Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: A randomised, double-blind, placebo-controlled trial

Objectives Open-labelled clinical trials suggested that low-dose IL-2 might be effective in treatment of systemic lupus erythematosus (SLE). A double-blind and placebocontrolled trial is required to formally evaluate the safety and efficacy of low-dose IL-2 therapy. Methods A randomised, double-blind and placebocontrolled clinical trial was designed to treat 60 patients with active SLE. These patients received either IL-2 (n=30) or placebo (n=30) with standard treatment for 12 weeks, and were followed up for additional 12 weeks. IL-2 at a dose of 1 million IU or placebo was administered subcutaneously every other day for 2 weeks and followed by a 2-week break as one treatment cycle. The primary endpoint was the SLE Responder Index-4 (SRI-4) at week 12. The secondary endpoints were other clinical responses, safety and dynamics of immune cell subsets. Results At week 12, the SRI-4 response rates were 55.17% and 30.00% for IL-2 and placebo, respectively (p=0.052). At week 24, the SRI-4 response rate of IL-2 group was 65.52%, compared with 36.67% of the placebo group (p=0.027). The primary endpoint was not met at week 12. Low-dose IL-2 treatment resulted in 53.85% (7/13) complete remission in patients with lupus nephritis, compared with 16.67% (2/12) in the placebo group (p=0.036). No serious infection was observed in the IL-2 group, but two in placebo group. Besides expansion of regulatory T cells, low-dose IL-2 may also sustain cellular immunity with enhanced natural killer cells. Conclusions Low-dose IL-2 might be effective and tolerated in treatment of SThe work was supported by the National Natural Science Foundation of China (31530020,31570880,81471601,81601417 and 81701598), Peking-Tsinghua Center for Life Sciences to ZG LI, Beijing Sci-Tech Committee Z171100000417007,Clinical Medicine Plus X-Young Scholars Project of Peking University (PKU2019LCXQ013) supported by the Fundamental Research Funds for the Central Universities, Beijing Nova Program Z171100001117025, National Key Research and Development Program of China (2017YFC0909003 to DY), BellberryViertel Senior Medical Research Fellowship to DY and Beijing SL PHARM

Research on light weight of thin-walled beam for automobile body

The developing trend of the light-weight car is the using of new light-weight materials and the optimization of the car body structure. The beam construction is the major bearing part of the car body. The thin–walled beam of the light-material plays a significant role in lightening the car' own weight, saving the materials, reducing fuel consumption and air pollution. Firstly, the relationship between the thin-walled beam that is fixed in both points and the attribute of the material can be infered from the stiffness coefficient which used as the quantitative index to estimate materials. Then take the body-in-white produced by domestic car factory as an object of study, and use Cu or Al or Mg as the materials of the thin-walled beam to calculate the bending rigidity and torsional stiffness of thewhole car body by using the FEM simulation conducted in HyperMesh.The results show that under the condition of bending and torsion, the SME value is lower when the lighten materials such as Al or Cu are used as the bodywork of the thin-walled beam than steel is. Lighten material can greatly reduce the weight of the vehicle. But it also decreased the bending and torsional stiffness of the bodywork. Therefore, in order to avoid decreasing mechanical properties which caused by adopting lighten materials, we must consider the structural design of the thin-walled beam when adopt material for lightweight

Circ_0008657 regulates lung DNA damage induced by hexavalent chromium through the miR-203a-3p/ATM axis

Hexavalent chromium [Cr (VI)] is an important environmental pollutant and may cause lung injury when inhaled into the human body. Cr (VI) is genotoxic and can cause DNA damage, although the underlying epigenetic mechanisms remain unclear. To simulate the real-life workplace exposure to Cr (VI), we used a novel exposure dose calculation method. We evaluated the effect of Cr (VI) on DNA damage in human bronchial epithelial cells (16HBE and BEAS-2B) by calculating the equivalent real-time exposure dose of Cr (VI) (0 to 10 μM) in an environmental population. Comet experiments and olive tail moment measurements revealed increased DNA damage in cells exposed to Cr (VI). Cr (VI) treatment increased nuclear γ-H2AX foci and γ-H2AX protein expression, and caused DNA damage in the lung tissues of mice. An effective Cr (VI) dose (6 μM) was determined and used for cell treatment. Cr (VI) exposure upregulated circ_0008657, and knockdown of circ_0008657 decreased Cr (VI)-induced DNA damage, whereas circ_0008657 overexpression had the opposite effect. Mechanistically, we found that circ_0008657 binds to microRNA (miR)-203a-3p and subsequently regulates ATM serine/threonine kinase (ATM), a key protein involved in homologous recombination repair downstream of miR-203a-3p, thereby regulating DNA damage induced by Cr (VI). The present findings suggest that circ_0008657 competitively binds to miR-203a-3p to activate the ATM pathway and regulate the DNA damage response after environmental chemical exposure in vivo and in vitro

Circulating immune complexome analysis identified anti-tubulin-α-1c as an inflammation associated autoantibody with promising diagnostic value for Behcet's Disease.

BACKGROUND:Behcet's disease (BD) is a chronic, multisystem-involved vasculitis and its pathogenesis remains elusive. No specific serological markers for BD diagnosis have been established. Identification of novel diagnostic biomarkers will be helpful in timely diagnostic and treatment for Behcet's disease. OBJECTIVE:To screen novel autoantigens or autoantibodies with potential diagnostic value in circulating immune complexes (CICs) from BD patients. METHODS:A proteomic strategy for immune complexome analysis was developed, in which CICs were separated from serum sample of 10 BD patients and 10 healthy controls and then subjected to Orbitrap mass spectrometry for autoantigen profiling. Anti-tubulin-α-1c antibody levels were further determined by enzyme-linked immunosorbent assay (ELISA) in sera of patients with BD, systemic lupus erythematosus (SLE), recurrent aphthous ulcers (RAU), ANCA associated systemic vasculitis (AASV), Takayasu's arteritis (TA) and 59 healthy controls. RESULT:A total of 17 potential antigens were identified in CICs from BD patients, but not in HC. The autoantibody to one of the identified antigens, tubulin-α-1c, was significantly increased in BD patients compared with that in healthy and disease controls. The sensitivity and specificity of tubulin-α-1c antibody in the diagnosis of BD in this study were 61.36% and 88.4%, respectively. Further analysis demonstrated that anti-tubulin-α-1c was associated with complications of deep venous thrombosis and erythema nodosum in BD. The levels of anti-tubulin-α-1c were also significantly correlated with the BD inflammation and disease activity markers ESR, CRP and BVAS. CONCLUSION:Anti-tubulin-α-1c antibody is a promising biomarker in diagnosis and severity evaluation of BD and in indicating the risk of deep venous thrombosis and erythema nodosum. The immune complexome analysis by proteomic CIC autoantigen screening is a feasible way of identifying novel biomarkers in BD

Sites of gastrointestinal lesion induced by mycophenolate mofetil: a comparison with enteric-coated mycophenolate sodium in rats

Abstract Background Immunosuppressant drugs for renal transplant mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) cause gastrointestinal (GI) disorders. The specific site of GI tract targeted by MMF and EC-MPS remains unclear. Methods In this study, we investigated the effects of MMF and EC-MPS on stomach, duodenum, jejunum, ileum, colon and rectum using a rat model. Rats were randomized into five groups: control, MMF (100 mg/kg·d), mofetil (30 mg/kg·d), EC-MPS (72 mg/Kg·d), mofetil + EC-MPS. Each group was treated with drugs once a day for 7 days through intra-gastric gavage. Diarrhea grade of each rat were measured every day, as well as the body weight. Blood was collected by tail nick and Seven days later, the rats were sacrificed, GI tissues were collected for Histological research. Results The results showed that diarrhea grade and weight loss were significantly higher in MMF group than other groups. The pathological score of MMF group was significantly higher than EC-MPS group and EC-MPS + mofetil group in jejunum and ileum tissues, but not other segments of GI tract. Absorption of EC-MPS is delayed, compared to that of MMF. MPAG concentration in duodenum, jejunum and ileum tissues of MMF group is higher than EC-MPS group. Mofetil may increase the magnitude of MPA absorption. Conclusions Our data suggested that MMF might target jejunum and ileum and induce GI injury. EC-MPS causes less injury in GI tract than MMF, probably due to its kinetic property

Hypoxia-inducible factor-1α and interleukin 33 form a regulatory circuit to perpetuate the inflammation in rheumatoid arthritis.

Hyperplasia of synovial fibroblasts, infiltration with inflammatory cytokines, and tissue hypoxia are the major characteristics of rheumatoid arthritis (RA). Interleukin 33 (IL-33) is a newly identified inflammatory cytokine exacerbating the disease severity of RA. Hypoxia-inducible factor-1α (HIF-1α) showed increased expression in RA synovium and could regulate a number of inflammatory cytokine productions. Nevertheless, its correlation with IL-33 remains largely unknown. Here, we showed that elevated levels of IL-33 were demonstrated in RA patient synovial fluids, with upregulated expression of HIF-1α and IL-33 in the synovial fibroblasts. Knocking down HIF-1α compromised IL-33 expression in rheumatoid arthritis synovial fibroblasts (RASF), while enforcing HIF-1α expression in RASF substantially upregulated IL-33 levels. HIF-1α promoted the activation of the signalling pathways controlling IL-33 production, particularly the p38 and ERK pathways. Moreover, we showed for the first time that IL-33 in turn could induce more HIF-1α expression in RASF, thus forming a HIF-1α/IL-33 regulatory circuit that would perpetuate the inflammatory process in RA. Targeting this pathological pathway and HIF-1α may provide new therapeutic strategies for overcoming the persistent and chronic inflammatory disease