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.

Triple-negative breast cancer is therapeutically challenging due to the low expression of tumor markers and 'cold' tumor immunosuppressive microenvironment. Here, we present a dual-targeting peptide-drug conjugate (PDC) for tumor inhibition. Our PDC efficiently and selectively delivers cytotoxic Monomethyl Auristatin E (MMAE) into tumor cells via C-X-C chemokine receptor type 4 (CXCR4) and folate receptor 1 (FOLR1) for synergistic inhibition of growth and metastasis. Our results show that the dual-targeting PDC has potent antitumor activity in cultured human cells and several murine transplanted tumor models without apparent toxicity. The combination of dual-targeting PDC and radiotherapy modulates the tumor immunosuppressive microenvironment by increasing CD8⁺ T cell infiltration and attenuating the proportion of myeloid-derived suppressor and regulatory T cells. Therefore, our dual-targeting PDC represents a promising new strategy for cancer therapy that rebalances the immune system and promotes tumor regression.

Objective To analyze the factors affecting pathological complete response(pCR)of triple-negative breast cancer(TNBC)patients after neoadjuvant chemotherapy,and construct a nomogram to forecast the pCR rate.Methods The clinical and pathological data of 348 TNBC patients who received neoadjuvant chemotherapy in the Air Force Medical University-Affiliated Xijing Hospital from May 2018 to May 2021 were collected and set as modeling set.The clinical and pathological data of 69 TNBC patients who received neoadjuvant chemotherapy in the Xi'an No.3 Hospital from May 2018 to May 2021 were collected and set as validation set.The clinical and pathological characteristics were compared between the modeling set and the validation set.In the modeling set,the independent risk factors of pCR in TNBC patients after neoadjuvant chemotherapy were screened by LASSO regression model analysis,and the nomogram model was constructed.Internal validation of the model was conducted using Bootstrap method,and the discrimination of the model was assessed by receiver operating characteristic(ROC)curve.The accuracy of the model was evaluated by the calibration curve and the clinical benefits and application value of the model were evaluated by clinical decision curve analysis(DCA).Results There were significant differences in surgical method and T stage between the patients in modeling set and validation set(P<0.05).The results of analysis of LASSO regression model showed that T stage,N stage,the use of platinum drugs and clinical efficacy evaluation were independent risk factors of pCR in TNBC patients after neoadjuvant chemotherapy(P<0.05).Based on the above variables,the nomogram models were constructed.In modeling set,area under curve(AUC)was 0.811(95%CI 0.763-0.859);in validation set,AUC was 0.801(95%CI 0.727-0.928).The Bootstrap method showed the C-index for internal validation was 0.79,indicating the model has good discrimination in both the modeling and validation sets.The calibration curve analysis showed that model predicted pCR rates had a good consistency with the actual observed values,and the DCA showed that model can bring clinical benefit.Conclusion The nomogram can accurately predict the pCR rates of TNBC patients after neoadjuvant chemotherapy and provide scientific basis for clinical diagnosis and treatment.

Objective:To measure the magnetic field correction factor of reference ionization chamber in a 1.5 T magnetic field and to explore the response of the ionization chamber among different angles between magnetic field and ionization chamber axis.Methods:A home-made magnetic compatible one-dimensional water tank was used to measure the response of PTW30013 and IBA FC65-G in 7 MV photon beam of Elekta Unity with and without magnetic field. The ionizing current was collected by PTW UNIDOS Tango electrometer. The effective measurement point of ionization chamber was positioned to the isocenter of MR-linac using electronic portal image device. The influence on water absorbed dose of reference point was obtained by Monte Carlo calculations.Results:The response of ionization chambers in strong magnetic field was related to the angle between chamber axis and magnetic field. The response of ionization chamber was significantly affected in perpendicular magnetic field with a deviation up to 4.54% compared to parallel magnetic field. The deviation between the magnetic field correction factors measured for parallel or reverse-parallel was 0.03%-0.24%. The magnetic field correction factors for PTW30013 and FC65-G measured in parallel magnetic field were 0.9934±0.0077 and 0.9990±0.0076, respectively.Conclusions:This study experimentally verifies that positioning the ionization chamber axis parallel to the magnetic field direction in MR-linac reference dosimetry can minimize the magnetic field impact. The determined magnetic field correction factor and uncertainty in 1.5 T magnetic field can provide necessary data for establishing an MR-linac reference dosimetry protocol.

Objective To investigate the mechanism of Yes-associated protein 1(YAP1)ameliorating aristolochic acid 1(AAI)-induced liver injury in mice based on untargeted metabolomics techniques.Methods There were 83-week-old male hepatocyte-specific Yap1 gene knockout mice(genotyped as Yap1Flox/Flox,Albumin-Cre,aka.Yap1LKO)were randomly selected as the Yap1LKO+AAI group,and 8 Yap1Flox control mice as the Yap1Flox+AAI group.Both groups were injected intraperitoneally with AAI at a dose of 2.5 mg·kg-1·d-1 for 14 consecutive days.Genotypes were identified by tail PCR;serum alanine transaminase(ALT)and aspartate transaminase(AST)activities were determined by microplate assay;histopathological changes of liver tissue were observed by HE staining;and the protein expression of YAP1 in liver tissue was determined by immunohistochemistry.The untargeted metabolomics approach was used to analyze the liver tissue differential metabolites,and the samples were analyzed by ultra performance liquid chromatography-quadrupole-electrostatic field orbit trap high-resolution mass spectrometry,and the differential metabolites were screened by principal component analysis(PCA),Partial least square-discriminant analysis(PLS-DA),and orthogonal partial least squares-discriminant analysis(OPLS-DA);using HMDB database and METLIN database to identify metabolites,and the pathway enrichment of differential metabolites was analyzed by KEGG database.Results(1)After 14 days of AAI induction,the increase of body mass in Yap1LKO mice was lower than that in Yap1Flox mice,but there was no statistical significance(P＞0.05).On day 14,compared with the Yap1Flox+AAI group,the serum ALT and AST enzyme activities in the Yap1LKO+AAI group of mice were significantly increased(P＜0.05),and the histopathological damage of the liver was significantly aggravated.The livers of the Yap1Flox mice had a positive protein expression of YAP1,whereas the Yap1LKO mice did not have a positive protein expression of YAP1.(2)A total of 139 differential metabolites with significant changes(VIP＞1 and P＜0.05)were screened by metabonomic analysis;compared with Yap1LKO+ AAI group,62 liver metabolites in Yap1Flox+AAI group were up-regulated,including choline,taurine,hypotaurine,α-linolenic acid,eleostearic acid,chenodeoxycholic acid and so on.Seventy-seven metabolites were down-regulated including glycerophosphocholine,L-phosphatidylcholine,L-glutamine,L-serine,L-glutathione,5-methionine,phenylalanine,glucose 6-phosphate,lactic acid,uric acid glycosides,etc..KEGG-enriched pathways were mainly choline metabolism,glycerophospholipid metabolism,insulin resistance,glutathione metabolism,etc..Conclusion Hepatocyte-specific Yap1 gene knockout exacerbated AAI-induced liver injury in mice,and YAP1 was involved in the regulation of choline metabolism and glycerophospholipid metabolism through the up-regulation of unsaturated fatty acids,such as choline and taurine,which ameliorated AAI-induced liver injury in mice.

Objective: This study aimed to evaluate the effects of 2 endoscopic spine surgeries on the biomechanical properties of normal and osteoporotic spines. Methods: Based on computed tomography images of a healthy adult volunteer, 6 finite element models were created. After validating the normal intact model, a concentrated force of 400 N and a moment of 7.5 Nm were exerted on the upper surface of L3 to simulate 6 physiological activities of the spine. Five types of indices were used to assess the biomechanical properties of the 6 models, range of motion (ROM), maximum displacement value, intervertebral disc stress, maximum stress value, and articular protrusion stress, and by combining them with finite element stress cloud. Results: In normal and osteoporotic spines, there was no meaningful change in ROM or disc stress in the 2 surgical models for the 6 motion states. Model N1 (osteoporotic percutaneous transforaminal endoscopic discectomy model) showed a decrease in maximum displacement value of 20.28% in right lateral bending. Model M2 (unilateral biportal endoscopic model) increased maximum displacement values of 16.88% and 17.82% during left and right lateral bending, respectively. The maximum stress value of L4–5 increased by 11.72% for model M2 during left rotation. In addition, using the same surgical approach, ROM, maximum displacement values, disc stress, and maximum stress values were more significant in the osteoporotic model than in the normal model. Conclusion In both normal and osteoporotic spines, both surgical approaches were less disruptive to the physiologic structure of the spine. Furthermore, using the same endoscopic spine surgery, normal spine biomechanical properties are superior to osteoporotic spines.

Objective: This study aimed to evaluate the effects of 2 endoscopic spine surgeries on the biomechanical properties of normal and osteoporotic spines. Methods: Based on computed tomography images of a healthy adult volunteer, 6 finite element models were created. After validating the normal intact model, a concentrated force of 400 N and a moment of 7.5 Nm were exerted on the upper surface of L3 to simulate 6 physiological activities of the spine. Five types of indices were used to assess the biomechanical properties of the 6 models, range of motion (ROM), maximum displacement value, intervertebral disc stress, maximum stress value, and articular protrusion stress, and by combining them with finite element stress cloud. Results: In normal and osteoporotic spines, there was no meaningful change in ROM or disc stress in the 2 surgical models for the 6 motion states. Model N1 (osteoporotic percutaneous transforaminal endoscopic discectomy model) showed a decrease in maximum displacement value of 20.28% in right lateral bending. Model M2 (unilateral biportal endoscopic model) increased maximum displacement values of 16.88% and 17.82% during left and right lateral bending, respectively. The maximum stress value of L4–5 increased by 11.72% for model M2 during left rotation. In addition, using the same surgical approach, ROM, maximum displacement values, disc stress, and maximum stress values were more significant in the osteoporotic model than in the normal model. Conclusion In both normal and osteoporotic spines, both surgical approaches were less disruptive to the physiologic structure of the spine. Furthermore, using the same endoscopic spine surgery, normal spine biomechanical properties are superior to osteoporotic spines.

This study adopted the policy text analysis method,review the historical background of the enactment,aimed to comparatively analyze the international pharmaceutical trade policies of the BRICS countries.The main objectives of the BRICS countries'international pharmaceutical trade policies included ensuring stable and accessible drug supply,expanding exports of domestic products and creating a favorable political environment.For these purposes,Brazil,Russia,and South Africa all ensure drug supply through substantial imports.However,they have also taken measures such as compulsory patent licensing and promoting localization of production by foreign companies to reduce import dependence.India,on the other hand,protects its domestic industry by resisting drug imports to ensure drug supply while simultaneously promoting the export of pharmaceutical products.China continually optimizes approval and data monitoring procedures to align with international standards,creating a favorable trade environment and expanding exports.China should further refine its international pharmaceutical trade policies while ensuring the autonomy of domestic drug research and supply,fostering stronger collaboration within BRICS nations and promoting global access to public healthcare products.

Objective: This study aimed to evaluate the effects of 2 endoscopic spine surgeries on the biomechanical properties of normal and osteoporotic spines. Methods: Based on computed tomography images of a healthy adult volunteer, 6 finite element models were created. After validating the normal intact model, a concentrated force of 400 N and a moment of 7.5 Nm were exerted on the upper surface of L3 to simulate 6 physiological activities of the spine. Five types of indices were used to assess the biomechanical properties of the 6 models, range of motion (ROM), maximum displacement value, intervertebral disc stress, maximum stress value, and articular protrusion stress, and by combining them with finite element stress cloud. Results: In normal and osteoporotic spines, there was no meaningful change in ROM or disc stress in the 2 surgical models for the 6 motion states. Model N1 (osteoporotic percutaneous transforaminal endoscopic discectomy model) showed a decrease in maximum displacement value of 20.28% in right lateral bending. Model M2 (unilateral biportal endoscopic model) increased maximum displacement values of 16.88% and 17.82% during left and right lateral bending, respectively. The maximum stress value of L4–5 increased by 11.72% for model M2 during left rotation. In addition, using the same surgical approach, ROM, maximum displacement values, disc stress, and maximum stress values were more significant in the osteoporotic model than in the normal model. Conclusion In both normal and osteoporotic spines, both surgical approaches were less disruptive to the physiologic structure of the spine. Furthermore, using the same endoscopic spine surgery, normal spine biomechanical properties are superior to osteoporotic spines.

Objective: This study aimed to evaluate the effects of 2 endoscopic spine surgeries on the biomechanical properties of normal and osteoporotic spines. Methods: Based on computed tomography images of a healthy adult volunteer, 6 finite element models were created. After validating the normal intact model, a concentrated force of 400 N and a moment of 7.5 Nm were exerted on the upper surface of L3 to simulate 6 physiological activities of the spine. Five types of indices were used to assess the biomechanical properties of the 6 models, range of motion (ROM), maximum displacement value, intervertebral disc stress, maximum stress value, and articular protrusion stress, and by combining them with finite element stress cloud. Results: In normal and osteoporotic spines, there was no meaningful change in ROM or disc stress in the 2 surgical models for the 6 motion states. Model N1 (osteoporotic percutaneous transforaminal endoscopic discectomy model) showed a decrease in maximum displacement value of 20.28% in right lateral bending. Model M2 (unilateral biportal endoscopic model) increased maximum displacement values of 16.88% and 17.82% during left and right lateral bending, respectively. The maximum stress value of L4–5 increased by 11.72% for model M2 during left rotation. In addition, using the same surgical approach, ROM, maximum displacement values, disc stress, and maximum stress values were more significant in the osteoporotic model than in the normal model. Conclusion In both normal and osteoporotic spines, both surgical approaches were less disruptive to the physiologic structure of the spine. Furthermore, using the same endoscopic spine surgery, normal spine biomechanical properties are superior to osteoporotic spines.