Demethylation and Up-Regulation of an Oncogene after Hypomethylating Therapy.

BACKGROUND: Although hypomethylating agents are currently used to treat patients with cancer, whether they can also reactivate and up-regulate oncogenes is not well elucidated. METHODS: We examined the effect of hypomethylating agents on SALL4, a known oncogene that plays an important role in myelodysplastic syndrome and other cancers. Paired bone marrow samples that were obtained from two cohorts of patients with myelodysplastic syndrome before and after treatment with a hypomethylating agent were used to explore the relationships among changes in SALL4 expression, treatment response, and clinical outcome. Leukemic cell lines with low or undetectable SALL4 expression were used to study the relationship between SALL4 methylation and expression. A locus-specific demethylation technology, CRISPR-DNMT1-interacting RNA (CRISPR-DiR), was used to identify the CpG island that is critical for SALL4 expression. RESULTS: SALL4 up-regulation after treatment with hypomethylating agents was observed in 10 of 25 patients (40%) in cohort 1 and in 13 of 43 patients (30%) in cohort 2 and was associated with a worse outcome. Using CRISPR-DiR, we discovered that demethylation of a CpG island within the 5' untranslated region was critical for SALL4 expression. In cell lines and patients, we confirmed that treatment with a hypomethylating agent led to demethylation of the same CpG region and up-regulation of SALL4 expression. CONCLUSIONS: By combining analysis of patient samples with CRISPR-DiR technology, we found that demethylation and up-regulation of an oncogene after treatment with a hypomethylating agent can indeed occur and should be further studied. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).

New sights of low dose IL-2: Restoration of immune homeostasis for viral infection.

Viral infection poses a significant threat to human health. In addition to the damage caused by viral replication, the immune response it triggers often leads to more serious adverse consequences. After the occurrence of viral infection, in addition to the adverse consequences of infection, chronic infections can also lead to virus-related autoimmune diseases and tumours. At the same time, the immune response triggered by viral infection is complex, and dysregulated immune response may lead to the occurrence of immune pathology and macrophage activation syndrome. In addition, it may cause secondary immune suppression, especially in patients with compromised immune system, which could lead to the occurrence of secondary infections by other pathogens. This can often result in more severe clinical outcomes. Therefore, regarding the treatment of viral infections, restoring the balance of the immune system is crucial in addition to specific antiviral medications. In recent years, scientists have made an interesting finding that low dose IL-2 (ld-IL-2) could potentially have a crucial function in regulating the immune system and reducing the chances of infection, especially viral infection. Ld-IL-2 exerts immune regulatory effects in different types of viral infections by modulating CD4+ T subsets, CD8+ T cells, natural killer cells, and so on. Our review summarised the role of IL-2 or IL-2 complexes in viral infections. Ld-IL-2 may be an effective strategy for enhancing host antiviral immunity and preventing infection from becoming chronic; additionally, the appropriate use of it can help prevent excessive inflammatory response after infection. In the long term, it may reduce the occurrence of infection-related autoimmune diseases and tumours by promoting the restoration of early immune homeostasis. Furthermore, we have also summarised the application of ld-IL-2 in the context of autoimmune diseases combined with viral infections; it may be a safe and effective strategy for restoring immune homeostasis without compromising the antiviral immune response. In conclusion, focusing on the role of ld-IL-2 in viral infections may provide a new perspective for regulating immune responses following viral infections and improving prognosis.

Scalable, Green, Flexible Photochromic Bacterial Cellulose for Multicolor Switching, Photo-patterning, and Daily Sunlight UV Monitoring.

Sustainable, durable, and diverse photochromic smart textiles based on bacterial cellulose (BC) have emerged as attractive candidates in UV-sensing applications due to the green and easy functionalization of BC. However, existing BC-based photochromic textiles lack photochromic efficiency and combining fastness. In this study, a green strategy for in situ fermentation is developed to achieve the directional distribution of functional particles and remarkable photochromism in photochromic bacterial cellulose (PBC). The unique functional design obtained by regulating the photochromic dye distribution in 3D nanonetworks of PBCs during in situ growth affords a more uniform distribution and high fastness. Benefiting from the uniform distribution of photochromic dyes and adequate utilization of the 3D network structure, more surface area is provided to receive and utilize the photon energy from the UV rays, making the photochromic process more effective. The as-prepared PBCs exhibited rapid (within 1 min) and stable (30 cycles) discoloration and multicolor selectivity. Their simple preparation process and exceptional wearability, e.g., their flexibility, lightweight, and air permeability, make them suitable for various applications, including tunable color switching systems, photopatterning, and daily sunlight UV monitoring. This study provides empirical value for the biofabrication of photochromic textiles and wearable flexible UV sensors.

Clinical Performance of Immunonephelometric Assay and Chemiluminescent Immunoassay for Detection of IgG Subclasses in Chinese.

BACKGROUND: Detection of IgG subclasses (IgGSc) is vital for the diagnosis and management of disease, especially IgG4-related diseases (IgG4-RD). This study aimed to evaluate the performances of the chemiluminescent immunoassay (CLIA) for detecting IgGSc and diagnosing IgG4-RD by IgGSc. METHODS: A total of 40 individuals with IgG4-RD, 40 with primary Sjogren's syndrome (pSS), and 40 healthy controls (HCs) were enrolled. Serum samples were collected for the simultaneous detection of IgG1, IgG2, IgG3, and IgG4 by the Siemens immunonephelometric assay and the CLIA. The correlation analysis was performed, and diagnostic value was analyzed by the receiver operating characteristic (ROC) curve. RESULTS: Patients with IgG4-RD had higher IgG4 (p < 0.001) and lower IgG1 (p < 0.001) than those with pSS, and HC. The results by the Siemens immunonephelometric assay and the CLIA showed a strong correlation in detecting IgG1, IgG2, IgG3, and IgG4 (r = 0.937, r = 0.847, r = 0.871, r = 0.990, all p < 0.001, respectively). The sum of IgG1, IgG2, IgG3, and IgG4 using two assays strongly correlated with total IgG by the IMMAGE 800 (r = 0.866, r = 0.811, both p < 0.001, respectively). For discriminating IgG4-RD from pSS and HC, no significant differences were observed in CLIA IgG4 and Siemens immunonephelometric assay IgG4 (z = 0.138, p = 0.891), which provided the area under the curves (AUCs) of 0.951 (p < 0.001) and 0.950 (p < 0.001), respectively. The AUCs of CLIA IgG1 and Siemens immunonephelometric assay IgG1 in distinguishing pSS from IgG4-RD and HC were 0.761 (p < 0.001) and 0.765 (p < 0.001), respectively, with no significant differences (z = 0.228, p = 0.820). CONCLUSIONS: The CLIA and the Siemens immunonephelometric assay appeared to have good consistency with comparable diagnostic value in detecting IgGSc, especially IgG4, and IgG1 that can accurately identify IgG4-RD or pSS in clinical practice.

Diallyl disulfide, the bioactive component of Allium species, ameliorates pulmonary fibrosis by mediating the crosstalk of farnesoid X receptor and yes-associated protein 1 signaling pathway.

Environmental pollution, virus infection, allergens, and other factors may cause respiratory disease, which could be improved by dietary therapy. Allium species are common daily food seasoning and have high nutritional and medical value. Diallyl disulfide (DADS) is the major volatile oil compound of Allium species. The present study aims to explore the preventive effect and potential mechanism of DADS on pulmonary fibrosis. C57BL/6J mice were intratracheally injected with bleomycin (BLM) to establish pulmonary fibrosis and then administrated with DADS. Primary lung fibroblasts or A549 were stimulated with BLM, followed by DADS, farnesoid X receptor (FXR) agonist (GW4064), yes-associated protein 1 (YAP1) inhibitor (verteporfin), or silencing of FXR and YAP1. In BLM-stimulated mice, DADS significantly ameliorated histopathological changes and interleukin-1ß levels in bronchoalveolar lavage fluid. DADS decreased fibrosis markers, HIF-1α, inflammatory cytokines, and epithelial-mesenchymal transition in pulmonary mice and activated fibroblasts. DADS significantly enhanced FXR expression and inhibited YAP1 activation, which functions as GW4064 and verteporfin. A deficiency of FXR or YAP1 could result in the increase of these two protein expressions, respectively. DADS ameliorated extracellular matrix deposition, hypoxia, epithelial-mesenchymal transition, and inflammation in FXR or YAP1 knockdown A549. Taken together, targeting the crosstalk of FXR and YAP1 might be the potential mechanism for DADS against pulmonary fibrosis. DADS can serve as a potential candidate or dietary nutraceutical supplement for the treatment of pulmonary fibrosis.

Multi-Functional Integration of Phosphor, Initiator, and Crosslinker for the Photo-Polymerization of Flexible Phosphorescent Polymer Gels.

A general approach to constructing room temperature phosphorescence (RTP) materials involves the incorporation of a phosphorescent emitter into a rigid host or polymers with high glass transition temperature. However, these materials often suffer from poor processability and suboptimal mechanical properties, limiting their practical applications. In this work, we developed benzothiadiazole-based dialkene (BTD-HEA), a multifunctional phosphorescent emitter with a remarkable yield of intersystem crossing (ΦISC, 99.83 %). Its high triplet exciton generation ability and dialkene structure enable BTD-HEA to act as a photoinitiator and crosslinker, efficiently initiating the polymerization of various monomers within 120 seconds. A range of flexible phosphorescence gels, including hydrogels, organogels, ionogels, and aerogels were fabricated, which exhibit outstanding stretchability and recoverability. Furthermore, the unique fluorescent-phosphorescent colorimetric properties of the gels provide a more sensitive method for the visual determination of the polymerization process. Notably, the phosphorescent emission intensity of the hydrogel can be increased by the formation of ice, allowing for the precise detection of hydrogel freezing. The versatility of this emitter paves the way for fabricating various flexible phosphorescence gels with diverse morphologies using microfluidics, film-shearing, roll coating process, and two/three-dimensional printing, showcasing its potential applications in the fields of bioimaging and bioengineering.

The decreased of peripheral blood natural killer cell is associated with serum IL-2 level in the renal tubular acidosis in patients with primary sjogren's syndrome.

BACKGROUND: Primary Sjogren's Syndrome (pSS) is a lymphoproliferative disease with autoimmune characteristics, which is characterized by lymphocyte infiltration of exocrine glands and involvement and dysfunction of extraglandular organs. Renal tubular acidosis (RTA) is a common renal involvement in pSS. This study investigated the phenotypic characteristics of peripheral blood lymphocyte subsets and cytokines in pSS patients complicated with RTA (pSS-RTA). METHOD: This retrospective study included 25 pSS patients complicated with RTA and 54 pSS patients without RTA (pSS-no-RTA). To examine the level of peripheral lymphocytes subsets, flow cytometry analysis was used. The level of serum cytokines were detected by flow cytometry bead array(CBA). The influencing factors related to the occurrence of pSS-RTA were identified through logistic regression analyze. RESULTS: The absolute number of CD4 + T cells and Th2 cells in peripheral blood were decreased in pSS-RTA patients than pSS-no-RTA patients. Moreover, the absolute number of NK cells and Treg cells were also decreased in pSS-RTA patients than pSS-no-RTA. The level of serum IL-2 was higher in pSS-RTA patients than pSS-no-RTA patients, and is negatively correlated with the number of NK cells, the number and percentage of Th17 cells, and Th17/Treg. Serum IL-2 level is also correlated with various cytokines. Multivariate logistic analysis proved that elevated ESR and ALP were risk factors for pSS complicated with RTA, while Treg was a protective factor. CONCLUSION: The increase of serum IL-2 level and the decrease of peripheral blood NK cells and Treg cells may be the immune mechanism of the development of pSS-RTA disease.

Deep stratification by transcriptome molecular characters for precision treatment of patients with systemic lupus erythematosus.

OBJECTIVES: To leverage the high clinical heterogeneity of systemic lupus erythematosus (SLE), we developed and validated a new stratification scheme by integrating genome-scale transcriptomic profiles to identify patient subtypes sharing similar transcriptomic markers and drug targets. METHODS: A normalized compendium of transcription profiles was created from peripheral blood mononuclear cells (PBMCs) of 1046 SLE patients and 86 healthy controls (HCs), covering an intersection of 13 689 genes from six microarray datasets. Upregulated differentially expressed genes were subjected to functional and network analysis in which samples were grouped using unsupervised clustering to identify patient subtypes. Then, clustering stability was evaluated by the stratification of six integrated RNA-sequencing datasets using the same method. Finally, the Xgboost classifier was applied to the independent datasets to identify factors associated with treatment outcomes. RESULTS: Based on 278 upregulated DEGs of the transcript profiles, SLE patients were classified into three subtypes (subtype A-C) each with distinct molecular and cellular signatures. Neutrophil activation-related pathways were markedly activated in subtype A (named NE-driving), whereas lymphocyte and IFN-related pathways were more enriched in subtype B (IFN-driving). As the most severe subtype, subtype C [NE-IFN-dual-driving (Dual-driving)] shared functional mechanisms with both NE-driving and IFN-driving, which was closely associated with clinical features and could be used to predict the responses of treatment. CONCLUSION: We developed the largest cohesive SLE transcriptomic compendium for deep stratification using the most comprehensive microarray and RNA sequencing datasets to date. This result could guide future design of molecular diagnosis and the development of stratified therapy for SLE patients.

A pilot study of several environmental endocrine disrupting chemicals in children with autism spectrum disorder in south China.

Autism spectrum disorders (ASD) is a group of heterogeneous neurodevelopmental disorders. Evidence has implied that environmental pollutants are important factors related to ASD. In this study, several environmental endocrine-disrupting chemicals, including parabens, benzophenone-type ultraviolet filters, hydroxyl polycyclic aromatic hydrocarbons, triclosan and tetrabromobisphenol A were analyzed in blood plasma in ASD children (n = 34) and the control children (n = 28). The results showed that parabens were the most concentrated chemicals (2.18 ng/mL, median value), followed by hydroxyl polycyclic aromatic hydrocarbons (0.73 ng/mL), benzophenone-type ultraviolet filters (0.14 ng/mL), triclosan (0.13 ng/mL) and tetrabromobisphenol A (0.03 ng/mL). ASD children accumulated significantly lower 2-hydroxy-4-methoxybenzophenone, 2,4-dihydroxybenzophenone, 4-hydroxybenzophenone and triclosan but higher 2-hydroxyphenanthrene and tetrabromobisphenol A than the control children (0.02/0.09 ng/mL of 2-hydroxy-4-methoxybenzophenone, p < 0.05; 0.04/0.07 ng/mL of 2,4-dihydroxybenzophenone, p < 0.05; 0.03/0.04 ng/mL of 4-hydroxybenzophenone, p < 0.05; 0.13/1.22 ng/mL of triclosan, p < 0.01; 0.03 ng/mL/not detected of 2-hydroxyphenanthrene, p < 0.05; 0.03/0.004 ng/mL of tetrabromobisphenol A, p < 0.05). Gender differences in certain environmental endocrine-disrupting chemicals were evident, and the differences were more inclined toward boys. Positive associations between 2-hydroxy-4-methoxybenzophenone and triclosan, and tetrabromobisphenol A and 2-hydroxyphenanthrene were found in ASD boys. Binary logistic regression analysis showed that the adjusted odds ratio value of 2-hydroxyphenanthrene in ASD boys was 11.0 (1.45-84.0, p < 0.05). This is the first pilot study on multiple environmental endocrine-disrupting chemicals in children with ASD in China.

Tissue-resident memory T cells: The key frontier in local synovitis memory of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a highly disabling, systemic autoimmune disease. It presents a remarkable tendency to recur, which renders it almost impossible for patients to live without drugs. Under such circumstances, many patients have to suffer the pain of recurrent attacks as well as the side effects of long-term medication. Current therapies for RA are primarily systemic treatments without targeting the problem that RA is more likely to recur locally. Emerging studies suggest the existence of a mechanism mediating local memory during RA, which is closely related to the persistent residence of tissue-resident memory T cells (TRM). TRM, one of the memory T cell subsets, reside in tissues providing immediate immune protection but driving recurrent local inflammation on the other hand. The heterogeneity among synovial TRM is unclear, with the dominated CD8+ TRM observed in inflamed synovium of RA patients coming into focus. Besides local arthritis relapse, TRM may also contribute to extra-articular organ involvement in RA due to their migration potential. Future integration of single-cell RNA sequencing (scRNA-seq) with spatial transcriptomics to explore the gene expression patterns of TRM in both temporal dimension and spatial dimension may help us identify specific therapeutic targets. Targeting synovial TRM to suppress local arthritis flares while using systemic therapies to prevent extra-articular organ involvement may provide a new perspective to address RA recurrence.

Elevated Th17 cells are associated with cardiovascular complications in ankylosing spondylitis.

OBJECTIVE: Patients with ankylosing spondylitis (AS) carry an increased burden of cardiovascular diseases (CVD), but features denoting the development of CVD in AS are unclear. This study aimed to evaluate the percentage and absolute number of lymphocytes and CD4+T cells in AS patients complicated with CVD (AS-CVD) and determine whether circulating T helper 17 (Th17) cells are associated with the development of CVD in AS. METHOD: A total of 117 AS patients (46 had CVD and 71 had no CVD) were enrolled in this retrospective study. The percentage and absolute number of lymphocytes and CD4+T cells were determined by flow cytometry. Associations between CVD and clinical markers were analysed using logistic regression. RESULTS: The ratio of Th17/Treg cells (0.30 vs 0.19, P = 0.014) and the absolute number of Th17 cells (7.27 cells/µL vs 4.34 cells/µL, P < 0.001) was significantly elevated in AS-CVD group compared with AS-no-CVD group. Multivariate logistic regression revealed that elevated Th17 cells (OR = 1.20, P = 0.016) were associated with CVD complications in AS. Receiver operating characteristic (ROC) curves showed a contribution of Th17 cell for distinguishing AS patients with CVD, with the areas under the ROC curve (AUCs) of 0.729 (95% CI: 0.632, 0.825, P < 0.001). CONCLUSION: Our findings provide evidence for the association between Th17 cells and increased cardiovascular risk in AS. Th17 cells may contribute to accelerated atherogenesis and increased cardiovascular burden in AS and be valuable for early assessment and management of AS-CVD.

Heparin-Induced Thrombocytopenia Caused by Preventive Anticoagulation After Femoral Intertrochanteric Fracture Surgery: a Case Report.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a severe complication caused by heparin. It is characterized by occult onset and missed diagnosis. Misdiagnosis easily occurs. METHODS: This paper reported an 85-year-old woman with an intertrochanteric fracture of the femur which was treated with low molecular weight heparin (LMWH) and fondaparinux sodium to prevent venous thrombosis. Then, the patient developed HIT. This is the first case report of HIT induced by LMWH and fondaparinux in a patient with a hip fracture. This case highlights the severity of HIT in elderly patients with hip fractures using LMWH and fondaparinux and the need for platelet monitoring in these patients. RESULTS: LMWH was ceased in this HIT-confirmed patient, and non-heparin treatment was begun instead. Apixaban was given twice daily for therapeutic anticoagulation therapy. In the end, the platelet levels gradually returned to normal. CONCLUSIONS: We should pay more attention to HIT and platelets during the perioperative period of orthopedic surgery, especially in elderly patients. Once the disease is confirmed, it is necessary to stop heparin-related drugs immediately and administer oral anticoagulants instead.

Absolute decrease in regulatory T cells and low-dose interleukin-2 therapy: restoring and expanding regulatory T cells to treat systemic sclerosis: a 24-week study.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular lesions, immunological alterations and tissue fibrosis. There is some evidence of an imbalance between T-cell subsets in this disease. Interleukin (IL)-2 is a cytokine that can regulate the activity of immune cells and there is evidence that low-dose IL-2 therapy can be used to treat immune diseases. AIM: To investigate the changes of peripheral lymphocyte subsets, especially T helper (Th)17 and regulatory T (Treg) cells and the effects of low-dose IL-2 therapy in patients with SSc. METHODS: In total, 66 patients with SSc and 49 sex- and age-matched healthy controls (HCs), were enrolled. The absolute numbers of peripheral lymphocyte subsets in these individuals were determined by flow cytometry. The 66 patients, were divided into 2 groups: 23 (the IL-2 group) were treated with low-dose (5.0 × 105 IU) IL-2 by subcutaneous injection daily for 5 days combined with conventional therapy, while the remaining 23 patients received conventional therapy only. RESULTS: Compared with HCs, the absolute numbers of peripheral T, CD4+ T, CD8+ T, natural killer and Treg cells were significantly lower in patients with SSc, with the most dramatic difference seen in both the absolute number and percentage of Treg cells in these patients, including new (previously untreated) cases, resulting in an imbalance (elevated ratio) between Th17 and Treg cells. At Week 24 after commencement of IL-2 treatment, Treg cells were markedly increased and tended to restore the balance of Th17 to Treg cells compared with baseline. Erythrocyte sedimentation rate, C-reactive protein, modified Rodnan Skin Score and visual analogue scale score were significantly decreased in both the IL-2 and non-IL-2 groups, indicating disease improvement. Notably, compared with those in the non-IL-2 group, patients treated with IL-2 had greater improvement. CONCLUSION: Our study showed that the absolute numbers of peripheral Treg cells together with total T, CD4+ T, CD8+ T and NK is significantly decreased, leading to an imbalance of Th17 to Treg cells in patients with SSc, and that low-dose IL-2 treatment could restore the balance of the two immune cells and reduce disease activity without obvious adverse effects.

Analytical and clinical performance of different platforms simultaneously detecting 15 antinuclear antibodies.

BACKGROUND: Antinuclear antibodies (ANAs) are invaluable biomarkers for the diagnosis of autoimmune diseases (AIDs). This study aims to compare the performances of line immunoassay (LIA), multiplex bead-based flow fluorescent immunoassay (MBFFI), and magnetic bar code immunofluorescence assay (MBC-IF) to detect ANA-Profile-15S. METHODS: In total, 184 samples from AID patients and 50 healthy controls (HCs) were collected. Fifteen ANAs (anti-dsDNA, nucleosome, histone, Sm, PCNA, ribosomal-P, SS-A/Ro52, SS-A/Ro60, SS-B/La, centromere B [CENP-B], Scl-70, U1-snRNP, AMA-M2, Jo-1, and Pm/Scl) were subjected to parallel detection by the LIA, MBFFI, and MBC-IF. The consistency between assays was analyzed. The discrepant results were further examined by chemiluminescent immunoassay (CLIA). RESULTS: Anti-SS-A/Ro52 and SS-A/Ro60 autoantibodies were the most common autoantibodies in ANA positive-profiles, and were detected with equal efficiency by the LIA, MBFFI, and MBC-IF (p = 0.101 and p = 0.732, respectively). The three assays showed excellent agreement (consistency range: 66.5%-97.5%), and total consistency was 85.8%. The MBFFI and MBC-IF assays were in good agreement in terms of ANA-Profile-15S determination; the kappa coefficient ranged from 0.59 to 0.95, except for the PCNA and PM-Scl. Of the 262 re-assessed divergent results, 124 (47.33%) were positive on CLIA; the various autoantibodies exhibited variable patterns. More importantly, the ANA-Profile-15S results of the MBFFI and MBC-IF accurately identified patients with AID; the area under the curves ranged from 0.642 to 0.919. CONCLUSIONS: The novel MBFFI and MBC-IF assay performed well in detecting ANA-Profile-15S. The application of MBFFI and MBC-IF play important roles in laboratory diagnosis of AIDs.

Reduction of peripheral regulatory T cells in active rheumatoid arthritis patients with coronary artery disease.

OBJECTIVE: To identify lymphocyte and CD4 + T cell subset characteristics, particularly regulatory T cells (Tregs), in active rheumatoid arthritis (RA) patients with coronary artery disease (CAD). METHODS: A total of 54 RA patients with CAD (RA-CAD group), 43 RA patients without CAD (pure RA group), and 43 healthy controls (HC group) were enrolled. The absolute number and frequency of lymphocyte subpopulations and CD4 + T cell subsets were analyzed by flow cytometry. Serum levels of cytokines were analyzed using a cytometric bead array. Clinical and laboratory data were collected retrospectively and their correlation with CD4 + T subsets were analyzed. RESULTS: There was a significant decrease in the absolute number of Treg cells (CD4 + CD25 + Foxp3 + T cells) in the RA-CAD group compared to the pure RA group (p < 0.001). Similarly, both the absolute number (p = 0.001) and frequency (p = 0.011) of Tregs in the RA-CAD group were decreased compared to the HCs, causing a Th17/Treg imbalance (p = 0.044). No difference was found in the absolute number and frequency of Treg cells between the pure RA and HC groups. However, the absolute Th17 cell count was increased in the pure RA group (p = 0.032). The serum level of cytokine IL-17 was lower in the RA-CAD group than in the pure RA group (p = 0.023). In the RA-CAD group, the Treg number was negatively correlated with the RA disease activity score and ESR value, and LDL and ApoB100 levels were negatively correlated with the number of Th17 cells. CONCLUSIONS: Active RA patients with CAD sustain more severe immune tolerance damage and Th17/Treg disorder. Monitoring of lymphocyte and CD4 + T cell subsets, particularly Treg cells, is crucial to understanding immune status in this group. Focusing on RA activity and CAD risk control, immune-regulatory therapy based on the Treg level may be more beneficial for RA patients with CAD.

Identification of novel hub genes associated with gastric cancer using integrated bioinformatics analysis.

BACKGROUND: Gastric cancer (GC) is one of the most common solid malignant tumors worldwide with a high-recurrence-rate. Identifying the molecular signatures and specific biomarkers of GC might provide novel clues for GC prognosis and targeted therapy. METHODS: Gene expression profiles were obtained from the ArrayExpress and Gene Expression Omnibus database. Differentially expressed genes (DEGs) were picked out by R software. The hub genes were screened by cytohubba plugin. Their prognostic values were assessed by Kaplan-Meier survival analyses and the gene expression profiling interactive analysis (GEPIA). Finally, qRT-PCR in GC tissue samples was established to validate these DEGs. RESULTS: Total of 295 DEGs were identified between GC and their corresponding normal adjacent tissue samples in E-MTAB-1440, GSE79973, GSE19826, GSE13911, GSE27342, GSE33335 and GSE56807 datasets, including 117 up-regulated and 178 down-regulated genes. Among them, 7 vital upregulated genes (HMMR, SPP1, FN1, CCNB1, CXCL8, MAD2L1 and CCNA2) were selected. Most of them had a significantly worse prognosis except SPP1. Using qRT-PCR, we validated that their transcriptions in our GC tumor tissue were upregulated except SPP1 and FN1, which correlated with tumor relapse and predicts poorer prognosis in GC patients. CONCLUSIONS: We have identified 5 upregulated DEGs (HMMR, CCNB1, CXCL8, MAD2L1, and CCNA2) in GC patients with poor prognosis using integrated bioinformatical methods, which could be potential biomarkers and therapeutic targets for GC treatment.

Double Phase Inversion of Pickering Emulsion Induced by Magnesium Hydroxide Nanosheets Adsorbed with Sodium Dodecyl Sulfate.

Surfactants are often used as a cooperation stabilizer with solid particles for increasing the efficiency of Pickering emulsion. Accordingly, the effects of interaction between surfactants and solid particles on stabilizing Pickering emulsions have been attracting great attention. In this study, magnesium hydroxide (MH) nanosheets adsorbed with different amounts of sodium dodecyl sulfate (SDS) surfactants were designed and used to stabilize paraffin-water emulsions. Using SDS-adsorbed MH nanosheets as a stabilizer, the phenomenon of double phase inversion was found for Pickering emulsion. Pickering emulsion was inverted initially from O/W to W/O at about 0.022 mmol/g of the adsorption amount of SDS on the MH nanosheets, and subsequently back to O/W at about 2.312 mmol/g. The first phase inversion was because of the increased hydrophobicity of modified MH nanosheets, where SDS molecules were monolayer-adsorbed on the MH nanosheets surface. The second phase inversion occurred due to the bilayer adsorption of SDS on MH nanosheets, which converted the modified MH nanosheets hydrophilic again. These results are of great importance to understanding the double phase inversion of Pickering emulsions with the addition of surfactants and finding prospective applications in fields such as reversible drilling fluids and oil extraction.

Low-dose IL-2 effectively restored decreased regulatory T cells in patients with Behçet's disease.

OBJECTIVES: Although Behçet's disease (BD) is associated with immune mechanisms, the changes in circulating lymphocytes, especially regulatory T (Treg) cells remain unclear. Furthermore, low dose IL-2 has been reported to promote the expansion of Treg cells. This study aimed to investigate the significance of these subsets in the pathogenesis and the effect of low dose IL-2 on BD. METHODS: Lymphocyte subsets and cytokines from 177 BD patients and 160 healthy controls (HCs) were characterised. Then the efficacy and safety of low dose IL-2 for refractory BD patients were explored. RESULTS: There was a decrease in the absolute number of Treg cells and IL-10 in patients, while no difference in Th1, Th2, Th17 cells or their related cytokines. Accordingly, the ratio of Th17/Treg cells in patients was greatly higher than those of healthy controls. Furthermore, circulating Treg levels were negatively correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and Behçet's disease current activity form (BDCAF), respectively. Lastly, after IL-2 treatment, all subsets were increased to some degree, while only Treg cells were amplified more dramatically, with a four-fold increase. Meanwhile, we found that the symptoms were mitigated without observed side effects. CONCLUSIONS: BD might be triggered by the defect of immunotolerance with decreased Treg. Moreover, low-dose IL-2 proposes a potential treatment by restoring Treg and promoting rapidly remission.

Absolute reduction of peripheral regulatory T cell in patients with relapsing polychondritis.

OBJECTIVES: Although relapsing polychondritis (RP) is considered as an immune-mediated systemic disease, the levels of peripheral lymphocyte subpopulations are rarely studied in patients with RP. In this study, we focused on changes of peripheral CD4+T cell subsets in patients with RP. METHODS: Absolute numbers and percentages of CD4+T cell subsets including helper T(Th)1, Th2, Th17 cells and regulatory T (Treg) cells in peripheral blood (PB) from 19 RP patients, healthy controls and RA patients respectively were assessed by flow cytometry combined a microbead-based single-platform method. We compared the CD4+T cell levels in all RP patients and healthy controls. In addition, we analysed the difference of the absolute number and percentage of Treg cells between RP and RA patients. RESULTS: Compared with healthy controls, all RP patients had significantly both lower absolute number and proportion of Treg cells (absolute number, 45.10/µl vs. 22.48/µl, p<0.001; proportion, 5.19% vs. 3.78%, p<0.001) no matter whether they had received treatment or not. Similarly, the absolute number of Th2 cells in all RP patients was decreased (10.19/µl vs. 7.44/µl, p=0.030). However, there were no significant differences in percentages and absolute numbers of Th1 and Th17 cells between RP patients and healthy controls. The above results led to increased ratios of Th1/Treg (3.68 vs. 2.06, p=0.020), Th2/Treg (0.29 vs. 0.21, p=0.037) and Th17/Treg (0.25 vs. 0.14, p<0.001) in RP patients, and untreated RP patients were mainly characterised by the imbalance of Th17/Treg (0.25 vs. 0.14, p<0.01). There was no significant difference in Treg cells between RP and RA patients (p>0.05). CONCLUSIONS: Our data suggest that the reduction of Treg cells and its imbalance with Th cells play an important role in the pathogenesis of RP.

Comprehensive analysis of multiple cytokines and blood parameters for the diagnosis of bacterial infections in rheumatoid arthritis.

Patients with rheumatoid arthritis (RA) are more susceptible to infections, which elevate the levels of relative cytokines. However, the ability of the cytokines levels to predicate bacterial infections in RA patients remains unclear. Here, we assessed the ability of the combination of serum cytokine levels and blood parameters to diagnose bacterial infections in RA patients. We measured the levels of a panel of serum cytokine and blood parameters in 168 RA patients and 81 healthy individuals. RA patients were divided into the bacterial infection (INFE) group (n = 76) and RA flare without INFE group (n = 92). Bacterial infection was confirmed by microbial culture, imaging, antibiotic response, and typical clinical symptoms. The discriminative ability of the combination of the cytokine levels and inflammatory parameters was assessed using the receiver-operating characteristic (ROC) curves analysis and a novel bioscore system. The levels of interleukin (IL)-6 (p = 0.006), IL-10 (p = 0.019), interferon (IFN)-γ (p = 0.033), CRP (p < 0.001), and ESR (p < 0.001) were higher in patients of the INFE group than in patients with RA flare, and the absolute numbers of CD19+ B cells (p < 0.001) and CD4+ T cells (p = 0.009) were lower. For discriminating bacterial infection, the combination of IL-6, IL-10, IFN-γ, ESR, CRP, CD19+ B cells, and CD4+ T cells, provided an area under the curve (AUC) of 0.827 [(95% confidence interval (CI): 0.760-0.881)], which was profoundly larger than that of IL-6, IL-10, IFN-γ, ESR, CRP, CD19+ B cells, or CD4+ T cells alone. In addition, we also developed a bioscore system based on the combination of these seven biomarkers. Seventeen (100%) patients with a bioscore of 0 were non-infected, while seven (100%) patients with a score of 7 had bacterial infections. The bioscore based on the combination of ESR, CRP, IL-6, IL-10, IFN-γ, CD19+ B cells and CD4+ T cells may be a promising and robust tool to diagnose bacterial infections in RA patients.