Uncovering lupus nephritis-specific genes and the potential of TNFRSF17-targeted immunotherapy: a high-throughput sequencing study

IntroductionLupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE). This study aimed to identify LN specific-genes and potential therapeutic targets.MethodsWe performed high-throughput transcriptome sequencing on peripheral blood mononuclear cells (PBMCs) from LN patients. Healthy individuals and SLE patients without LN were used as controls. To validate the sequencing results, qRT-PCR was performed for 5 upregulated and 5 downregulated genes. Furthermore, the effect of the TNFRSF17-targeting drug IBI379 on patient plasma cells and B cells was evaluated by flow cytometry.ResultsOur analysis identified 1493 and 205 differential genes in the LN group compared to the control and SLE without LN groups respectively, with 70 genes common to both sets, marking them as LN-specific. These LN-specific genes were significantly enriched in the ‘regulation of biological quality’ GO term and the cell cycle pathway. Notably, several genes including TNFRSF17 were significantly overexpressed in the kidneys of both LN patients and NZB/W mice. TNFRSF17 levels correlated positively with urinary protein levels, and negatively with complement C3 and C4 levels in LN patients. The TNFRSF17-targeting drug IBI379 effectively induced apoptosis in patient plasma cells without significantly affecting B cells.DiscussionOur findings suggest that TNFRSF17 could serve as a potential therapeutic target for LN. Moreover, IBI379 is presented as a promising treatment option for LN

Potential factors of cytokeratin fragment 21-1 and cancer embryonic antigen for mediastinal lymph node metastasis in lung cancer

Objective: Lung cancer is a common malignant tumor, characterized by being difficult to detect and lacking specific clinical manifestations. This study aimed to find out the risk factors of mediastinal lymph node metastasis and explore the correlation between serum tumor markers and mediastinal lymph node metastasis and lung cancer prognosis. Methods: A retrospective study of 3,042 lung cancer patients (330 patients with mediastinal lymph node metastasis and 2,712 patients without mediastinal lymph node metastasis) collected from the First Affiliated Hospital of Nanchang University from April 1999 to July 2020. The patients were divided into two groups, namely, mediastinal lymph node metastasis group and non-mediastinal lymph node metastasis group. Student’s t test, non-parametric rank sum test and chi-square test were used to describe whether there is a significant difference between the two groups. We compared the serum biomarkers of the two groups of patients, including exploring serum alkaline phosphatase (ALP), calcium hemoglobin (HB), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), CA125, CA-199, CA -153, cytokeratin fragment 19 (CYFRA 21-1), total prostate specific antigen (TPSA), neuron-specific enolase (NSE) levels and the incidence and prognosis of lung cancer mediastinal lymph node metastasis. Binary logistic regression analysis was used to determine its risk factors, and receiver operating curve (ROC) analysis was used to evaluate its diagnostic value for mediastinal lymph node metastasis. Results: Binary logistic regression analysis showed that carcinoembryonic antigen and CYFRA 21-1 were independent risk factors for mediastinal lymph node metastasis in patients with lung cancer (p < 0.001 and p = 0.002, respectively). The sensitivity and specificity of CEA for the diagnosis of mediastinal lymph node metastasis were 90.2 and 7.6%, respectively; CYFRA 21-1 were 0.6 and 99.0%, respectively. Conclusion: Serum CEA and CYFRA 21-1 have predictive value in the diagnosis of mediastinal lymph node metastasis in patients with lung cancer

Yersinia pseudotuberculosis Exploits CD209 Receptors for Promoting Host Dissemination and Infection

Yersinia pseudotuberculosis is a Gram-negative enteropathogen and causes gastrointestinal infections. It disseminates from gut to mesenteric lymph nodes (MLNs), spleen, and liver of infected humans and animals. Although the molecular mechanisms for dissemination and infection are unclear, many Gram-negative enteropathogens presumably invade the small intestine via Peyer's patches to initiate dissemination. In this study, we demonstrate that Y. pseudotuberculosis utilizes its lipopolysaccharide (LPS) core to interact with CD209 receptors, leading to invasion of human dendritic cells (DCs) and murine macrophages. These Y. pseudotuberculosis CD209 interactions result in bacterial dissemination to MLNs, spleens, and livers of both wild-type and Peyer's patch-deficient mice. The blocking of the Y. pseudotuberculosis CD209 interactions by expression of 0-antigen and with oligosaccharides reduces infectivity. Based on the well-documented studies in which HIV-CD209 interaction leads to viral dissemination, we therefore propose an infection route for Y. pseudotuberculosis where this pathogen, after penetrating the intestinal mucosal membrane, hijacks the Y. pseudotuberculosis CD209 interaction antigen-presenting cells to reach their target destinations, MLNs, spleens, and livers.Peer reviewe

A simulation study on the measurement of D0-D0bar mixing parameter y at BES-III

We established a method on measuring the \dzdzb mixing parameter $y$ for BESIII experiment at the BEPCII $e^+e^-$ collider. In this method, the doubly tagged $\psi(3770) \to D^0 \overline{D^0}$ events, with one $D$ decays to CP-eigenstates and the other $D$ decays semileptonically, are used to reconstruct the signals. Since this analysis requires good $e/\pi$ separation, a likelihood approach, which combines the $dE/dx$, time of flight and the electromagnetic shower detectors information, is used for particle identification. We estimate the sensitivity of the measurement of $y$ to be 0.007 based on a $20fb^{-1}$ fully simulated MC sample.Comment: 6 pages, 7 figure

Planck Galactic Cold Clumps at High Galactic Latitude-a Study with CO Lines

Gas at high Galactic latitude is a relatively little noticed component of the interstellar medium. In an effort to address this, 41 Planck Galactic Cold Clumps at high Galactic latitude (HGal; divide b divide > 25 degrees) were observed in (CO)-C-12, (CO)-C-13, and (CO)-O-18 J = 1-0 lines, using the Purple Mountain Observatory 13.7 m telescope. (CO)-C-12 (1-0) and (CO)-C-13 (1-0) emission was detected in all clumps, while (CO)-O-18 (1-0) emission was only seen in 16 clumps. The highest and average latitudes are 71.degrees 4 and 37.degrees 8, respectively. Fifty-one velocity components were obtained, and then each was identified as a single clump. Thirty-three clumps were further mapped at 1 ' resolution, and 54 dense cores were extracted. Among dense cores, the average excitation temperature T (ex) of (CO)-C-12 is 10.3 K. The average line widths of thermal and nonthermal velocity dispersions are 0.19 and 0.46 km s(-1), respectively, suggesting that these cores are dominated by turbulence. Distances of the HGal clumps given by Gaia dust reddening are about 120-360 pc. The ratio of X (13)/X (18) is significantly higher than that in the solar neighborhood, implying that HGal gas has a different star formation history compared to the gas in the Galactic disk. HGal cores with sizes from 0.01 to 0.1 pc show no notable Larson's relation, and the turbulence remains supersonic down to a scale of slightly below 0.1 pc. None of the HGal cores that bear masses from 0.01 to 1 M (circle dot) are gravitationally bound, and all appear to be confined by outer pressure.Peer reviewe

PgtE Enzyme of Salmonella enterica Shares the Similar Biological Roles to Plasminogen Activator (Pla) in Interacting With DEC-205 (CD205), and Enhancing Host Dissemination and Infectivity by Yersinia pestis

Yersinia pestis, the cause of plague, is a newly evolved Gram-negative bacterium. Through the acquisition of the plasminogen activator (Pla), Y. pestis gained the means to rapidly disseminate throughout its mammalian hosts. It was suggested that Y. pestis utilizes Pla to interact with the DEC-205 (CD205) receptor on antigen-presenting cells (APCs) to initiate host dissemination and infection. However, the evolutionary origin of Pla has not been fully elucidated. The PgtE enzyme of Salmonella enterica, involved in host dissemination, shows sequence similarity with the Y. pestis Pla. In this study, we demonstrated that both Escherichia coli K-12 and Y. pestis bacteria expressing the PgtE-protein were able to interact with primary alveolar macrophages and DEC-205-transfected CHO cells. The interaction between PgtE-expressing bacteria and DEC-205-expressing transfectants could be inhibited by the application of an anti-DEC-205 antibody. Moreover, PgtE-expressing Y. pestis partially re-gained the ability to promote host dissemination and infection. In conclusion, the DEC-205-PgtE interaction plays a role in promoting the dissemination and infection of Y. pestis, suggesting that Pla and the PgtE of S. enterica might share a common evolutionary origin.Peer reviewe

Radioiodine therapy for castration-resistant prostate cancer following prostate-specific membrane antigen promoter-mediated transfer of the human sodium iodide symporter

Radioiodine therapy, the most effective form of systemic radiotherapy available, is currently useful only for thyroid cancer because of the thyroid-specific expression of the human sodium iodide symporter (hNIS). Here, we explore the efficacy of a novel form of gene therapy using prostate-specific membrane antigen (PSMA) promoter-mediated hNIS gene transfer followed by radioiodine administration for the treatment of castration-resistant prostate cancer (CRPC). The androgen-dependent C33 LNCaP cell line and the androgen-independent C81 LNCaP cell line were transfected by adenovirus. PSMA promoter-hNIS (Ad.PSMApro-hNIS) or adenovirus.cytomegalovirus-hNIS containing the cytomegalovirus promoter (Ad.CMV-hNIS) or a control virus. The iodide uptake was measured in vitro. The in vivo iodide uptake by C81 cell xenografts in nude mice injected with an adenovirus carrying the hNIS gene linked to PSMA and the corresponding tumor volume fluctuation were assessed. Iodide accumulation was shown in different LNCaP cell lines after Ad.PSMApro-hNIS and Ad.CMV-hNIS infection, but not in different LNCaP cell lines after adenovirus.cytomegalovirus (Ad.CMV) infection. At each time point, higher iodide uptake was shown in the C81 cells infected with Ad.PSMApro-hNIS than in the C33 cells (P < 0.05). An in vivo animal model showed a significant difference in 131 I radioiodine uptake in the tumors infected with Ad.PSMApro-hNIS, Ad.CMV-hNIS and control virus (P < 0.05) and a maximum reduction of tumor volume in mice infected with Ad.PSMApro-hNIS. These results show prostate-specific expression of the hNIS gene delivered by the PSMA promoter and effective radioiodine therapy of CRPC by the PSMA promoter-driven hNIS transfection

Identify Molecular Mechanisms of Jiangzhi Decoction on Nonalcoholic Fatty Liver Disease by Network Pharmacology Analysis and Experimental Validation

Background. Jiangzhi Decoction (JZD), a traditional herb mixture, has shown significant clinical efficacy against nonalcoholic fatty liver disease (NAFLD). However, its multicomponent and multitarget characteristics bring difficulty in deciphering its pharmacological mechanisms. Our study is aimed at identifying the core molecular mechanisms of JZD against NAFLD. Methods. The active ingredients were searched from Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and Traditional Chinese Medicine Integrated Database (TCMID). The targets of those ingredients were identified using ChemMapper database based on 3D structure similarity. NAFLD-related genes were searched from DisGeNET database and Gene Expression Omnibus (GEO) database. Then, we performed protein-protein interaction (PPI) analysis, functional enrichment analysis, and constructed pathway networks of “herbs-active ingredients-candidate targets” and identified the core molecular mechanisms and key active ingredients in the network. Also, molecular docking was carried out to predict the ligands of candidate targets using SwissDock. Finally, the human hepatic L02 cell line was used to establish the NAFLD model in vitro. The effect and key molecules were validated by Oil Red O staining, biochemical assays, and quantitative real-time PCR (qRT-PCR). Results. We found 147 active ingredients in JZD, 1285 targets of active ingredients, 401 NAFLD-related genes, and 59 overlapped candidate targets of JZD against NAFLD. 22 core targets were obtained by PPI analysis. Finally, nuclear receptor transcription and lipid metabolism regulation were found as the core molecular mechanisms of JZD against NAFLD by functional enrichment analysis. The candidate targets PPARα and LXRα were both docked with hyperin as the most favorable interaction, and HNF4α was docked with linolenic acid ethyl ester. According to in vitro experiments, it was found that JZD had an inhibitory effect on lipid accumulation and regulatory effects on cholesterol and triglycerides. Compared with OA group, the mRNA expression levels of PPARα and HNF4α were significantly upregulated in JZD group (P<0.05), and LXRα was significantly downregulated (P<0.001). Conclusion. JZD might alleviate hepatocyte steatosis by regulating some key molecules related to nuclear receptor transcription and lipid metabolism, such as PPARα, LXRα, and HNF4α. Our study will provide the scientific evidences of the clinical efficacy of JZD against NAFLD