Several types of arthritis share the common feature that the generation of inflammatory mediators leads to joint cartilage degradation. However, the shared mechanism is largely unknown. H2BK120ub1 was reportedly involved in various inflammatory diseases but its role in the shared mechanism in inflammatory joint conditions remains elusive. The present study demonstrated that levels of cartilage degradation, H2BK120ub1, and its regulator WW domain-containing adapter protein with coiled-coil (WAC) were increased in cartilage in human rheumatoid arthritis (RA) and osteoarthritis (OA) patients as well as in experimental RA and OA mice. By regulating H2BK120ub1 and H3K27me3, WAC regulated the secretion of inflammatory and cartilage-degrading factors. WAC influenced the level of H3K27me3 by regulating nuclear entry of the H3K27 demethylase KDM6B, and acted as a key factor of the crosstalk between H2BK120ub1 and H3K27me3. The cartilage-specific knockout of WAC demonstrated the ability to alleviate cartilage degradation in collagen-induced arthritis (CIA) and collagenase-induced osteoarthritis (CIOA) mice. Through molecular docking and dynamic simulation, doxercalciferol was found to inhibit WAC and the development of cartilage degradation in the CIA and CIOA models. Our study demonstrated that WAC is a key factor of cartilage degradation in arthritis, and targeting WAC by doxercalciferol could be a viable therapeutic strategy for treating cartilage destruction in several types of arthritis.

SARS-CoV-2 and its emerging variants continue to pose a significant global public health threat. The SARS-CoV-2 main protease (M^pro) is a critical target for the development of antiviral agents that can inhibit viral replication and transcription. In this study, we identified chebulagic acid (CHLA), isolated from Terminalia chebula Retz., as a potent non-peptidomimetic and non-covalent M^pro inhibitor. CHLA exhibited intermolecular interactions and provided significant protection to Vero E6 cells against a range of SARS-CoV-2 variants, including the wild-type, Delta, Omicron BA.1.1, BA.2.3, BA.4, and BA.5, with EC₅₀ values below 2 μmol/L. Moreover, in vivo studies confirmed the antiviral efficacy of CHLA in K18-hACE2 mice. Notably, CHLA bound to a unique groove at the interface between M^pro domains I and II, which was revealed by the high-resolution crystal structure (1.4 Å) of the M^pro-CHLA complex, shrinking the substrate binding pocket of M^pro and inducing M^pro aggregation. CHLA was proposed to act as an allosteric inhibitor. Pharmacokinetic profiling and safety assessments underscore CHLA's potential as a promising broad-spectrum antiviral candidate. These findings report a novel binding site on M^pro and identify antiviral activity of CHLA, providing a robust framework for lead compounds discovery and elucidating the underlying molecular mechanisms of inhibition.

Objective:To evaluate the treatment persistence and long-time safety of infliximab (IFX) in the real-world in Chinese patients with Crohn′s disease (CD).Methods:From January 2009 to December 2021, at Sir Run Run Shaw Hospital, School of medicine, Zhejiang University, the clinical data of 1 309 patients with CD and treated with IFX were retrospectively analyzed, which included baseline data (gender, age at diagnosis, follow-up time, etc.), usage of IFX (the duration of treatment and situation of discontinuation) and adverse effects of IFX. Kaplan-Meier method was used to calculate the rate of consistent use of IFX and Cox regression was performed to analyze the influencing factors of treatment persistence. The chi-square test was used to analyze the associations between different factors and safety outcomes.Results:Among 1 309 patients, 936 (71.5%) were male, age at diagnosis was 28.7 years (28.1 years, 29.3 years). The follow-up time was 3.9 years (3.7 years, 4.0 years). The longest time of IFX treatment was 9.4 years. During the follow-up period, a total of 421 (32.2%) patients discontinued use of IFX and the sustained use of IFX at year 1, 3, 5 and 10 were 84.0%, 65.8%, 56.7% and 30.9% respectively. The results of Cox regression analysis revealed that patients with perianal lesions had an increased rate of sustained use of IFX ( HR(95% confidence interval) 0.75 (0.61, 0.92), P=0.006), while patients with adverse reactions had a decreased rate of sustained use of IFX ( HR(95% confidence interval) 1.23(1.01, 1.50), P=0.038). A total of 445 patients experienced adverse events, with an incidence rate of 34.0% (445/1 309). The acute infusion reaction was the most common side with an incidence rate of 13.7% (179/1 309), of which the rate of severe acute infusion reaction was 2.8% (5/1 309). The rate of infection was 10.5% (138/1 309), among which the rate of severe infection was 2.6% (34/1 309), and the rate of special pathogens infection was 5.5% (72/1 309). The rate of tuberculosis infection was 1.0% (13/1 309), and the most common affected site was the lungs (10 cases). The incidence of skin lesions (non-allergic, non-infectious and non-tumor skin) was 6.9% (90/1 309). The incidence of tumor was 1.1% (14/1 309). Patients who discontinued IFX due to adverse reactions accounted for 20.7% (92/445) of the patients with adverse reactions, among them patients who discontinued IFX due to acute infusion reaction, infections, neoplasms, delayed infusion reaction, skin lesions, abnormal liver function, hematological disorder, acute pancreatitis, joint pain and seizure accounted for 47.8% (44/92), 18.5% (17/92), 8.7% (8/92), 6.5% (6/92), 5.4% (5/92), 5.4% (5/92), 3.3% (3/92), 2.2% (2/92), 1.1% (1/92) and 1.1% (1/92), respectively. Among 14 patients with tumor, 11 were malignant tumors, 1 case of chronic leukemia was related with IFX. Multi-round of IFX treatment increased the risk of acute infusion reaction and severe acute infusion reaction, combination of immunosuppressants decreased the risk of liver injury, and IFX treatment for more than 1 year increased the risk of skin lesions ( χ2=6.16, 11.30, 18.20 and 9.47; P=0.013, =0.001, <0.001, =0.002). Conclusions:The rate of constant use of IFX is relatively high in Chinese Crohn′s disease patients. The long-term safety is good. Clinicians should pay more attention on the safety of patients receiving multiple rounds and long courses of IFX treatment.

Objective:To evaluate the survival outcome and toxicity of hypofractionated radiotherapy (45 Gy/15f) in patients with locally advanced/advanced non-small cell lung cancer (NSCLC) who are ineligible for conventional fractionated radiotherapy.Methods:The early efficacy, survival and toxicity of inoperable patients ( n=64) with locally advanced/advanced NSCLC patients admitted to Cancer Hospital of Tianjin Medical University from 2014 to 2018 were retrospectively analyzed. Hypofractionated radiotherapy (45 Gy/15f) were performed by using intensity-modulated radiotherapy or volumetric-modulated arc therapy technologies on Pinnacle 9 planning system. Results:The median follow-up time was 26 months. The early efficacy was available in 58 patients: complete response for 2 cases (3%), partial response for 22(38%), stable disease for 28(44%) and progressive disease for 6(9%), respectively. The local control rate was 90%. The median time to progression (TTP) and the median overall survival (OS) for all patients was 8.2 months and 21.0 months, respectively. The 1-, 2-and 3-year TTP rate was 37%, 28%, 14% and the OS rate was 66%, 43% and 27%, respectively. The incidence of esophagitis was 17%( n=11), 19%( n=12) for radiation pneumonitis and 20%( n=13) for myelosuppression. No grade ≥3 esophagitis or pneumonia was found. Conclusion:Hypofractionated radiotherapy (45 Gy/15f) is efficacious and safe for patients with locally advanced/advanced NSCLC, which yields controllable adverse events.

Objective To assess the safety of infliximab (IFX) treatment in patients with Crohn's disease(CD).Methods From January 2009 to May 2018,at inflammatory bowel disease (IBD) center of Sir Run Run Shaw Hospital,School of Medicine,Zhejiang University,486 CD patients received the treatment of IFX were enrolled and their clinical data were collected.Univariate and multivariate regression of binary logistic were performed for statistical analysis.Results The median follow-up duration was 31.1 months (12.0 months to 40.0 months).The median duration of IFX therapy was 13.0 months (7.0 months to 21.0 months).Among 486 patients,98 (20.16％) patients reported adverse effects,and 12 (2.47％) patients discontinued the therapy because of adverse effects.Acute infusion reaction was the most common adverse effect in CD patients who received IFX treatment accounting for 41.84％ (41/98) of all the adverse effects,and the incidence was 8.44％.Thirty-nine patients had mild and moderate infusion reaction,and all improved after symptomatic treatment (eight patients discontinued IFX therapy because of recurrent infusion reaction).Two patients developed severe infusion reaction as allergic shock,and both relieved after emergency rescue.Four patients developed late-phase allergic reactions.Among 486 patients,39 (8.02％) patients had infections,including infections of Clostridium difficile,cytomegalovirus,herpeszoster virus,Mycobacterium tuberculosis,and other opportunistic pathogens.There was no cases of infection related death.Thirty-six patients continued with IFX treatment after infection controlled.Among 486 patients,14 (2.88％) patients had severe infection,and all the cases improved after anti-infection treatment.Twenty-seven CD patients with hepatitis B virus (HBV) infection received anti-viral treatments,no active HBV infection was observed.Colon adenocarcinoma was found in one patient under colonoscopy at 22 months after discontinuation of IFX therapy.There were six patients with the history of benign tumors,and no evidence of recurrence,progress or malignancy during treatment.In terms of other rare adverse effects in 486 patients,there were eight (1.64％) patients with liver function injury,two (0.41％) patients with anemia,one (0.21％) patient with peripheral neuropathy,and four (0.82％) patients with skin lesion.Prolonged duration of IFX therapy,without combination of immune-suppressors and with increased baseline body mass index (BMI) were the risk factors of acute infusion reactions.Prolonged duration of IFX therapy and with low baseline albumin level were the risk factors of infections.Conclusions IFX is generally safe as the treatment for CD patients,and its adverse effects can be clinically controlled.Screening before therapy and monitoring during therapy may reduce the risks of adverse effects.