B-cell lymphoma with cytokine storm in serosal effusion: A case report and literature review.

RATIONALE: Cytokine storm is now considered to be a systemic inflammatory response, but local cytokine storm may exist in systemic diseases of the blood system. Monitoring of regional cytokine storm is an important clue for the diagnosis of systemic diseases. PATIENT CONCERNS: A 72-years-old male presented to our hospital with multiple serosal effusion without solid mass or enlarged lymph nodes. We found that the level of cytokines in ascites was tens to hundreds of times higher than that in plasma, mainly IL-6 and IL-8. DIAGNOSES: The patient was diagnosed with multiple serous effusion, hemophagocytic syndrome, B-cell lymphoma, Epstein-Barr virus infection, and hypoproteinemia. INTERVENTIONS: During hospitalization, the patient was treated with 5 courses of R-CVEP therapy and supportive treatment. OUTCOMES: After the first R-CVEP regimen, the patient's condition was evaluated as follows: hemophagocytic syndrome improved: no fever; Serum triglyceride 2.36 mmol/L; Ferritin 70.70 ng/L; no hemophagocyte was found in the bone marrow; the lymphoma was relieved, ascites disappeared, and bone marrow cytology showed: the bone marrow hyperplasia was reduced, and small platelet clusters were easily seen. Bone marrow flow cytometry showed that lymphocytes accounted for 13.7%, T cells increased for 85.7%, CD4/CD8 = 0.63, B cells decreased significantly for 0.27%, and NK cells accounted for 10.2%. Blood routine returned to normal: WBC 5.27 × 109/L, HB 128 g/L, PLT 129 × 109/L; Epstein-Barr virus DNA < 5.2E + 02 copies/mL; correction of hypoproteinemia: albumin 39.7 g/L. LESSONS: Cytokines in ascites are significantly higher than those in plasma by tens to hundreds of times, suggesting that "regional cytokine storms" may cause serosal effusion.

[Inhibitory Effect of Cinobufotalin on Macrophage Inflammatory Factor Storm and Its Mechanism].

OBJECTIVE: To investigate the inflammatory effects of Cinobufotalin on monocytes in resting state and macrophages in activated state and its molecular mechanism. METHODS: THP-1 cells were stimulated with Phorbol 12-myristate 13-acetate to induce differentiation into macrophages. Lipopolysaccharides was added to activate macrophages in order to establish macrophage activation model. Cinobufotalin was added to the inflammatory cell model for 24 h as a treatment. CCK-8 was used to detect cell proliferation, Annexin V /PI double staining flow cytometry was used to detect cell apoptosis, flow cytometry was used to detect macrophage activation, and cytometric bead array was used to detect cytokines. Transcriptome sequencing was used to explore the gene expression profile regulated by Cinobufotalin. Changes in the significantly regulated molecules were verified by real-time quantitative polymerase chain reaction and Western blot. RESULTS: 1∶25 concentration of Cinobufotalin significantly inhibited the proliferation of resting monocytes(P<0.01), and induced apoptosis(P<0.01), especially the activated macrophages(P<0.001, P<0.001). Cinobufotalin significantly inhibited the activation of macrophages, and significantly down-regulated the inflammatory cytokines(IL-6, TNF-α, IL-1ß, IL-8) released by activated macrophages(P＜0.001). Its mechanism was achieved by inhibiting TLR4/MYD88/P-IκBa signaling pathway. CONCLUSION: Cinobufotalin can inhibit the inflammatory factors produced by the over-activation of macrophages through TLR4/MYD88/P-IκBa pathway, which is expected to be applied to the treatment and research of diseases related to the over-release of inflammatory factors.

Exploration of effective biomarkers and infiltrating Immune cells in Osteoarthritis based on bioinformatics analysis.

Osteoarthritis (OA) is a multi-factorial chronic joint disease mainly identified by synovial inflammation, cartilage damage, and degeneration. Our study applied bioinformatics analysis to uncover the immunity in OA and tried to explore the underlying immune-related molecular mechanism. First, OA-related gene-expression profiling data were retrieved from GEO database. Then, we analysed a series of datadata with using the xCell algorithm, GEO2R, enrichment analysis of SangerBox website, CytoHubba, ROC logistic regression and correlation analysis. Finally, Nine infiltrating immune cells with differential abundance between OA and normal samples were obtained. There were 42 IODEGs in OA, and their functions were associated with immune cells and corresponding biological processes. Moreover, 5 hub genes, including GREM1, NRP1, VEGFA, FYN and IL6R, were identified. Correlation analysis demonstrated that NRP1 was negatively associated with NKT cells, NRP1 and GREM1 were positively associated with aDC, VEGFA was positively associated with CD8+ naïve T cells, while VEGFA, FYN and IL6R were negatively associated with Macrophages M1. The 5 hub genes could be employed as effective diagnostic biomarkers for OA. In addition, they may participate in OA pathogenesis via interactions with infiltrating immune cells.

Establishment and observation of a mouse model of IL-12-CAR-T cell-induced cytokine release syndrome / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：通过构建表达IL-12的小鼠CAR-T细胞，探讨经尾静脉将其输注于小鼠体内建立细胞因子释放综合征（CRS）模型的方法。方法：构建基于靶向鼠源CD19的CAR分子，包装逆转录病毒载体并感染小鼠T细胞构建mCD19-CAR-T、mCD19/IL-12-CAR-T细胞。通过构建小鼠体内胰腺癌Panc02-CD19细胞移植瘤模型，检测mCD19/IL-12-CAR-T细胞的抗肿瘤活性，ELISA法检测两种CAR-T细胞IL-12和IFN-γ分泌水平；经小鼠尾静脉输注mCD19/IL-12-CAR-T 细胞构建CAR-T细胞CRS小鼠模型，流式细胞术检测小鼠血清中IL-6、MCP-1、IL-1、IL-10、TNF-α、IFN-γ等细胞因子的含量，H-E染色法观察荷瘤小鼠肝、脾、肺和肾的病理组织学变化。结果：经过培养扩增的mCD19/IL-12-CAR-T细胞能有效分泌IL-12，CAR阳性率达（56.9±5.4）%；与非靶细胞Panc02或靶细胞Panc02-CD19共培养时，均能高分泌IFN-γ。成功构建小鼠胰腺癌Panc02-CD19细胞移植瘤模型，经小鼠尾静脉注射1×106个mCD19/IL-12-CAR-T细胞能显著抑制移植瘤的生长，但未能诱发严重CRS；输注2×106个mCD19/IL-12-CAR-T细胞后，小鼠出现体质量减轻、血清炎性因子水平升高、组织损伤，最终导致死亡等一系列典型CRS表现。结论：成功构建IL-12-CAR-T细胞诱发的小鼠CRS模型，其稳定性好、重复性高，具有广泛的应用前景。

Identification and antibiotic resistance of Cronobacter spp. isolated from dried edible mushrooms.

Cronobacter spp. is an important foodborne pathogen that can cause life-threatening diseases in infants and immunocompromised adults. The present study was carried out to understand the prevalence and characterization of Cronobacter spp. in dried edible mushrooms in Jiangsu province, China. Cronobacter isolates were identified and genotyped by multilocus sequence typing (MLST); the antimicrobial susceptibility of Cronobacter strains was determined by the disk diffusion method; the biofilm formation ability of Cronobacter spp. was assessed using the microtiter plate method. The overall prevalence of Cronobacter spp. in dried edible mushrooms was 14.8%, with the highest contamination rate of after 37.2% found in Auricularia auricular. The Cronobacter isolates were identified as C. sakazakii (n = 26), C. malonaticus (n = 2), C. dublinensis (n = 2) and C. turicensis (n = 1). The MLST scheme produced 20 sequence types (STs), two of which were newly identified. ST148 was the most prevalent ST (n = 5), followed by ST4 (n = 3), ST17 (n = 3), ST64 (n = 3), and ST540 (n = 2). One (3.2%) and 15 (48.4%) Cronobacter isolates were resistant to tetracycline and meropenem, respectively. In contrast, all of the tested isolates were susceptible to the remaining 14 antibiotics. Moreover, 20 (64.5%) Cronobacter isolates showed weak ability to produce biofilm, but no isolates showed strong or moderate biofilm-forming ability. PRACTICAL APPLICATION: Our findings revealed a high genetic diversity of Cronobacter spp. in dried edible mushrooms and provided new epidemiological evidence for the widespread existence of Cronobacter spp. in such products. The presence of Cronobacter spp. in dried edible mushrooms may pose potential risks to human health and enhancing the hygiene of such products are necessary to ensure food safety.

Significantly Increased Public Interest in Major Depressive Disorder During the COVID-19 Pandemic: Insights From a Google Trends Analysis.

Background As early as before the coronavirus disease 2019 (COVID-19) pandemic, nearly one billion people worldwide suffered from mental health problems. Of all the mental health conditions, major depressive disorder (MDD) is the leading cause of global health-related burden. During the COVID-19 pandemic, many uncertain factors affecting mental health accumulated, such as virus transmission, blockade and ban, public transport restrictions, closure of schools and enterprises, and reduction of social interaction, which led to an increase in the potential risk of MDD, further increasing the global health-related burden. Methodology To better clarify the public interest in major depressive disorder during the COVID-19 pandemic, a Google Trends analysis was employed with data from December 2019 to December 2021, taking the cumulative diagnosis rate and cumulative mortality rate of COVID-19 as the reference standard, The changes in public interest and behavior in online searching for major depressive disorder in the three countries most affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus (i.e. the United States, Brazil, and India) were evaluated. Results We observed that during the COVID-19 pandemic, public interest in major depressive disorder increased significantly on the Internet. At the same time, compared with the United States, this upward trend is more prominent in India and Brazil. The study found that the major depressive disorder search index of the United States reached the maximum at the end of September 2021, the major depressive disorder search index of Brazil reached the maximum at the beginning of July 2021, and the major depressive disorder search index of India reached the maximum at the beginning of June 2021. The above time nodes are the first turning point of decline after the continuous surge of COVID-19 confirmed cases in the United States, Brazil, and India, indicating that there is an important time correlation between the surge of COVID-19 cases and the public online search term major depressive disorder. Conclusion The Google Trends analysis shows that public interest in major depressive disorder is on the rise under the COVID-19 pandemic and that COVID-19 may be associated with MDD. These findings deserve further exploration, especially as a growing body of research reports suggests that the COVID-19 pandemic has led to a surge in the prevalence of MDD. The epidemic alerts the vast majority of countries to urgently strengthen mental health systems and provide patients with the necessary interventions based on the determinants of poor mental health.

Family capital, social stratification, and access to higher education: An empirical study in mainland China.

This paper employs Bourdieu's theory of capital-focusing on family cultural, social, and economic capital-to research the early-stage mechanism through which access to higher education is formed. While all three types of capital play a significant role in acquiring higher education, most studies tend to focus on just one type of capital. In recent years, domestic scholars have also analyzed in detail the family factors affecting children's access to higher education (CAHE); however, they have not yet explained the mechanism by which these factors influence CAHE, and authentic tests are rare. Therefore, based on existing research, this paper uses the theoretical concept of family capital to reveal how contemporary Chinese families affect their CAHE. This paper analyzes the relationship between family capital, social stratification, and access to higher education opportunities using an econometric model based on baseline data from the China Family Panel Studies (CFPS) from 2010 to 2020, with 10,318 participants, including 4,419 females and 5,899 males. The results of a binary logistic regression analysis show that the possession of family cultural and economic capital has a direct positive influence on CAHE. Children from the elite stratum often benefit more from the accumulation of family cultural capital. Moreover, although it does not form a distinct stratum, the possession of family social capital also significantly influences children's access to higher education. Driven by China's political, economic, and social environment, some children from the blue-collar stratum have a comparative advantage in terms of access to higher education. The possession of family capital is an important factor in the stratification of CAHE, and cultural capital is the most influential type of capital. Parents with a low level of education should be encouraged to become engaged in schools and communities to take professional courses in assisted learning, emotional counseling, decision-making, and voluntary service.

Micropeptide MIAC Inhibits HNSCC Progression by Interacting with Aquaporin 2.

Several important micropeptides encoded by noncoding RNAs have been identified in recent years; however, there have never been any reports of micropeptides in head and neck squamous cell carcinoma (HNSCC). Here we report the discovery and characterization of a human endogenous peptide named micropeptide inhibiting actin cytoskeleton (MIAC). Comprehensive analysis of the TCGA (The Cancer Genome Atlas) database (n = 500), clinical fresh samples (n = 94), and tissue microarrays (n = 60) revealed that lower MIAC expression is correlated with poor overall survival of HNSCC patients. Meanwhile, RNA-sequencing analysis of 9657 human tissues across 32 cancer types from TCGA cohorts found that MIAC is significantly associated with the progression of 5 other different tumors. Mechanistically, MIAC directly interacts with AQP2 (Aquaporin 2) to inhibit the actin cytoskeleton by regulating SEPT2 (Septin 2)/ITGB4 (Integrin Beta 4) and ultimately suppressing the tumor growth and metastasis of HNSCC. Collectively, the mechanism investigation and evaluation of MIAC activity in vivo and in vitro highlights that MIAC plays an important role in HNSCC tumorigenesis.

A novel arthritis model induced by wind, damp, cold and heat in female rats.

Animal models are in constant development to benefit scientific research. Rheumatoid arthritis (RA) is considered a very complex disease due to its complicated pathogenesis, and patients with rheumatic disease around the world are still unable to obtain effective, simple and curable treatment. In order to obtain a clear insight into the pathogenesis of RA, a rat model was established based on the concept of Bi syndrome in Traditional Chinese Medicine by simulating the conditions of RA as much as possible via the change in the physical conditions wind, damp, cold and heat (WDCH). For the first time, a new WDCH-induced RA model in female rats was successfully established and evaluated by body-weight change, paw swelling, blood cells analysis, spleen and thymus coefficients, autoantibodies and serum cytokine changes and histopathology. This model is characterised by its objectivity, no exogenous induction, short modelling time, extremely elevated expression level of autoantibodies and obvious histopathological change. The establishment of such a new model may provide more benefits in the research of the pathogenesis of RA.

Peptide PD29 treats bleomycin-induced pulmonary fibrosis by inhibiting the TGF-ß/smad signaling pathway.

Pulmonary fibrosis (PF) is an end-stage change in lung disease characterized by fibroblast proliferation, massive extracellular matrix (ECM) aggregation with inflammatory damage, and severe structural deterioration. PD29 is a 29-amino acid peptide which has the potential to alleviate PF pathogenesis via three mechanisms: anti-angiogenesis, inhibition of matrix metalloproteinase activities, and inhibition of integrins. In this study, fibrotic lung injuries were induced in SD rats by a single intratracheal instillation of 5 mg/kg bleomycin (BLM). Then, these rats were administered 7.5, 5, or 2.5 mg/kg PD29 daily for 30 days. BLM induced-syndromes including structure distortion, excessive deposition of ECM, excessive inflammatory infiltration, and pro-inflammatory cytokine release were used to evaluate the protective effect of PD-29. Oxidative stress damage in lung tissues was attenuated by PD29 in a dose-dependent manner. The expression of TGF-ß1 and the phosphorylation of Smad-2/-3-its downstream targets-were enhanced by BLM and weakened by PD29. In vitro, PD29 inhibited TGF-ß1-induced epithelial-mesenchymal transition (EMT) and transformation in A549 cells and mouse primary fibroblasts into myofibroblasts. In summary, PD29 reversed EMT and transformation of fibroblasts into myofibroblasts in vitro and prevented PF in vivo possibly by suppressing the TGF-ß1/Smad pathway.

Facile Synthesis and Cytotoxicity of Phenazine-Chromene Hybrid Molecules Derived from Phenazine Natural Product.

AIM AND OBJECTIVE: Small molecule targeted drugs can effectively reduce the toxicity and side effects of drugs, and improve the efficacy of drugs by their specific antitumor activity. Hence, the development of small molecular targeted drugs for cancer has important significance. This study was undertaken to design and synthesize novel phenazine-chromene hybrid molecules in order to optimize the structure and improve the efficacy of this kind of hybrids. MATERIALS AND METHODS: O-diaminobenzene was used as starting material to synthesize twentyfour heterocyclic compounds designed as hybrid molecules of phenazine and 4H-chromene pharmacophores by facile methods. The structures of the compound were confirmed by 1H NMR, 13C NMR and HRMS. Furthermore, the synthesized compounds were evaluated for in vitro activity against four human cancer cell lines and two non-cancer cell lines by MTT test. RESULTS: Some compounds showed strong cytotoxic activities against HepG2 and A549 cancer lines (IC50 = 5-10 µM). Comparing 2i with 2l, the introduction of hydrophilic groups on the phenazine core could not improve the antiproliferative activity significantly. Except 2d and 3c, compounds owning chlorine substituent on the 4H-chromene pharmacophore seemingly contribute to enhance the compounds' antiproliferative activity. Specially, compound 3c showed highest cytotoxicity against A549 cells with IC50 values of 3.3±0.4 µM. Furthermore, all compounds showed low or no cytotoxicity against HUVEC and L02 non-cancer cells in vitro. CONCLUSION: Compound 3c may be used as potential lead molecule against A549 cancer cells.

Differentially Private Distributed Online Learning.

In the big data era, the generation of data presents some new characteristics, including wide distribution, high velocity, high dimensionality, and privacy concern. To address these challenges for big data analytics, we develop a privacy-preserving distributed online learning framework on the data collected from distributed data sources. Specifically, each node (i.e., data source) has the capacity of learning a model from its local dataset, and exchanges intermediate parameters with a random part of their own neighboring (logically connected) nodes. Hence, the topology of the communications in our distributed computing framework is unfixed in practice. As online learning always performs on the sensitive data, we introduce the notion of differential privacy (DP) into our distributed online learning algorithm (DOLA) to protect the data privacy during the learning, which prevents an adversary from inferring any significant sensitive information. Our model is of general value for big data analytics in the distributed setting, because it can provide rigorous and scalable privacy proof and have much less computational complexity when compared to classic schemes, e.g., secure multiparty computation (SMC). To tackle high-dimensional incoming data entries, we study a sparse version of the DOLA with novel DP techniques to save the computing resources and improve the utility. Furthermore, we present two modified private DOLAs to meet the need of practical applications. One is to convert the DOLA to distributed stochastic optimization in an offline setting, the other is to use the mini-batches approach to reduce the amount of the perturbation noise and improve the utility. We conduct experiments on real datasets in a configured distributed platform. Numerical experiment results validate the feasibility of our private DOLAs.

Clinical impact of circulating miR-26a, miR-191, and miR-208b in plasma of patients with acute myocardial infarction.

BACKGROUND: Aberrant expression of several types of miRNAs has been reported in acute myocardial infarction (AMI). The objective of our study was to compare miRNA expression in AMI patients and normal healthy people and determine whether miR-26a, miR-191, and miR-208b could be measured in plasma as indicators for AMI. METHODS: Detection of AMI patients and normal persons by using miRNA microarray chip analysis and miR-26a, miR-191, and miR-208b was screened out. Eighty-seven AMI patients and eighty-seven homogeneous healthy individuals were recruited. Total mRNA including miRNA was isolated and miR-26a, miR-191, and miR-208b expression were determined by qRT-PCR. Receiver operating characteristic curve analysis was performed to evaluate the instructive power of miR-26a, miR-191, and miR-208b for AMI. Dual-luciferase reporter assays indicated p21 is a direct target of miR-208b. RESULTS: miR-26a and miR-191 were low expressed in AMI compared with normal healthy people, but miR-208b was expressed at a high level in AMI. miR-26a showed an area under the curve (AUC) of 0.745, with a sensitivity of 73.6 % and a specificity of 72.4 %.The AUC for miR-191 was 0.669, with a sensitivity of 62.1 % and a specificity of 69.0 %.The AUC for miR-208b was 0.674, with a sensitivity of 59.8 % and a specificity of 73.6 %. CONCLUSIONS: miR-208b was significantly increased in the AMI compared with healthy people, while miR-26a and miR-191 were decreased. miR-26a, miR-191, and miR-208b were potential indices of AMI, and miR-208b was more effective in patients with non-ST-elevation myocardial infarction.