CX-4945 inhibits fibroblast-like synoviocytes functions through the CK2-p53 axis to reduce rheumatoid arthritis disease severity.

Fibroblast-like synoviocytes (FLS) mediate many pathological processes in rheumatoid arthritis (RA), including pannus formation, bone erosion, and inflammation. RA FLS have unique aggressive phenotypes and exhibit several tumor cell-like characteristics, including hyperproliferation, excessive migration and invasion. Casein kinase 2 (CK2) is reportedly overexpressed in numerous tumor types, and targeted inhibition of CK2 has therapeutic benefits for tumors. However, the expression level of CK2 and its functions in RA FLS remain unclear. Herein, we aimed to elucidate whether CK2 is responsible for the aggressive phenotypes of RA FLS and whether targeted therapy can alleviate the severity of RA. We found that CK2 subunits were elevated in RA FLS compared with osteoarthritis FLS, and the activity of CK2 also markedly increased in RA FLS. Targeted inhibition of CK2 using CX-4945 suppressed RA FLS proliferation through cell cycle arrest. Cell migration and invasion were also inhibited by CX-4945 treatment. Moreover, CX-4945 reduced Interleukin-6 (IL-6), CC motif chemokine ligand 2 (CCL2) and Matrix metalloproteinase-3 (MMP-3) secretion in RA FLS. Further proteomic investigation revealed that p53 signaling pathway significantly changes after CX-4945 treatment in RA FLS. The siRNA-mediated p53 knockdown partly abolished the anti-proliferation and reduced IL-6, MMP-3 secretion effects of CX-4945. Furthermore, CX-4945 administration alleviates arthritis severity in CIA mice. Collectively, our results demonstrated the abnormal elevation of CK2 and its positive association with abnormal phenotypes in RA FLS. Our novel findings suggest the possible therapeutic potential of CX-4945 for RA.

Sex differences of small airway function and fractional exhaled nitric oxide in patients with mild asthma.

BACKGROUND: Sex differences of small airway function (SAF) and fractional exhaled nitric oxide (FeNO) in patients with mild asthma remain unclear. OBJECTIVE: To evaluate sex differences of SAF and FeNO in patients with mild asthma confirmed by positive methacholine challenge test (MCT) result. METHODS: This cross-sectional, double-centered, observational study enrolled 1609 adult patients with forced expiratory volume in 1 second greater than or equal to 80% and suspected asthma symptoms. Data of spirometry, FeNO, impulse oscillometry measurements, and peripheral blood test result were compared between males and females. The receiver-operating characteristic curves of SAF parameters and FeNO in predicting positive MCT result were also calculated. RESULTS: In patients with mild asthma matched by age, males had better SAF but higher FeNO levels than females (60 [29.27%] vs 187 [46.75%] for small airway dysfunction, 78.6% vs 72.0% for forced expiratory flow [FEF]50%, 67.5% vs 60.1% for FEF75%, 73.7% vs 67.4% for FEF25%-75%, and 42.0 ppb vs 29.0 ppb for FeNO, respectively, all P ≤ .001). The FeNO levels in male current smokers were considerably lower than those of nonsmokers. SAF and FeNO values declined more rapidly with age among female than male patients with asthma. The optimal cutoff values of FEF25%-75%, FEF50%, and FeNO for predicting a positive MCT result were 81.5%, 86.4%, and 41.0 ppb in males vs 73.7%, 76.9%, and 35.0 ppb in females. CONCLUSION: In patients with mild asthma, the female patients have worse SAF, lower FeNO levels, and a more prominent decline trend of those parameters with age than males. Sex-specific cutoff values should be considered when SAF parameters (FEF25%-75%, FEF50%), alone or combined with FeNO, are used to predict positive MCT result in asthma diagnosis.

Prediction of bronchodilation test in adults with chronic cough suspected of cough variant asthma.

Background: Many patients with cough variant asthma (CVA) are underdiagnosed and undertreated due to the atypical symptoms, low diagnostic sensitivity of bronchodilator response (BDR), and limited application of bronchial challenge test. Objective: To investigate whether airway reversibility in BDR can predict CVA diagnosis in patients with chronic cough and negative BDR. Methods: This open-label, prospective cohort study included patients with chronic cough, nearly normal chest CT scan, and negative BDR results. Inhaled corticosteroids and long-acting ß2 agonists were given for 4 weeks. The confirmed diagnosis of CVA was defined as improved symptoms and an increase of forced expiratory volume in 1 s (FEV1) by >12% and >200 mL after 4 weeks of treatment. Results: Of 155 patients recruited, 140 completed the study. Patients in the CVA positive diagnosis group had greater absolute (Δ) and percent (Δ%) improvements in FEV1 and forced expiratory flows (FEFs), and higher fractional exhaled nitric oxide (FENO) than in the CVA negative diagnosis group. The area under the receiver operating characteristic curves (AUCs) of ΔFEV1%, FEF25-75%pred (percentage of predicted forced expiratory flow at 25% to 75%) and FENO for CVA positive diagnosis was 0.825, 0.714, and 0.637, with cutoff values of 5.90%, 61.99% and 41.50 ppb, respectively. A joint model of ΔFEV1% combined with FEF25-75%pred or FENO increased the AUC to 0.848 and 0.847, respectively. Conclusion: ΔFEV1% in BDR can predict a CVA diagnosis and response to anti-asthma treatment in patients with chronic cough and negative BDR. Clinical trial registration: [http://www.chictr.org.cn/index.aspx], identifier [ChiCTR2000029065].