ABSTRACT
OBJECTIVE: To explore the prognostic value of multiple immune inflammatory indicators for diffuse large B-cell lymphoma (DLBCL). METHODS: The clinical data of 175 patients with DLBCL who were diagnosed and received Immunochemotherapy in The Qinzhou First People's Hospital between January 2015 and December 2021 were retrospectively analyzed for this study. Patients were classified into a death group (n = 54) and a survival group (n = 121) depending on their prognosis. The clinical data of the patients with lymphocytes-to-beads (LMR), neutrophils-to-lymphocytes (NLR), and platelets-to-lymphocytes (PLR) were collected. The receiver operator characteristic curve (ROC) was used to determine the optimal critical value of the immune index. The Kaplan-Meier was used to draw the survival curve. The Cox regression model was used to analyze the factors affecting the prognosis of DLBCL. A nomogram risk prediction model was constructed to verify its effectiveness. RESULTS: By the ROC curve analysis, the optimal cut-off value was 3.93 × 109/L for neutrophil count, 2.42 for LMR, 23.6 mg/L for C-reactive protein (CPR), 2.44 for NLR, 0.67 × 109/L for Monocyte, and 195.89 for PLR. The survival rate of patients with neutrophil number ≤ 3.93 × 109/L, LMR > 2.42, CRP ≤ 23.6 mg/L, NLR ≤ 2.44, Monocyte ≤ 0.67 × 109/L, PLR ≤ 195.89 was higher than that of patients with neutrophil number > 3.93 × 109/L, LMR ≤ 2.42, CRP > 23.6 mg/L, NLR > 2.44, and Monocyte > 0.67 × 109/L, PLR > 195.89. The nomogram was constructed based on the results of the multivariate analysis. The AUC of the nomogram was 0.962 (95% CI: 0.931-0.993) and 0.952 (95% CI: 0.883-1) in the training set and the test set, respectively. The calibration curve showed that the predicted value of the nomogram was in good agreement with the actual observed value. CONCLUSION: IPI score, neutrophil count, NLR, and PLR are risk factors impacting the prognosis of DLBCL. The combined prediction of IPI score, neutrophil count, NLR, and PLR can better reflect the prognosis of DLBCL. It can be used as a clinical index to predict the prognosis of diffuse large B-cell lymphoma, and provide clinical basis for improving the prognosis of patients.
ABSTRACT
Two dimensional (2D) van der Waals (vdW) heterostructures have potential applications in novel low dimensional spintronic devices due to their unique electronic and magnetic properties. Here, the electronic and magnetic properties of 2D Zr2CO2/H-FeCl2heterostructures are calculated by first principles calculations. The 2D Zr2CO2/H-FeCl2heterostructures are magnetic semiconductor. The electronic structure and magnetic anisotropy of Zr2CO2/H-FeCl2heterostructure can be regulated by the biaxial strain and external electric field. The band gap and potential difference of Zr2CO2/H-FeCl2heterostructure can be affected by in-plane biaxial strain. At a compressive strain of -8%, the Zr2CO2/H-FeCl2heterostructure becomes metallic. All of the Zr2CO2/H-FeCl2heterostructures are magnetic with in-plane magnetic anisotropy (IMA). The Zr2CO2/H-FeCl2heterostructure is a semiconductor at the electric field from -0.5 V Å-1to +0.5 V Å-1. Furthermore, Zr2CO2/H-FeCl2heterostructure shows IMA at the negative electric field, while it shows perpendicular magnetic anisotropy at the positive electric field. These results show that Zr2CO2/H-FeCl2heterostructure has potential applications in multifunctionalnanoelectronic devices.
ABSTRACT
Monoclonal antibodies represent important weapons in our arsenal to against the COVID-19 pandemic. However, this potential is severely limited by the time-consuming process of developing effective antibodies and the relative high cost of manufacturing. Herein, we present a rapid and cost-effective lipid nanoparticle (LNP) encapsulated-mRNA platform for in vivo delivery of SARS-CoV-2 neutralization antibodies. Two mRNAs encoding the light and heavy chains of a potent SARS-CoV-2 neutralizing antibody HB27, which is currently being evaluated in clinical trials, were encapsulated into clinical grade LNP formulations (named as mRNA-HB27-LNP). In vivo characterization demonstrated that intravenous administration of mRNA-HB27-LNP in mice resulted in a longer circulating half-life compared with the original HB27 antibody in protein format. More importantly, a single prophylactic administration of mRNA-HB27-LNP provided protection against SARS-CoV-2 challenge in mice at 1, 7 and even 63 days post administration. In a close contact transmission model, prophylactic administration of mRNA-HB27-LNP prevented SARS-CoV-2 infection between hamsters in a dose-dependent manner. Overall, our results demonstrate a superior long-term protection against SARS-CoV-2 conferred by a single administration of this unique mRNA antibody, highlighting the potential of this universal platform for antibody-based disease prevention and therapy against COVID-19 as well as a variety of other infectious diseases.
Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , COVID-19/prevention & control , Cricetinae , Humans , Liposomes , Mice , Nanoparticles , Pandemics/prevention & control , RNA, Messenger/genetics , Spike Glycoprotein, CoronavirusABSTRACT
Background: Proton pump inhibitors (PPIs) are validated gastric acid suppressors and have been widely used to treat patients with active duodenal ulcers. Although existing PPIs have shown great efficacy, many scientists are still devoted to developing more effective PPIs with better safety profile. Herein, we aimed to compare the safety and efficacy of anaprazole in duodenal mucosal healing, a novel PPI, to that of rabeprazole. Methods: In this multicenter, randomized, positive-controlled, double-blinded, parallel-group phase II clinical trial, a total of 150 qualified patients with endoscopically confirmed active duodenal ulcers were randomized (1:1:1) to receive rabeprazole 10 mg, anaprazole 20 mg or anaprazole 40 mg for 4 weeks. The ulcer healing rates after 4 weeks of treatment were compared between groups by independent central review and investigator review. In addition, symptoms and safety were evaluated. Results: Based on the independent central review, the ulcer healing rates of the 10 mg rabeprazole, 20 mg anaprazole and 40 mg anaprazole groups were 88.0, 85.1, and 87.5%, respectively, in the FAS population and 88.9, 86.0, and 90.9%, respectively, in the PPS population. The ulcer healing rate difference between anaprazole 20 mg and Rabeprazole 10 mg is -2.9% (95% CI, -16.5-10.7%), and -0.5% (95% CI, -13.5-12.5%) between anaprazole 40 mg and Rabeprazole 10 mg, in the FAS population. Based on the investigator review, the ulcer healing rates of the 10 mg rabeprazole, 20 mg anaprazole, and 40 mg anaprazole groups were 72.0, 70.2, and 77.1%, respectively, in the FAS population and 75.6, 72.1, and 79.5%, respectively, in the PPS population. The ulcer healing rate difference between anaprazole 20 mg and Rabeprazole 10 mg is -1.8% (95% CI, -19.8-16.3%), and 5.1% (95% CI, -12.2-22.3%) between anaprazole 40 mg and Rabeprazole 10 mg, in the FAS population. Most patients (>90%) eventually achieved complete symptom relief. The incidence rates of adverse events were of no significant differences among the treatment groups. Potential possible better liver tolerance was observed in two anaprazole dose groups than rabeprazole 10 mg group. Conclusion: Both at a dosage of 20 and 40 mg daily, anaprazole, is effective with good safety profile in the treatment of active duodenal ulcers in this Phase 2 study, which allows anaprazole to be advanced to a phase III clinical trial. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/results?cond=&term=NCT04503629&cntry=&state=&city=&dist=, Identifier: CTR20181464, NCT04503629.
ABSTRACT
Bone marrow-derived monocytes/macrophages (BMMs) play a vital role in liver inflammation and fibrogenesis. Cannabinoid receptor 1 (CB1) mediates the recruitment of BMMs into the injured liver. In this study, we revealed the molecular mechanisms under CB1-mediated BMM infiltration. Carbon tetrachloride (CCl4 ) was employed to induce mouse liver injury. In vivo, human antigen R (HuR) was upregulated in macrophages of injured liver. HuR messenger RNA (mRNA) expression was positively correlated with CB1 and F4/80 mRNA expression. Furthermore, we detected the binding between HuR and CB1 mRNA in CCl4 -treated livers. In vitro, HuR modulated arachidonyl-2'-chloroethylamide (ACEA, CB1 agonist)-induced BMM migration by regulating CB1 expression. HuR promoted CB1 expression via binding to CB1 mRNA. ACEA promoted the association between HuR and CB1 mRNA via inducing HuR nucleoplasmic transport. In the cytoplasm, HuR competed with the miR-29 family to improve CB1 expression and BMM migration. In conclusion, our results prove that HuR regulates CB1 expression and influences ACEA-induced BMM migration by competing with miR-29 family.
Subject(s)
ELAV-Like Protein 1/genetics , Lung Injury/genetics , MicroRNAs/genetics , Receptor, Cannabinoid, CB1/genetics , Animals , Bone Marrow/metabolism , Bone Marrow/pathology , Carbon Tetrachloride/toxicity , Cell Movement/genetics , Disease Models, Animal , Humans , Liver/injuries , Liver/metabolism , Liver/pathology , Lung Injury/chemically induced , Lung Injury/metabolism , Lung Injury/pathology , Macrophages/metabolism , Macrophages/pathology , Mice , Monocytes/metabolism , Monocytes/pathologyABSTRACT
Sphingosine 1-phosphate (S1P) participates in migration of bone marrow (BM)-derived mesenchymal stem cells (BMSCs) toward damaged liver via upregulation of S1P receptor 3 (S1PR3) during mouse liver fibrogenesis. But, the molecular mechanism is still unclear. HuR, as an RNA-binding protein, regulates tumor cell motility. Here, we examined the role of HuR in migration of human BMSCs (hBMSCs) in liver fibrosis. Results showed that HuR messenger RNA (mRNA) level was increased in human or mouse fibrotic livers, and correlated with S1PR3 mRNA expression. Using immunofluorescence, we found that HuR mainly localized in the nuclei of hepatocytes and non-parenchymal cells in normal livers. However, in fibrotic livers, we detected an increased HuR cytoplasmic localization in non-parenchymal cells. In chimeric mice of BM cell-labeled by EGFP, significant numbers of EGFP-positive cells (BM origin) were positive for HuR in fibrotic areas. Meanwhile, HuR-positive cells were also positive for α-SMA (myofibroblasts). In vitro, S1P induced hBMSCs migration via S1PR3 upregulation. HuR involved in S1P-induced hBMSCs migration and increased stabilization of S1PR3 mRNA via competing with miR-30e. RNA immunoprecipitation showed that HuR interacted with S1PR3 mRNA 3'UTR. Moreover, S1P resulted in phosphorylation and cytoplasmic translocation of HuR via S1PR3 and p38MAPK. Furthermore, we transplanted EGFP+ BMSCs with or without HuR small interfering RNA (siRNA) into carbon tetrachloride-treated mice and found that knockdown of HuR inhibited the migration of BMSCs toward injured livers by flow cytometric analysis in vivo. We identified a positive feedback regulation mechanism between HuR and S1PR3 in S1P-induced BMSCs migration. HuR participates in upregulation of S1PR3 induced by S1P. S1P results in phosphorylation and translocation of HuR via S1PR3. Our results provide a new regulatory manner to the mechanism of liver fibrogenesis. KEY MESSAGE: HuR expression and cytoplasmic localization were increased in fibrotic livers. S1P induced migration of human bone marrow Mesenchymal Stem Cells via S1PR3 and HuR. HuR regulated S1PR3 mRNA expression by binding with S1PR3 mRNA 3'UTR. S1P induced HuR phosphorylation and cytoplasmic translocation via S1PR3. HuR regulated S1PR3 expression by competing with miR-30e.
Subject(s)
ELAV-Like Protein 1/genetics , Liver Cirrhosis/genetics , Liver Cirrhosis/metabolism , Lysophospholipids/metabolism , Mesenchymal Stem Cells/metabolism , Sphingosine/analogs & derivatives , Adult , Aged , Animals , Cell Movement/genetics , Disease Models, Animal , ELAV-Like Protein 1/metabolism , Female , Gene Expression Regulation , Humans , Liver Cirrhosis/pathology , Male , Mice , MicroRNAs/genetics , Middle Aged , Models, Biological , Phosphorylation , RNA Stability , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Lysosphingolipid/genetics , Receptors, Lysosphingolipid/metabolism , Signal Transduction , Sphingosine/metabolism , Sphingosine-1-Phosphate Receptors , p38 Mitogen-Activated Protein KinasesABSTRACT
RNA-binding protein HuR mediates transforming growth factor (TGF)-ß1-induced profibrogenic actions. Up-regulation of Sphingosine kinase 1 (SphK1) is involved in TGF-ß1-induced activation of hepatic stellate cells (HSCs) in liver fibrogenesis. However, the molecular mechanism of TGF-ß1 regulates SphK1 remains unclear. This study was designed to investigate the role of HuR in TGF-ß1-induced SphK1 expression and identify a new molecular mechanism in liver fibrogenensis. In vivo, HuR expression was increased, translocated to cytoplasm, and bound to SphK1 mRNA in carbon tetrachloride- and bile duct ligation-induced mouse fibrotic liver. HuR mRNA expression had a positive correlation with mRNA expressions of SphK1 and fibrotic markers, α-smooth muscle actin (α-SMA) and Collagen α1(I), respectively. In vitro, up-regulation of SphK1 and activation of HSCs stimulated by TGF-ß1 depended on HuR cytoplasmic accumulation. The effects of TGF-ß1 were diminished when HuR was silenced or HuR cytoplasmic translocation was blocked. Meanwhile, overexpression of HuR mimicked the effects of TGF-ß1. Furthermore, TGF-ß1 prolonged half-life of SphK1 mRNA by promoting its binding to HuR. Pharmacological or siRNA-induced SphK1 inhibition abrogated HuR-mediated HSC activation. In conclusion, our data suggested that HuR bound to SphK1 mRNA and played a crucial role in TGF-ß1-induced HSC activation.