Targeting tumorous Circ-E-Cadherinencoded C-E-Cad inhibits the recruitment and function of breast cancer-associated myeloid-derived suppressor cells.

We previously demonstrated that the C-E-cad protein encoded by circ-E-cadherin promotes the self-renewal of glioma stem cells. The expression pattern of C-E-cad in breast cancer and its potential function in the tumor microenvironment are unclear. The expression of circ-E-cadherin and C-E-cad was detected in breast cancer specimens. The influence of C-E-cad expression on MDSCs was assessed using FACS and in vivo tumorigenesis experiments. The synergistic effect of anti-C-E-cad and anti-PD-1 antibodies was validated in vivo. circ-E-cadherin and the encoded protein C-E-cad were found to be upregulated in breast cancer vs. normal samples. C-E-cad promotes the recruitment of MDSCs, especially PMN-MDSCs. C-E-cad activates EGFR signaling in tumor cells and promotes the transcription of CXCL8; moreover, C-E-cad binds to MDSCs and maintains glycolysis in PMN-MDSCs. Targeting C-E-cad enhanced anti-PD-1 efficiency. Our data suggested that C-E-cad is markedly overexpressed in breast cancer and promotes MDSC recruitment and survival. Targeting C-E-cad increases the efficacy of immune checkpoint inhibitor therapy.

Cyr61 participates in the pathogenesis of rheumatoid arthritis via promoting MMP-3 expression by fibroblast-like synoviocytes.

OBJECTIVES: The aim of this study was to investigate the effect and potential mechanism of Cysteine-rich 61 (Cyr61) on stimulating MMP-3 expression by fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients. METHODS: Primarily cultured RA FLS were treated with exogenous Cyr61 protein or Cyr61-siRNA, then, MMP-3 expression was analyzed by real-time PCR, western blotting and ELISA. Signal transduction pathways in Cyr61-induced MMP-3 production were examined by real-time PCR, western blotting, confocal microscopy, luciferase reporter assay. Mice with collagen-induced arthritis (CIA) were treated with anti-Cyr61 monoclonal antibodies (mAb), or IgG1 as control and MMP-3 in the joint was detected by IHC, real-time PCR and western blotting. RESULTS: High expressed MMP-3 and Cyr61 were positively correlated in RA ST; Cyr61 stimulated MMP-3 production in FLS of RA patients in an IL-1ß and TNF-α independent manner. Cyr61 induced MMP-3 could further enhance the invasive ability of RA FLS. Mechanistically, we found that Cyr61 promoted MMP-3 production via the P38, JNK-dependent AP-1 signaling pathway. Blockage of Cyr61 function with monoclonal antibody could decrease MMP-3 expression in the joints of CIA mice. CONCLUSION: This study provides new evidence that Cyr61 participates in RA pathogenesis not only as a pro-inflammatory factor but also plays a key role in bone erosion via promoting MMP-3 expression. We suggest that targeting of Cyr61 may represent a potential strategy in RA treatment.

Cyr61 participates in the pathogenesis of rheumatoid arthritis by promoting proIL-1ß production by fibroblast-like synoviocytes through an AKT-dependent NF-κB signaling pathway.

IL-1ß plays a major role in the development of rheumatoid arthritis (RA). We previously showed that Cyr61 participates in RA pathogenesis as a proinflammatory factor. Here, we found that the levels of IL-1ß and Cyr61 were higher in RA SF than in osteoarthritis (OA) SF. IL-1ß mRNA and proIL-1ß protein levels were remarkably increased in Cyr61-stimulated FLS; however, IL-1ß was hardly detectable in the supernatant. We also found that the level of adenosine triphosphate (ATP) in SF and ST was significantly increased in RA patients and that the level of IL-1ß in supernatants from Cyr61-activated FLS increased significantly when we added exogenous ATP to the culture. Mechanistically, Cyr61 induced proIL-1ß production in FLS via the AKT-dependent NF-κB signaling pathway, and ATP caused Cyr61-induced proIL-1ß to generate IL-1ß in a caspase-1-dependent manner. Our results reveal a novel role of Cyr61 in RA that involves the promotion of proIL-1ß production in FLS.

Selenite resistance and biotransformation to SeNPs in Sinorhizobium meliloti 1021 and the synthetic promotion on alfalfa growth.

Toxic selenite, commonly found in soil and water, can be transformed by microorganisms into selenium nanoparticles (SeNPs) as part of a detoxification process. In this study, a comprehensive investigation was conducted on the resistance and biotransformation of selenite in Sinorhizobium meliloti 1021 and the synergistic impact of SeNPs and the strain on alfalfa growth promotion was explored. Strain 1021 reduced 46% of 5 mM selenite into SeNPs within 72 h. The SeNPs, composed of proteins, lipids and polysaccharides, were primarily located outside rhizobial cells and had a tendency to aggregate. Under selenite stress, many genes participated in multidrug efflux, sulfur metabolism and redox processes were significantly upregulated. Of them, four genes, namely gmc, yedE, dsh3 and mfs, were firstly identified in strain 1021 that played crucial roles in selenite biotransformation and resistance. Biotoxic evaluations showed that selenite had toxic effects on roots and seedlings of alfalfa, while SeNPs exhibited antioxidant properties, promoted growth, and enhanced plant's tolerance to salt stress. Overall, our research provides novel insights into selenite biotransformation and resistance mechanisms in rhizobium and highlights the potential of SeNPs-rhizobium complex as biofertilizer to promote legume growth and salt tolerance.

A novel diagnostic model based on lncRNA PTPRE expression, neutrophil count and red blood cell distribution width for diagnosis of seronegative rheumatoid arthritis.

Diagnosis of seronegative rheumatoid arthritis (SNRA) is difficult due to the lack of diagnostic markers. The study aims to construct a novel diagnostic model based on long noncoding RNAs (lncRNAs) expression and laboratory indicators to provide a new idea for diagnostic methods of SNRA. Differentially expressed lncRNAs in peripheral blood cells of RA patients were screened through eukaryotic long noncoding RNA sequencing and validated by quantitative real-time PCR. Meanwhile, the correlation between lncRNAs expression and laboratory indicators was analyzed. The diagnostic value was evaluated by receiver operating characteristic curve analysis. Finally, combined with laboratory indicators, a diagnostic model for SNRA was constructed based on logistic regression and visualized by nomogram. Expression of ADGRE5, FAM157A, PTPN6 and PTPRE in peripheral blood was significantly increased in RA than healthy donors. Meanwhile, we analyzed the relationship between lncRNAs and erythrocyte sedimentation rate, C-reactive protein and CD4 + T cell-related cytokines and transcription factors. Results showed that FAM157A and PTPN6 were positively related to RORγt, and negatively related to GATA3. Moreover, PTPRE has potential discrimination ability between SNRA and healthy donor (AUC = 0.6709). Finally, we constructed a diagnostic model based on PTPRE, neutrophil count and red blood cell distribution width (RDW). The AUC of the model was 0.939 and well-fitted calibration curves. Decision curve analysis indicated the model had better predict performance in SNRA diagnosis. Our study constructed a novel diagnostic model based on PTPRE, neutrophil count and RDW which may serve as a potential tool for the diagnosis of SNRA.

Role and Therapeutic Potential for Targeting Fibroblast Growth Factor 10/FGFR1 in Relapsed Rheumatoid Arthritis.

OBJECTIVE: Fibroblast-like synoviocytes (FLSs) contribute to inflammation and joint damage in rheumatoid arthritis (RA). However, the regulatory mechanisms of FLSs in relapse and remission of RA remain unknown. Identifying FLS heterogeneity and their underlying pathogenic roles may lead to discovering novel disease-modifying antirheumatic drugs. METHODS: Combining single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, we sequenced six matched synovial tissue samples from three patients with relapse RA and three patients in remission. We analyzed the differences in the transcriptomes of the FLS subsets between the relapse and remitted phases. We validated several key signaling pathways using quantitative real-time PCR (qPCR) and multiplex immunohistochemistry (mIHC). We further targeted the critical signals in vitro and in vivo using the collagen-induced arthritis (CIA) model in rats. RESULTS: Lining and sublining FLS subsets were identified using scRNA-seq. Differential analyses indicated that the fibroblast growth factor (FGF) pathway was highly activated in the lining FLSs from patients with relapse RA for which mIHC confirmed the increased expression of FGF10. Although the type I interferon pathway was also activated in the lining FLSs, in vitro stimulation experiment suggested that it was independent of the FGF10 pathway. FGF10 knockdown by small interfering RNA in FLSs significantly reduced the expression of receptor activator of NF-κB ligand. Moreover, recombinant FGF10 protein enhanced bone erosion in the primary human-derived pannus cell culture, whereas the FGF receptor (FGFR) 1 inhibitor attenuated this process. Finally, administering an FGFR1 inhibitor displayed a therapeutic effect in a CIA rat model. CONCLUSION: The FGF pathway is a critical signaling pathway in relapse RA. Targeted tissue-specific inhibition of FGF10/FGFR1 may provide new opportunities to treat patients with relapse RA.

Recent Advances in Transition-Metal Based Nanomaterials for Noninvasive Oncology Thermal Ablation and Imaging Diagnosis.

With the developments of nanobiotechnology and nanomedicine, non-invasive thermal ablation with fewer side effects than traditional tumor treatment methods has received extensive attention in tumor treatment. Non-invasive thermal ablation has the advantages of non-invasiveness and fewer side effects compared with traditional treatment methods. However, the clinical efficiency and biological safety are low, which limits their clinical application. Transition-metal based nanomaterials as contrast agents have aroused increasing interest due to its unique optical properties, low toxicity, and high potentials in tumor diagnosis. Transition-metal based nanomaterials have high conversion efficiency of converting light energy into heat energy, good near-infrared absorption characteristics, which also can targetedly deliver those loaded drugs to tumor tissue, thereby improving the therapeutic effect and reducing the damage to the surrounding normal tissues and organs. This article mainly reviews the synthesis of transition-metal based nanomaterials in recent years, and discussed their applications in tumor thermal ablation and diagnosis, hopefully guiding the development of new transition metal-based nanomaterials in enhancing thermal ablation.

Bioresponsive Nanomaterials: Recent Advances in Cancer Multimodal Imaging and Imaging-Guided Therapy.

Cancer is a serious health problem which increasingly causes morbidity and mortality worldwide. It causes abnormal and uncontrolled cell division. Traditional cancer treatments include surgery, chemotherapy, radiotherapy and so on. These traditional therapies suffer from high toxicity and arouse safety concern in normal area and have difficulty in accurately targeting tumour. Recently, a variety of nanomaterials could be used for cancer diagnosis and therapy. Nanomaterials have several advantages, e.g., high concentration in tumour via targeting design, reduced toxicity in normal area and controlled drug release after various rational designs. They can combine with many types of biomaterials in order to improve biocompatibility. In this review, we outlined the latest research on the use of bioresponsive nanomaterials for various cancer imaging modalities (magnetic resonance imaging, positron emission tomography and phototacoustic imaging) and imaging-guided therapy means (chemotherapy, radiotherapy, photothermal therapy and photodynamic therapy), followed by discussing the challenges and future perspectives of this bioresponsive nanomaterials in biomedicine.

[Effects of Drynaria total flavonoids on apoptosis of osteoblasts mediated by tumor necrosis factor-α].

OBJECTIVE: To investigate the influence of Drynaria total flavonoids on proliferation and apoptosis of osteoblasts in tumor necrosis factor-α (TNF-α)- mediated medium, so as to explore the mechanism of Drynaria total flavonoids in preventing and treating osteoporosis of rheumatoid arthritis. METHODS: Twenty Wistar rats with average weight of (200±20) g were randomly divided into two groups: blank control group and Qianggu capsule (Drynaria total flavonoids) group. Rats in Qianggu capsule group were fed with 75 mg Qianggu capsule daily for continuous 3 d. One hour after the last feed, blood samples were collected. The in vitro experiment of four groups was designed: blank control serum group, Drynaria total flavonoids-containing serum group, blank control serum plus TNF-α group and Drynaria total flavonoids-containing serum plus TNF-α group. Methyl thiazolyl tetrazolium method was used to detect the proliferation of osteoblasts. Flow cytometry was used to detect the apoptosis of osteoblasts and real-time fluorescent quantitative polymerase chain reaction to detect the expressions of Bcl-2 and Bax mRNAs in osteoblasts. RESULTS: Compared with the control serum, Drynaria total flavonoids-containing serum promoted the proliferation and decreased the apoptosis of osteoblasts in TNF-α-mediated inflammatory environment (P<0.05), and increased the ratio of Bcl-2 mRNA to Bax mRNA. CONCLUSION: In TNF-α-mediated inflammatory environment, Drynaria total flavonoids can promote the proliferation and decrease the apoptosis of osteoblasts by improving the ratio of Bcl-2 mRNA to Bax mRNA, which may be one of the mechanisms of Drynaria total flavonoids in preventing and treating osteoporosis of rheumatoid arthritis.

[Patellofemoral arthroplasty for the treatment of patellofemoral arthritis].

OBJECTIVE: To explore the clinical effect of patellofemoral joint replacement in the treatment of patellofemoral arthritis. METHODS: From July 2013 to June 2017, 35 patients with 42 knees underwent patellofemoral arthroplasty, including 34 females and 1 male, aged 45 to 70 (55.0±8.2) years old, with a course of 6 to 36 (13.7±2.5) months. Before and at the end of the follow-up, the patients were assessed with Oxford knee score, satisfaction with the operation was assessed at the end of the follow-up. In addition, X-ray films of the front and side of the knee joint and axial films of the patella were taken to assess whether the prosthesis was loose, and complications such as hematoma and joint infection were recorded. RESULTS: Forty-two knees of 35 patients were followed up for 18 to 65 (35.0±7.2) months, and the operation time was (56.2±8.7) min. Oxford knee joint score increased from preoperative 28.14±0.36 to 37.19±0.47 at the end of the follow-up (P<0.05) . The score of pain items increased from preoperative 10.12±0.26 to 15.83±0.30 at the end of the follow-up, and the score of functional items increased from preoperative 18.02±0.13 to 21.36±0.23 at the end of the follow-up (P<0.05) , there was statistical significance (P <0.05) . In one case, there was wound suture reaction in the early postoperative period, which was improved after debridement; in the other case, there was swelling around the wound 5 weeks after operation, which was improved after antibiotic treatment; in one case, there was tear at the suture of quadriceps femoris muscle at 1 month after operation, which was improved after re suture; no loosening of prosthesis was found. CONCLUSION: The second generation of patellofemoral arthroplasty for the treatment of simple severe patellofemoral arthritis has satisfactory early clinical effect and few complications, but the indication of operation should be strictly grasped. For severe cases, CT scan of knee joint can be used to customize the patellofemoral prosthesis, so as to reduce postoperative complications and improve the clinical effect.

[Clinical study on the control of intra-articular hemorrhage by tranexamic acid after shoulder arthroscopy].

OBJECTIVE: To explore clinical effects of tranexamic acid on postoperative intra-articular hemorrhage after shoulder arthroscopy. METHODS: From February to July 2018, 60 patients with rotator cuff tears treated by shoulder arthroscopy were randomly divided into observation group and control group, 30 cases in each group. In observation group, there were 6 males and 24 females; aged from 55 to 70 years old with an average age of (62.3±5.5) years; the courses of disease ranged from 2 to 36 months with an average of (11.7±1.7) months; received 0.5 g tranexamic acid (1 g of tranexamic acid was diluted with normal saline to 20 ml) in each articular cavity and subacromial space after operation. In control group, there were 5 males and 25 females; aged from 56 to 72 years old with an average of (63.4±5.8) years old; the courses of disease ranged from 4 to 36 months with an average of (10.8±1.4) months; 10 ml of normal saline was injected into joint cavity and subacromial space. Hemoglobin values between two groups before and after operation at 1 day were recorded, circumference of shoulder joint was measured preoperatively and the 1st and 7th days after operation, and circumference difference of shoulder joint was recorded. Complications such as subcutaneous blood stasis and DVT were recorded. RESULTS: There was no significant difference in hemoglobin values between two groups before and after operation at 1 day (P>0.05) . On the first day after surgery, peripheral diameter of shoulder joint in observation group [(32.9±0.3) cm ] was significantly lower than that in control group [(35.1±0.5) cm ], and the circumference difference of shoulder joint in observation group [(8.7±0.4) mm ] was also significantly lower than that in control group [(12.3±0.5) mm ], the difference was statistically significant (P<0.05) . However, there was no significant difference in circumference of shoulder joint and the difference in circumference of shoulder joint between two groups on the 7th day after operation (P>0.05) . Two patients in observation group occurred subcutaneous ecchymosis, while 6 patients occurred in control group, but without statistical difference between two groups (P>0.05) . CONCLUSION: Subacromial and articular injection of tranexamic acid could significantly reduce early swelling of soft tissue after arthroscopic shoulder surgery, and it has better safety.

Efficacy of different-frequency TEAS on acute pain after the total knee arthroplasty: a study protocol for a parallel group randomized trial.

BACKGROUND: Total knee arthroplasty (TKA) is an optimal option for patients with middle-to-end-stage knee osteoarthritis. However, the management of postoperative acute pain remains inefficient. Transcutaneous electrical acupoint stimulation (TEAS) is a nonpharmacological method to manage postoperative acute pain. Different frequencies of TEAS have been tested using varying parameters, but the optimal analgesic frequency remains controversial. The aim of this study was to explore the optimal analgesic frequency of TEAS for treating acute pain after the primary unilateral TKA. METHODS/DESIGN: This is a double-blind, randomized controlled trial. A total of 156 patients are randomly assigned to: G1, 5 Hz TEAS; G2, 100 Hz TEAS; G3, mixed TEAS (alternative use of daily 5 Hz and 100 Hz TEAS) and G4, placebo TEAS. In the G1, G2 and G3 groups, TEAS is conducted at acupoints SP9 and GB34 of the leg that was operated on (at a wave of continuous, balanced and asymmetrical biphasic square, with a pulse width of 200 µs, and a strong but comfortable current) for 30 min prior to a 30-min rehabilitation session per day for 2 weeks. In G4 group, TEAS is delivered at a strong but comfortable current for 30 s, then the current is gradually decreased to none over the next 15 s. The primary outcomes are measured before surgery, at baseline (POD 3, before TEAS intervention), week 1 and 2 after TEAS intervention with the Numeric Pain Rating Scale and The American Knee Society Score. The secondary outcomes include: (1) Active range of motion of the knee that was operated on; (2) Surface electromyography of both quadriceps; (3) Modified 30-s sit to stand test; (4) Additional usage of analgesia; and (5) SF-36. The additional outcomes include: (1) Patients' satisfaction rate; (2) Patient's expectation rate; and (3) Incidence of analgesia-related side effects. To test the blinding of participants and assessors, they are asked to guess whether the subjects received active or placebo TEAS within 5 min after the latest intervention. The safety and financial cost of TEAS are assessed. DISCUSSION: Mixed TEAS has more favorable effect on acute pain control than the placebo or 5 Hz or 100 Hz TEAS. TRIAL REGISTRATION: ChiCTR1800016347 . Date of registration was 26 May 2018. Retrospectively registered.

[Comparison of analgesic effects between multimodal and patient-controlled intravenous analgesia in patients with rheumatoid arthritis in the perioperative period of total knee arthroplasty].

OBJECTIVE: To compare the analgesic effect between multimodal and patient-controlled intravenous analgesia(PCIA) in patients with rheumatoid arthritis(RA) in the perioperative period of knee joint replacement. METHODS: From June 2015 to June 2016, 40 RA patients undergoing total knee arthroplasty were randomly divided into two groups. There were 20 patients in PCIA group, including 3 males and 17 females, with an average age of(59.6±2.3) years old, who received controlled instillation of sufentanil analgesia controlled by an intravenous analgesia pump. There were 20 patients in multiple model analgesia group, including 2 males and 18 females, with an average age of(56.3±1.3) years old, who were treated with continuous femoral nerve block, local injection of knee joint and combined buprenorphine patches. The VAS score and the incidence of adverse reactions and HSS score were compared between the two groups after operation. The advantages and disadvantages of the two modes of analgesia were evaluated. RESULTS: On the 6 th and 24 th hours after surgery, the VAS scores of the multimodal analgesia group were significantly lower than those of the PCIA group(P<0.01). On the 48 th hour after surgery, the VAS scores was significantly lower in the multimodal analgesia group than those in PCIA group(P<0.000 1), both in the state of motion and at rest. On the 1 st week after surgery, the HSS score of the multimodal analgesia group was significantly higher than that in the PCIA group(P<0.000 1). The pain score and the degree of activity in HSS score of the multimodal analgesia group were better than those in PCIA group (P<0.05). The functional score of multimodal analgesia group was significantly better than that of PCIA group(P<0.01). But there was no significant difference in muscle strength scores between two groups. CONCLUSIONS: Multimodal analgesia is an ideal analgesic plan for total knee arthroplasty TKA patients with RA in perioperative period, which has good effects and little adverse reaction.

[Experimental study on effect of rhizoma drynariae flavone on bone destruction of collagen inducted arthritis rat].

OBJECTIVE: Through establishing the rat model of CIA to evaluate the effect and mechanism of Rhizoma Drynariae Flavone on bone destruction of CIA rat. METHODS: Subcutaneous injection of bovine type II collagen was used to induce Wistar rats to fall ill, and then established the rat model of CIA. The rats whose inflammation scores reached to two points or above were randomly divided into four groups, and were treated accordingly. The effect of Rhizoma Drynariae Flavone on bone destruction was evaluated. RESULTS: At 12 weeks after treatment, bone trabecular area percentage and bone trabecular number in Rhizoma Drynariae Flavone group, Rhizoma Drynariae Flavone-1/2 Etanercept group, Etanercept group was obviously higher than that of sterilization water group (P < 0.05); and the trabecular resolving power of these groups was obviously less than that of sterilization water group (P < 0.05). CONCLUSION: Rhizoma Drynariae Flavone can obviously inhibit inflammation of joint bone destruction of CIA rats,the effect may be related with bone trabecular number reduction and trabecular resolving power increasing.

[Effect of Bushen Qianggu decoction on the proliferation of synovial fibroblasts and expression of PCNA and Bcl-2].

OBJECTIVE: To observe the effects of Bushen Qianggu decoction proliferation and PCNA and Bcl-2 expression. METHODS: Serum containing BQD was made and synovial fibroblasts were separated and cultured and passaged in vitro. Four groups were divided as 20% blank control group, serum containing 20% Tripterygium wilfordii multi-glycosides drug (TWMD), 20% of serum containing high and low of BQD, respectively. Serum containing drugs of different concentration were added into the synovial fibroblasts of the third generation, and then the synovial fibroblasts were cultured continued. The effects of different drugs on synovial fibroblasts and PCNA and Bcl-2 expression were observed. RESULTS: Compared with the control serum, BQD-containing serum promoted the apoptosis of synovial fibroblasts (P < 0.000 1); especially, high dose could inhibit proliferation. The expression of PCNA and Bcl-2 was significantly lower in BQD-containing serum (P < 0.000 1 vs control group). CONCLUSION: BQD can promote the apoptosis of synovial fibroblasts by improving of expression of PCNA and Bcl-2, which may be one of the mechanisms of BQD in preventing and treating osteoporosis of rheumatoid arthritis.