SARS-CoV-2 spike protein induces abnormal inflammatory blood clots neutralized by fibrin immunotherapy

Blood clots are a central feature of coronavirus disease-2019 (COVID-19) and can culminate in pulmonary embolism, stroke, and sudden death. However, it is not known how abnormal blood clots form in COVID-19 or why they occur even in asymptomatic and convalescent patients. Here we report that the Spike protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the blood coagulation factor fibrinogen and induces structurally abnormal blood clots with heightened proinflammatory activity. SARS-CoV-2 Spike virions enhanced fibrin-mediated microglia activation and induced fibrinogen-dependent lung pathology. COVID-19 patients had fibrin autoantibodies that persisted long after acute infection. Monoclonal antibody 5B8, targeting the cryptic inflammatory fibrin epitope, inhibited thromboinflammation. Our results reveal a procoagulant role for the SARS-CoV-2 Spike and propose fibrin-targeting interventions as a treatment for thromboinflammation in COVID-19.

A mouse-adapted SARS-CoV-2 strain replicating in standard laboratory mice.

SARS-CoV-2 has infected almost 200 million humans and caused over 4 million deaths worldwide. Evaluating countermeasures and improving our understanding of COVID-19 pathophysiology require access to animal models that replicate the hallmarks of human disease. Mouse infection with SARS-CoV-2 is limited by poor affinity between the virus spike protein and its cellular receptor ACE2. We have developed by serial passages the MACo3 virus strain which efficiently replicates in the lungs of standard mouse strains and induces age-dependent lung lesions. Compared to other mouse-adapted strains and severe mouse models, infection with MACo3 results in mild to moderate disease and will be useful to investigate the role of host genetics and other factors modulating COVID-19 severity.

Laryngeal mask combined with bronchial tube achieves one-lung ventilation for transthoracic oesophagectomy

Laryngeal mask combined with bronchial blocker provides an alternative for lung isolation but lacks adequate access to the non-dependent lung. Substituting the blocker with a bronchial tube may overcome this limitation. In this report, a #4.5 cuffed bronchial tube was introduced into the non-dependent lung through a second-generation laryngeal mask for transthoracic oesophagectomy. During the 2.5-hour thoracotomy, one-lung ventilation was achieved by isolating the left lung with the bronchial tube and ventilating the right lung via the laryngeal mask, using volume-control mode (7 mL/kg × 12/min) with PIP21–23 cm H2O, pH 7.36 and PaCO2 38.3. Prior to thoracotomy closure, suction and reinflation of the left lung were performed through the bronchial tube. Bronchoscopy via the laryngeal mask revealed no injury to the airway after removal of the bronchial tube. The case shows that laryngeal mask combined with bronchial intubation provides one-lung ventilation with access to the isolated lung.

Chinese advanced fusion-dependent lung cancer patients: Molecular spectrum and treatment options using next generation sequencing—A multicenter study (Yangtze River Delta Lung Cancer Cooperation Group-001).

e21036 Background: Lung cancer with drug receptor protein kinase fusion is regarded as a large class of molecular event, which is called fusion-dependent lung cancer. Fusion-dependent lung cancer accounts for about 10%-15% of non-small cell lung cancer. Therefore, the identification and detection of fusion-dependent lung cancer patients are very important in China. Here we reported a total of 4111 patients with Chinese fusion-dependent lung cancer. Methods: A multicenter study in China was initiated from Dec. 2019, and lung patients have been enrolled as of Dec. 2020. A total of 4111 patients with fusion-dependent were analyzed based on medical records and detailed patient questionnaires. Results: Of this entire cohort, 4111 patients were identified with fusion-dependent, including ALK fusions (2190, 53.27%), ROS1 fusions (894, 21.75%), RET fusions (521, 12.67%), NTRK fusions (128, 3.11%), FGFR fusions (84, 2.04%), NRG1 fusions (41, 1.00%), ERBB2 fusions (55, 1.34%), BRAF fusions (44, 1.07%), MET fusions (34, 0.83%), EGFR fusions (74, 1.80%), Other fusions (46, 1.12%). In ALK fusions, there were 1856 cases (84.75%) of EML4-, including A20(94.64%) and non-A20(5.36%), and other partners STRN-, KIF5B-, HIP1-, KLCl-, successively; In ROS1 fusions, there were 461 cases (51.57%) of CD74-, and other partners EZR-, SDC4-, SLC34A2-, TPM3-, GOPC-, successively; In RET fusions, there were 329 cases (63.15%) of KIF5B-, and other partners CCDC6-, NCOA4-, ERC1-, successively; In NTRK fusions, there were 22 cases (17.19%) of TPM3-NTRK1, and other types ETV6-NTRK3, LMNA-NTRK1, AGTPBP1-NTRK2 successively; In FGFR fusions, there were 40 cases (47.61%) of FGFR3-TACC3, and other types FGFR2-TACC2, ATE1-FGFR2, BAG4-FGFR1, successively; In NRG1 fusions, there were 11 cases (26.83%) of CD74-, and other partners SDC4-, RBPMS-, successively; In MET fusions, there were 9 cases (26.47%) of CD74-, and other partners HLA-DRB1-, KIF5B-, successively; In ERBB2, BRAF and EGFR fusions, the partners were scattered. And 3643 patiens (88.68%) of the detection were used DNA-based NGS, and Others were used RNA-based NGS. Patients with ALK and ROS1 fusions were routinely treated with targeted therapy. Patients with RET, NTRK, FGFR and NRG1 fusions were actively enrolled in the clinical trial. Patients with ERBB2, BRAF, MET and EGFR fusions were only treated with end-line trial target therapy, and they were eager to be included in the corresponding clinical trials. Conclusions: The common fusions of ALK, ROS1, RET are routine standardized treatment is very important. Although fusions are rare, it can not be ignored. Morever, these patients are eager to receive active targeted therapy. DNA+RNA based NGS is not widely used in China, but it is of great value to detect fusions, especially rare fusions, which is the future development trend.

Decitabine Reactivation of FoxM1-Dependent Endothelial Regeneration and Vascular Repair for Potential Treatment of Elderly ARDS and COVID-19 Patients

Aging is a major risk factor of high incidence and increased mortality of acute respiratory distress syndrome (ARDS) and COVID-19. We repot that aging impairs the intrinsic FoxM1-dependent endothelial regeneration and vascular repair program and causes persistent lung injury and high mortality following sepsis. Therapeutic gene transduction of FOXM1 in vascular endothelium or treatment with FDA-approved drug Decitabine was sufficient to reactivate FoxM1-dependent lung endothelial regeneration in aged mice, reverse aging-impaired resolution of inflammatory injury, and promote survival. In COVID-19 lung autopsy samples, FOXM1 expression was not induced in vascular endothelial cells of elderly patients in contrast to mid-age patients. Thus, Decitabine reactivation of FoxM1-dependent vascular repair represents a potential effective therapy for elderly COVID-19 and non-COVID-19 ARDS patients.

Leflunomide Induces Dose-Dependent Lung Injury in Mice via Stimulating Vimentin and NLRP3 Inflammasome Production

Recently, the therapeutic importance of the anti-rheumatic drug, leflunomide, has been increased after the involvement of leflunomide in treating other autoimmune diseases and its promising role in retarding human malignancies. Few studies have focused on the safety in human or animals without clear outlining of the pathologic features on target organs. One clinical study related leflunomide with significant pulmonary complications in predisposed individuals. The current study examined the dose-dependent lung injury produced by leflunomide in healthy mice. Albino mice were allocated into four different groups. Group (1): Vehicle control group, Group (2–4): mice received leflunomide (2.5, 5 or 10 mg/kg), respectively, for 8 weeks and then lungs were dissected from the mice for histopathological examination and fibrosis evaluation (Masson’s trichrome staining and α-smooth muscle actin immunohistochemistry). Enzyme linked immunosorbent assay was used to assess the vimentin and other inflammatory factors in the lung homogenate whereas Western blot analysis was employed to assess α-smooth muscle actin, vimentin and collagen 1. Results indicated that leflunomide induced dose-dependent pulmonary injury and the high dose and increased the vimentin, inflammatory markers (NLRP3 and interlukin-1β). Histologic examination showed distorted architecture, marked inflammatory cells infiltrate and increase collagen content. The findings were supported by Western blotting and the immunohistochemical study which showed greater pulmonary α-smooth muscle actin and vimentin content. In conclusion, the current results highlighted that leflunomide produced dose-dependent pulmonary toxicities that requires further investigation of the nature of injury.