Coronavirus-related diseases pose a significant challenge to the global health system. Given the diversity of coronaviruses and the unpredictable nature of disease outbreaks, the traditional "one bug, one drug" paradigm struggles to address the growing number of emerging crises. Therefore, there is an urgent need for therapeutic agents with broad-spectrum anti-coronavirus activity. Here, we provide evidence that ATV006, an anti-SARS-CoV-2 nucleoside analog targeting RNA-dependent RNA polymerase (RdRp), has broad antiviral activity against human and animal coronaviruses. Using mouse hepatitis virus (MHV) and human coronavirus NL63 (HCoV-NL63) as a model, we show that ATV006 has potent prophylactic and therapeutic activity against murine coronavirus infection in vivo. Remarkably, ATV006 successfully inhibits viral replication in mice even when administered 96 h after infection. Due to its oral bioavailability and potency against multiple coronaviruses, ATV006 has the potential to become a useful antiviral agent against SARS-CoV-2 and other circulating and emerging coronaviruses in humans and animals.

Quantum dots are an emerging semiconductor nanocrystalline material with optical and electronic properties. Quantum dots in the environment are transmitted into human body mainly via digestive system. Quantum dots in the workplace are transmitted into human body via various pathways such as the respiratory tract and mucocutaneous surface. They cross the blood brain barrier to affect the nervous system, eventually leading to irreversible damage. Quantum dots have more complex biological toxicity than ordinary nanomaterials and metal ions, due to their core-shell structure and surface modifiers. The physicochemical properties of quantum dots, such as particle size, surface modification, and charge, greatly influence their neurotoxic effects. Quantum dots can induce oxidative stress and inflammatory responses, causing neuronal damage and functional impairment, thereby affecting learning, memory, and synaptic plasticity. Its mechanisms may be the modulation of signaling pathways such as the mitogen-activated protein kinase/extracellular signal regulated kinase pathway. In the future, the neurotoxicity of different types of quantum dots should be systematically analyzed, and multi-omics methods should be used to elucidate the mechanism of quantum dots on neuronal damage to improve the safety of workers exposed to quantum dots.

Objective:To investigate the biological behavior spectrum of platelet-derived growth factor alpha receptor (PDGFRA)-mutant gastrointestinal stromal tumor (GIST), and to compare the clinical values of the Zhongshan method of benign and malignant evaluation with the modified National Institutes of Health (NIH) risk stratification.Methods:A total of 119 cases of GIST with PDGFRA mutation who underwent surgical resection at Zhongshan Hospital, Fudan University from 2009 to 2020 were collected. The clinicopathological data, follow-up records, and subsequent treatment were reviewed and analyzed statistically.Results:There were 79 males and 40 females. The patients ranged in age from 25 to 80 years, with a median age of 60 years. Among them, 115 patients were followed up for 1-154 months, and 13 patients progressed to disease. The 5-year disease-free survival (DFS) and overall survival (OS) were 90.1% and 94.1%, respectively. According to the modified NIH risk stratification, 8 cases, 32 cases, 38 cases, and 35 cases were very-low risk, low risk, intermediate risk, and high risk, and 5-year DFS were 100.0%, 95.6%, 94.3%, and 80.5%, respectively. There was no significant difference in prognosis among the non-high risk groups, only the difference between high risk and non-high risk groups was significant ( P=0.029). However, the 5-year OS was 100.0%, 100.0%, 95.0% and 89.0%, and there was no difference ( P=0.221). According to the benign and malignant evaluation Zhongshan method, 43 cases were non-malignant (37.4%), 56 cases were low-grade malignant (48.7%), 9 cases were moderately malignant (7.8%), and 7 cases were highly malignant (6.1%). The 5-year DFS were 100.0%, 91.7%, 77.8%, 38.1%, and the difference was significant ( P<0.001). The 5-year OS were 100.0%, 97.5%, 77.8%, 66.7%, the difference was significant ( P<0.001). Conclusions:GIST with PDGFRA gene mutation shows a broad range of biological behavior, ranging from benign to highly malignant. According to the Zhongshan method, non-malignant and low-grade malignant tumors are common, the prognosis after surgery is good, while the fewer medium-high malignant tumors showed poor prognosis after surgical resection. The overall biological behavior of this type of GIST is relatively inert, which is due to the low proportion of medium-high malignant GIST. The modified NIH risk stratification may not be effective in risk stratification for PDGFRA mutant GIST.

The fat mass and obesity-associated protein (FTO) is an RNA demethylase required for catalytic demethylation of N ⁶-methyladenosine (m⁶A); it is highly expressed and functions as an oncogene in acute myeloid leukemia (AML). Currently, the overarching objective of targeting FTO is to precisely inhibit the catalytic activity. Meanwhile, whether FTO degradation also exerts antileukemic effects remains unknown. Herein, we designed the first FTO-targeting proteolysis targeting chimera (PROTAC) degrader QP73 using our FTO inhibitor Dac85-which potently inhibits FTO demethylation in AML cell lines-as a warhead. Notably, QP73 significantly induced FTO degradation in a time-, dose-, and ubiquitin-proteasome system-dependent manner and had superior antiproliferative activities to the FTO inhibitor Dac85 in various AML cell lines. Moreover, QP73 treatment significantly increased m⁶A modification on mRNA, promoted myeloid differentiation, and induced apoptosis of AML cells. Quantitative proteomics analysis showed that QP73 induced complete FTO degradation, upregulating RARA and ASB2 abundance and downregulating CEBPA, MYC, PFKP, and LDHB levels in AML cells. Lastly, QP73 exhibited antileukemic activity by increasing m⁶A modification and decreasing FTO levels in xenograft AML tumors. This proof-of-concept study shows that FTO-targeting PROTAC degraders can regulate the FTO signaling pathway and have potential antileukemia applications.

Objective To analyze clinical prognosis, risk factors and predictive indexes of hyperkalemia in recipients after heart transplantation. Methods Clinical data of 158 recipients were retrospectively analyzed. According to the serum potassium levels within postoperative 1-year follow-up, all recipients were divided into the normal serum potassium level group (n=83), hyperkalemia group (n=43) and severe hyperkalemia group (n=32). The incidence and prognosis of hyperkalemia after heart transplantation were summarized. The risk factors and predictive indexes of hyperkalemia after heart transplantation were identified. Results The incidence of hyperkalemia and severe hyperkalemia within postoperative 1 year was 47.5%(75/158) and 20.3%(32/158), respectively. In the severe hyperkalemia group, the fatality was 16%(5/32), higher than 8%(7/83) in the normal serum potassium level group and 7%(3/43) in the hyperkalemia group. The mean serum creatinine (Scr) within 6 months before heart transplantation, the final total bilirubin level before heart transplantation, postoperative hemodialysis time, the Scr level and N-terminal pro-brain natriuretic peptide level at postoperative 1 d were the independent risk factors for hyperkalemia following heart transplantation (all P < 0.05). The mean Scr level within 6 months before heart transplantation, postoperative hemodialysis time, and Scr levels at postoperative 1 and 7 d could be used to predict postoperative severe hyperkalemia. Conclusions The recipients with severe hyperkalemia after heart transplantation obtain poor prognosis. The mean Scr level within 6 months before heart transplantation, the final total bilirubin level before heart transplantation, postoperative hemodialysis time, and the Scr level and N-terminal pro-brain natriuretic peptide level at postoperative 1 d are the independent risk factors for hyperkalemia after heart transplantation. Perioperative Scr level and postoperative hemodialysis time may be used to predict the incidence of severe hyperkalemia within 1 year after heart transplantation.

Objective:To investigate the value of synthetic MRI quantitative parameters in identifying different molecular types of breast cancer and triple negative breast cancer (TNBC) and non-TNBC.Methods:A retrospective analysis was performed on 208 patients diagnosed with invasive ductal breast cancer in the First Affiliated Hospital of China Medical University from March 2019 to September 2020. All patients underwent synthetic MR examinations and the following quantitative parameters were measured, including tumor diameter, volume, apparent diffusion coefficient (ADC), and corresponding values of T 1, T 2, and proton density (PD). According to the immunohistochemical results, there were 122 cases of progesterone receptor (PR) positive and 86 cases of PR negative, 123 cases of estrogen receptor (ER) positive and 85 cases of ER negative, 79 cases of human epidermal growth factor receptor-2 (HER2) positive and 129 cases of HER2 negative, 149 cases of Ki-67 high expression and 59 cases of Ki-67 low expression; there were 36 cases of TNBC and 172 cases of non-TNBC. Independent samples t test or Mann-Whitney U test were used to compare the quantitative parameters of different molecular types, TNBC and non-TNBC patients. Multivariate logistic regression was used to analyze independent predictors of TNBC, and receiver operating characteristic curve and area under the curve (AUC) were used to evaluate the efficacy of sole and combined parameters in identifying TNBC. Results:T 1 and T 2 values in PR negative breast cancer patients were higher than those in PR positive patients ( t=2.30, Z=2.04, P<0.05); the values of T 1 and T 2 in ER negative patients were higher than those in ER positive patients ( t=2.52, Z=2.48, P<0.05); ADC value and tumor diameter of HER2 positive patients were larger than those in HER2 negative patients ( t=-3.21, Z=-3.22, P<0.05). T 2 value, tumor volume and diameter in patients with Ki-67 high expression were significantly higher than those in patients with Ki-67 low expression ( Z=-3.47, -2.51, -2.84, P<0.05); ADC value in Ki-67 high expression group was less than that in Ki-67 low expression group ( t=3.94, P<0.001). T 1, T 2 values and tumor volume in TNBC patients were higher than those in non-TNBC patients ( t=-3.26, Z=-5.58, Z=-2.02, P<0.05], and ADC value in TNBC patients was lower than that in non-TNBC patients ( t=3.07, P=0.002). Multivariate logistic regression analysis showed that T 2 (OR=1.060, 95%CI 1.028-1.093, P<0.001) and ADC value (OR=0.947, 95%CI 0.911-0.984, P=0.005) were independent predictors of TNBC. The efficacy of each parameter alone and in combination to identify TNBC showed that the T 2 value in the single parameter had the largest AUC (0.759), and there was no significant difference between T 2 value and its combined parameters in the diagnosis of TNBC. Conclusions:The quantitative parameters based on synthetic MRI, especially T 2 value, have value in differentiating different molecular types of breast cancer, TNBC and non-TNBC may be another non-contrast parameter for evaluating tumor aggressiveness beyond ADC value.

Objective : To analyze the effect of different cavosurface angles on the stress distribution of ClassⅠ cavity composite resin filling of molars through the three-dimensional finite element method and to provide references for the preparation of ClassⅠ cavities. Methods: Three-dimensional finite element models of ClassⅠ composite resin filling of mandibular first molars with three different cavosurface angles (group A: 90°, group B: 120°, group C: 135°) were established. Polymerization shrinkage of composites was simulated with a thermal expansion approach. The mechanical behavior of the restored models in terms of stress and displacement distributions under the combined effects of polymerization shrinkage and occlusal load (600 N) was analyzed. Results: For ClassⅠ cavities with the same cavity size, the total stress of the restoration model and the maximum stress of the enamel in group A were less than those in groups B and C after cavity composite resin restoration with three cavity cavosurface angles (in which the width of the enamel bevel was 1 mm in groups B and C). The maximum stress of the dentin and adhesive was similar in the three groups, the maximum stress of the composite in group C was the largest, and the maximum stress of the composite in group B was the smallest. In terms of stress distribution, the maximum stress in each restoration model was mainly concentrated in the enamel at the cavosurface, near the enamel-dentin interface and at the edge of the restoration material. Conclusion From the point of reducing the stress of residual tooth tissue, the preparation of 90° angle without enamel bevel is an ideal method for cavity preparation when composite resin is used to fill ClassⅠ cavities of molars.

Primary liver cancer ( PLC) , the most com-mon malignant carcinoma in the world , greatly impairs the hu-man health .Various treatments for PLC have been practiced but the therapeutic effects are still unsatisfied .Nowadays, interven-tional therapy , chemotherapy , radiotherapy , molecular targeted therapy and radiofrequency ablation are playing a key role in hepatocellular carcinoma treatment .In near future , more ad-vancements on comprehensive therapy for PLC are being expec-ted.This review aimed to describe the recent scenario and cur-rent advancement on non-surgical treatment for hepatocellular carcinoma .

Objective To analyze the effect of high and low dose radiation on the expressions of Th1,Th2 and Th3 /Tr1 related-genes in mice thymocytes and investigate the possible underlying molecular mechanism.Methods ICR mice were randomly divided into low-dose group (0.075 Gy),high-dose group (2.0 Gy) and sham-control group.The mouse thymus tissue was extracted at 16 hours after irradiation and the expressions of Th1-Th2-Th3 related genes were measured by PCR array.Results Eight genes were up-regulated and five genes were down-regulated after low dose radiation (0.075 Gy);while 54 genes were up-regulated and three genes were down-regulated after high dose (2.0 Gy) radiation.These genes included Th1 cell related genes,Th2 cell related genes,Th3/Tr1 cell related genes,Th1/Th2 immune response genes and transcription factor related genes.Low dose radiation induced up-regulation of Stat4 and Socs1 of genes related to the Th1 cells,and it induced down-regulation of IL-4ra,Cebpb,Gata3 and Tgfb3 associated with Th2 and Th3 cells,which lead to Sftpd genes up-regulation of Th1 immune response eventually.The high dose radiation up-regulated all of Th1,Th2 and Th3/Tr related genes and also enhanced the expressions of Cd86,IL-18,IL-10 and Irf4 genes related to Th2 immune response,but it did not alter the gene expression of Th1 immune response.Conclusions Low-dose radiation induces Th1-type immune response,while high doses radiation triggers Th2 type immune response.

BACKGROUND:Chronic visceral pain is one of major complaints of irritable bowel syndrome which seriously affects patient’s quality of life. Recent researches have shown that moxibustion therapy has positive effects on aleviating chronic visceral pain in irritable bowel syndrome patients.
OBJECTIVE: To study the clinical utility of moxibustion in coping with chronic visceral pain of irritable bowel syndrome patients, and shed light on the theoretical basis of moxibustion analgesia, thereby to give insights into the further research and application on moxibustion.
METHODS: With the key words of “moxibustion, irritable bowel syndrome, visceral pain, abdominal pain” in Chinese and in English, respectively, a computer-based search was performed in CNKI, VIP, Wanfang and PubMed databases for articles published from January 1990 to October 2014. After the initial screening, the remained articles went through further selection and categorization.
RESULTS AND CONCLUSION:The result shows promising results of moxibustion on relieving chronic visceral pain for both two subtypes of irritable bowel syndrome patients, diarrhea type and constipation type. Moxibustion may exert an analgesic effect on chronic visceral pain in irritable bowel syndrome patients through regulation of visceral hypersensitivity, gastrointestinal motility disorders, brain-gut axis and neuroendocrine system disorders, immune dysfunction and low-grade inflammation in the gut, psychological abnormalities, and alteration of intestinal flora. However, to fuly understand the analgesia effect of moxibustion and elucidate its mechanism, more standardized randomized controled trials employing advanced scientific techniques and equipments wil stil be needed in the future.