The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment

Purpose: This study aims to comprehensively evaluate the clinical efficacy of chemotherapy or endocrine therapy maintenance in metastatic breast cancer (MBC) patients. Materials and Methods: The meta-analysis of randomized clinical trials (RCTs) and propensity score matching of multicenter cohort study evaluated MBC patients who underwent first-line chemotherapy or endocrine therapy maintenance. This study is registered with PROSPERO: CRD42017071858 and ClinicalTrials.gov: NCT04258163. Results: A total of 2,867 patients from 15 RCTs and 760 patients from multicenter cohort were included. The results from meta-analysis showed that chemotherapy maintenance improved progression-free survival (PFS) (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.54 to 0.73; p < 0.001; moderate-quality evidence) and overall survival (OS) (HR, 0.87; 95% CI 0.78 to 0.97; p=0.016; high-quality evidence) than observation. In the cohort study, for hormone receptor–positive MBC patients, chemotherapy maintenance improved PFS (HR, 0.67; 95% CI, 0.52 to 0.85; p < 0.001) and OS (HR, 0.55; 95% CI 0.42 to 0.73; p < 0.001) compared with observation, and endocrine therapy maintenance also improved PFS (HR, 0.65; 95% CI, 0.53 to 0.80; p < 0.001) and OS (HR, 0.55; 95% CI, 0.44 to 0.69; p < 0.001). There were no differences between chemotherapy and endocrine therapy maintenance in PFS and OS (all p > 0.05). Regardless of the continuum or switch maintenance therapy, showed prolonged survival in MBC patients who were response to first-line treatment. Conclusion This study provided evidences for survival benefits of chemotherapy and endocrine therapy maintenance in MBC patients, and there was no difference efficacy between chemotherapy and endocrine therapy maintenance for hormone receptor–positive patients.

Objective:To observe the changes of abdominal aortic calcification and biochemical indicators after parathyroidectomy (PTX) in the maintenance hemodialysis (MHD) patients with secondary hyperparathyroidism (SHPT).Methods:The MHD patients with SHPT who were followed up for 2 years were analyzed retrospectively and divided into PTX surgery group ( n=26) and non-surgery group ( n=18) according to whether they underwent PTX, and then the abdominal aortic calcification score (AACS), intact parathyroid hormone (iPTH), blood calcium and phosphorus after 2 years were observed in the two groups. The PTX surgery group was divided into advanced group and non-advanced group according to whether abdominal aortic calcification had progressed or not 2 years after the operation. Indicators such as age, dialysis age, iPTH, blood calcium, blood phosphorus, calcium and phosphorus product were compared between the two groups to analyze the possible factors related to the development of abdominal aortic calcification. Results:A total of 44 patients meeting the inclusion criteria were included, with 26 in the PTX surgery group and 18 in the non-surgery group. The baseline data of the PTX surgery group and the non-surgery group showed statistical difference in the age of dialysis ( P<0.05), but no statistical differences in gender, age and history of hypertension. Compared with preoperative indicators, postoperative iPTH, blood calcium and phosphorus significantly reduced (all P<0.05), and there was no significant difference in AACS. There were 8 cases (30.77%) of accelerating progress of calcification, 8 cases (30.77%) of improvement in calcification, 10 cases (38.46%) of calcification stability. After 2 years, iPTH value of non-advanced group was significantly lower than advanced group [(20.62±6.44) ng/L vs (132.72±76.83) ng/L], while the preoperative AACS progress was higher in non-advanced group [(13.11±2.71) vs (2.00±1.41)] (all P<0.05). In non-surgery group, AACS was significantly higher after 2 years [(10.44±1.65) vs (8.05±1.26)], blood phosphorus and the product of blood calcium and phosphorus significantly decreased (all P<0.05) , and the levels of iPTH and blood calcium did not significantly change. Pearson correlation analysis showed that the decreased value between preoperative AACS and 2-year postoperative AACS was positively correlated with the decreased value of iPTH ( r=0.534, P=0.012), blood calcium ( r=0.643, P=0.004), blood phosphorus ( r=0.897, P<0.001) and calcium-phosphorus product ( r=0.568, P=0.021) , and negatively correlated with preoperative AACS ( r=-0.647, P=0.014). Conclusions:Small sample data shows that PTX can correct parathyroid hormone, calcium and phosphorus for long term, and prevent abdominal aortic calcification progression, even reverse vascular calcification. Whether abdominal aortic calcification improves or not may be associated with the decrease of iPTH, calcium, phosphorus and the product of blood calcium and phosphorus.

Objective:To investigate the clinical application of cervix-uterine internal target volume (ITV) in volume-modulated arc therapy (VMAT) for cervical cancer under different bladder filling conditions, aiming to obtain more accurate planning target volume (PTV).Methods:Sixty-two patients with cervical cancer receiving radiotherapy rather than surgery were selected and randomly divided into the study ( n=31) and control groups ( n=31). In the study group, individualized ITV, PTV and PTV margin were obtained under three bladder filling status by localization CT scan to compare the VMAT. The target area and organs at risk (OARs) within the target area were statistically compared between two groups. The target missing rate in CBCT, adverse events and short-term efficacy of radiotherapy were analyzed in two groups. Results:There was no significant difference in the volume of target area and OARs in the target area between two groups (both P>0.05). In the study group, the target missing rate and target missing volume were significantly lower compared with those in the control group (both P<0.05). There was no significant difference in the incidence of acute radiation-induced adverse events between two groups ( P>0.05). The 1-, 2-year overall survival and progress-free survival did not significantly differ between two groups (all P>0.05). One patient in the study group had uterine recurrence and 2 cases in the control group. Conclusion:Application of individualized cervix-uterine ITV and PTV in definitive VMAT under different bladder filling conditions can improve the accuracy of target area contouring and improve the local control rate in cervical cancer patients.

Objective:To analyze the level and trend of low birth weight mortality in children under 1 year old in China from 2004 to 2018.Methods:The published Data Set of National Mortality Surveillance from 2004 to 2018 was used to analyze the low birth weight mortality rate, constituent ratio and changing trend in boys and girls, in urban area and rural area and in different regions in China. The Joinpoint regression model fitted by the weighted least square method was used to analyze the time variation trend and calculate the annual percentage change (APC), the average annual percentage change (AAPC) and their 95 % confidence intervals in each time period. Results:From 2004 to 2018, the low birth weight mortality rate in children under 1 year old in China showed a decreasing trend with an AAPC of -8.0 % (95 %CI: -10.6 % --5.4 %). The differences between boys and girls, between urban area and rural area and among different regions gradually reduced. From 2004 to 2018, the constituent ratio of low birth weight mortality showed an increasing trend with an AAPC of 1.6 % (95 %CI: 0.1 %-3.2 %). The mortality rate in urban area (38.74 per 100 000) was higher than that in rural area (30.44 per 100 000). The annual average declining speed of low birth weight mortality rate in urban area (AAPC=-3.4 %, 95 %CI: -7.0 %-0.3 %) was slower than that in rural area (AAPC=-9.3 %, 95 %CI: -12.0 % --6.6 %). The low birth weight mortality rate of boys (36.25 per 100 000) was higher than that of girls (28.22 per 100 000). The low birth weight mortality constituent ratio in western region showed an increasing trend, its average annual percentage change (AAPC=3.2 %, 95 %CI: 1.7 %-4.8 %) increased faster than that of the eastern region (AAPC=-0.5 %, 95 %CI: -2.3 %-1.4 %). In urban and rural areas and different regions, the rate of low birth weight mortality in boys was higher than that in girls. Conclusions:From 2004 to 2018, the mortality rate of low birth weight in children under 1 year old showed a downward trend, and the constituent ratio showed an upward trend. Boys and children living in central and western regions should be the key population for maternal and child health care.

Objective:To analyze the trend of the congenital heart disease mortality rate in children aged under 1 year old from 2004 to 2018.Methods:The mortality rate and constituent ratio of congenital heart disease in different genders, urban and rural areas and regions were calculated by using the publicly available Dataset of National Mortality Surveillance in China from 2004 to 2018. The Joinpoint regression model was used to analyze the changing trend of mortality rate and constituent ratio, and calculate the annual percentage change (APC) in each time period, the average annual percentage change (AAPC) in all time period and their 95% values.Results:From 2004 to 2018, a total of 15 969 children aged 0 to 1 years died of congenital heart disease, of which 58.12% (9 281) were boys and 71.79% (11 464) were in rural areas. The deaths of congenital heart disease in eastern, central and western regions accounted for 34.30%, 37.06% and 28.64% of total deaths, respectively. From 2004 to 2018, the mortality rate of congenital heart disease in children decreased from 106.81 per 100 000 to 38.70 per 100 000, with an AAPC (95%) about -7.2% (-11.5%, -2.6%). The mortality rate of congenital heart disease showed a downward trend in girls [AAPC (95%) =-7.7% (-13.0%, -2.0%)], boys [AAPC (95%)=-6.8% (-12.0%, -1.2%)], urban areas [AAPC (95%) =-5.9% (-9.9%, -1.7%)], rural areas [AAPC (95%) =-7.4% (-10.5%, -4.2%)], eastern region [AAPC (95%)=-8.6% (-14.2%, -2.6%)], and central region [AAPC (95%)=-7.8% (-11.5%, -4.0%)]. The gaps of mortality rate gradually shrank in different genders, urban and rural areas and regions. From 2004 to 2018, the constituent ratio of congenital heart disease in children showed an upward trend [AAPC (95%) = 3.3% (1.7%, 4.9%)].Conclusion:From 2004 to 2018, the mortality rate of congenital heart disease in children aged 0 to 1 years showed a downward trend, and the constituent ratio showed an upward trend.

Objective:To analyze the trend of the congenital heart disease mortality rate in children aged under 1 year old from 2004 to 2018.Methods:The mortality rate and constituent ratio of congenital heart disease in different genders, urban and rural areas and regions were calculated by using the publicly available Dataset of National Mortality Surveillance in China from 2004 to 2018. The Joinpoint regression model was used to analyze the changing trend of mortality rate and constituent ratio, and calculate the annual percentage change (APC) in each time period, the average annual percentage change (AAPC) in all time period and their 95% values.Results:From 2004 to 2018, a total of 15 969 children aged 0 to 1 years died of congenital heart disease, of which 58.12% (9 281) were boys and 71.79% (11 464) were in rural areas. The deaths of congenital heart disease in eastern, central and western regions accounted for 34.30%, 37.06% and 28.64% of total deaths, respectively. From 2004 to 2018, the mortality rate of congenital heart disease in children decreased from 106.81 per 100 000 to 38.70 per 100 000, with an AAPC (95%) about -7.2% (-11.5%, -2.6%). The mortality rate of congenital heart disease showed a downward trend in girls [AAPC (95%) =-7.7% (-13.0%, -2.0%)], boys [AAPC (95%)=-6.8% (-12.0%, -1.2%)], urban areas [AAPC (95%) =-5.9% (-9.9%, -1.7%)], rural areas [AAPC (95%) =-7.4% (-10.5%, -4.2%)], eastern region [AAPC (95%)=-8.6% (-14.2%, -2.6%)], and central region [AAPC (95%)=-7.8% (-11.5%, -4.0%)]. The gaps of mortality rate gradually shrank in different genders, urban and rural areas and regions. From 2004 to 2018, the constituent ratio of congenital heart disease in children showed an upward trend [AAPC (95%) = 3.3% (1.7%, 4.9%)].Conclusion:From 2004 to 2018, the mortality rate of congenital heart disease in children aged 0 to 1 years showed a downward trend, and the constituent ratio showed an upward trend.

Objective: To investigate the impact of bladder filling status on the movement of uterine and on the volume of organs at risk(OAR), so as to provide theoretical basis for individualized internal target volume (ITV) and planning target volume (PTV). Methods: Simulation CT images for a total of 27 patients with locally advanced cervical cancer were acquired with empty bladder, 1.0 h after bladder filling, 1.5 h after bladder filling, respectively. The volumes of uterine corpus, cervix, OARs, CTV and PTV 1.0 h after bladder filling were delineated. The impact of bladder filling status on the displacements of cervix and corpus, volumetric changes of rectum, small intestine, and the volumes of small intestine, bladder and rectum within PTV were analyzed. The correlation between bladder filling status and uterine displacement and volume of OAR was also investigated, as well as the volume of cervix and corpus in the PTV with empty bladder and 1.5 h after bladder filling. Results: Bladder filling status is different for individual cases. The maximum movement range of cervix and uterine body with bladder filling state was 0-3.04 cm and 0-4.31 cm respectively. The anterior displacements of corpus (F=7.818, P<0.05), the volumetric changes of blander, as well the volume of bladder and small intestine in the PTV (F=46.197, 44.609, 29.546, P<0.05) were significantly different between different bladder filling status. The bladder filling status was correlated with the displacements of the anterior of corpus, volumetric changes of small intestine, and the volumes of bladder and small intestine within the PTV (r=-0.232, -0.298, 0.915, -0.336, P<0.05). The volumes of cervix and corpus out of the PTV were significantly different between the empty bladder and 1.5 h after bladder filling (t=-1.326, -1.559, P<0.05). Conclusions Bladder filling status was different for individual patients. The displacements of the anterior of the corpus were significantly affected by the bladder filling status. Increasing the anterior margin of PTV was recommended. The consistency of bladder filling status was critical for the precise cervical cancer IMRT.

Objective To observe the effects of different dosages of ginsenoside Rb1 preconditioning on spinal cord ischemia-reperfusion injury in rats, and the possible mechanism. Methods Sprague-Dawley rats were randomly divided into sham group (n=12), model group (n=12), and 10 mg/kg (D10, n=12), 20 mg/kg (D20, n=12), 40 mg/kg (D40, n=12) and 80 mg/kg (D80, n=12) drug groups. Spinal cord ischemia for ten minutes and reperfusion model was established, and the drug groups were injected ginsenoside Rb1 intraperitoneally in their dosages 30 minutes before modeling. They were assessed with BBB score 48 hours after reperfusion, and then were sacrificed for HE staining, TUNEL staining and immunohistochemistry staining of survivin.Results The BBB score was more in the drug groups than in the model group (P<0.05), and was the most in D40 and D80 groups. The expression of survivin was more in the drug groups than in the model group (P<0.05), and was the most in D40 and D80 groups. The apoptosis of neurons was less in the drug groups than in the model group (P<0.05), and was the least in D40 and D80 groups.Conclusion The ginsenoside Rb1 could promote the expression of survivin, inhibit apoptosis of neurons, to protect the neural function, in dose-dependent manner somehow.

Although still in its infant stage, synthetic biology has achieved remarkable development and progress during the past decade. Synthetic biology applies engineering principles to design and construct gene circuits uploaded into living cells or organisms to perform novel or improved functions, and it has been widely used in many fields. In this review, we describe the recent advances of mammalian synthetic biology for the treatment of diseases. We introduce common tools and design principles of synthetic gene circuits, and then we demonstrate open-loop gene circuits induced by different trigger molecules used in disease diagnosis and close-loop gene circuits used for biomedical applications. Finally, we discuss the perspectives and potential challenges of synthetic biology for clinical applications.