Diagnosis of poorly differentiated adenocarcinoma of the stomach by confocal laser endomicroscopy: A case report.

BACKGROUND: In recent years, confocal laser endomicroscopy (CLE) has become a new endoscopic imaging technology at the microscopic level, which is extensively performed for real-time in vivo histological examination. CLE can be performed to distinguish benign from malignant lesions. In this study, we diagnosed using CLE an asymptomatic patient with poorly differentiated gastric adenocarcinoma. CASE SUMMARY: A 63-year-old woman was diagnosed with gastric mucosal lesions, which may be gastric cancer, in the small curvature of the stomach by gastroscopy. She consented to undergo CLE for morphological observation of the gastric mucosa. Through the combination of CLE diagnosis and postoperative pathology, the intraoperative CLE diagnosis was considered to be reliable. According to our experience, CLE can be performed as the first choice for the diagnosis of gastric cancer. CONCLUSION: CLE has several advantages over pathological diagnosis. We believe that CLE has great potential in the diagnosis of benign and malignant gastric lesions.

Multifaceted Characterization of Human Embryonic Stem Cell-Derived Mesenchymal Stem/Stromal Cells Revealed Amelioration of Acute Liver Injury in NOD-SCID Mice.

Human embryonic stem cells (hESCs) are advantaged sources for large-scale and homogeneous mesenchymal stem/stromal cells (MSCs) generation. However, due to the limitations in high-efficiency procedures for hESC-MSCs induction, the systematic and detailed information of mesengenesis and early MSC development are largely obscure. In this study, we took advantage of the well-established twist-related protein 1 (TWIST1)-overexpressing hESCs and two small molecular cocktails (CHIR99021, decitabine) for high-efficient MSC induction. To assess the multidimensional biological and transcriptomic characteristics, we turned to cellular and molecular methods, such as flow cytometry (FCM), quantitative reverse transcription-polymerase chain reaction (qRT-PCR), in vitro tri-lineage differentiation, cytokine secretion analysis, in vivo transplantation for acute liver injury (ALI) management, and bioinformatics analyses (eg, gene ontology-biological processes [GO-BP], Kyoto Encyclopedia of Genes and Genomes [KEGG], HeatMap, and principal component analysis [PCA]). By combining TWIST1 overexpression (denoted as T) and the indicated small molecular cocktails (denoted as S), hESCs high-efficiently differentiated into MSCs (denoted as TS-MSCs, induced by T and S combination) within 2 weeks. TS-MSCs satisfied the criteria for MSC definition and revealed comparable tri-lineage differentiation potential and ameliorative efficacy upon ALI mice. According to RNA-sequencing (SEQ) analysis, we originally illuminated the gradual variations in gene expression pattern and the concomitant biofunctions of the programmed hESC-MSCs. Overall, our data indicated the feasibility of high-efficient generation of hESC-MSCs by TWIST1 and cocktail-based programming. The generated hESC-MSCs revealed multifaceted in vivo and in vitro biofunctions as adult BM-MSCs, which collectively suggested promising prospects in ALI management in future.

Cause of death during nasopharyngeal carcinoma survivorship: a population-based analysis.

Background: Recently, the survival rate of nasopharyngeal carcinoma (NPC) patients has improved greatly due to developments in NPC treatments. But cause-specific mortality in NPC patients remains unclear. This study aims to investigate the common causes of death in NPC patients. Methods: Eligible patients with NPC were included from the Surveillance, Epidemiology, and End Results (SEER) database. Standardized mortality ratios(SMRs) were calculated to compare death rates in NPC patients with those in the general population. Results: A total of 3475 patients with NPC were included, of whom 1696 patients died during the follow-up period. 52.83% of deaths were caused by NPC, followed by other cancers (28.13%) and non-cancer causes (18.46%). The proportion of patients who died of NPC decreased over survival time. Moreover, non-cancer causes of death increase from 12.94% to 51.22% over time after 10 years of diagnosis. Heart diseases was the most common non-cancer cause of death in NPC patients. Conclusions: Although NPC remains the leading cause of death after NPC diagnosis, other non-NPC causes of death represent an increased number of death in NPC patients. These findings support the involvement of multidisciplinary care for follow-up strategy in NPC patients.

Proliferative glomerulonephritis with monoclonal IgG Lambda deposits caused by plasmablastic lymphoma: a case report.

INTRODUCTION: As a very rare form of B-cell lymphoma, plasmablastic lymphoma (PBL) typically occurs in patients with underlying immunosuppression, including human immunodeficiency virus (HIV), organ transplantation, and autoimmune diseases. For HIV-positive patients, PBL normally originates in the gastrointestinal tract, especially from the oral cavity in most cases. It is extremely rare to find abdominal cavity involvement in PBL, and there has been no previously reported instance of proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) attributed to monoclonal IgG (MIgG) lambda secreted by PBL. CASE PRESENTATION: We report the case of an HIV-negative female with nephrotic syndrome, renal insufficiency, and multiple swollen lymph nodes. Ascitic fluid cytology revealed a high level of plasmablast-like lymphocytes with the restriction of lambda light chains. Besides, the renal biopsy revealed PGNMID, which could presumably be secondary to MIgG-lambda-secreting by PBL. MIgG-lambda-restricted expression was discovered earlier in the kidney tissue than in the blood. CONCLUSION: The diagnostic landscape for PBL is notoriously intricate, necessitating a multifaceted and nuanced approach to mitigate the risks of erroneous identification.

Exploring the challenge of early gastric cancer diagnostic AI system face in multiple centers and its potential solutions.

BACKGROUND: Artificial intelligence (AI) performed variously among test sets with different diversity due to sample selection bias, which can be stumbling block for AI applications. We previously tested AI named ENDOANGEL, diagnosing early gastric cancer (EGC) on single-center videos in man-machine competition. We aimed to re-test ENDOANGEL on multi-center videos to explore challenges applying AI in multiple centers, then upgrade ENDOANGEL and explore solutions to the challenge. METHODS: ENDOANGEL was re-tested on multi-center videos retrospectively collected from 12 institutions and compared with performance in previously reported single-center videos. We then upgraded ENDOANGEL to ENDOANGEL-2022 with more training samples and novel algorithms and conducted competition between ENDOANGEL-2022 and endoscopists. ENDOANGEL-2022 was then tested on single-center videos and compared with performance in multi-center videos; the two AI systems were also compared with each other and endoscopists. RESULTS: Forty-six EGCs and 54 non-cancers were included in multi-center video cohort. On diagnosing EGCs, compared with single-center videos, ENDOANGEL showed stable sensitivity (97.83% vs. 100.00%) while sharply decreased specificity (61.11% vs. 82.54%); ENDOANGEL-2022 showed similar tendency while achieving significantly higher specificity (79.63%, p < 0.01) making fewer mistakes on typical lesions than ENDOANGEL. On detecting gastric neoplasms, both AI showed stable sensitivity while sharply decreased specificity. Nevertheless, both AI outperformed endoscopists in the two competitions. CONCLUSIONS: Great increase of false positives is a prominent challenge for applying EGC diagnostic AI in multiple centers due to high heterogeneity of negative cases. Optimizing AI by adding samples and using novel algorithms is promising to overcome this challenge.

Setting 6-Minute Minimal Examination Time Improves the Detection of Focal Upper Gastrointestinal Tract Lesions During Endoscopy: A Multicenter Prospective Study.

INTRODUCTION: Positive correlation between examination time and neoplasm detection using esophagogastroduodenoscopy (EGD) has been described by observational studies, but the effect of setting minimal examination time still requires investigation. METHODS: This prospective, 2-stage, interventional study was conducted in 7 tertiary hospitals in China, enrolling consecutive patients undergoing intravenously sedated diagnostic EGDs. In stage I, the baseline examination time was collected without informing the endoscopists. In stage II, the minimal examination time was set for the same endoscopist according to the median examination time of normal EGDs in stage I. The primary outcome was the focal lesion detection rate (FDR), defined as the proportion of subjects with at least one focal lesion among all subjects. RESULTS: A total of 847 and 1,079 EGDs performed by 21 endoscopists were included in stages I and II, respectively. In stage II, the minimal examination time was set as 6 minutes, and the median time for normal EGD increased from 5.8 to 6.3 minutes ( P < 0.001). Between the 2 stages, the FDR was significantly improved (33.6% vs 39.3%, P = 0.011), and the effect of the intervention was significant (odds ratio, 1.25; 95% confidence interval, 1.03-1.52; P = 0.022) even after adjusting for subjects' age, smoking status, endoscopists' baseline examination time, and working experience. The detection rate of high-risk lesions (neoplastic lesions and advanced atrophic gastritis) was also significantly higher in stage II (3.3% vs 5.4%, P = 0.029). In the endoscopist-level analysis, all practitioners reached a median examination time of 6 minutes, and the coefficients of variation of FDR (36.9%-26.2%) and examination time (19.6%-6.9%) decreased in stage II. DISCUSSION: Setting a 6-minute minimal examination time significantly improved the detection of focal lesions during EGDs and has the potential to be implemented for quality improvement.

Efficacy and safety of tofacitinib in Chinese patients with active psoriatic arthritis: a phase 3, randomised, double-blind, placebo-controlled study.

OBJECTIVES: Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, were evaluated in a 6-month, double-blind, phase 3 study in Chinese patients with active (polyarthritic) psoriatic arthritis (PsA) and inadequate response to ≥1 conventional synthetic disease-modifying antirheumatic drug. METHODS: Patients were randomised (2:1) to tofacitinib 5 mg twice daily (N=136) or placebo (N=68); switched to tofacitinib 5 mg twice daily after month (M)3 (blinded). PRIMARY ENDPOINT: American College of Rheumatology (ACR50) response at M3. Secondary endpoints (through M6) included: ACR20/50/70 response; change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI); ≥75% improvement in Psoriasis Area and Severity Index (PASI75) response, and enthesitis and dactylitis resolution. Safety was assessed throughout. RESULTS: The primary endpoint was met (tofacitinib 5 mg twice daily, 38.2%; placebo, 5.9%; p<0.0001). M3 ACR20/ACR70/PASI75 responses, and enthesitis and dactylitis resolution rates, were higher and HAQ-DI reduction was greater for tofacitinib 5 mg twice daily versus placebo. Incidence of adverse events (AEs)/serious AEs (M0-3): 68.4%/0%, tofacitinib 5 mg twice daily; 75.0%/4.4%, placebo. One death was reported with placebo→tofacitinib 5 mg twice daily (due to accident). One serious infection, non-serious herpes zoster, and lung cancer case each were reported with tofacitinib 5 mg twice daily; four serious infections and one non-serious herpes zoster case were reported with placebo→tofacitinib 5 mg twice daily (M0-6). No non-melanoma skin cancer, major adverse cardiovascular or thromboembolism events were reported. CONCLUSION: In Chinese patients with PsA, tofacitinib efficacy was greater than placebo (primary and secondary endpoints). Tofacitinib was well tolerated; safety outcomes were consistent with the established safety profile in PsA and other indications. TRIAL REGISTRATION NUMBER: NCT03486457.

Clinical value of the prognostic nutritional index and red blood cell distribution width-to-albumin ratio for the prediction of severity of and mortality associated with Stevens-Johnson syndrome/toxic epidermal necrolysis.

The prognostic nutritional index (PNI) and red blood cell distribution width-to-albumin ratio (RAR) are considered to be related to the prognosis of disease severity. However, the role of these biomarkers in predicting Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) severity and mortality is unclear. The aim of the current study was to investigate the association of PNI and RAR with severity and mortality in individuals with SJS/TEN. Clinical data were retrospectively collected from 74 individuals with SJS/TEN and 74 healthy individuals, who were matched for age and sex during the same period. PNI, RAR, and other indicators were compared between individuals with SJS/TEN and healthy controls. The association of PNI and RAR with SJS/TEN severity was assessed using Spearman or Pearson correlation analyses. Individuals with SJS/TEN were categorized into two groups, either survivors or nonsurvivors. The correlation between PNI, RAR, and SJS/TEN mortality was analyzed using univariate and multivariate logistic regression. The predictive value of the previously mentioned indicators on the mortality of patients with SJS/TEN was assessed using receiver operating characteristic curve analysis. The RAR level of patients with SJS/TEN was greater than that of the control group (p < 0.05), whereas PNI was lower. In compliance with correlation analysis, RAR was positively correlated with SCORTEN (Score of Toxic Epidermal Necrolysis) and ABCD-10 (age, bicarbonate, cancer, dialysis, 10% body surface area) (p < 0.05), and PNI was negatively correlated (p < 0.05). RAR is a risk factor for death in patients with SJS/TEN, but an elevated PNI level is a protective factor for mortality. The best cutoff values of PNI and RAR for predicting death in patients with SJS/TEN were 31.375 (sensitivity, 84.7%; specificity, 80%) and 0.486 (sensitivity, 73.3%; specificity, 84.7%). These results underscore the potential clinical value of PNI and RAR as appropriate and meaningful biomarkers to assess the severity of SJS/TEN and the mortality associated with it.

New hope for esophageal stricture prevention: A prospective single-center trial on acellular dermal matrix.

BACKGROUND: Given the high incidence of esophageal cancer in China, an increasing number of patients there are undergoing endoscopic mucosal dissection (ESD). Although the 5-year survival rate after ESD can exceed 95%, esophageal stricture, the most common and serious postoperative complication, affects the long-term prognosis of patients and the quality of life. Autologous mucosal grafts have proven to be successful in preventing stricture after ESD for early esophageal cancer. AIM: To examine the viability of acellular dermal matrix (ADM) as an alternative to autologous mucosa for the prevention of stricture after ESD. METHODS: This is a prospective, single-center, controlled study. Consecutive patients who underwent ESD surgery and were willing to undergo autologous mucosal transplantation were recruited between January 1 and December 31, 2017. Consecutive patients who underwent ESD surgery and were willing to undergo ADM transplantation were recruited between January 1 to December 31, 2019. A final three-year follow-up of patients who received transplants was conducted. RESULTS: Based on the current incidence of esophageal stricture, the sample size required for both the autologous mucosal graft group and the ADM group was calculated to be 160 cases. Due to various factors, a total of 20 patients with autologous mucosal grafts and 25 with ADM grafts were recruited. Based on the inclusion exclusion and withdrawal criteria, 9 patients ultimately received autologous mucosal grafts and completed the follow-up, while 11 patients received ADM grafts and completed the follow-up. Finally, there were 2 cases of stenosis in the autologous mucosal transplantation group with a stenosis rate of 22.22% and 2 cases of stenosis in the ADM transplantation group with a stenosis rate of 18.18%, with no significant difference noted between the groups (P = 0.94). CONCLUSION: In this prospective, single-center, controlled trial, we compared the effectiveness of autologous mucosa transplantation and ADM for the prevention of esophageal stricture. Due to certain condition limitations, we were unable to recruit sufficient subjects meeting our target requirements. However, we implemented strict inclusion, exclusion, and withdrawal criteria and successfully completed three years of follow-up, resulting in valuable clinical insights. Based on our findings, we hypothesize that ADM may be similarly effective to autologous mucosal transplantation in the prevention of esophageal stricture, offering a comparable and alternative approach. This study provides a new therapeutic idea and direction for the prevention of esophageal stricture.

Sex differences in systemic lupus erythematosus (SLE): an inception cohort of the Chinese SLE Treatment and Research Group (CSTAR) registry XVII.

BACKGROUND: The onset and clinical presentation of systemic lupus erythematosus (SLE) are sex-related. Few studies have investigated the distinctions in clinical characteristics and treatment preferences in male and female SLE patients in the initial cohort. This study aimed to improve the understanding of Chinese SLE patients by characterizing the different sexes of SLE patients in the inception cohort. METHODS: Based on the initial patient cohort established by the Chinese SLE Treatment and Research Group, a total of 8713 patients (795 men and 7918 women) with newly diagnosed SLE were enrolled between April 2009 and March 2021. Of these, 2900 patients (347 men and 2553 women) were eligible for lupus nephritis (LN). A cross-sectional analysis of the baseline demographic characteristics, clinical manifestations, laboratory parameters, organ damage, initial treatment regimens, and renal pathology classification was performed according to sex. RESULTS: In the SLE group, as compared to female patients, male patients had a later age of onset (male vs. female: 37.0 ±â€Š15.8 years vs. 35.1 ±â€Š13.7 years, P  = 0.006) and a higher SLE International Collaborative Clinic/American College of Rheumatology damage index score (male vs. female: 0.47 ±â€Š1.13 vs. 0.34 ±â€Š0.81, P  = 0.015), LN (male vs. female: 43.6% vs. 32.2%, P < 0.001), fever (male vs. female: 18.0% vs. 14.6%, P  = 0.010), thrombocytopenia (male vs. female: 21.4% vs. 18.5%, P  = 0.050), serositis (male vs. female: 14.7% vs. 11.7%, P  = 0.013), renal damage (male vs. female: 11.1% vs. 7.4%, P < 0.001), and treatment with cyclophosphamide (CYC) (P < 0.001). The frequency of leukopenia (male vs. female: 20.5% vs. 25.4%, P  = 0.002) and arthritis (male vs. female: 22.0% vs. 29.9%, P < 0.001) was less in male patients with SLE. In LN, no differences were observed in disease duration, SLE Disease Activity Index score, renal biopsy pathological typing, or 24-h urine protein quantification among the sexes. In comparisons with female patients with LN, male patients had later onset ages (P  = 0.026), high serum creatinine (P < 0.001), higher end-stage renal failure rates (P  = 0.002), musculoskeletal damage (P  = 0.023), cardiovascular impairment (P  = 0.009), and CYC use (P  = 0.001); while leukopenia (P  = 0.017), arthritis (P  = 0.014), and mycophenolate usage (P  = 0.013) rates were lower. CONCLUSIONS: Male SLE patients had more severe organ damage and a higher LN incidence compared with female SLE patients; therefore, they may require more aggressive initial treatment compared to female patients.

Blood HDAC4 Variation Links With Disease Activity and Response to Tumor Necrosis Factor Inhibitor and Regulates CD4+ T Cell Differentiation in Ankylosing Spondylitis.

Purpose: Histone deacetylase 4 (HDAC4) regulates the progression of autoimmune diseases. This study aimed to further investigate the correlation between HDAC4 and Th cells, inflammation, disease activity, and treatment response in patients with ankylosing spondylitis (AS). Methods: A total of 132 active patients with AS were enrolled, of whom 54 patients received TNF inhibitor (TNFi) and 78 patients received NSAID. Serum HDAC4 was measured by ELISA in patients with AS before treatment (W0) and at week (W)4, W8, and W12 after treatment. Meanwhile, serum HDAC4 was detected in 30 patients with osteoarthritis and in 30 healthy controls (HCs) by ELISA. Besides, naïve CD4+ T cells from patients with AS were isolated, followed by modulation of HDAC4 and then polarization toward Th1, Th2, and Th17. Results: Histone deacetylase 4 was reduced in patients with AS compared with HCs and patients with osteoarthritis (both P < 0.01). In patients with AS, HDAC4 was negatively correlated with TNF (P < 0.001), IL-1ß (P = 0.003), Th17 proportion (P = 0.008), C-reactive protein (P < 0.001), and ASDAS (P = 0.038), but not with IL-6, Th1 proportion, or other characteristics. Meanwhile, HDAC4 increased from W0 to W12 (P < 0.001); HDAC4 at W8 (P = 0.014) and W12 (P = 0.006) was raised in ASAS40-response patients than ASAS40-non-response patients; further subgroup analysis showed that HDAC4 at W12 was higher in ASAS40-response patients than ASAS40-non-response patients (P = 0.016) in the TNFi-treated group, but not in the NSAID-treated group. In addition, HDAC4 negatively regulated the polarization of naïve CD4+ T cells toward Th17 (P < 0.01), but not Th1 or Th2. Conclusion: Histone deacetylase 4 is associated with lower inflammation, and the disease activity negatively regulates Th17 polarization, whose increment after treatment reflects favorable outcomes in patients with AS.

Clinical characteristics of multicentric reticulohistiocytosis and distinguished features from rheumatoid arthritis: a single-center experience in China.

OBJECTIVE: To investigate the clinical features of multicentric reticulohistiocytosis (MRH). METHODS: The clinical manifestations, laboratory examination results and histologic characteristics of eleven patients with MRH were collected and compared with those of 33 patients with rheumatoid arthritis. RESULTS: In total, 72.7% of the MRH patients were women. The median age was 46 years (range 33-84 years). Diagnosed by specific pathologic features, all MRH patients exhibited cutaneous involvement. The dorsa of the hands, arms, face and auricle were the most commonly affected areas. Nodules were also located on the legs, scalp, trunk, neck, and even the hypoglossis and buccal mucosa. Ten MRH patients (90.9%) had symmetric polyarthritis. Compared with rheumatoid arthritis (RA) patients, MRH patients were more likely to have distal interphalangeal joint (DIP) involvement (63.6% vs 24.2%, P = 0.017) and less likely to have elbow (36.4% vs 72.7%, P = 0.003), ankle (45.5% vs 93.9%, P < 0.001) and metacarpophalangeal joint (MCP) (36.4% vs 78.8%, P = 0.009) involvement. Positivity for rheumatoid factor (RF) (36.4% vs 84.6%, P = 0.001) and anti-CCP antibody (9.1% vs 81.8%, P = 0.000), as well as the median RF titer [43.8 (31.7-61.0) vs 175.4 (21.3-940.3), P = 0.021], in MRH patients was lower than in RA patients. Elevation of the erythrocyte sedimentation rate (ESR) was also less common in MRH patients than in RA patients (36.4% vs 72.7%, P = 0.030). After treatment with median- to large-dose corticosteroids and disease-modifying antirheumatic drugs, 8 patients achieved complete remission and 2 patients partial remission (skin lesions ameliorated, joint lesions not ameliorated). CONCLUSION: Always pathologically diagnosed, MRH is a systemic disease involving RA-like erosive polyarthritis and a specific distribution of skin nodules characterized by "coral beads". More DIP involvement and less elbow, ankle and MCP involvement are seen in MRH than in RA. In addition, less positivity and lower-titer RF, uncommon presence of anti-CCP antibodies and ESR elevation may be helpful to distinguish MRH from RA.

Circ_0003159 upregulates LIFR expression through competitively binding to miR-221-3p/miR-222-3p to block gastric cancer development.

Gastric cancer (GC) remains a major cause of cancer-related deaths. Increasing studies suggest that cancer development is accompanied by the deregulation of circular RNAs. We investigated the function of circ_0003159 in GC. The expression levels of circ_0003159, miR-221-3p/miR-222-3p and leukemia inhibitory factor receptor (LIFR) mRNA were measured by real-time quantitative polymerase chain reaction. Cell colony formation ability was assessed by colony formation assay, and cell viability was assessed by cell counting kit-8 assay. Cell apoptosis was assessed by flow cytometry assay and caspase3 activity. Cell migration and invasion were assessed by transwell assay. Glycolysis energy metabolism was assessed by 5'-triphosphate production, glucose uptake and lactate production. The protein levels of related marker proteins and LIFR were detected by western blot. The relationship between circ_0003159 and miR-221-3p/miR-222-3p, or LIFR and miR-221-3p/miR-222-3p was obtained from bioinformatics tools and verified by dual-luciferase reporter assay. A cancer tumorogenicity xenograft experiment in nude mice was conducted to determine the role of circ_0003159 in tumor growth by AGS cells. Our results showed that circ_0003159 expression was decreased in GC tissues and cells. Circ_0003159 overexpression sequestered GC cell viability, migration, invasion and glycolysis and induced cell apoptosis. MiR-221-3p and miR-222-3p were targets of circ_0003159, and the inhibition of miR-221-3p and miR-222-3p also blocked GC cell viability, migration, invasion and glycolysis and promoted cell apoptosis. LIFR was a common target of miR-221-3p and miR-222-3p. Interestingly, LIFR knockdown reversed the effects of circ_0003159 overexpression on GC cell behaviors. Circ_0003159 increased the expression level of LIFR by targeting miR-221-3p and miR-222-3p. The tumorigenicity assay showed that circ_0003159 overexpression inhibited tumor growth in vivo. In conclusion, circ_0003159 inhibited GC development in vitro and in vivo by enriching the level of LIFR via direct binding to miR-221-3p/miR-222-3p.

Identification of Key Genes and Immune Infiltrate in Nonalcoholic Steatohepatitis: A Bioinformatic Analysis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) can progress to cirrhosis and hepatic carcinoma and is closely associated with changes in the neurological environment. The discovery of new biomarkers would aid in the treatment of NASH. METHODS: Data GSE89632 were downloaded from the Gene Expression Omnibus (GEO) database, and R package "limma" was used to identify differentially expressed genes (DEGs) for NASH vs. normal tissues. The STRING database was used to construct a protein-protein interaction (PPI) network, and the Cytoscape software program (Version 3.80) was used to visualize the PPI network and identify key genes. The immune infiltration of NASH was determined using the R package "CIBERSORT". RESULTS: We screened 41 DEGs. GO and KEGG enrichment analyses of the DEGs revealed the enrichment of pathways related to NAFLD steatosis and inflammation. A PPI network analysis was also performed on the DEGs, and seven genes (MYC, CXCL8, FOS, SOCS1, SOCS3, IL6, and PTGS2) were identified as hub genes. An immune infiltration assessment revealed that macrophages M2, memory resting CD4+ T cells, and Î³Δ T cells play important roles in the immune microenvironment of NASH, which may be mediated by the seven identified hub genes.

Efficacy and safety of a selective URAT1 inhibitor SHR4640 in Chinese subjects with hyperuricaemia: a randomized controlled phase II study.

OBJECTIVE: To evaluate the efficacy and safety of SHR4640, a highly selective urate transporter 1 inhibitor, in Chinese subjects with hyperuricaemia. METHODS: This was a randomized double-blind dose-ranging phase II study. Subjects whose serum uric acid (sUA) levels were ≥480 µmol/l with gout, ≥480 µmol/l without gout but with comorbidities, or ≥540 µmol/l were enrolled. Subjects were randomly assigned (1:1:1:1:1) to receive once daily 2.5 mg, 5 mg, 10 mg of SHR4640, 50 mg of benzbromarone or placebo, respectively. The primary end point was the proportion of subjects who achieved target sUA level of ≤360 µmol/l at week 5. RESULTS: 99.5% of subjects (n = 197) were male and 95.9% of subjects had gout history. The proportions of subjects who achieved target sUA at week 5 were 32.5%, 72.5% and 61.5% in the 5 mg, 10 mg SHR4640 and benzbromarone groups, respectively, significantly higher than the placebo group (0%; P < 0.05 for 5 mg and 10 mg SHR4640 group). The sUA was reduced by 32.7%, 46.8% and 41.8% at week 5 with 5 mg, 10 mg SHR4640 and benzbromarone, respectively, vs placebo (5.9%; P < 0.001 for each comparison). The incidences of gout flares requiring intervention were similar among all groups. Occurrences of treatment-emergent adverse events (TEAEs) were comparable across all groups, and serious TEAEs were not reported. CONCLUSIONS: The present study indicated a superior sUA-lowering effect and well tolerated safety profile after 5-week treatment with once-daily 5 mg/10 mg of SHR4640 as compared with placebo in Chinese subjects with hyperuricaemia. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03185793.

Infective endocarditis mimicking ANCA-associated vasculitis: does it require immunosuppressive therapy?: A case report and literature review.

RATIONALE: In the course of endocarditis, the development of antineutrophil cytoplasmic antibody (ANCA)-mediated disease introduces the dilemma of determining the best treatment approach for immune conditions, whether immunosuppressant therapy should be added to antibiotic treatment has remained controversial. PATIENT CONCERNS: A 33-year-old man presented with progressive fever lasting for 7 months, and swelling, pain, and purpura in the arms and legs. The patient showed multiple autoantibodies including cytoplasmic ANCA, antiproteinase 3, rheumatoid factor, and anti-beta 2 glycoprotein I. Blood culture was positive for viridans streptococcus, and renal biopsy revealed glomerulonephritis and interstitial nephritis. DIAGNOSIS: Endocarditis caused by viridans streptococci, ANCA-associated vasculitis, and congenital ventricular septal defect. INTERVENTIONS: In addition to effective antibiotics, he also received twice intravenous corticosteroids and intravenous immunoglobulin therapy, and a low dose of cyclophosphamide. At last, the patient received congenital ventricular septal defect repair and debridement. OUTCOMES: The abnormal clinical manifestations, including renal failure and loss of strength, recovered rapidly with corticosteroid therapy in addition to antibiotic treatment. After 6 months without any medications, he remained asymptomatic and was able to live normally. LESSONS: In this case with endocarditis and ANCA-associated vasculitis, we highlighted the importance of biopsy and immunosuppressive therapy. Histopathologic examination is required for diagnosis and treatment in such case. Identifying patients who have endocarditis and ANCA positivity with vasculitis pathologic features will require corticosteroid/immunosuppressives in addition to the antibiotics therapy.

The Plasma Interleukin (IL)-35 Level and Frequency of Circulating IL-35+ Regulatory B Cells are Decreased in a Cohort of Chinese Patients with New-onset Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that is associated with the destruction of immune tolerance and activation of B cells. Interleukin (IL)-35 and IL-35-producing (IL-35+) regulatory B cells (Bregs) have been demonstrated to possess immunosuppressive functions, but their roles in the initiation and early development of SLE have not been explored. Here, we measured and compared the frequencies of blood regulatory B cell subsets and the concentrations of plasma IL-35, IL-10, IL-17A, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in 47 Chinese patients with newly diagnosed SLE and 20 matched healthy controls (HCs). The SLE patients had decreased percentages of IL-35+ B cells and IL-10+ B cells among the total blood B cells as well as decreased concentrations of plasma IL-35. In addition, higher levels of plasma IL-10, IFN-γ, TNF-α, and IL-17 along with higher frequencies of circulating plasma and memory B cells were observed in the SLE patients. The percentage of IL-35+ Bregs and the serum IL-35 level were inversely correlated with the SLE disease activity index and the erythrocyte sedimentation rate (ESR) levels. Our results indicate that IL-35+ Bregs and IL-35 may play protective roles in SLE initiation and progression.

Gm40600 suppressed SP 2/0 isograft tumor by reducing Blimp1 and Xbp1 proteins.

BACKGROUND: Multiple myeloma (MM), characterized by cancerous proliferation of plasmablasts (PB) and plasma cells (PC), remains incurable in many patients. Differentially expressed molecules between MM PCs and healthy PCs have been explored in order to identify novel targets for treating MM. In the present study, we searched for novel MM therapeutic targets by comparing mRNA expression patterns between the Mus musculus myeloma plasmablast-like SP 2/0 cell line and LPS-induced PB/PC. METHODS: Gene expression profiles of LPS-induced PB/PC and SP 2/0 cells were determined using RNA-sequencing. A predicted gene (Gm40600) was found to be expressed at a low level in SP 2/0 cells. To study the role of Gm40600 in malignant PC, Gm40600 cDNA was cloned into a lentiviral vector (LV201) containing a puromycin selectable marker that was then transfected into SP 2/0 cells. Stable Gm40600-expressing SP 2/0 cells were selected using puromycin. The effect of Gm40600 on SP 2/0 cell proliferation, cell cycle/apoptosis, and tumor progression was assessed by cell counting kit-8 (CCK8), flow cytometry (FACS), and the SP 2/0 isograft mouse model, respectively. The effect of Gm40600 on mRNA and protein expression was evaluated by RNA-sequencing and western blotting, respectively. RESULTS: We found that SP 2/0 cells expressed lower level of Gm40600 mRNA as compared to LPS-induced PB/PC. Overexpression of Gm40600 significantly suppressed SP 2/0 cell proliferation and isograft tumor progression in an isograft mouse model by promoting apoptosis. In addition, Gm40600 overexpression suppressed transcription of the gene encoding Bcl2. Gm40600 overexpression also reduced the expression of PC-associated transcription factors Blimp1 and Xbp1, which promote transcription of the gene that encodes Bcl2. CONCLUSIONS: Gm40600 reduced SP 2/0 cell proliferation and isograft tumor growth and progression by suppressing Blimp1 and Xbp1-mediated Bcl2 transcription to induce apoptosis. Thus, regulation of a human homolog of Gm40600, or associated factors, may be a potential therapeutic approach for treating MM.