortex, hippocampus, thalamus, lung, and kidney in COVID-19-infected female K18-hACE2 mice.

BACKGROUND: Neurological damage caused by coronavirus disease 2019 (COVID-19) has attracted increasing attention. Recently, through autopsies of patients with COVID-19, the direct identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in their central nervous system (CNS) has been reported, indicating that SARS-CoV-2 might directly attack the CNS. The need to prevent COVID-19-induced severe injuries and potential sequelae is urgent, requiring the elucidation of large-scale molecular mechanisms in vivo. METHODS: In this study, we performed liquid chromatography-mass spectrometry-based proteomic and phosphoproteomic analyses of the cortex, hippocampus, thalamus, lungs, and kidneys of SARS-CoV-2-infected K18-hACE2 female mice. We then performed comprehensive bioinformatic analyses, including differential analyses, functional enrichment, and kinase prediction, to identify key molecules involved in COVID-19. FINDINGS: We found that the cortex had higher viral loads than did the lungs, and the kidneys did not have SARS-COV-2. After SARS-CoV-2 infection, RIG-I-associated virus recognition, antigen processing and presentation, and complement and coagulation cascades were activated to different degrees in all five organs, especially the lungs. The infected cortex exhibited disorders of multiple organelles and biological processes, including dysregulated spliceosome, ribosome, peroxisome, proteasome, endosome, and mitochondrial oxidative respiratory chain. The hippocampus and thalamus had fewer disorders than did the cortex; however, hyperphosphorylation of Mapt/Tau, which may contribute to neurodegenerative diseases, such as Alzheimer's disease, was found in all three brain regions. Moreover, SARS-CoV-2-induced elevation of human angiotensin-converting enzyme 2 (hACE2) was observed in the lungs and kidneys, but not in the three brain regions. Although the virus was not detected, the kidneys expressed high levels of hACE2 and exhibited obvious functional dysregulation after infection. This indicates that SARS-CoV-2 can cause tissue infections or damage via complicated routes. Thus, the treatment of COVID-19 requires a multipronged approach. INTERPRETATION: This study provides observations and in vivo datasets for COVID-19-associated proteomic and phosphoproteomic alterations in multiple organs, especially cerebral tissues, of K18-hACE2 mice. In mature drug databases, the differentially expressed proteins and predicted kinases in this study can be used as baits to identify candidate therapeutic drugs for COVID-19. This study can serve as a solid resource for the scientific community. The data in this manuscript will serve as a starting point for future research on COVID-19-associated encephalopathy. FUNDING: This study was supported by grants from the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the National Natural Science Foundation of China, and the Natural Science Foundation of Beijing.

[Cancer of the nasal cavity].

OBJECTIVE: To analyze the factors affecting prognosis of patients with nasal carcinoma. METHODS: 163 patients treated from 1985 to 1998 were analyzed. The survival analysis was performed by Kaplan-Meier estimate and the comparison between groups by Log-rank test. Multivariate analysis was carried out by Cox proportional hazard model. RESULTS: The overall 5-year survival rate was 58.2%. The 5-year survival rate was 55.8% in squamous-cell carcinoma, 44.0% in adenocarcinoma, 59.7% in undifferentiated carcinoma, 76.3% in adenoid cystic carcinoma, 71.4% in mucoepidermoid carcinoma, 25.0% in rhabdomyosarcoma, 26.7% in malignant melanoma, 50.0% in neuroblastoma (P > 0.05). Patients with cervical metastasis gave a 5-year survival of 53.5% while those without gave 58.9% (P > 0.05). Patients with involvement of sphenoidal sinus or maxillary sinus gave the worse survival. The 5-year survival rate was 73.8% in patients whose cancer completely disappeared after treatment. It was 41.6% in patients whose cancer incompletely disappeared, and 34.3% in patients whose cancer remained refractory (P < 0.01). The 5-year survival was 78.3% in stage I disease, 56.4% in stage II disease, 54.2% in stage III and 35.9% in stage IV (P < 0.05). The 5-year survival rate of patients who were treated with radiotherapy only was 56.9%. That of patients who were treated with surgery only was 56.6%. That with chemotherapy only was 25.0% whereas that of patients treated with combination treatment was 61.8% (P > 0.05). So far, 85 patients have died up to writing this report, 57.6% (49 patients) of recurrence or uncontrolled. CONCLUSION: Clinical stage, immediate therapeutic response and involvement of sphenoidal or maxillary sinus; but not the pathologic type, the presence of cervical metastasis nor the method of treatment, are the factors affecting the prognosis of patients with nasal carcinoma. Recurrence and uncontrolled disease are the cause of death.

[Prognosis and treatment for 98 patients with carcinoma of nasal cavity].

BACKGROUND & OBJECTIVE: Carcinoma of nasal cavity is a rare disease without standard treatment. This study was designed to evaluate treatment outcome, and prognostic factors of patients with carcinoma of nasal cavity. METHODS: Records of 98 patients with carcinoma of nasal cavity were reviewed,43 patients received radiotherapy alone, 55 patients received surgery plus radiotherapy. Survival analysis was performed by Kaplan-Meier method,differences between groups were tested by log-rank test,multivariate analysis was carried out by Cox proportional hazard model. RESULTS: The overall 5-, and 10-year survival rates were 65.3%, and 37.1%. The 5-, and 10-year survival rates of patients with tumor of stage I, II were 87.3%, and 51.1%, those of patients with tumor of stage III, IV were 56.1%, and 32.2% (P=0.02). The patients with squamous cell carcinoma had lower survival rates than those with adenocarcinoma (P< 0.01). There was significant difference in survival rates between patients received radiotherapy alone and patients received radiotherapy plus surgery in advanced lesions (P=0.04) and in squamous cell carcinoma (P< 0.01), but not in early lesions (P=0.41) and in adenocarcinoma (P=0.73). Patients who were initially diagnosed cervical lymph node metastasis had a reduced survival rate compared with node-negative patients (P=0.01). In Cox's regression, clinical stage and node-positive were independent prognostic factors. CONCLUSIONS: The criteria should be taken into account when choosing treatment method for patients with carcinoma of nasal cavity: radiotherapy plus surgery is preferred for advanced lesions and for squamous cell carcinoma, radiotherapy alone is better for early lesions and for adenocarcinoma. Clinical stage, and node-positive may be independent prognostic factors of patients with carcinoma of nasal cavity.