A potential alternative systemic treatment option for epithelioid sarcoma (preprint)

Background: Epithelioid sarcoma is a rare soft tissue sarcoma characterized by SMARCB1/INI1 deficiency. Much attention has been paid to the selective EZH2 inhibitor tazemetostat, where other systemic treatments are generally ignored. To explore alternative treatment options, we studied the effects of irinotecan-based chemotherapy in a series of epithelioid sarcoma patients. Methods: We retrospectively reviewed data from patients with metastatic or unresectable epithelioid sarcoma at the Peking University People’s Hospital treated with irinotecan (50 mg/m2/d d1-5 Q3W) in combination with Anlotinib (12 mg Qd, 2 weeks on and 1 week off) from July 2015 to November 2021. Results: A total of 54 courses were administered. With a median follow up of 21.2 months (95% CI, 12.2, 68.1), the 5-year overall survival rate was 83.3%. Five of eight (62.5%) patients presented with unresectable localized lesions, including local tumor thrombosis and lymphatic metastasis. The other patients had unresectable pulmonary metastases. Six of eight (75%) patients had progressed following two lines of systemic therapy. The objective response rate reached 37.5% (three of eight patients) while stabilized disease was observed in 62.5% (five of eight) of patients. No patient had progressed at initial evaluation. At the last follow up, two patients were still using the combination and three patients had ceased the therapy due to toxicities such as diarrhea, nausea, and emesis. One patient changed to tazemetostat for maintenance and one patient stopped treatment due to coronavirus disease 2019 (COVID-19). Another patient stopped therapy as residual lesions had been radiated. Conclusions: The combination of irinotecan and Anlotinib as a salvage regimen may be considered another effective treatment option for refractory epithelioid sarcoma. Trial registration: This trial was approved in the Medical Ethics Committee of Peking University People’s Hospital on October 28, 2022 (No.: 2022PHD015-002). The trial was registered in Clinicaltrials.gov with identifier no. NCT05656222.

Artificial Intelligence-Empowered Chatbot for Effective COVID-19 Information Delivery to Older Adults

The coronavirus disease 2019 (COVID-19) epidemic poses a threat to the everyday life of people worldwide and brings challenges to the global health system. During this outbreak, it is critical to find creative ways to extend the reach of informatics into every person in society. Although there are many websites and mobile applications for this purpose, they are insufficient in reaching vulnerable populations like older adults who are not familiar with using new technologies to access information. In this paper, we propose an AI-enabled chatbot assistant that delivers real-time, useful, context-aware, and personalized information about COVID-19 to users, especially older adults. To use the assistant, a user simply speaks to it through a mobile phone or a smart speaker. This natural and interactive interface does not require the user to have any technical background. The virtual assistant was evaluated in the lab environment through various types of use cases. Preliminary qualitative test results demonstrate a reasonable precision and recall rate.

Prolonged SARS-CoV-2 Viral Shedding in Patients with COVID-19 was Associated with Delayed Initiation of Arbidol Treatment and Consulting Doctor Later: A Retrospective Cohort Study.

OBJECTIVE: To study data about SARS-CoV-2 virus shedding and clarify the risk factors for prolonged virus shedding. METHODS: Data were retrospectively collected from adults hospitalized with laboratory-confirmed coronavirus disease-19 (COVID-19) in Wuhan Union Hospital. We compared clinical features among patients with prolonged (a positive SARS-CoV-2 RNA on day 23 after illness onset) and short virus shedding and evaluated risk factors associated with prolonged virus shedding by multivariate regression analysis. RESULTS: Among 238 patients, the median age was 55.5 years, 57.1% were female, 92.9% (221/238) were administered with arbidol, 58.4% (139/238) were given arbidol in combination with interferon. The median duration of SARS-CoV-2 virus shedding was 23 days (IQR, 17.8-30 days) with a longest one of 51 days. The patients with prolonged virus shedding had higher value of D-dimer (P=0.002), IL-6 (P<0.001), CRP (P=0.005) and more lobes lung lesion (P=0.014) on admission, as well as older age (P=0.017) and more patients with hypertension (P=0.044) than in those the virus shedding less than 23 days. Multivariate regression analysis revealed that prolonged viral shedding was significantly associated with initiation arbidol >8 days after symptom onset [OR: 2.447, 95% CI (1.351-4.431)], ≥3 days from onset of symptoms to first medical visitation [OR: 1.880, 95% CI (1.035-3.416)], illness onset before Jan. 31, 2020 [OR: 3.289, 95% CI (1.474-7.337)]. Arbidol in combination with interferon was also significantly associated with shorter virus shedding [OR: 0.363, 95% CI (0.191-0.690)]. CONCLUSION: Duration of SARS-CoV-2 virus shedding was long. Early initiation of arbidol and arbidol in combination with interferon as well as consulting doctor timely after illness onset were helpful for SARS-CoV-2 clearance.

Co-infection of SARS-COV-2 and Influenza A Virus: A Case Series and Fast Review.

Coronavirus disease 2019 (COVID-19) occurs in the influenza season and has become a global pandemic. The present study aimed to examine severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) co-infection with influenza A virus (IAV) in an attempt to provide clues for the antiviral interventions of co-infected patients. We described two patients who were co-infected with SARS-CoV-2 and IAV treated at Wuhan Union Hospital, China. In addition, we performed a review in PubMed, Web of Science and CNKI (from January 1 up to November 1, 2020) with combinations of the following key words: "COVID-19, SARS-COV-2, influenza A and co-infection". A total of 28 co-infected patients were enrolled in the analysis. Of the 28 patients, the median age was 54.5 years (IQR, 34.25-67.5) and 14 cases (50.0%) were classified as severe types. The most common symptoms were fever (85.71%), cough (82.14%) and dyspnea (60.71%). Sixteen patients had lymphocytopenia on admission and 23 patients exhibited abnormal radiological changes. The median time from symptom onset to hospital admission was 4 days (IQR, 3-6), and the median time of hospital stay was 14 days (IQR, 8.5-16.75). In conclusion, patients with SARS-COV-2 and IAV co-infection were similar to those infected with SARS-COV-2 alone in symptoms and radiological images. SARS-COV-2 co-infection with IAV could lead to more severe clinical condition but did not experience longer hospital stay compared with patients infected with SARS-COV-2 alone.

Corticosteroids Treatment of Patients with Coronavirus Disease 2019: A Propensity Score Matching Study.

The role of corticosteroids in the treatment of Coronavirus disease 2019 (COVID-19) is controversial. In the present study, we evaluated the effects of adjuvant corticosteroids treatment on the outcome of patients with COVID-19 (n=966), using Propensity Score Matching to adjust for potential differences between the corticosteroids group (n=289) and the non-corticosteroids group (n=677). Analysis of data without adjusting differences in baseline characteristics indicated that the proportion of mechanical ventilation and the mortality was higher in the corticosteroids treatment group in total or severe/critical patients. The duration of viral shedding was longer in the non-corticosteroids treatment group in total or general/mild patients. After adjusting the difference between the corticosteroids and non-corticosteroids treatment group, the analysis revealed that the use of corticosteroids had no effect on the duration of viral shedding, in-hospital mortality or 28-day mortality.

An update review of emerging small-molecule therapeutic options for COVID-19.

The SARS-CoV-2 outbreak and pandemic that began near the end of 2019 has posed a challenge to global health. At present, many candidate small-molecule therapeutics have been developed that can inhibit both the infection and replication of SARS-CoV-2 and even potentially relieve cytokine storms and other related complications. Meanwhile, host-targeted drugs that inhibit cellular transmembrane serine protease (TMPRSS2) can prevent SARS-CoV-2 from entering cells, and its combination with chloroquine and dihydroorotate dehydrogenase (DHODH) inhibitors can limit the spread of SARS-CoV-2 and reduce the morbidity and mortality of patients with COVID-19. The present article provides an overview of these small-molecule therapeutics based on insights from medicinal chemistry research and focuses on RNA-dependent RNA polymerase (RdRp) inhibitors, such as the nucleoside analogues remdesivir, favipiravir and ribavirin. This review also covers inhibitors of 3C-like protease (3CLpro), papain-like protease (PLpro) and other potentially innovative active ingredient molecules, describing their potential targets, activities, clinical status and side effects.

Early Use of Corticosteroid May Prolong SARS-CoV-2 Shedding in Non-Intensive Care Unit Patients with COVID-19 Pneumonia: A Multicenter, Single-Blind, Randomized Control Trial.

BACKGROUND: There is still no clinical evidence available to support or to oppose corticosteroid treatment for coronavirus disease 2019 (COVID-19) pneumonia. OBJECTIVE: To investigate the efficacy and safety of corticosteroid given to the hospitalized patients with COVID-19 pneumonia. METHODS: This was a prospective, multicenter, single-blind, randomized control trial. Adult patients with COVID-19 pneumonia who were admitted to the general ward were randomly assigned to either receive methylprednisolone or not for 7 days. The primary end point was the incidence of clinical deterioration 14 days after randomization. RESULTS: We terminated this trial early because the number of patients with COVID-19 pneumonia in all the centers decreased in late March. Finally, a total of 86 COVID-19 patients underwent randomization. There was no difference of the incidence of clinical deterioration between the methylprednisolone group and control group (4.8 vs. 4.8%, p = 1.000). The duration of throat viral RNA detectability in the methylprednisolone group was 11 days (interquartile range, 6-16 days), which was significantly longer than that in the control group (8 days [2-12 days], p = 0.030). There were no significant differences between the 2 groups in other secondary outcomes. Mass cytometry discovered CD3+ T cells, CD8+ T cells, and NK cells in the methylprednisolone group which were significantly lower than those in the control group after randomization (p < 0.05). CONCLUSIONS: From this prematurely closed trial, we found that the short-term early use of corticosteroid could suppress the immune cells, which may prolong severe acute respiratory syndrome coronavirus 2 shedding in patients with COVID-19 pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04273321.

The development of Coronavirus 3C-Like protease (3CLpro) inhibitors from 2010 to 2020.

This review fully describes the coronavirus 3CLpro peptidomimetic inhibitors and nonpeptidic small molecule inhibitors developed from 2010 to 2020. Specifically, the structural characteristics, binding modes and SARs of these 3CLpro inhibitors are expounded in detail by division into two categories: peptidomimetic inhibitors mainly utilize electrophilic warhead groups to covalently bind the 3CLpro Cys145 residue and thereby achieve irreversible inhibition effects, whereas nonpeptidic small molecule inhibitors mainly interact with residues in the S1', S1, S2 and S4 pockets via hydrogen bonds, hydrophobic bonds and van der Waals forces. Based on the emerging PROTAC technology and the existing 3CLpro inhibitors, 3CLpro PROTAC degraders are hypothesised to be next-generation anti-coronavirus drugs.

Temporal Dynamics in Clinical and Laboratory Manifestations During COVID-19 Progression (preprint)

BAckground Severe COVID-19 patients account for most of the mortality of this disease. Early detection of severe cases of the disease remains a major challenge. Here, we performed clinical and laboratory profiling of COVID-19 to explore the early warning indicators of severe cases.Methods An analysis of the evolution during the hospitalization of clinical and laboratory findings from 78 confirmed COVID-19 patients and the associated risk factors.Results Of the 78 patients who were classified as un-severe at admission, 60 patients(stable group) were stable as mild cases until discharge, and the remaining 18 patients progressed to severe cases(exacerbated group) during hospitalization. Compared with stable patients, exacerbated patients exhibited older, higher BMI values and higher proportion of smokers. In the exacerbated patients, the median time from onset to deterioration was 7.5 days. Before the time point(days 0–7 from onset), we observed higher-levels of White blood cells(WBC), neutrophil, Neutrophi-Lymphocyte-Ratio(NLR), Lactose-dehydrogenase(LDH), D-dimer, and lower-levels of albumin in the exacerbated group, compared with the stable group. In the second week after the time point, the exacerbated patients displayed lower numbers of lymphocytes, CD3+, and CD8+T-cells, and higher-levels of C-reactive protein(CRP), erythrocyte-sedimentation-rate(ESR), Alanine-aminotransferase(ALT),Aspartate-aminotransferase(AST), and Interleukin-6. In the third week, the highest temperature and the proportion of febrile patients declined. All of the laboratory indicators gradually improved.Conclusions Advanced age and smoking history could be risk factors for COVID-19 progression. In the early stage, high-levels of WBC and neutrophils, with noticeably increased LDH and D-dimer, could be early indicators of the disease’s conversion from mild to severe, followed by elevated inflammatory markers, liver enzymes, and decreased T-lymphocytes in the next week.

Co-infection of SARS-COV-2 and influenza A virus: a case series and fast review (preprint)

Background: COVID-19 has become a global pandemic. Studies about SARS-CoV-2 co-infection with influenza A virus (IAV) in the influenza season will contribute to the antiviral interventions of co-infected patients.Methods: A cohort of 145 COVID-19 patients in Wuhan union hospital were reviewed and we found 2 patients were co-infected with both SARS-CoV-2 and IAV. Then we searched from PubMed, Web of Science and CNKI with combinations of the following key words: “COVID-19, SARS-COV-2, influenza A and co-infection” from January 1 up to May 1, and 6 studies were included in this descriptive analysis. Results: Of the 13 co-infected patients, 2 were from Wuhan union hospital, another 11 were collected from the reports published on PubMed, Web of Science and CNKI. Of the 13 patients, the median age was 50 years (IQR, 40.5-67.5). Among the 13 patients, 7 (53.8%) were severe types. The most common symptoms among the 13 patients were cough (100%), fever (92.3%) and dyspnea (76.9%). 8 patients had lymphocytopenia on admission and all the 13 patients had abnormal radiological changes. The median time from symptom onset to hospital admission was 4.5 days (IQR, 2.75-5.5), and the median time of hospital stay was 17 days (IQR,15-20). Conclusion: Patients with both SARS-COV-2 and IAV infection showed similar changes in symptoms and radiological images with patients infected with SARS-COV-2 only.  SARS-COV-2 co-infection with IAV can lead to more severe clinical condition but had similar hospital stay compared with patients infected with SARS-COV-2 only in the fast review.