SARS-CoV-2 is the underlying cause for the COVID-19 pandemic. Like most enveloped RNA viruses, SARS-CoV-2 uses a homotrimeric surface antigen to gain entry into host cells. Here we describe S-Trimer, ...a native-like trimeric subunit vaccine candidate for COVID-19 based on Trimer-Tag technology. Immunization of S-Trimer with either AS03 (oil-in-water emulsion) or CpG 1018 (TLR9 agonist) plus alum adjuvants induced high-level of neutralizing antibodies and Th1-biased cellular immune responses in animal models. Moreover, rhesus macaques immunized with adjuvanted S-Trimer were protected from SARS-CoV-2 challenge compared to vehicle controls, based on clinical observations and reduction of viral loads in lungs. Trimer-Tag may be an important platform technology for scalable production and rapid development of safe and effective subunit vaccines against current and future emerging RNA viruses.
Chronic pancreatitis leads to irreversible damage in pancreatic endocrine and exocrine functions. However, there is no clinically available antifibrotic drug. Pancreatic stellate cells (PSCs) can be ...activated by Toll-like receptor 4 (TLR4) responses to its ligands and they contribute to the formation of pancreatic fibrosis. Silencing the expression of TLR4 in PSCs by RNAi may be a novel therapeutic strategy for the treatment of pancreatic fibrosis. In addition, PSCs have a remarkable capacity for vitamin A uptake most likely through cellular retinol binding protein (CRBP). In our study, to ensure the efficient delivery of RNAi therapeutic agents to PSCs, VitA-coupled liposomes (VA-lips) were used as drug carriers to deliver plasmids expressing TLR4-specific short hairpin RNA (shRNA) to treat pancreatic fibrosis. Our study demonstrated that silencing the expression of TLR4 could induce mitochondrial apoptosis in aPSCs and might be an effective therapeutic strategy for the treatment of pancreatic fibrosis.
Key messages
VA-lip-shRNA-TLR4 recovers pancreatic tissue damage.
VA-lip-shRNA-TLR4 resolution of pancreatic fibrosis.
VA-lip-shRNA-TLR4 accelerates ECM degradation and inhibits ECM synthesis.
Silencing TLR4 induces aPSCs mitochondrial apoptosis.
Silencing TLR4 inhibits the activation of NF-κB.
Introduction
Post-hepatectomy liver failure (PHLF) is one of the most serious complications and causes of death in patients with hepatocellular carcinoma (HCC) after hepatectomy. This study aimed to ...develop a novel machine learning (ML) model based on the light gradient boosting machines (LightGBM) algorithm for predicting PHLF.
Methods
A total of 875 patients with HCC who underwent hepatectomy were randomized into a training cohort (n=612), a validation cohort (n=88), and a testing cohort (n=175). Shapley additive explanation (SHAP) was performed to determine the importance of individual variables. By combining these independent risk factors, an ML model for predicting PHLF was established. The area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value, negative predictive value, and decision curve analyses (DCA) were used to evaluate the accuracy of the ML model and compare it to that of other noninvasive models.
Results
The AUCs of the ML model for predicting PHLF in the training cohort, validation cohort, and testing cohort were 0.944, 0.870, and 0.822, respectively. The ML model had a higher AUC for predicting PHLF than did other non-invasive models. The ML model for predicting PHLF was found to be more valuable than other noninvasive models.
Conclusion
A novel ML model for the prediction of PHLF using common clinical parameters was constructed and validated. The novel ML model performed better than did existing noninvasive models for the prediction of PHLF.
Two heterodimeric receptors consisting of either IL-20R1 or IL-22R1 in complex with a common β receptor subunit IL-20R2 are shared by three of the IL-20 family of cytokines: IL-19, IL-20, and IL-24. ...These proinflammatory cytokines have been implicated in the pathogenesis of some autoimmune diseases, including rheumatoid arthritis (RA), psoriasis, and atopic dermatitis. Although mAbs against IL-19 and IL-20 have each been shown to modulate disease severity of collagen-induced arthritis in animal models, and anti-IL-20 therapeutic Ab has exhibited some efficacy in the treatment of RA in clinical trials, benefits for a complete blockade of these functionally redundant cytokines remain to be explored. In this report, we show that recombinant human soluble IL-20R2-Fc fusion protein binds to IL-19, IL-20, and IL-24 with similar high affinity and blocks their signaling in vitro. In DBA/1 mouse collagen-induced arthritis model, recombinant human IL-20R2-Fc exhibits comparable efficacy as TNF blocker etanercept in the treatment of established arthritis, whereas the combined use of both biologics manifests little synergistic therapeutic effects. In situ ligand-receptor functional binding analysis shows that a large amount of immune infiltrates expressing high levels of TNFR and IL-20 subfamily cytokines congregate within the inflamed disease tissues. Colocalization experiments reveal that signals from IL-20R2 and TNF transduction pathways seem to converge in macrophages and function in tandem in orchestrating the pathogenesis of RA. Elucidation of this interaction provides a better understanding of cytokine cross-talk in RA and a rationale for more effective biologic therapies that target IL-20R2 instead of individual cytokines from IL-20 family.
Purpose
To determine the predictive value of portal hypertension (PH) for the development of post-hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC).
Patients and ...methods
This study enrolled a total of 659 patients with HCC that received hepatectomy as a first-line therapy. PH was classified as grade 0, 1, and 2 according to whether the indirect criteria for PH were met: 1) patients had obvious varicose veins and 2) splenomegaly was present and platelet count < 100 × 10
9
/L. The effects of each variable on the occurrence of PHLF were assessed using univariate and multivariate analyses.
Results
PH grade 2 (odds ratio OR = 2.222, p = 0.011), higher age (OR = 1.031, p = 0.003), hepatitis C infection (OR = 3.711, p = 0.012), open surgery (OR = 2.336, p < 0.001), portal flow blockage (OR = 1.626, p = 0.023), major hepatectomy (OR = 2.919, p = 0.001), hyperbilirubinemia (≥ 17.2 μmol/L, OR = 2.113, p = 0.002), and high levels of alpha-fetoprotein (> 400n g/ml, OR = 1.799, p = 0.008) were significantly associated with PHLF occurrence. We performed a subgroup analysis of liver resection and found that the extent of liver resection and PH grade were good at distinguishing patients at high risk for PHLF, and we developed an easy-to-view roadmap.
Conclusion
PH is significantly related to the occurrence of PHLF in patients who underwent hepatectomy. Noninvasively assessing PH grade can predict PHLF risk.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. The in-depth study of genes and metabolites related to nucleotide metabolism will provide new ideas for ...predicting the prognosis of HCC patients. This study integrated the transcriptome data of different cancer types to explore the characteristics and significance of nucleotide metabolism-related genes (NMGRs) in different cancer types. Then, we constructed a new HCC classifier and prognosis model based on HCC samples from TCGA and GEO, and detected the gene expression level in the model through molecular biology experiments. Finally, nucleotide metabolism-related products in serum of HCC patients were examined using untargeted metabolomics. A total of 97 NMRGs were obtained based on bioinformatics techniques. In addition, a clinical model that could accurately predict the prognostic outcome of HCC was constructed, which contained 11 NMRGs. The results of PCR experiments showed that the expression levels of these genes were basically consistent with the predicted trends. Meanwhile, the results of untargeted metabolomics also proved that there was a significant nucleotide metabolism disorder in the development of HCC. Our results provide a promising insight into nucleotide metabolism in HCC, as well as a tailored prognostic and chemotherapy sensitivity prediction tool for patients.
Tumor vaccines that induce effective and sustained antitumor immunity are highly promising for cancer therapy. However, the antitumor potential of these vaccines is weakened due to the ...immunosuppressive characteristics of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells within the TME; they play an important role in tumor growth, metastasis, immunosuppression, and drug resistance. Fibroblast activation protein-α (FAP) is overexpressed in CAFs in more than 90% of human tumor tissues. Further, FAP+CAFs are an ideal interstitial target for the immunotherapy of solid tumors. Exosomes derived from tumor cells contain many tumor antigens, which can be used as the basis of tumor vaccines that elicit strong antitumor immunity. Almost all exosome-based cancer vaccines have been designed and developed for tumor parenchymal cells. Moreover, the exosome production is very low and the purification is very difficult, limiting their clinical application as tumor vaccines. In this study, we developed FAP gene–engineered tumor cell–derived exosome-like nanovesicles (eNVs-FAP) as a tumor vaccine that can be prepared easily and in large quantities. The eNVs-FAP vaccine inhibited tumor growth by inducing strong and specific cytotoxic T lymphocyte (CTL) immune responses against tumor cells and FAP+CAFs and reprogramming the immunosuppressive TME in the colon, melanoma, lung, and breast cancer models. Moreover, eNVs-FAP vaccine–activated cellular immune responses could promote tumor ferroptosis by releasing interferon-gamma (IFN-γ) from CTLs and depleting FAP+CAFs. Thus, eNVs-FAP is a candidate tumor vaccine targeting both the tumor parenchyma and the stroma.
Nanovaccines can activate immune cells and promote an antitumor immune response. In this study, we developed the fibroblast activation protein-α (FAP) gene–engineered tumor cell–derived exosome-like vesicle vaccines (eNVs-FAP). A large number of eNVs-FAP were obtained by continuously squeezing FAP gene–engineered tumor cells. eNVs-FAP showed excellent antitumor effects in a variety of tumor-bearing mouse models. The mechanistic analysis showed that eNVs-FAP promoted the maturation of dendritic cells (DCs), increased the infiltration of effector T cells into target tumor cells and FAP-positive cancer-associated fibroblasts (FAP+CAFs), and reduced the proportion of immunosuppressive cells, including M2-like tumor-associated macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), in the tumor microenvironment (TME). Moreover, the clearance of FAP+CAFs helped enhance interferon-gamma-induced tumor cell ferroptosis.
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Preclinical and clinical studies have validated the antitumor effects of several oncolytic viruses (OVs). However, the efficacy of OVs is limited when they are administered as monotherapies. ...Combination therapy is a promising direction for oncolytic virotherapy in the future. A high dose of vitamin C (VitC) exerts anticancer effects by triggering the accretion of substantial amounts of reactive oxygen species (ROS). OVs can induce immunogenic tumor cell death and elicit an antitumor immune response. ROS play an important role in immunogenic cell death (ICD). This study aimed to explore whether high-dose VitC in combination with oncolytic adenoviruses (oAds) exhibited a synergistic antitumor effect. High-dose VitC synergized with oAds against tumor by enhancing immunogenic tumor cell death. Combination therapy with high-dose VitC and oAds significantly increased the number of T cells in the tumor microenvironment (TME) and promoted the activation of T cells. Furthermore, the antitumor effect of the combination therapy was CD8+ T cell dependent. In addition, combination therapy with high-dose VitC and oAds reprogramed the immunosuppressive TME. Our study provides a new strategy for combination therapy of OVs.
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Oncolytic adenoviruses (oAds) have limited antitumor efficacy when administered as monotherapy. Ping Cheng and colleagues found that high-dose vitamin C and oAds combination therapy exhibited a synergistic antitumor effect by enhancing immunogenic tumor cell death and reprogramming the tumor immune microenvironment. The study provides a new strategy for combination therapy of oAds.
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