Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog Pathway Inhibitor-1 (preprint)

Target deconvolution of small molecule hits from phenotypic screens presents a major challenge. Illustrative of these are the many screens that have been conducted to find inhibitors for the Hedgehog (Hh) signaling pathway – a major developmental pathway with many implications in health and disease - with many hits but very few identified cellular targets. We here present a strategy for target identification based on Proteolysis-Targeting Chimeras (PROTACs), combined with label-free quantitative proteomics. We developed a PROTAC based on the downstream Hedgehog Pathway Inhibitor-1 (HPI-1), a phenotypic screen hit with unknown cellular target. Using our Hedgehog Pathway PROTAC (HPP) we identified and validated BET bromodomains to be the cellular targets of HPI-1. Furthermore, we found that HPP-9 has a unique mechanism of action as a long-acting Hh pathway inhibitor through prolonged BET bromodomain degradation. Collectively, we provide a powerful PROTAC-based approach for target deconvolution, that has answered the longstanding question of the cellular target of HPI-1 and yielded the first PROTAC that acts on the Hh pathway.

Long Duration and Increase in Pediatric Complicated Appendicitis During the Period of Lockdown in April 2022 in Shanghai (preprint)

Objective: The Corona Virus Disease 2019 (COVID-19) has tremendously transformed medical care worldwide, and elective surgery has been affected. The aim of the current study was to determine whether complicated appendicitis rates in children were influenced by the lockdown in April 2022 in Puxi region of Shanghai due to COVID-19.Background: The progression of acute appendicitis from simple to complicated is affected by the presentation timeliness. In the context of city-mandated control, the influences of lockdown in Puxi April on children suffering from acute appendicitis will be investigated in this study. Methods: The medical records of all children presenting in 2 hospitals with acute appendicitis between April 1 and April 30, 2022 (The first lockdown month in Puxi region) were reviewed and analyzed as the lockdown group. Moreover, the medical records of the latest 2 years of acute appendicitis in the same period were reviewed and analyzed as the control group. In addition, the clinical and laboratory parameters, treatment ways, intraoperative and pathological findings, and postoperative outcomes were analyzed.Results: A total of 22 children were diagnosed with acute appendicitis in the first month of the lockdown period in 2 hospitals. Compared with a 2-year control cohort of acute appendicitis, we observed a longer mean duration of symptoms (67.2±77.6 vs 31.9±34.7 h, P=0.01) and higher rate (72.73% vs 43.75%, P=0.038) in children with complicated appendicitis and a long operation time (92.5±35.46 vs 71.25±34.44 min, P=0.03), as well as a higher CRP (61.82±49.75 vs 23.43±28.19 mg/dL, P<0.001) and serum bilirubin (19.07±11.07 vs 10.74±4.37 umol/L, P<0.0001). The mean length of stay was longer in the lockdown group than that in the control group (10.77±5.37 vs 7.70±3.74 d, P=0.0072). The admission WBC and neutrophil percentage had no significant differences, the mean number of hospital or clinic visits had no differences, and the interval between diagnosis and operation has no statistical differences (5.28±2.94 vs 3.73±3.11 h, P=0.076). However, the overall conservative treatment cases, postoperative morbidity and mortality did not change.Conclusions: The lockdown affected the symptoms’ duration time of pediatric acute appendicitis. The children in the lockdown period demonstrated higher complicated appendicitis compared with the historical controls, as well as longer mean length of hospital stay. 

Systematic evaluation of COVID-19 related Internet health rumors during the breaking out period of COVID-19 in China.

Background: To adapt the scientific evaluation tool for the confusion evaluation of health rumors and to test this tool to the confusion evaluation of coronavirus disease 2019 (COVID-19)-related health rumors on Chinese online platforms during the outbreak period of COVID-19in China. Methods: The design of our study was systematic evaluation of COVID-19-related health rumors. Retrieved from 7 rumor-repellent platforms, rumors about COVID-19 were collected during the publication from December 1, 2019, to February 6, 2020, and their origins were traced. Researchers evaluated rumors using the confusion evaluation tool in 6 dimensions(creators, evidence selection, evidence evaluation, evidence application, backing and publication platform, conflict of interest). Items were scored using a seven-point Likert scale. The scores were converted into percentages, and the median of rumors from different sources was compared with rank-sum test. Results: Our research included 127 rumors. Scores were converted to percentages, median and interquartile range are used to describe the data. The median score: creators 25.00%(interquartile range, IQR, 16.67-37.50%), evidence selection 27.78% (IQR, 13.89-44.44%),evidence evaluation 33.33% (IQR, 25.00-45.83%), evidence application 36.11% (IQR, 22.22-47.22%), backing and publication platform 8.33% (IQR, 4.17-20.83%), conflict of interest75.00% (IQR, 50.00-83.33%). Almost 40% rumors came from WeChat and the rumors with the lowest scores were concentrated on the WeChat platform. The rumors about prevention methods have relatively lower scores. Conclusion: Most rumors included were not highly confusing for evaluators of this project.WeChat is the "worst-hit area" of COVID-19 related health rumors. More than half rumors focus on the description of prevention methods, which reflects the panic, anxiety and blind conformity of the public under public health emergencies.

The comparison of vaccine hesitancy of COVID-19 vaccination in China and the United States (preprint)

Background: To investigate the differences in vaccine hesitancy and preference of the currently available COVID-19 vaccines between two countries, viz. China and the United States (US). Method: A cross-national survey was conducted in both China and the US, and discrete choice experiments as well as Likert scales were utilized to assess vaccine preference and the underlying factors contributing to the vaccination acceptance. A propensity score matching (PSM) was performed to enable a direct comparison between the two countries. Results: A total of 9,077 (5,375 and 3,702, respectively, from China and the US) respondents have completed the survey. After propensity score matching, over 82.0% respondents from China positively accept the COVID-19 vaccination, while 72.2% respondents form the US positively accept it. Specifically, only 31.9% of Chinese respondents were recommended by a doctor to have COVID-19 vaccination, while more than half of the US respondents were recommended by a doctor (50.2%), local health board (59.4%), or friends and families (64.8%). The discrete choice experiments revealed that respondents from the US attached the greatest importance to the efficacy of COVID-19 vaccines (44.41%), followed by the cost of vaccination (29.57%), whereas those from China held a different viewpoint that the cost of vaccination covers the largest proportion in their trade-off (30.66%), and efficacy ranked as the second most important attribute (26.34%). Also, respondents from China tend to concern much more about the adverse effect of vaccination (19.68% vs 6.12%) and have lower perceived severity of being infected with COVID-19. Conclusion: While the overall acceptance and hesitancy of COVID-19 vaccination in both countries are high, underpinned distinctions between countries are observed. Owing to the differences in COVID-19 incidence rates, cultural backgrounds, and the availability of specific COVID-19 vaccines in two countries, the vaccine rollout strategies should be nation-dependent.