Expression of PD-1 mitigates phagocytic activities TAM in osteosarcoma.

The high expression of programmed death 1 (PD-1) is a hallmark of T cell exhaustion, consequently inhibiting the anti-tumor immunity, tumor-associated macrophages (TAMs) aggravate Osteosarcoma (OS) progression. However, PD-1 expression on TAMs in OS metastasis remains unclear. Here, we used scRNA-Seq of 15500 individual cells from human OS lung metastatic lesion, identified thirteen major cell clusters. Our data revealed that tumor-infiltrating lymphocytes (TILs) OS lung metastatic accompanied by accumulation of exhausted T cells and regulatory T cells (Tregs). CD3+ T cells from human OS lung metastatic exhibited lower proliferation than in primary tissue. Importantly, TAMs mainly comprise immunosuppressive M2 phenotype in OS metastasis. Mechanistically, we found that PD-1 of TAMs inhibits the phagocytic potency, further promoting the progression of OS metastasis. Therefore, the study provides a strong technical support for OS immunotherapy based on PD-1 inhibitors.

A deep learning model for the differential diagnosis of benign and malignant salivary gland tumors based on ultrasound imaging and clinical data.

Background: The preoperative differentiation between benign parotid gland tumors (BPGTs) and malignant parotid gland tumors (MPGTs) is of great significance for therapeutic decision-making. Deep learning (DL), an artificial intelligence algorithm based on neural networks, can help overcome inconsistencies in conventional ultrasonic (CUS) examination outcomes. Therefore, as an auxiliary diagnostic tool, DL can support accurate diagnosis using massive ultrasonic (US) images. This current study developed and validated a DL-based US diagnosis for the preoperative differentiation of BPGT from MPGT. Methods: A total of 266 patients, including 178 patients with BPGT and 88 patients with MPGT, were consecutively identified from a pathology database and enrolled in this study. Ultimately, considering the limitations of the DL model, 173 patients were selected from the 266 patients and divided into 2 groups: a training set, and a testing set. US images of the 173 patients were used to construct the training set (including 66 benign and 66 malignant PGTs) and testing set (consisting of 21 benign and 20 malignant PGTs). These were then preprocessed by normalizing the grayscale of each image and reducing noise. Processed images were imported into the DL model, which was then trained to predict the images from the testing set and evaluated for performance. Based on the training and validation datasets, the diagnostic performance of the 3 models was assessed and verified using receiver operating characteristic (ROC) curves. Ultimately, before and after combining the clinical data, we compared the area under the curve (AUC) and diagnostic accuracy of the DL model with the opinions of trained radiologists to evaluate the application value of the DL model in US diagnosis. Results: The DL model showed a significantly higher AUC value compared to doctor 1 + clinical data, doctor 2 + clinical data, and doctor 3 + clinical data (AUC =0.9583 vs. 0.6250, 0.7250, and 0.8025 respectively; all P<0.05). In addition, the sensitivity of the DL model was higher than the sensitivities of the doctors combined with clinical data (97.2% vs. 65%, 80%, and 90% for doctor 1 + clinical data, doctor 2 + clinical data, and doctor 3 + clinical data, respectively; all P<0.05). Conclusions: The DL-based US imaging diagnostic model has excellent performance in differentiating BPGT from MPGT, supporting its value as a diagnostic tool for the clinical decision-making process.

Polysaccharide from Echinacea purpurea plant ameliorates oxidative stress-induced liver injury by promoting Parkin-dependent autophagy.

BACKGROUND: Acetaminophen (APAP) overdose represents one of the most common drug-induced liver injuries (DILI) worldwide. Oxidative damage to the hepatocytes and their resultant autophagy are the key components in the APAP-induced DILI. Echinacea purpurea polysaccharide (EPPS), the component extracted from the root of Echinacea purpurea (L.) Moench, shows various biological functions including immunoregulation and antioxidant activity. PURPOSE: This study aimed to elucidate the protective effect of EPPS against APAP-induced DILI and the underlying mechanisms. RESULTS: EPPS attenuates APAP overdose induced DILI in mice and ameliorates inflammation and oxidative stress in mice with APAP overdose-induced DILI. Furthermore, EPPS protected the hepatocytes against APAP-induced liver injury by suppressing apoptosis. EPPS ameliorates APAP-induced DILI via an autophagy-dependent mechanism in vivo and increases autophagy with a reduction in oxidative stress and inflammation in vitro. Parkin knockdown prevents the autophagic-dependent manner of EPPS effects in APAP-treated hepatocytes. CONCLUSIONS: EPPS exhibited a strong hepatoprotective effect against APAP-induced DILI and was correlated with reduction of autophagy-dependent oxidant response, inflammation, and apoptosis. Moreover, the findings indicated that EPPS exerts its hepatoprotective effect against APAP mainly via Parkin-dependent autophagy, and the use of EPPS can serve as a promising novel therapeutic strategy for APAP-induced DILI.

CD24 aggravates acute liver injury in autoimmune hepatitis by promoting IFN-γ production by CD4+ T cells.

The T-cell-mediated immune response is implicated in many clinical hepatic injuries, such as autoimmune hepatitis and acute virus hepatitis. CD24 is widely expressed by different immune cells and plays an important role in the pathogenesis of many autoimmune diseases. However, the role of CD24 in T-cell-mediated liver injury has not been elucidated until now. Here we showed that CD24 deficiency protects mice from concanavalin A (ConA)-induced fulminant liver injury by reducing serum interferon-γ (IFN-γ) levels. CD24 expression by hepatic T cells was markedly increased following ConA challenge. Moreover, decreased IFN-γ production by hepatic CD4+ T cells in CD24-deficient mice was detected, which was correlated with downregulated phosphorylation of STAT1 in hepatic tissue. In vitro experiments also supported the conclusion that CD24 deficiency impaired IFN-γ production by CD4+ T cells following ConA, CD3/CD28 and phorbol myristate acetate/ionomycin stimulation. Our study suggests that CD24 deficiency confers hepatoprotection by decreasing CD4+ T-cell-dependent IFN-γ production in vivo, which suggests that CD24 might be a potential target molecule for reducing clinical hepatitis.

Comparison of ultrasound-guided endovenous laser ablation and radiofrequency for the varicose veins treatment: An updated meta-analysis.

PURPOSE: To investigate and compare the relative efficacy, recurrence and complications of endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) for the treatment of varicose veins patients. METHODS: Searches were applied to the Cochrane Library as well as MEDLINE, EMBASE, BIOSIS databases. 12 articles published in English (10 randomized controlled trials and 2 cohort study) were identified from specialized trails. Fixed effect model and Random effect model were applied to compare the vein ablated length, pain scores (3days and 10days), quality of Life, occlusion, over all complication, thrombophlebitis, haematoma and recanalization between the EVLA and RFA group. The results were expressed as odds ratio (OR) or relative risk (RR) and 95% confidence intervals (CI) for categorical outcomes. RESULTS: 12 reported studies with a combined total of 1577 patients were included. vein ablated length (SMD:0.37, 95%CI: 0.04 to 0.77), 3days pain scores (SMD:11.25, 95%CI: 3.42 to 25.92) and 10days (SMD:0.79,95%CI: 0.48 to 2.05),1 month quality of Life (SMD: 0.09,95%CI: 0.28 to 0.10) and 1 year (SMD: 0.04,95%CI: 0.21 to 0.13), occlusion (OR:1.05,95%CI:0.41 to 2.73), thrombophlebitis (RR:1.03,95%CI:0.56 to 1.92), haematoma (OR:1.55, 95%CI:0.54 to 4.45) and recanalization (OR:0.68,95%CI:0.43 to 1.09) following RFA showed no difference when compared with EVLA. These results were not statistically significant. RFA was associated with the lower overall complication (OR: 3.49, 95%CI:1.36 to 8.96) in patients with varicose veins compared to the EVLA treatment. CONCLUSION: EVLA and RFA seem to be the same safe and effective on clinical efficacy (vein ablated length, 3days and 10days pain scores, 1 month and 1 year quality of life, occlusion, thrombophlebitis, haematoma and recanalization). Data on RFA seems to having potential benefits from reducing risk of overall complication than EVLA, which is needed by large high-quality prospective randomized trials.

TACE combined with dendritic cells and cytokine-induced killer cells in the treatment of hepatocellular carcinoma: A meta-analysis.

Patients with hepatocellular carcinoma (HCC), a fatal cancer, have benefited significantly from TACE (transcatheter arterial chemoembolization) and immunotherapy treatments. Immunotherapy that includes dendritic cells and cytokine-induced killer cells (DC-CIK) in combination with TACE has been extensively applied in cases of HCC. Few decisive conclusions about these combined effects on the outcomes of HCC patients have been reached. Therefore, the present meta-analysis was performed to compare the efficacy of the combined usage of DC-CIK with TACE with a TACE therapy alone on the outcomes of HCC patients. Participants were enrolled in eight eligible trials. The efficiency and safety of TACE followed by DC-CIK immunotherapy (experimental group) and of TACE alone (control group) were compared. The meta-analysis results demonstrated that TACE plus DC-CIK immunotherapy is possibly superior to TACE alone in promoting a better overall response, for half-year, 1-year, and 2-year overall survival (OS), median overall survival (OS) and progression-free survival rates (PFS) in HCC patients. Further studies should be performed to confirm the effect of the combined therapy.

Meta-analysis of chemotherapy and dendritic cells with cytokine-induced killer cells in the treatment of non-small-cell lung cancer.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is one of the most fatal cancers, which leads to large number of people dead. Followed by surgery, chemotherapy and radiotherapy, chemotherapy combined dendritic cells with cytokine-induced killer cells (DC-CIK) immunotherapy has been applied in NSCLC for some time, but little consistent beneficial results are provided. So, it is essential to weigh the pros and cons of the new therapeutic method. METHODS: We searched the randomized controlled trials of NSCLC mainly by PubMed database. Terms combination of "cytokine-induced killer cells", "tumor" and "cancer" were used. After evaluating the heterogeneity of selected studies, then we performed the meta-analysis. Pooled risk ratios (RRs) were estimated and 95% confidence intervals (CIs) were calculated using a fixed-effect model. Sensitivity analysis was also performed. RESULTS: Six eligible trials were enrolled. Efficiency and safety of chemotherapy followed by DC-CIK immunotherapy (experimental group) and chemotherapy alone (control group) were compared. 1-year overall survival (OS) (P=0.02) and progression free survival (PFS) (P=0.005) in the experimental group were significantly increased compared with the control. Disease control rate (DCR) (P=0.006) rose significantly in experimental group. However, no significant differences between the two groups were observed in 2-year OS (P=0.21), 2-year PFS (P=0.10), overall response rate (ORR) (P=0.76) and partial response (PR) (P=0.22). Temporary fever, anemia, leukopenia and nausea were the four major adverse events (AEs) treated by chemotherapy. The incidence of anemia, leukopenia and nausea in the experimental group was obviously lower than the control group. Temporary fever rate was higher in experimental group than that in the control, but could be alleviated by taking sufficient rest. CONCLUSIONS: Chemotherapy combined with DC-CIK immunotherapy showed superiority in DCR, 1-year OS and PFS, and no more AEs appeared, however, there was no significant improvement in ORR, PR, 2-year OS and PFS. As a whole, the combination therapy is safer but modest in efficacy for advanced NSCLC patients.

Anti-tumor angiogenesis effect of genetic fusion vaccine encoding murine beta-defensin 2 and tumor endothelial marker-8 in a CT-26 murine colorectal carcinoma model.

Tumor endothelial marker 8 (TEM8) is an endothelial-specific marker that is upregulated during tumor angiogenesis. We previously demonstrated that DNA-based vaccine encoding xenogeneic TEM8 can potentiate anti-angiogenesis immunotherapy of malignancy; nevertheless, it remains to be improved in minimizing immune tolerance. Recently, it has been reported that murine beta-defensin 2 (MBD2) is chemotactic for immature dendritic cells and plays a pivotal role in breaking immune tolerance. Herein, we constructed a genetic fusion vaccine encoding murine TEM8 and MBD2 to investigate whether the novel vaccine preferentially elicits therapeutic antitumor immune responses and suppresses cancerous angiogenesis in mouse models. The anti-angiogenesis effect was determined by microvessel density (MVD) using immunohistochemical staining. The efficacy of the fusion vaccine was primarily assessed by detecting cytotoxic T lymphocyte activity ((51)Cr-release assay). Enzyme-linked immunosorbent spot (ELISpot) assay was used to detect TEM8-specific INF-γ production, and the activity of CTL was further verified by a depletion of CD8(+) T cells via anti-CD8 monoclonal antibody. Our results showed that the DNA fusion vaccine possessed an enhanced therapeutic antitumor immunity through anti-angiogenesis in BALB/c mice inoculated with CT26 cells, and this effect was generally attributed to stimulation of an antigen specific CD8(+) T-cell response against mTEM8. In conclusion, our study demonstrated that the fusion vaccine based on mTEM8 and MBD2 induced autoimmunity against endothelial cells, resulting in deceleration of tumor growth, and could be potential therapeutical application in clinic.

Efficacy of edaravone on coronary artery bypass patients with myocardial damage after ischemia and reperfusion: a meta analysis.

OBJECTIVES: To assess the efficacy and safety of edaravone for myocardial damage during myocardial ischemia and reperfusion (I/R). METHODS: We included randomized controlled trials that compared edaravone with placebo or no intervention in patients with acute myocardial infarction or undergoing coronary artery bypass. Two authors selected eligible trials, assessed trial quality and independently extracted the data. RESULTS: Seven clinical trials were eventually included and analyzed in this study, involving 148 participants. Four trials were defined as waiting assessment. All of the three remaining trials compared edaravone and another treatment combined with other treatment alone, used the same dose of edaravone injections (60 mg per day) and course of treatment (14 days), evaluated the effect of edaravone at different times, applied different methods, reported adverse events, and showed no differences between the treatment group and the control group. When pooling all of the trials in one dataset, edaravone appeared to decrease the proportion of participant with marked myocardial damage during I/R as compared with the control group. The meta-analysis also revealed decreased CK-MB, cTnI and MDA, and increased content of SOD. CONCLUSIONS: Due to the moderate risk of bias and small sample, our observation of an effective treatment trend of edaravone for I/R requires future larger, high-quality trials to confirm.

Minimally invasive video-assisted versus conventional open thyroidectomy on immune response: a meta analysis.

OBJECTIVES: The aim of this study was to compare the immune response between the minimally invasive video-assisted thyroidectomy (MIVAT) and conventional thyroidectomy (CT). METHODS: An exhaustive literature search was performed in the Medline, Embase, and Cochrane Library to identify the randomized controlled trials comparing the immune response between MIVAT and CT. Relevant data were extracted and statistical analysis was done using RevMan 5.0. RESULTS: Twelve trials including 389 patients were identified. Immune-competent cells demonstrated no significant differences between MIVAT and CT. The including trails were assessed various perioperative plasma cytokine concentrations with no significant differences in interleukin-6 (IL-6), T lymphocytes (CD4(+), CD8(+), CD4/CD8) and NK cells between the MIVAT and CT. However, meta-analysis showed lower counts on postoperative days at 72 h was showed lower C-reactive protein (CRP) level compared to the preoperation levels but showed no significant difference within 24 h in MIVAT S group compared with CT group. Tumor necrosis factor alpha (TNF-α) level after surgery within 24 h and 72 h showed lower TNF-α level after MIVAT surgery within 24 h and 72 h. CONCLUSIONS: This meta-analysis demonstrates that, MIVAT has less immune response outcomes and that it is a more ideal choice for the patients relative to the conventional surgery.

The same chromosome 9p21.3 locus is associated with type 2 diabetes and coronary artery disease in a Chinese Han population.

OBJECTIVE: Recent genome-wide association studies (GWAS) revealed that a 9p21.3 locus was associated with type 2 diabetes. In this study, we carried out a large-scale case-control study in the GeneID Chinese Han population to 1) further replicate the association of 9p21.3 type 2 diabetes GWAS single nucleotide polymorphisms (SNPs) and 2) assess the association of these SNPs with coronary artery disease. RESEARCH DESIGN AND METHODS: Three SNPs (rs2383208, rs10811661, and rs10757283) were genotyped in two GeneID cohorts of 3,167 Chinese Han individuals. Case-control association design was used to determine the association of the SNPs with type 2 diabetes and coronary artery disease. Gensini scores were calculated in the coronary artery disease subjects and were tested for association with the variants. Multivariate logistic regressions were performed on association studies. RESULTS: The association between two of the three SNPs and type 2 diabetes was replicated in the GeneID population (rs2383208, P = 0.936; rs10811661-T, P = 0.02, odds ratio [OR] = 1.23; rs10757283-C, P = 0.003, OR = 1.30). The same two SNPs also contributed to the risk of coronary artery disease (CAD) (rs10811661-T, P = 0.002, OR = 1.19; rs10757283-C, P = 0.003, OR = 1.18). In addition, rs10757283 was associated with severity of coronary atherosclerosis estimated by the Gensini scoring system (risk allele C, quantitative-trait regression adjusted P = 0.002). CONCLUSIONS: For the first time to our knowledge, our results indicated that the same 9p21.3 locus, represented by SNPs rs10811661 and rs10757283, contributed to the risk of type 2 diabetes and coronary artery disease in our GeneID Chinese Han population.

Semaphorin3F down-regulates the expression of integrin alpha(v)beta3 and sensitizes multicellular tumor spheroids to chemotherapy via the neuropilin-2 receptor in vitro.

BACKGROUND: Multicellular resistance (MCR), i.e. decreased sensitivity to anticancer drugs compared with common monolayer cell (MC) cultures, depends partly on tumor cell-cell adhesion. Previous studies have shown that anti-adhesive therapies, including integrin alpha(v), beta(1) and alpha(v)beta(3) targeting, induced apoptosis and reversed the sensitivity of MCR. METHODS: A model of three-dimensional cell culture was used to establish HT29 multicellular spheroid cells (MCS) and explore the effect of semaphorin3F (Sema3F) on integrin-mediated cell-cell interactions in MCS of a human colorectal adenocarcinoma cell line (HT29) and sensitization of HT29 MCS to 5-fluorouracil and oxaliplatin via a decrease in integrin alpha(v)beta(3). RESULTS: Elevated expression of Sema3F led to the up-regulation neuropilin-2 (Nrp2) receptor expression and the down-regulation of integrin alpha(v)beta(3) expression. Furthermore, short interfering RNA of Nrp2 could reverse MCR. CONCLUSION: Our study demonstrates that Sema3F can sensitize MCR by decreasing integrin alpha(v)beta(3)expression via the Nrp2 receptor.