Background: Small cell lung cancer (SCLC) is the most deadly and aggressive type of primary lung cancer, with the 5-year survival rate lower than 5%. The FDA has approved arsenic trioxide (As 2 O 3 ) for acute promyelocytic leukemia (APL) treatment. However, its role in SCLC-derived cancer stem cells (CSCs) remains largely unknown.Methods: CSCs were enriched from SCLC cell lines by culturing them as spheres in conditioned serumfree medium. Then, qPCR, western blot, serial passage, limiting dilution, Transwell, and tumorigenesis assay were performed to verify the cells' stem phenotypic characteristics. Anticancer efficiency of As 2 O 3 was assessed in these cells using CCK8, colony formation, sphere formation, flow cytometry, qPCR, western blot analysis in vitro, and tumor growth curve, immunofluorescence, and TUNEL staining analyses in vivo.Results: The fifth-passage SCLC spheres showed a potent self-renewal capacity, higher clonal formation efficiency (CFE), SOX2, c-Myc, NANOG, and OCT4 levels, and invasion ability, and stronger tumorigenesis capacity than the parental SCLC cells, indicating that the SCLC sphere cells displayed CSC features. As 2 O 3 inhibited the proliferation, clonality and sphere forming ability of SCLC-derived CSCs and suppressed the tumor growth of CSCs-derived xenograft tumors. As 2 O 3 induced apoptosis and downregulation of SOX2 and c-Myc in vitro and in xenografts. Besides, SOX2 knockdown suppressed SCLC-derived CSCs to selfrenew and induced apoptosis. Mechanistically, expression of GLI1 (a key transcription factor of Hedgehog pathway) and its downstream genes increased in SCLC-derived CSCs, compared to the parental cells. As 2 O 3 dramatically downregulated GLI1 and its downstream genes in vitro and in vivo. The GLI inhibitor (GANT-61) recapitulated and enhanced the effects of As 2 O 3 on SCLC-derived CSCs, including growth suppression, apoptosis induction, and GLI1, SOX2 and c-Myc downregulation. Conclusions: Altogether, As 2 O 3 effectively suppressed SCLC-derived CSCs growth by downregulating stem cell-maintenance factors and inducing apoptosis. These effects are mediated at least partly via the Hedgehog signaling blockade.

Background No specific therapeutic agents or vaccines are available for the treatment of Coronavirus disease 2019 (Covid-19) yet. In this study, we aimed to assess the efficacy of high dose ulinastatin for patients with Covid-19.Methods Twelve patients hospitalized with confirmed SARS-CoV-2 infection were treated with high dose of ulinastatin beyond standard care. The changes of clinical manifestations, laboratory examinations and chest images were retrospectively analyzed. Results A total of 10 patients with severe Covid-19 and 2 patients with moderate Covid-19 received ulinastatin treatment. The average age of the patients was 68.0 ± 11.9 years, ranging from 48 to 87 years. Nine of 12 patients (75.0%) had one or more comorbidities. The most common symptoms on admission were fever (8/12, 66.7%), cough (5/12, 41.7%) and dyspnea (5/12, 41.7%). The percentage of lymphocytes was decreased in 41.7% of patients (5/12), and 58.3% of patients (7/12) had elevated hypersensitive C-reactive protein (CRP) levels (mean, 49.70 ± 77.70 mg/L). The white blood cell levels and the percentage of lymphocytes returned to normal in all of the patients, and CRP decreased significantly and returned to normal in 83.3% of patients (10/12; mean, 6.87 ± 6.63 mg/L) on the seventh day after ulinastatin treatment. Clinical symptoms were relieved synchronously. The peripheral oxygen saturation improved and 66.7% of the patients (8/12) did not need further oxygen therapy seven days after ulinastatin treatment. No patients required intensive care unit admission or mechanical ventilation. All patients revealed different degrees of absorption of pulmonary lesions after treatment. No obvious adverse events were observed.Conclusions Our preliminary data revealed that high dose of ulinastatin treatment was safe and showed a potential beneficial effect for patients with Covid-19.

Currently, there are no specific therapeutic agents available for the treatment of coronavirus disease 2019 . The present study aimed to assess the efficacy of high-dose ulinastatin for the treatment of patients with Covid-19. A total of 12 patients hospitalized with confirmed severe acute respiratory syndrome coronavirus 2 infection were treated with a high dose of ulinastatin alongside standard care. Changes in clinical manifestations, laboratory examinations and chest images were retrospectively analyzed. A total of 10 patients with severe Covid-19 and two patients with moderate Covid-19 received ulinastatin treatment. The average age of the patients was 68.0±11.9 years (age range, 48-87 years). In total, nine of the 12 patients (75.0%) had one or more comorbidities. The most common symptoms on admission were fever (8/12, 66.7%), cough (5/12, 41.7%) and dyspnea (5/12, 41.7%). The percentage of lymphocytes was decreased in 41.7% of patients (5/12) and 58.3% of patients (7/12) had elevated hypersensitive C-reactive protein (CRP) levels (mean, 49.70±77.70 mg/l). The white blood cell levels and the percentage of lymphocytes returned to normal in all of the patients, and CRP was significantly decreased and returned to normal in 83.3% of patients (10/12; mean, 6.87±6.63 mg/l) on day 7 after ulinastatin treatment. Clinical symptoms were relieved synchronously. The peripheral oxygen saturation improved and 66.7% of the patients (8/12) did not require further oxygen therapy 7 days after ulinastatin treatment. No patients required intensive care unit admission or mechanical ventilation. All patients revealed different degrees of absorption of pulmonary lesions after treatment. Compared with the standard care group, ulinastatin treatment significantly prevented illness deterioration. In conclusion, these preliminary data revealed that high-dose ulinastatin treatment was safe and exhibited a potential beneficial effect for patients with Covid-19.

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BackgroundMuch remains unknown about COVID-19 onset and rehabilitation's symptomatic features, especially the long-term health consequences of patients with COVID-19 who have been discharged from the hospital.MethodsIn this cohort study, we collected the first pandemic data of hospitalized patients in Wuhan from February 20 to March 31, 2020. All patients completed a 3-month follow-up after discharge. We carefully analyzed the detailed symptomatic characteristics of severe COVID-19 at illness onset and three months after discharge, compared it with non-severe patients, and used multiple logistic regression to determine potential symptomatic risk factors for severe COVID-19.ResultsA total of 932 hospitalized patients with COVID-19 were enrolled, including 52 severe cases and 880 non-severe cases. Fever (60%), cough (50.8%), and fatigue (36.4%) were the most common symptoms, followed by anorexia (21.8%) and dyspnea (19.2%). The median duration of fever was seven days, which was characterized by persistent low fever. The median duration of cough was 17 days, characterized by dry cough without sputum. Most dyspnea occurred on the fourth day after symptom onset, with a median duration of 16 days. The incidences of taste loss and olfactory disturbance were only 6.2% and 3.1%, respectively. Multivariate logistic regression analysis showed that age over 65 years old (OR 6.52, 95% CI 3.27-13.02, P<0.0001), male sex (3.71, 1.90-7.26, P = 0.0001), fever lasting for more than five days (1.90, 1.00-3.62, P=0.0498), anorexia at onset (2.61, 1.26-5.40, P=0.0096), and modified Medical Research Council level above grade 2 when dyspnea occurred (14.19,7.01-28.71, P<0.0001) were symptomatic risk factors for severe COVID-19. Three months after discharge from the hospital, 6.2% of patients still cough, 7.2% of patients still dyspnea, and 1.8% still fatigue, and 1.5% of patients had olfactory or taste disorders.ConclusionsCOVID-19 caused clusters of symptoms, with multiple systems involved. Specific symptomatic features at the onset of illness have predictive value for severe COVID-19. Persistent legacy symptoms are more frequent in severe COVID-19 patients.