Efficacy and safety of tocilizumab in Chinese patients with systemic juvenile idiopathic arthritis: a multicentre phase IV trial.

OBJECTIVES: Given the limited tocilizumab (TCZ) treatment data for systemic juvenile idiopathic arthritis (sJIA) in China, we evaluated the long-term efficacy and safety of TCZ in Chinese patients with sJIA. METHOD: In this multicentre, interventional Phase IV study, patients with sJIA and inadequate clinical response to non-steroidal anti-inflammatory drugs/corticosteroids received TCZ infusions every 2 weeks based on body weight (< 30 kg, 12 mg/kg; ≥ 30 kg, 8 mg/kg), over a 52-week open-label period and an 8-week safety follow-up period. The primary endpoint was the proportion of patients with a JIA American College of Rheumatology (ACR) 30 response and absence of fever at Week 12. RESULTS: Sixty-two patients were enrolled and treated (12-mg/kg group, 34; 8-mg/kg group, 28). At Week 12, 87.1% (95% confidence interval 78.8%-95.4%) of patients had JIA ACR 30 response and absence of fever; Week 52 results were similar. The proportion of JIA ACR 30/50/70/90 responders rapidly increased at Week 12, up to Week 52. High-sensitivity C-reactive protein (hsCRP) levels decreased within 4 weeks; 44/58 patients (75.9%) with elevated baseline hsCRP recovered at Week 52. Childhood Health Assessment Questionnaire pain scores, disability index scores, and mean corticosteroid dose decreased over time. Height standard deviation score changes at Week 52 indicated catch-up growth. Most adverse events (AEs) were mild (serious AE incidence, 17.7%). No deaths or macrophage activation syndrome occurred. CONCLUSION: This is the first multicentre trial to report the efficacy and safety of TCZ in Chinese patients with sJIA at 52 weeks. No new safety concerns were found.

Clinical manifestations, treatment and prognosis of juvenile idiopathic arthritis with pulmonary involvement in China: a single centre study.

OBJECTIVES: In recent years, the distinct clinical presentations and elevated mortality rates of various subtypes of juvenile idiopathic arthritis (JIA) with pulmonary involvement have garnered significant attention. This study aimed to elucidate the clinical characteristics of pulmonary involvement in patients with JIA to improve clinicians' knowledge. METHODS: This single-centre retrospective study analysed the baseline data, treatment options, follow-up of sixty patients of JIA with pulmonary involvement in China. Patients with interstitial lung disease (ILD) were further classified in accordance with the 2013 American Thoracic Society/European Respiratory Society International multidisciplinary consensus on idiopathic interstitial pneumonia. RESULTS: Sixty patients (5.03%) with JIA were complicated with pulmonary involvement. The highest subtype was systemic JIA (sJIA, 63.3%), followed by rheumatoid factor (RF)-positive polyarthritis (pJIA, 25.0%). The incidence of macrophage activation syndrome (MAS) was 21.6%. The most common diagnosis was ILD (90%). Respiratory symptoms/signs were initially experienced by 61.7% of the patients, and respiratory support was required by 21.7%. High-resolution CT classification of sJIA revealed non-specific interstitial pneumonia (NSIP) and organising pneumonia. High-resolution CT classification of pJIA was NSIP and usually interstitial pneumonia (UIP). Patients were treated with NSAIDs, along with glucocorticoids, DMARDs, and biological agents. The survival rates after 1 and 5 years were approximately 93.3% and 90.0%, respectively. CONCLUSIONS: Patients with JIA with pulmonary involvement present with early onset, high mortality rate. JIA patients should undergo physical examination thoroughly and high-resolution CT scans, lung function tests for evaluating and monitoring the occurrence and development of pulmonary involvement in early stages to improve prognosis.

NMN Synbiotics: A Multifaceted Therapeutic Approach for Alzheimer's Disease.

With the aging global population, Alzheimer's disease (AD) has become a significant social and economic burden, necessitating the development of novel therapeutic strategies. This study investigates the therapeutic potential of nicotinamide mononucleotide (NMN) synbiotics, a combination of NMN, Lactiplantibacillus plantarum CGMCC 1.16089, and lactulose, in mitigating AD pathology. APP/PS1 mice were supplemented with NMN synbiotics and compared against control groups. The effects on amyloid-ß (Aß) deposition, intestinal histopathology, tight junction proteins, inflammatory cytokines, and reactive oxygen species (ROS) levels were assessed. NMN synbiotics intervention significantly reduced Aß deposition in the cerebral cortex and hippocampus by 67% and 60%, respectively. It also ameliorated histopathological changes in the colon, reducing crypt depth and restoring goblet cell numbers. The expression of tight junction proteins Claudin-1 and ZO-1 was significantly upregulated, enhancing intestinal barrier integrity. Furthermore, NMN synbiotics decreased the expression of proinflammatory cytokines IL-1ß, IL-6, and TNF-α, and reduced ROS levels, indicative of attenuated oxidative stress. The reduction in Aß deposition, enhancement of intestinal barrier function, decrease in neuroinflammation, and alleviation of oxidative stress suggest that NMN synbiotics present a promising therapeutic intervention for AD by modulating multiple pathological pathways. Further research is required to elucidate the precise mechanisms, particularly the role of the NLRP3 inflammasome pathway, which may offer a novel target for AD treatment.

Case Report: Infant-onset Degos disease with nervous system involvement and a literature review.

Degos disease also known as malignant atrophic papulosis (MAP), is an autoinflammatory disease that mainly affects small- to medium-sized arteries. Gastrointestinal and nervous system are most commonly affected systems. Herein, we reported a case of Degos disease with disease onset during infantile and had severe neurological involvement.

Immunosuppressant-resistant nephrotic syndrome and primary amenorrhea: A case report of adult Frasier syndrome and literature review.

We present a case of a 19-year-old who developed nephrotic syndrome with preserved renal function. Renal biopsy confirmed focal segmental glomerular sclerosis (FSGS). No remission was achieved despite 2 years of treatment with glucocorticoids, mycophenolate mofetil, tacrolimus, and cyclophosphamide. After transfer to our center, we performed re-examination of renal pathology by electron microscope (EM), chromosomal karyotype, and gene analysis. EM revealed uneven thickness of the glomerular basement membrane without obvious stratification or fracture. Gene analysis revealed a splice mutation (1447+1G>A) in IVS9 and chromosomal karyotype was (46, XY), confirming the diagnosis of Frasier syndrome, which was consistent with primary amenorrhea overlooked by local nephrologists. Cyclosporin A was prescribed to reduce the proteinuria, but serum creatinine increased to 152 µmol/L.

Long noncoding nuclear enriched abundant transcript 1_2 is a promising biomarker for childhood-onset systemic lupus erythematosus.

Importance: Systemic lupus erythematosus (SLE) is a diffuse connective tissue disease with complex clinical manifestations and prolonged course. The early diagnosis and condition monitoring of SLE are crucial to disease prognosis. Objective: To assess the diagnostic value of long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) in childhood-onset SLE (cSLE). Methods: Fifty-seven children diagnosed with SLE, 40 children diagnosed with juvenile idiopathic arthritis (JIA), and 40 healthy children were included. Peripheral blood samples from each patient were collected. A quantitative polymerase chain reaction was used to confirm the expression of lncNEAT1_1 and lncNEAT1_2 in peripheral blood. Associations among parameters were analyzed using the Mann-Whitney U test or independent sample t-test. Results: The expression of both lncNEAT1_1 and lncNEAT1_2 in patients with cSLE were significantly higher than that of healthy control and patients with JIA. Receiver operating characteristic curves revealed an area under the curve (AUC) of 0.633 (95% confidence interval [CI], 0.524-0.742; P = 0.024) for lncNEAT1_1. The AUC of lncNEAT1_2 was 0.812 (95% CI, 0.727-0.897; P < 0.0001) to discriminate individuals with cSLE from health control and children with JIA with a sensitivity of 0.622 and a specificity of 0.925. Moreover, lncNEAT1_2 expression was higher in patients with cSLE presenting with fever, lupus nephritis, elevated erythrocyte sedimentation rate, active disease activity, and decreased C3 level, compared with those without these conditions. However, no similar correlation was observed for lncNEAT1_1. Interpretation: The expression of lncNEAT1_2 was significantly elevated in children with SLE, especially those with fever, renal involvement, and low C3 levels. These findings suggest that lncNEAT1_2 may represent a potential biomarker for cSLE.

Microfluidics-enabled mesenchymal stem cell derived Neuron like cell membrane coated nanoparticles inhibit inflammation and apoptosis for Parkinson's Disease.

Parkinson's disease (PD) is the second largest group of neurodegenerative diseases, and its existing drug treatments are not satisfactory. Natural cell membrane drugs are used for homologous targeting to enhance efficacy. In this study, microfluidic electroporation chip prepared mesenchymal stem cell-derived neuron-like cell membrane-coated curcumin PLGA nanoparticles (MM-Cur-NPs) was synthesized and explored therapeutic effect and mechanism in PD. MM-Cur-NPs can protect neuron from damage, restore mitochondrial membrane potential and reduce oxidative stress in vitro. In PD mice, it also can improve movement disorders and restore damaged TH neurons. MM-Cur-NPs was found to be distributed in the brain and metabolized with a delay within 24 h. After 1 h administration, MM-Cur-NPs were distributed in brain with a variety of neurotransmitters were significantly upregulated, such as dopamine. Differentially expressed genes of RNA-seq were enriched in the inflammation regulation, and it was found the up-expression of anti-inflammatory factors and inhibited pro-inflammatory factors in PD. Mechanically, MM-Cur-NPs can not only reduce neuronal apoptosis, inhibit the microglial marker IBA-1 and inflammation, but also upregulate expression of neuronal mitochondrial protein VDAC1 and restore mitochondrial membrane potential. This study proposes a therapeutic strategy provide neuroprotective effects through MM-Cur-NPs therapy for PD.

Spatial Transcriptomics: A Powerful Tool in Disease Understanding and Drug Discovery.

Recent advancements in modern science have provided robust tools for drug discovery. The rapid development of transcriptome sequencing technologies has given rise to single-cell transcriptomics and single-nucleus transcriptomics, increasing the accuracy of sequencing and accelerating the drug discovery process. With the evolution of single-cell transcriptomics, spatial transcriptomics (ST) technology has emerged as a derivative approach. Spatial transcriptomics has emerged as a hot topic in the field of omics research in recent years; it not only provides information on gene expression levels but also offers spatial information on gene expression. This technology has shown tremendous potential in research on disease understanding and drug discovery. In this article, we introduce the analytical strategies of spatial transcriptomics and review its applications in novel target discovery and drug mechanism unravelling. Moreover, we discuss the current challenges and issues in this research field that need to be addressed. In conclusion, spatial transcriptomics offers a new perspective for drug discovery.

Scutellarin activates IDH1 to exert antitumor effects in hepatocellular carcinoma progression.

Isochlorate dehydrogenase 1 (IDH1) is an important metabolic enzyme for the production of α-ketoglutarate (α-KG), which has antitumor effects and is considered to have potential antitumor effects. The activation of IDH1 as a pathway for the development of anticancer drugs has not been attempted. We demonstrated that IDH1 can limit glycolysis in hepatocellular carcinoma (HCC) cells to activate the tumor immune microenvironment. In addition, through proteomic microarray analysis, we identified a natural small molecule, scutellarin (Scu), which activates IDH1 and inhibits the growth of HCC cells. By selectively modifying Cys297, Scu promotes IDH1 active dimer formation and increases α-KG production, leading to ubiquitination and degradation of HIF1a. The loss of HIF1a further leads to the inhibition of glycolysis in HCC cells. The activation of IDH1 by Scu can significantly increase the level of α-KG in tumor tissue, downregulate the HIF1a signaling pathway, and activate the tumor immune microenvironment in vivo. This study demonstrated the inhibitory effect of IDH1-α-KG-HIF1a on the growth of HCC cells and evaluated the inhibitory effect of Scu, the first IDH1 small molecule agonist, which provides a reference for cancer immunotherapy involving activated IDH1.

Incidence, prevalence, and mortality of schizophrenia from 2016 to 2020 in Shandong, China.

The epidemiology of schizophrenia has been reported in many countries. However, due to the limitations of those studies, the findings cannot be generalized to other parts of the world, especially in China. In this study, the incidence, prevalence, and mortality of schizophrenia in Shandong, China were calculated using data from the National Severe Mental Disorder Registration System collected between 2016 and 2020 and census data from 2010 to 2020. The overall incidence decreased from 9.61 per 100,000 in 2016 to 4.40 per 100,000 in 2020, the aggregate prevalence was approximately 3.20 per 1000, and the overall mortality ranged from 6.17 per 100,000 to 7.71 per 100,000. The evidence from this study indicated that the incidence, prevalence, and mortality of schizophrenia were higher in rural areas than in urban areas. Females had higher incidence, prevalence, and mortality than males. This study provided epidemiological information on schizophrenia and opened avenues for future research.

Competition-cooperation mechanism between Escherichia coli and Staphylococcus aureus based on systems mapping.

Introduction: Interspecies interactions are a crucial driving force of species evolution. The genes of each coexisting species play a pivotal role in shaping the structure and function within the community, but how to identify them at the genome-wide level has always been challenging. Methods: In this study, we embed the Lotka-Volterra ordinary differential equations in the theory of community ecology into the systems mapping model, so that this model can not only describe how the quantitative trait loci (QTL) of a species directly affects its own phenotype, but also describe the QTL of the species how to indirectly affect the phenotype of its interacting species, and how QTL from different species affects community behavior through epistatic interactions. Results: By designing and implementing a co-culture experiment for 100 pairs of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), we mapped 244 significant QTL combinations in the interaction process of the two bacteria using this model, including 69 QTLs from E. coli and 59 QTLs from S. aureus, respectively. Through gene annotation, we obtained 57 genes in E. coli, among which the genes with higher frequency were ypdC, nrfC, yphH, acrE, dcuS, rpnE, and ptsA, while we obtained 43 genes in S. aureus, among which the genes with higher frequency were ebh, SAOUHSC_00172, capF, gdpP, orfX, bsaA, and phnE1. Discussion: By dividing the overall growth into independent growth and interactive growth, we could estimate how QTLs modulate interspecific competition and cooperation. Based on the quantitative genetic model, we can obtain the direct genetic effect, indirect genetic effect, and genome-genome epistatic effect related to interspecific interaction genes, and then further mine the hub genes in the QTL networks, which will be particularly useful for inferring and predicting the genetic mechanisms of community dynamics and evolution. Systems mapping can provide a tool for studying the mechanism of competition and cooperation among bacteria in co-culture, and this framework can lay the foundation for a more comprehensive and systematic study of species interactions.

Development of youth tennis players: A study based on the ranking history of top ATP/WTA players worldwide and China.

BACKGROUND: The top 100 ATP/WTA ranking points are a crucial indicator of entry into the high-level world of tennis players, and the number of players from a nation in this ranking reflects the overall level of their tennis. However, the growth time series characteristics of elite tennis athletes are unclear. OBJECTIVE: This study aims to examine the historical career ranking changes of elite players and provide valuable insights for aspiring young players looking to achieve success in the sport. At the same time, it is of great significance for the efficient and sustainable cultivation of Chinese tennis players. METHODS: Data on the rankings of 202 players were analyzed, Spearman and Pearson correlations were employed to investigate the association between ranking and time-use patterns. The variance test was utilized to compare disparities in time characteristics of the ranking, with a statistical significance level of p<0.05. RESULTS: There was a significant correlation between the time of entering the professional tournament ranking system and the ranking, top 100 time, top 100 age, and age of starting tennis. Top 50 ATP players are earlier than those ranked 51-100. There was a significant difference between the age of starting tennis and the time to top 10 among the ATP and WTA players. Chinese female players showed no significant differences compared to their global Top 10 counterparts in terms of time-to-success characteristics. CONCLUSION: The elite tennis players who achieve success typically start playing and competing in the sport at a young age, with professional competition often commencing around 18 years of age. Notably, these players frequently attain high rankings before reaching the age of 20. Furthermore, top 10 ATP male players tend to start tennis at an earlier age and require a shorter time to achieve a top 10 ranking compared with WTA female players.

Age-related differences in clinical and laboratory characteristics of childhood-onset systemic lupus erythematosus: Pre-puberal-onset SLE is prone to delayed diagnosis.

OBJECTIVE: This study aimed to analyze age-specific characteristics of childhood-onset systemic lupus erythematosus (cSLE) at a health center in China. METHODS: The children with SLE were grouped based on age at disease-onset: pre-pubertal (≤7 years), peri-pubertal (8-13 years), and adolescence (14-18 years). The retrospective study included patients with cSLE diagnosed at the Beijing Children's Hospital between 2013 and 2021. RESULTS: A total of 675 females and 178 males were eligible for inclusion in this study. Among them, 160 patients were diagnosed during pre-puberty, 635 during peri-puberty, and 58 during adolescence. The female-to-male ratio of pre-pubertal, peri-pubertal, and adolescent diagnosis was 3.5: 1, 3.6: 1, and 7.28:1, respectively. The median time from onset to diagnosis during the pre-puberal period was 3.0 (IQR 1.0-24.0 months), which was longer than that during the peri-puberal period (1.4; IQR 0.7-4) months and adolescence (1.0; IQR 0.4-2) months (p = <.0001). The proportion of LN in patients diagnosed during the peri-puberal period (304, 46.6%) and during adolescence (27, 47.9%) was higher than that of patients diagnosed during the pre-puberal period (59, 36.9%) (p = .044). 46 (28.8%), 233 (36.7%), and 32 (55.2%) of children diagnosed during the pre-pubertal period, peri-pubertal period, and adolescence, respectively, suffered from leukopenia. CONCLUSION: The proportion of renal involvement and leukopenia in the pre-pubertal group was lower than that of the pubertal group and adolescent group. More importantly, the younger the age of the patient, the more likely the diagnosis to be delayed.

Janus kinase inhibitor, tofacitinib, in refractory juvenile dermatomyositis: a retrospective multi-central study in China.

OBJECTIVES: Juvenile dermatomyositis (JDM) is a chronic autoimmune disease. Some patients remain in an active state even though they were administrated with a combination of corticosteroid and methotrexate. Existing research has suggested that interferon and Janus kinase played an important role in pathogenesis. Existing research has suggested the efficacy of JAK inhibitors (JAKi). Our retrospective study aimed to investigate the efficacy of tofacitinib in refractory JDM patients. METHODS: A total of eighty-eight patients in China who had been diagnosed with JDM and subjected to tofacitinib therapy for over 3 months were retrospectively analyzed. Skin and muscle manifestations were assessed using the Cutaneous Assessment Tool-binary method (CAT-BM), Childhood Myositis Assessment Scale (CMAS), and kinase. Pulmonary function was assessed using a high-resolution CT (computerized tomography) scan and pulmonary symptoms. All patients were subjected to regular follow-up, and core measures were assessed every 3 months after initiation. Furthermore, the data were analyzed using the Wilcoxon single test, Mann-Whitney U test, and chi-square test. RESULTS: Compared with the baseline data, skin and muscle manifestations were found significantly improved during the respective follow-up visit. At the most recent follow-up, nearly 50% of patients achieved a clinical complete response and six patients received tofacitinib monotherapy. Sixty percent of patients suffering from interstitial lung disease well recovered on high-resolution CT. Seventy-five percent of patients showed a reduction in the size or number of calcinosis, and 25% of patients showed completely resolved calcinosis. CONCLUSION: In this study, the result suggested that tofacitinib therapy exerted a certain effect on skin manifestations, muscle manifestations, interstitial lung disease (ILD), calcinosis, as well as downgrade of medication. In-depth research should be conducted to focus on the correlation between the pathogenesis of JDM and JAKi.

Programmed Cell Death Protein 2-like Promotes Inflammation and Oxidative Stress in Vascular Endothelial Cells.

Programmed cell death protein 2-like (PDCD2L) is a shuttle protein of the nucleus and cytoplasm and is related to the ribosome biogenesis. However, there are few reports on the relationship between PDCD2L and inflammation, and the exact relationship between PDCD2L and inflammation has not been determined in vascular endothelial cells yet. Accordingly, we focus on exploring the relationship between PDCD2L and inflammation and its potential mechanisms. Our research findings suggested that PDCD2L is a proinflammatory target. The result showed that, by interfering with the expression of PDCD2L, LPS-induced inflammation of vascular endothelial cells can be reduced, such as IL-6 and IL-1ß, as well as the adhesion factor ICAM1. Meanwhile, overexpression of PDCD2L can further increase LPS-induced inflammation levels, ICAM1, and ROS production, reduce CAT, GSH/GSSG levels, and increase SOD levels. Therefore, we determined that PDCD2L has a regulatory effect on inflammation and oxidative stress of vascular endothelial cells, and its regulatory mechanism may be related to inflammatory transcription factors STAT1, NF-κB regulation, transport of inflammatory messenger mRNA, and ribosome biogenesis. Then, we screened that andrographolide (Andro) can bind to PDCD2L, thus inhibiting inflammation and endothelial cell adhesion caused by the overexpression of PDCD2L. This study reveals that PDCD2L is a potential anti-inflammatory therapeutic target, providing new exploration for the development of anti-inflammatory drugs.

Effects of triclosan exposure on stem cells from human exfoliated deciduous teeth (SHED) fate.

Triclosan (TCS), a widely used broad-spectrum antibacterial agent and preservative, is commonly found in products and environments. Widespread human exposure to TCS has drawn increasing attention from researchers concerning its toxicological effect. However, minimal studies have focused on the impact of TCS exposure on human stem cells. Therefore, the aim of the present study was to evaluate the effects of TCS exposure on stem cells from human exfoliated deciduous teeth (SHED) and its molecular mechanisms. A series of experimental methods were conducted to assess cell viability, morphology, proliferation, differentiation, senescence, apoptosis, mitochondrial function, and oxidative stress after SHED exposure to TCS. Furthermore, transcriptome analysis was applied to investigate the response of SHED to different concentrations of TCS exposure and to explore the molecular mechanisms. We demonstrated that TCS has a dose-dependent proliferation and differentiation inhibition of SHED, while promoting cellular senescence, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and oxidative stress, as well as significantly induces apoptosis and autophagy flux inhibition at high concentrations. Interestingly, no significant morphological changes in SHED were observed after TCS exposure. Transcriptome analysis of normal and TCS-induced SHED suggested that SHED may use different strategies to counteract stress from different concentrations of TCS and showed significant differences. We discovered that TCS mediates cellular injury of SHED by enhancing the expression of PTEN, thereby inhibiting the phosphorylation levels of PI3K and AKT as well as mTOR expression. Collectively, our findings provide a new understanding of the toxic effects of TCS on human stem cell fate, which is important for determining the risk posed by TCS to human health.