PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2.

Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide isomerase family A member 3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein level and disease activity score 28. Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing T helper 1 (Th1) and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions, as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.

Modified technique of advanced core decompression for treatment of femoral head osteonecrosis.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a destructive condition most commonly affecting young and middle-aged patients. The leading consequence of ONFH is often a significant articular disability. Effective joint-preserving surgical treatments are urgently needed for patients with early stage ONFH when outcomes of treatment are in general better than the advanced stage disease. AIM: To introduce a new surgery procedure called percutaneous expanded core decompression and mixed bone graft technique, which is a new way of joint-preserving surgical treatments. METHODS: The clinical data of 6 patients with ONFH diagnosed and treated with the procedure called percutaneous expanded core decompression and mixed bone graft technique at The First Hospital of Qiqihar from March 2013 to August 2019 were retrospectively analyzed; the follow-up ended in December 2019. RESULTS: There were 6 male patients with an average age of 43 years in our study. Gratifying results have been obtained from the comparison of Harris hip score, visual analogue scale, and imaging examination before and after operation. CONCLUSION: This new modified technique is simple, safe, and reliable. No serious perioperative complications were observed in our cases. Advantages of the single blade expandable reamer are obvious. The adjuvant substance is inexpensive and easy to obtain. Thus, this technique is an effective joint-preserving surgical treatment for patients with early stage of ONFH.

High-sensitivity C-reactive protein is a strong risk factor for death after acute ischemic stroke among Chinese.

BACKGROUND AND PURPOSE: Elevated plasma C-reactive protein (CRP) has been suggested as a risk factor for ischemic stroke (IS) and coronary ischemic disease. Evidence has shown that high-sensitivity CRP (hs-CRP) is related to a worsening prognosis after IS, but hs-CRP was rare in a large-sample study in a Chinese population. We investigated the associations between hs-CRP and outcome of Chinese patients after acute IS. METHODS: Seven hundred and forty-one consecutive acute IS patients (74.9% male, mean age 60.9 years), with baseline characteristics and hs-CRP measured within 24 h after hospitalization, were admitted in this study. We also prospectively followed up for clinical outcome and death 3 months after disease onset. hs-CRP was divided into two categories: hs-CRP >3 mg/L and hs-CRP ≤3 mg/L. Survival analysis using multivariable Cox regression was performed to analyze the association between hs-CRP and stroke outcomes after adjusting for potential confounding factors. RESULTS: Compared with low hs-CRP, patients with high hs-CRP (>3 mg/L) had a significantly higher rate of all-cause death (0.71% vs. 10.00%; P < 0.001) at 3 months after stroke onset. High hs-CRP was an independent risk factor for all-cause death (HR, 6.48; 95% CI, 1.41 to 29.8; P= 0.016), as well as history of atrial fibrillation (HR, 5.24; 95% CI, 1.83 to 15.0; P= 0.002), no statin therapy during hospitalization (HR, 4.56; 95% CI, 2.18 to 9.55; P < 0.001), high homocysteine (>15.1 mmol/L) (HR, 2.66; 95% CI, 1.26 to 5.60; P= 0.01); fasting glucose (>6.1 mmol/L) (HR, 9.14; 95% CI, 3.34 to 25.0; P < 0.001), NIHSS at admission (HR, 2.35; 95% CI, 1.35 to 4.09; P= 0.003) and history of coronary heart disease (CHD) (HR, 2.34; 95% CI, 1.06 to 5.17; P= 0.035). Kaplan-Meier survival curves showed a higher risk of death for patients with hs-CRP >3 mg/L (P= 0.016). CONCLUSION: Elevated plasma hs-CRP independently predicted risk of all-cause death within 3 months after acute IS in Chinese patients.

Circulating MicroRNAs as potential risk biomarkers for hematoma enlargement after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: MicroRNAs have recently been shown to regulate the downstream bioprocesses of intracerebral hemorrhage. The aim of this study was to investigate whether miRNAs can be used as biomarkers to predict secondary hematoma enlargement (HE) in patients with ICH. METHODS: Consecutively, 79 ICH patients admitted within 6 h of symptom onset and 30 healthy individuals were enrolled in this study. Whole-genome miRNA expression profiles were generated in 32 patients (HE/non-HE: 14/18). Representative differentially expressed miRNAs were measured in all cases (HE/non-HE: 30/49) and normal controls (n = 30) by real-time PCR. RESULTS: Thirty miRNAs showed differential expressions in the plasma samples from patients with HE as compared with the non-HE controls. Compared to the hierarchical cluster analysis with all probes on microarray, all patients were separated into two main branches with only four exceptions by 30 differentially expressed miRNAs, improving the overall accuracy from 47.62 to 77.78% in the HE and 72.73 to 100% in the non-HE group. Further support vector machine (SVM) test can discriminate the two groups with 100% accuracy with 10 differentially expressed miRNAs. CONCLUSIONS: We demonstrated that multiple miRNAs are differentially expressed in the plasma of ICH patients with or without HE and may serve as circulating biomarkers for predicting HE after ICH.