Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity.

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti-B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8+ CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.

Operative treatment of pulmonary primitive neuroectodermal tumor: a case report and literature review.

BACKGROUND: Pulmonary primitive neuroectodermal tumor (PNET), a member of the Ewing sarcoma family of tumors, is a rare malignancy that is associated with a grim prognosis. To date, fewer than 30 cases of pulmonary PNET have been reported. In this case report, we present the clinical details of a 12-year-old girl with pulmonary PNET who underwent surgical treatment. We also conducted an analysis and summary of other relevant studies and the surgical outcomes. CASE PRESENTATION: In May 2018, a 12-year-old girl was admitted with symptoms of cough and blood-tinged phlegm. A computed tomography scan revealed a large mass, measuring 12.9 cm × 8.1 cm, in the right middle and lower lungs. A percutaneous lung biopsy confirmed poorly differentiated tumor cells with a nested growth pattern. Immunohistochemical staining demonstrated positive expression of CD99, CD56, Vimentin, and Synaptophysin. The patient was diagnosed with pulmonary PNET. Following three cycles of neoadjuvant chemotherapy, a substantial reduction in tumor volume was observed. Subsequently, the patient underwent a surgical procedure involving pneumonectomy and partial resection of the left atrium with the assistance of cardiopulmonary bypass. The patient was discharged 37 days after surgery. During a three-year follow-up period, she exhibited no signs of tumor recurrence and has successfully returned to school. CONCLUSIONS: This case highlights the successful management of an advanced PNET with neoadjuvant chemotherapy, pneumonectomy, and partial resection of the left atrium employing cardiopulmonary bypass. The patient remained disease-free after three years. Our analysis of surgically treated cases indicates that neoadjuvant chemotherapy can contribute to improved prognoses for PNET patients. It is crucial to emphasize that complete surgical excision remains the cornerstone of treatment, underscoring the importance of surgeons considering radical surgical approaches whenever feasible for patients with pulmonary PNETs.

B cell lineage reconstitution underlies CAR-T cell therapeutic efficacy in patients with refractory myasthenia gravis.

B-cell maturation antigen (BCMA), expressed in plasmablasts and plasma cells, could serve as a promising therapeutic target for autoimmune diseases. We reported here chimeric antigen receptor (CAR) T cells targeting BCMA in two patients with highly relapsed and refractory myasthenia gravis (one with AChR-IgG, and one with MuSk-IgG). Both patients exhibited favorable safety profiles and persistent clinical improvements over 18 months. Reconstitution of B-cell lineages with sustained reduced pathogenic autoantibodies might underlie the therapeutic efficacy. To identify the possible mechanisms underlying the therapeutic efficacy of CAR-T cells in these patients, longitudinal single-cell RNA and TCR sequencing was conducted on serial blood samples post infusion as well as their matching infusion products. By tracking the temporal evolution of CAR-T phenotypes, we demonstrated that proliferating cytotoxic-like CD8 clones were the main effectors in autoimmunity, whereas compromised cytotoxic and proliferation signature and profound mitochondrial dysfunction in CD8+ Te cells before infusion and subsequently defect CAR-T cells after manufacture might explain their characteristics in these patients. Our findings may guide future studies to improve CAR T-cell immunotherapy in autoimmune diseases.

Single-cell analysis of refractory anti-SRP necrotizing myopathy treated with anti-BCMA CAR-T cell therapy.

Immune-mediated necrotizing myopathy (IMNM) is an autoimmune disorder associated with the presence of autoantibodies, characterized by severe clinical presentation with rapidly progressive muscular weakness and elevated levels of creatine kinase, while traditional pharmacological approaches possess varying and often limited effects. Considering the pathogenic role of autoantibodies, chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA) have emerged as a promising therapeutic strategy. We reported here a patient with anti-signal recognition particle IMNM refractory to multiple available therapies, who was treated with BCMA-targeting CAR-T cells, exhibited favorable safety profiles, sustained reduction in pathogenic autoantibodies, and persistent clinical improvements over 18 mo. Longitudinal single-cell RNA, B cell receptor, T cell receptor sequencing analysis presented the normalization of immune microenvironment after CAR-T cell infusion, including reconstitution of B cell lineages, replacement of T cell subclusters, and suppression of overactivated immune cells. Analysis on characteristics of CAR-T cells in IMNM demonstrated a more active expansion of CD8+ CAR-T cells, with a dynamic phenotype shifting pattern similar in CD4+ and CD8+ CAR-T cells. A comparison of CD8+ CAR-T cells in patients with IMNM and those with malignancies collected at different timepoints revealed a more NK-like phenotype with enhanced tendency of cell death and neuroinflammation and inhibited proliferating ability of CD8+ CAR-T cells in IMNM while neuroinflammation might be the distinct characteristics. Further studies are warranted to define the molecular features of CAR-T cells in autoimmunity and to seek higher efficiency and longer persistence of CAR-T cells in treating autoimmune disorders.

A Bacillus subtilis Strain ZJ20 with AFB1 Detoxification Ability: A Comprehensive Analysis.

As a class I carcinogen, aflatoxin can cause serious damage to various tissues and organs through oxidative stress injuries. The liver, as the target organ of AFB1, is the most seriously damaged. Biological methods are commonly used to degrade AFB1. In our study, the aflatoxin B1-degrading strain ZJ20 was screened from AFB1-contaminated feed and soil, and the degradation of AFB1 by ZJ20 was investigated. The whole genome of strain ZJ20 was analyzed, revealing the genomic complexity of strain ZJ20. The 16S rRNA analysis of strain ZJ20 showed 100% identity to Bacillus subtilis IAM 12118. Through whole gene functional annotation, it was determined that ZJ20 has high antioxidant activity and enzymatic activity; more than 100 CAZymes and 11 gene clusters are involved in the production of secondary metabolites with antimicrobial properties. In addition, B. subtilis ZJ20 was predicted to contain a cluster of genes encoding AFB1-degrading enzymes, including chitinase, laccase, lactonase, and manganese oxidase. The comprehensive analysis of B. subtilis provides a theoretical basis for the subsequent development of the biological functions of ZJ20 and the combinatorial enzyme degradation of AFB1.

Chloroquine Inhibition of Autophagy Enhanced the Anticancer Effects of Listeria monocytogenes in Melanoma.

Listeria monocytogenes has been shown to exhibit antitumor effects. However, the mechanism remains unclear. Autophagy is a cellular catabolic process that mediates the degradation of unfolded proteins and damaged organelles in the cytosol, which is a double-edged sword in tumorigenesis and treatment outcome. Tumor cells display lower levels of basal autophagic activity than normal cells. This study examined the role and molecular mechanism of autophagy in the antitumor effects induced by LM, as well as the combined antitumor effect of LM and the autophagy inhibitor chloroquine (CQ). We investigated LM-induced autophagy in B16F10 melanoma cells by real-time PCR, immunofluorescence, Western blotting, and transmission electron microscopy and found that autophagic markers were increased following the infection of tumor cells with LM. The autophagy pathway in B16F10 cells was blocked with the pharmacological autophagy inhibitor chloroquine, which led to a significant increase in intracellular bacterial multiplication in tumor cells. The combination of CQ and LM enhanced LM-mediated cancer cell death and apoptosis compared with LM infection alone. Furthermore, the combination of LM and CQ significantly inhibited tumor growth and prolonged the survival time of mice in vivo, which was associated with the increased colonization and accumulation of LM and induced more cell apoptosis in primary tumors. The data indicated that the inhibition of autophagy by CQ enhanced LM-mediated antitumor activity in vitro and in vivo and provided a novel strategy to improving the anticancer efficacy of bacterial treatment.

Anti-BCMA CAR T-cell therapy CT103A in relapsed or refractory AQP4-IgG seropositive neuromyelitis optica spectrum disorders: phase 1 trial interim results.

Chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA) have great potentials in autoimmune diseases and could be novel therapeutics for relapsed/refractory neuromyelitis optica spectrum disorder (NMOSD). To evaluate the safety and efficacy of the CT103A, a self-developed BCMA-targeting CAR construct against BCMA, in patients with AQP4-IgG seropositive NMOSD, an ongoing, investigator-initiated, open-label, single-arm, phase 1 clinical trial is conducted at our center. In total, 12 patients were administered with a CAR-BCMA infusion. Ten of the 12 patients dosed were women (83.3%), with a median age of 49.5 years (range, 30-67). were The most common events of grade 3 or higher were hematologic toxic effects. Seven patients (58%) developed infections, but no grade 4 infections occurred. Cytokine release syndrome was reported in all patients with only events of grade 1 or 2 observed. During the follow-up of a median 5.5 months, 11 patients had no relapse; all patients generally reported improvement in disabilities and quality-of-life outcomes; 11 patients' AQP-4 antibodies in serum showed a downward trend by the cutoff date. CAR T-cell expansion was associated with responses, and persisted more than 6 months post-infusion in 17% of the patients. In summary, CAR T-cell therapy shows a manageable safety profile and therapeutic potentials for patients with relapsed/refractory AQP4-IgG seropositive NMOSD. Another expansion phase is currently underway to determine the safety and efficacy of CAR T-BCMA infusion in patients with other neuro-inflammatory diseases.

Deep learning approach identified a gene signature predictive of the severity of renal damage caused by chronic cadmium accumulation.

Epidemiology studies have indicated that environmental cadmium exposure, even at low levels, will result in chronic cadmium accumulation in the kidney with profound adverse consequences and that the diabetic population is more susceptible. However, the underlying mechanisms are yet not fully understood. In the present study, we applied an animal model to study chronic cadmium exposure-induced renal injury and performed whole transcriptome profiling studies. Repetitive CdCl2 exposure resulted in cadmium accumulation and remarkable renal injuries in the animals. The diabetic ob/ob mice manifested increased severity of renal injury compared with the wild type C57BL/6 J littermate controls. RNA-Seq data showed that cadmium treatment induced dramatic gene expression changes in a dose-dependent manner. Among the differentially expressed genes include the apoptosis hallmark genes which significantly demarcated the treatment effects. Pathway enrichment and network analyses revealed biological oxidation (mainly glucuronidation) as one of the major stress responses induced by cadmium treatment. We next implemented a deep learning algorithm in conjunction with cloud computing and discovered a gene signature that can predict the degree of renal injury induced by cadmium treatment. The present study provided, for the first time, a comprehensive mechanistic understanding of chronic cadmium-induced nephrotoxicity in normal and diabetic populations at the whole genome level.

Galectin-1 Contributes to Vascular Remodeling and Blood Flow Recovery After Cerebral Ischemia in Mice.

Galectin-1 is found in the vasculature and has been confirmed to promote angiogenesis in several cancer models. Furthermore, galectin-1 has been demonstrated to improve the recovery of cerebral ischemia. However, whether vascular remodeling contributes to this improvement is still unknown. In the present study, photochemical cerebral ischemia was induced in both galectin-1-treated (2 µg/day, i.c.v, 3 days) and galectin-1 knockout mice. Laser speckle imaging and immunofluorescent staining demonstrated that circulation and vascular remodeling in the ischemic cortex were improved by galectin-1 treatment but disrupted in galectin-1 knockout mice. Western blot analysis showed that the expression of matrix metallopeptidase-9 and vascular endothelial growth factor (VEGF) was regulated by galectin-1 in vivo. To determine how galectin-1 influences endothelial cells, the expression of galectin-1 in bEnd.3 cells was increased by transfection with an expression plasmid and knocked down by siRNA. As demonstrated by quantitative RT-PCR and western blot analysis, the expression of metallopeptidase-9, VEGF, and VEGF receptors was upregulated by galectin-1 overexpression but downregulated after galectin-1 knockdown. Flow cytometry, Transwell assay, and capillary-like tube formation assay were performed on cells after gene manipulation as well as cells treated by exogenous galectin-1 after anoxia. It demonstrated that galectin-1 potentiated the cell proliferation, migration capacity, and tube formation ability. Taken together, these data suggest that by targeting vascular remodeling, galectin-1 contributes to the restoration of blood flow, which promotes the recovery of mice after cerebral ischemic insults.

Predictors of futile recanalization after endovascular treatment in acute ischemic stroke: a meta-analysis.

BACKGROUND: Despite successful recanalization after endovascular treatment, many patients with acute ischemic stroke due to large vessel occlusion still show functional dependence, namely futile recanalization. METHODS: PubMed and Embase were searched up to April 30, 2021. Studies that reported risk factors for futile recanalization following endovascular treatment of acute ischemic stroke were included. The mean difference (MD) or odds ratio (OR) and 95% confidence interval (95% CI) of each study were pooled for a meta-analysis. RESULTS: Twelve studies enrolling 2138 patients were included. The pooled analysis showed that age (MD 5.81, 95% CI 4.16 to 7.46), female sex (OR 1.40, 95% CI 1.16 to 1.68), National Institutes of Health Stroke Scale (NIHSS) score (MD 4.22, 95% CI 3.38 to 5.07), Alberta Stroke Program Early CT Score (ASPECTS) (MD -0.71, 95% CI -1.23 to -0.19), hypertension (OR 1.73, 95% CI 1.43 to 2.09), diabetes (OR 1.78, 95% CI 1.41 to 2.24), atrial fibrillation (OR 1.24, 95% CI 1.01 to 1.51), admission systolic blood pressure (MD 4.98, 95% CI 1.87 to 8.09), serum glucose (MD 0.59, 95% CI 0.37 to 0.81), internal carotid artery occlusion (OR 1.85, 95% CI 1.17 to 2.95), pre-treatment intravenous thrombolysis (OR 0.67, 95% CI 0.55 to 0.83), onset-to-puncture time (MD 16.92, 95% CI 6.52 to 27.31), puncture-to-recanalization time (MD 12.37, 95% CI 7.96 to 16.79), and post-treatment symptomatic intracerebral hemorrhage (OR 6.09, 95% CI 3.18 to 11.68) were significantly associated with futile recanalization. CONCLUSION: This study identified female sex, comorbidities, admission systolic blood pressure, serum glucose, occlusion site, non-bridging therapy, and post-procedural complication as predictors of futile recanalization, and also confirmed previously reported factors. Further large-scale prospective studies are needed.

Apatinib in the treatment of gastric cancer in Henan Province: a multicenter prospective real-world observational study (Ahead-HAP01).

Background: Apatinib is approved in China for the treatment of advanced gastric adenocarcinoma that had progressed or relapsed after standard systemic chemotherapy treatments. However, the effectiveness of Apatinib under real-world condition has not been evaluated and the drug performance under ideal and controlled circumstances has not been validated. In fact, genetic factors, poor healthcare access, social economic status, comorbidities compliance and other factors play significant role in drug performance under "real-world" conditions. Real-world experience can help validate the safety and efficacy of apatinib. Methods: In this observational, prospective study we evaluated the safety and efficacy of Apatinib in patient treated in China. Between March 2018 and March 2019, a total of 943 patients with gastric cancer treated with Apatinib were enrolled. Response Evaluation Criteria in Solid Tumors, version 1.1 and Common Terminology Criteria for Adverse Events, version 4.0 were used to evaluate efficacy and adverse effects. Results: The median progression-free survival (PFS) was 5.65 months (5.22-6.05 months), and the median overall survival (OS) was 11.47 months (10.41-12.52 months). Apatinib in combination with more than two agents was superior to single agent apatinib in overall response rate (ORR) [18.18% vs. 9.43%, 95% confidence interval (CI): 1.03-5.90] and disease control rate (DCR) (82.82% vs. 77.87%, 95% CI: 1.21-2.59). Apatinib in combination with single agent chemotherapy was also superior to apatinib alone with DCR (86.29% vs. 77.87%, 95% CI: 1.47-2.99) irrespective of the dose (250 or 500 mg). In the patient cohort who received a starting dose of 250 mg, the DCRs of the combined treatment and monotherapy groups were 86.22% vs. 80.00% (95% CI: 1.18-3.09), respectively. The most common treatment-emergent adverse events were anemia, anorexia and thrombocytopenia (66.28%, 37.75%, 36.06%, respectively). Conclusions: Efficacy of Apatinib in this observational study is promising and toxicities are manageable. Combination of Apatinib with chemotherapy agents has a higher response rate and better disease control at the expense of increased serious adverse events. Better OS can be achieved by receiving apatinib treatment earlier. As a supplement and further validation of explanatory randomized controlled trials, the real-world study reflects the real efficacy of apatinib in practical application.

Tacrolimus as a therapeutic option in patients with acquired neuromyotonia.

OBJECTIVE: To analyze the clinical characteristics and outcomes of patients diagnosed with acquired neuromyotonia and who were treated with tacrolimus. METHODS: A single center, retrospective study was performed on patients with acquired meuromyotonia whose treatment included tacrolimus. The clinical information, antibody tests, and electromyography results were reviewed. The Numeric Rating Scale for pain and modified Rankin scale were used to quantify outcomes. RESULTS: This study included four patients who presented with fasciculation or myokymia in their limbs. Electromyography suggested peripheral nerve hyperexcitability. Autoantibodies including contactin-associated protein 2 (CASPR2), leucine-rich glioma inactivated protein 1 (LGl1) or IgLON5 antibody were detected in three patients, and another patient had Sjogren's syndrome. Initial treatment included membrane-stabilizing drugs and/or corticosteroids. Tacrolimus was administered at a dose of 3 mg once daily to all patients. All patients showed clinical improvement after the treatment. No recurrence was observed after gradual tapering or discontinuation of therapy during follow-up. CONCLUSIONS: Tacrolimus may be a therapeutic option for acquired neuromyotonia. Further studies on tacrolimus in larger patient cohort should be performed.

Acid- and Thiol-Cleavable Multifunctional Codelivery Hydrogel: Fabrication and Investigation of Antimicrobial and Anticancer Properties.

Hydrogels serving as a drug carrier was realized by entrapping small-sized drug molecules within their cross-linked interstitial networks. After covering the targeted location, hydrogels interact with the physiological fluids and swell, resulting in an increased interspace between networks for the outside diffusion of drugs. However, inevitable in vivo inflammatory responses or bacterial infection on the implant materials and persistent cargo release are still challenging. Herein, we report the fabrication of dual-responsive hydrogels based on acid-sensitive poly(ethylenimine) (PEI) derivative (PEI(-COOH/-vinyl)), thiol-responsive camptothecin prodrug monomer (CPTM), and hydrophilic oligo(ethylene glycol) methyl ether acrylate (OEGMA) by a conventional radical polymerization. Curcumin was then solubilized into the hydrogels to endow them with antimicrobial and cancer resistance properties. The in vitro experiments exhibited sustained hydrogel dissolution and CPT release in a simulated physiological environment. The antimicrobial and cytotoxicity tests of drug-loaded hydrogels using methicillin-resistant Staphylococcus aureus (MRSA) strains and HeLa cancer cell lines, respectively, indicated that the hydrogels possessed efficient antimicrobial effects and could successfully inhibit the growth of cancer cells.

Hypertrophic Pachymeningitis in Chinese Patients: Presentation, Radiological Findings, and Clinical Course.

BACKGROUND: Hypertrophic pachymeningitis (HP) is generally regarded as a rare inflammatory disease, which results in a diffuse thickening of the dura mater. We retrospectively collected data from patients with HP. METHODS: A total of 16 patients with HP were included in our study. The clinical features, laboratory evaluation, imaging findings, treatment, and outcome were reviewed. RESULTS: Of the 16 cases, half were male, with a mean age of 52.6 ± 13.2 years. The mean duration from onset to diagnosis was 8.6 months. The most frequent presenting symptoms in HP cases were a recurrently chronic headache (81.3%) and multiple cranial nerve injury (50%). Antineutrophil cytoplasmic antibody- (ANCA-) related HP was found in 5 cases and IgG4-related HP in 1 case. The intracranial pressure was elevated in 4 cases. The cerebrospinal fluid (CSF) had lymphocytosis in 5 cases and increased protein in 12 cases. Immunoglobulins (IgG, IgA, and IgM) and protein showed linear relationships in the CSF. On magnetic resonance imaging (MRI), localized or diffuse dura maters were thickened in all cases. HP combined with subacute subdural hemorrhage or hypertrophic spinal pachymeningitis was also observed in individual cases. Biopsy of the dura mater in one case showed amounts of inflammatory cells infiltrating, with an increased percentage of IgG4-positive plasma cells. Of all cases referring to glucocorticoid treatment, the symptoms have improved significantly in 10 cases. In other 6 cases, mycophenolate mofetil or azathioprine was added. All patients showed clinical improvement at the follow-up visits. CONCLUSION: The clinical characters of HP are chronic onset, recurrently chronic headache, and multiple cranial nerves paralysis. Inflammatory changes in CSF caused by intrathecal synthesis of immunoglobulin, characteristic dural enhancement on MRI, and pathologic biopsy are all helpful for diagnosis. The addition of immunosuppressant, especially mycophenolate mofetil, is a good choice for steroid-resistance HP.

Gene silencing of indoleamine 2,3-dioxygenase 1 inhibits lung cancer growth by suppressing T-cell exhaustion.

Indoleamine 2,3-dioxygenase 1 (IDO1), which degrades the essential amino acid tryptophan, exerts immunosuppressive functions and serves a crucial role in multiple types tumor progression, including non-small-cell lung cancer (NSCLC) and melanoma. Recent studies have reported that T-cell exhaustion is increased during tumor progression, which impairs the antitumor immune response. However, the association between IDO1 and T-cell exhaustion during tumor progression remains unknown. The present study evaluated the effect of IDO1 on T-cell exhaustion in lung cancer mice. The present study demonstrated that IDO1 knockdown by small interfering RNA in the LLC cell line inhibited T-cell exhaustion. Furthermore, the role of IDO1 in T-cell exhaustion during lung cancer progression was determined in an in vivo mouse model using IDO1 short hairpin RNA (shRNA). The results demonstrated that inhibition of IDO1 activity by shRNA administration in vivo significantly delayed the onset and growth of tumors. In addition, the expression levels of the inhibitory receptors programmed death-1 (PD-1) and B and T lymphocyte attenuator (BTLA) were increased in T-cells from the lung tumor-bearing mice, whereas interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) levels in serum were decreased compared with the control mice. However, no difference in the absolute number of T cells was observed, including CD4+ and CD8+ T cells. In addition, IDO1 knockdown by shRNA inhibited T-cell exhaustion in lung tumor-bearing mice, which was characterized by decreased expression of PD-1 and BTLA on T cells. By contrast, IL-2 and TNF-α levels in serum were increased in IDO1-shRNA-treated mice. By using a shRNA approach, the present study demonstrated that IDO1 activity may be involved in tumor growth, and that IDO1 silencing may inhibit tumor progression by impeding the process of T-cell exhaustion.

Higher Serum CCN3 Is Associated with Disease Activity and Inflammatory Markers in Rheumatoid Arthritis.

Nephroblastoma overexpressed protein (NOV/CCN3), the early discovered member of the CCN family, has recently been suggested to be involved in a number of inflammatory processes, including wound healing, alveolar epithelial cell inflammation, cancer metastasis, and macrophage foam cell formation. However, the role of CCN3 in rheumatoid arthritis (RA), a classic autoimmune and inflammatory disease, remains elusive. RA is a chronic systemic autoimmune disease that eventually leads to cartilage and bone destruction and joint dysfunction. In this study, we investigated the potential of serum CCN3 as a biomarker for RA. The serum levels of CCN3 were measured by ELISA. The clinical and laboratory parameters were collected from a clinical record system, and disease activity was determined by joint disease activity score 28 (DAS28). Our results showed that the serum levels of CCN3 were significantly increased in RA patients compared to healthy controls. Furthermore, the CCN3 level was positively correlated with DAS28 (CRP), DAS28 (ESR), and the level of anti-CCP Ab, an autoantibody highly specific for RA. Furthermore, CCN3 showed a positive correlation with inflammatory cytokine IL-6, while no significant correlation with TNF-α was observed. These data suggest that CCN3 plays an important role in the development of RA and might be a potential disease activity biomarker for RA.

Fingolimod promotes angiogenesis and attenuates ischemic brain damage via modulating microglial polarization.

INTRODUCTION: Microglial activation plays a crucial role in the pathology of ischemic stroke. Recently, we demonstrated that fingolimod (FTY720) exerted neuroprotective effects via immunomodulation in ischemic white matter damage induced by chronic cerebral hypoperfusion, which was accompanied by robust microglial activation. In this study, we assessed the pro-angiogenic potential of FTY720 in a murine model of acute cortical ischemic stroke. METHODS: The photothrombotic (PT) method was used to induce cortical ischemic stroke in mice. We evaluated cortical damage, behavioral deficits, microglial polarization, and angiogenesis to identify the neuroprotective effects and possible molecular mechanisms of FTY720 in acute ischemic stroke. RESULTS: In vivo, a reduction in neuronal loss and improved motor function were observed in FTY720-treated mice after PT stroke. Immunofluorescence staining revealed that robust microglial activation and the associated neuroinflammatory response in the peri-infarct area were ameliorated by FTY720 via its ability to polarize microglia toward the M2 phenotype. Furthermore, both in vivo and in vitro, angiogenesis was enhanced in the microglial M2 phenotype state. Behaviorally, a significant improvement in the FTY720-treated group compared to the control group was evident from days 7 to 14. CONCLUSIONS: Our research indicated that FTY720 treatment promoted angiogenesis via microglial M2 polarization and exerted neuroprotection in PT ischemic stroke.

Flame Retardancy, Fire Behavior, and Flame Retardant Mechanism of Intumescent Flame Retardant EPDM Containing Ammonium Polyphosphate/Pentaerythrotol and Expandable Graphite.

The intumescent flame retardant ethylene-propylene-diene rubber (EPDM) was prepared using intumescent flame retardant (IFR), including ammonium polyphosphate (APP) /pentaerythrotol (PER) and expandable graphite (EG), as the flame retardant agent. The effects of IFR and EG on the flame retardancy, fire behavior, and thermal stability of the EPDM were investigated. The results show that IFR and EG have excellent synergistic flame retardant effects. When the mass ratio of IFR to EG is 3:1 and the total addition content is 40 phr, the limiting oxygen index (LOI) value of the EPDM material (EPDM/IFR/EG) can reach 30.4%, and it can pass a V-0 rating in the vertical combustion (UL-94) test. Meanwhile, during the cone calorimetry test, the heat release rate and total heat release of EPDM/IFR/EG are 69.0% and 33.3% lower than that of the pure EPDM, respectively, and the smoke release of the material also decreases significantly, suggesting that the sample shows good fire safety. In addition, the flame retardant mechanism of IFR and EG is systematically investigated by thermogravimetric analysis/infrared spectrometry (TG-IR), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM), and the results indicate that IFR and EG have only physical interaction. Moreover, the reason why IFR exhibits a poor flame retardant effect in EPDM materials is explained.

Cerebral venous sinus thrombosis due to hyperhomocysteinemia with cystathionine-ß-synthase (CBS) gene mutation: A case report.

RATIONALE: Risk factors of cerebral venous sinus thrombosis (CVST) are usually divided into acquired risks (e.g., trauma and pregnancy) and genetic risks (inherited thrombophilia). It is essential but not easy to identify the exact one for each patient. PATIENT CONCERNS: A 14-year-old male patient was admitted in our hospital because of progressively exacerbated severe headache and vomiting for 3 days, accompanied by transient weakness once in his right leg. DIAGNOSIS: CVST due to hyperhomocysteinemia with cystathionine-ß-synthase (CBS) gene mutation. INTERVENTIONS: Persistent oral anticoagulant therapy. OUTCOMES: Follow-ups at 4 months and 1 year showed that the patient's symptoms alleviated and did not recur, accompanied with improved MRV image; however, the cranial MRV image did not display as a completely normal one. LESSONS: We recommend that in case of thrombophilic state, serum homocysteine (Hcy), folic acid, and vitamin B12 levels should be routinely screened; when serum Hcy level is extremely high, congenital diseases caused by gene mutations should be considered. We firstly discovered a new mutation of CBS c.949A>G which had not been reported before.

Influence of Capsaicin on Inflammatory Cytokines Induced by Lipopolysaccharide in Myoblast Cells Under In vitro Environment.

BACKGROUND: ellular damage initiated by reactive oxygen species (ROS) is the main cause of numerous severe diseases and therefore for this reason, the natural antioxidants have note worthy significance in human health. Capsaicin possesses noteworthy analgesic and anti-inflammatory properties. It also possesses healing effects for treatment of arthritis, diabetic neuropathy, gastric lesions, and cardiac excitability that is why it is incorporated in creams and gels. OBJECTIVE: The present study was carried out to estimate the in vitro antioxidant and ROS scavenging activities of capsaicin against muscle precursor cells. Till date, no investigation has been carried out to study the effect of capsaicin on myoblasts. MATERIALS AND METHODS: Herein, the cytotoxicity was induced by endotoxin lipopolysaccharide (LPS) to analyze the effect of capsaicin on LPS induced inflammation and apoptosis on muscle cells. To find out the toxicity of endotoxin, myoblasts were exposed to different concentrations of LPS, viability and morphology was checkedby the means of CCK-8 test and microscopy, respectively. Apoptotic cell death was examined by fluorescence staining. Additionally, LPS-induced apoptosis was determined by mRNAexpression of calpain, caspase-3 and tumor necrosisfactor alpha (TNF-α), and were quantified by qRT-PCR. RESULTS: The outcome of the presentstudy demonstrated that LPS stimulation generatestoxicity in dose-dependent manner. Pre-treatmentof myoblasts with capsaicin can considerably alleviate LPS-induced inflammation. CONCLUSION: In conclusion, this study indicates that dietetic supplementation of capsicum may help to alleviate/reduce the inflammatory effects and is therefore potent source of natural antioxidant agent which can be utilized to control muscle related diseases, such as myotube atrophy. SUMMARY: In the present study cytotoxicity was induced by LPS to analyze the effect of capsaicin on LPS induced inflammation and apoptosis on muscle cells.The results of this investigation demonstrated that LPS stimulation generates toxicity in dose dependent manner. Pre-treatment of myoblasts with capsaicin can considerably reduce LPS induced inflammation.It has been concluded on the basis of results that the dietetic supplementation of capsicum may help to minimize inflammatory effects and are potent sources of natural antioxidants which can be utilized to control muscle related diseases such as atrophy. Abbreviation used: AMP: Adenosine monophosphate, AO/EB: Acridine orange / Ethidium bromide, ATL: T-cell leukemi, CAP: Capsaicin, CCK-8: Cell counting Kit-8, CLSM: Laser Scanning Microscopy, DCF-DA: 2', 7'-dichlorofluorescein diacetate, DMEM: Dulbecco's modified Eagle's medium, DPPH: α, α-diphenyl-ß-picrylhydrazyl, FBS: Fetal bovine serum, KA: Kainic acid, LPS: Lipopolysaccharide, MDA: Malondialdehyde, NF-κB: Nuclear factor kgene binding, PBS: Phosphate buffer saline, pNA: p-nitroanilide, RNW: RNase free water, ROS: Reactive oxygen species, TNF-α: Tumor necrosis factor alpha, TRPV1: Transient receptor potential vanilloid 1.