B cell lymphoma 6 promotes hepatocellular carcinoma progression by inhibiting tumor infiltrating CD4+T cell cytotoxicity through ESM1.

Immunotherapy exhibited potential effects for advanced hepatocellular carcinoma, unfortunately, the clinical benefits are often countered by cancer adaptive immune suppressive response. Uncovering the mechanism how cancer cells evade immune surveillance would help to develop new immunotherapy approaches and combination therapy. In this article, by analyzing the transcriptional factors which modulate the differentially expressed genes between T cell infiltration high group and low group, we identified oncoprotein B cell lymphoma 6 (BCL6) suppresses the infiltration and activation of tumor infiltrating T lymphocytes, thus correlated with poorer clinical outcome. By using antibody deletion experiment, we further demonstrated that CD4+T cells but not CD8+T cells are the main lymphocyte population suppressed by Bcl6 to promote HCC development. Mechanistically, BCL6 decreases cancer cell expression of pro-inflammatory cytokines and T lymphocyte chemokines such as IL6, IL1F6, and CCL5. Moreover, BCL6 upregulates Endothelial cell-specific molecule 1 (ESM1) to inhibit T lymphocyte recruitment and activation possibly through ICAM-1/LFA-1 signaling pathway. Our findings uncovered an unappreciated paracrine mechanism how cancer cell-derived BCL6 assists cancer cell immune evasion, and highlighted the role of CD4+T cells in HCC immune surveillance.

A novel signature incorporating genes related to lipid metabolism and immune for prognostic and functional prediction of breast cancer.

PURPOSE: Breast cancer prognosis and functioning have not been thoroughly examined in relation to immunological and lipid metabolism. However, there is a lack of prognostic and functional analyses of the relationship between lipid metabolism and immunity in breast cancer. METHODS: DEGs in breast cancer were obtained from UCSC database, and lipid metabolism and immune-related genes were obtained from GSEA and Immune databases. A predictive signature was constructed using univariate Cox and LASSO regression on lipid metabolism and immune-related DEGs. The signature's prognostic significance was assessed using Kaplan-Meier, time-dependent ROC, and risk factor survival scores. Survival prognosis, therapeutic relevance, and functional enrichment were used to mine model gene biology. We selected IL18, which has never been reported in breast cancer before, in the signature to learn more about its function, potential to predict outcome, and immune system role. RT-PCR was performed to verify the true expression level of IL18. RESULTS: A total of 136 DEGs associated with breast cancer responses to both immunity and lipid metabolism. Nine key genes (CALR, CCL5, CEPT, FTT3, CXCL13, FLT3, IL12B, IL18, and IL24, p < 1.6e-2) of breast cancer were identified, and a prognostic was successfully constructed with a good predictive ability. IL18 in the model also had good clinical prognostic guidance value and immune regulation and therapeutic potential. Furthermore, the expression of IL18 was higher than that in paracancerous tissue. CONCLUSIONS: A unique predictive signature model could effectively predict the prognosis of breast cancer, which can not only achieve survival prediction, but also screen out key genes with important functional mechanisms to guide clinical drug experiments.

Study on the effect and mechanism of Lacticaseibacillus rhamnosus AFY06 on inflammation-associated colorectal cancer induced by AOM/DSS in mice.

Introduction: Lacticaseibacillus rhamnosus AFY06 (LR-AFY06) is a microorganism isolated from naturally fermented yogurt in Xinjiang, China. Methods: In this study, we investigated the effects and mechanisms of LR-AFY06 in a mouse model of inflammation-associated colon cancer. The mouse model was established by azoxymethane/dextran sulfate sodium (AOM/DSS) induction. The tumor number in intestinal tissues was counted, and the histopathological analysis was performed on colon tissues. Enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction were performed to measure relevant protein levels in colon tissues. Results: LR-AFY06 treatment alleviated weight loss, increased organ index, reduced intestinal tumor incidence, improved histopathological damage, decreased the levels of inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), nuclear factor κB (NF-κB), and inducible nitric oxide synthase (iNOS) in the serum and colon tissue, downregulated the mRNA expression of inhibitor of NF-κB beta (IκBß), p65, p50, p52, B-cell lymphoma-2 (Bcl-2), and B-cell lymphoma-extra large (Bcl-xL) in colon tissues, and increased the mRNA expression of Bid and caspase-8. The high concentration of LR-AFY06 exerted a better effect than the low concentration; however, the effect was slightly inferior to that of aspirin. Moreover, LR-AFY06 mitigated the intestinal inflammatory process and inhibited intestinal tumor development by regulating the NF-κB and apoptosis pathways. Discussion: The present study indicates the regulatory potential of LR-AFY06 in inflammation-associated colorectal cancer in mice, providing a valuable basis for further research.

Diversity and independent evolutionary profiling of rodent-borne viruses in Hainan, a tropical island of China.

The risk of emerging infectious diseases (EID) is increasing globally. More than 60% of EIDs worldwide are caused by animal-borne pathogens. This study aimed to characterize the virome, analyze the phylogenetic evolution, and determine the diversity of rodent-borne viruses in Hainan Province, China. We collected 682 anal and throat samples from rodents, combined them into 28 pools according to their species and location, and processed them for next-generation sequencing and bioinformatics analysis. The diverse viral contigs closely related to mammals were assigned to 22 viral families. Molecular clues of the important rodent-borne viruses were further identified by polymerase chain reaction for phylogenetic analysis and annotation of genetic characteristics such as arenavirus, coronavirus, astrovirus, pestivirus, parvovirus, and papillomavirus. We identified pestivirus and bocavirus in Leopoldoms edwardsi from Huangjinjiaoling, and bocavirus in Rattus andamanensis from the national nature reserves of Bangxi with low amino acid identity to known pathogens are proposed as the novel species, and their rodent hosts have not been previously reported to carry these viruses. These results expand our knowledge of viral classification and host range and suggest that there are highly diverse, undiscovered viruses that have evolved independently in their unique wildlife hosts in inaccessible areas.

Transcecum catheterization ileostomy is safe and effective to prevent anastomotic leakage in post-laparoscopic rectal cancer surgery: a single-center retrospective study.

Background: Preventive ileostomy (PI) is conventionally performed to prevent anastomotic leakage (AL) after laparoscopic total mesorectal excision (LTME) for low rectal cancer; however, secondary surgery is required to remove the ostomy tube. We designed a new type of ostomy, transcecum catheterization ileostomy (TCI) to prevent AL. Its principle is similar to PI, but no secondary operation is needed. We evaluated the safety and efficacy of TCI in AL prevention. Methods: We analyzed the data of patients who underwent LTME with low anastomosis in Chongqing University Cancer Hospital from October 2015 to August 2021. Patients were divided into three groups according to their choice: those who underwent TCI (TCI group), those who underwent PI (PI group), and those who undergo none (C group). Intra-operation situation, postoperative efficacy and safety indicators were compared between three groups. Results: Out of the total 534 patients included, 171 underwent TCI, 156 underwent PI, and 207 underwent none. No statistically difference was noted in baseline characteristics between three groups (all P>0.05). Operation time was longer in TCI group and PI group than in C group (P<0.001). No difference was noted in intraoperative blood loss or the number of lymph nodes dissected (P=0.685 and P=0.153). Moreover, no difference was noted in the serum levels of immune cells on postoperative day 1, 3, and 7 (all P>0.05) or in the levels of serum C-reactive protein (CRP), procalcitonin (PCT), and interleukin 6 (IL-6; all P>0.05). No difference was noted in postoperative incision, pulmonary infection rates and intestinal obstruction incidence (P=0.530, P=0.971, and P=0.938). AL incidence and AL-related reoperation rates were lower in TCI or PI group (P=0.002 and P<0.001). The rate of anastomotic stricture was lower in TCI group than in the other two groups (P<0.001). Conclusions: TCI is effective to prevent AL when performed during LTME. But TCI cannot completely avoid AL. When AL occurs, TCI can reduce the degree of abdominal infection and the secondary surgical rate related AL. TCI presents an alternative option to PI, that does not require secondary operation. Therefore, TCI is safe and worthy of application.

Preventive Effect of Flavonoid Extract from the Peel of Gonggan (Citrus reticulata Blanco Var. Gonggan) on CCl4-Induced Acute Liver Injury in Mice.

OBJECTIVE: Citrus peel, a waste product of citrus consumption and processing, is rich in flavonoids. This study aimed to study the protective effect of flavonoid extract from the peel of gonggan (Citrus reticulata Blanco var. gonggan) on acute chemical liver injury. MATERIALS AND METHODS: We established a chemical liver injury model induced by carbon tetrachloride (CCl4) in mice. The flavonoid composition in gonggan (Citrus reticulata Blanco var. gonggan) peel was detected by HPLC. The histopathological sections of liver, related biochemical indicators in serum and liver, and related genes were examined to evaluate the protective effect of gonggan peel flavonoid extract (GPFE). RESULTS: The results showed that GPFE contained narirutin, hesperidin, nobiletin, tangeretin, and 5-demethylnobiletin. After 14 days of intragastric administration of GPFE, the result showed GPFE could reduce the increase in liver index, serum alanine aminotransferase (ALT), and aspartate transaminase (AST) levels caused by CCl4. At the same time, pathological sections of liver confirmed that GPFE alleviated the damage to liver tissue. Moreover, biochemical indicator results showed that GPFE increased the activities of superoxide dismutase (SOD) and catalase (CAT) in liver tissue and reduced the content of malondialdehyde (MDA). Also, it reduced the levels of inflammation factors: tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin (IL)-1ß, and IL-6. In addition, q-PCR results showed that GPFE upregulated mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), copper/zinc superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), glutathione peroxidase (GSH-Px), γ-glutamylcysteine synthetase (γ-GCS), CAT, and downregulated IL-6 and TNF-α mRNA expression levels. The mechanism of GPFE may be related to the inhibition of oxidative stress and inflammation. CONCLUSION: The experiment indicates GPFE has a good protective effect on acute chemical liver injury in mice induced by CCl4 via antioxidant and anti-inflammatory pathways.

Predicting Progression-Free Survival Using MRI-Based Radiomics for Patients With Nonmetastatic Nasopharyngeal Carcinoma.

Objectives: This study aimed to explore the predictive value of MRI-based radiomic model for progression-free survival (PFS) in nonmetastatic nasopharyngeal carcinoma (NPC). Methods: A total of 327 nonmetastatic NPC patients [training cohort (n = 230) and validation cohort (n = 97)] were enrolled. The clinical and MRI data were collected. The least absolute shrinkage selection operator (LASSO) and recursive feature elimination (RFE) were used to select radiomic features. Five models [Model 1: clinical data, Model 2: overall stage, Model 3: radiomics, Model 4: radiomics + overall stage, Model 5: radiomics + overall stage + Epstein-Barr virus (EBV) DNA] were constructed. The prognostic performances of these models were evaluated by Harrell's concordance index (C-index). The Kaplan-Meier method was applied for the survival analysis. Results: Model 5 incorporating radiomics, overall stage, and EBV DNA yielded the highest C-indices for predicting PFS in comparison with Model 1, Model 2, Model 3, and Model 4 (training cohorts: 0.805 vs. 0.766 vs. 0.749 vs. 0.641 vs. 0.563, validation cohorts: 0.874 vs. 0.839 vs. 836 vs. 0.689 vs. 0.456). The survival curve showed that the high-risk group yielded a lower PFS than the low-risk group. Conclusions: The model incorporating radiomics, overall stage, and EBV DNA showed better performance for predicting PFS in nonmetastatic NPC patients.

HE4 as a biomarker for diagnosis of lung cancer: A meta-analysis.

BACKGROUND: The aim of our study was to assess the value of serum human epididymis protein 4 (HE4) to diagnose lung cancer and provide reliable scientific conclusions to guide clinical practice. METHODS: A systematic search of the PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature, and WANFANG databases was conducted to identify all studies examining serum HE4 in the diagnosis of lung cancer published up to June, 2017. The Quality Assessment of Diagnostic Accuracy Studies tool was used to evaluate the methodological quality of each trial. The meta-analysis was performed using STATA software and Review Manager 5.3. RESULTS: There were 21 studies involving 1883 cases and 1696 controls included in our meta-analysis. The pooled sensitivity and specificity of HE4 for diagnosing lung cancer were 0.73 (95% confidence interval [CI] 0.68-0.78) and 0.86 (95% CI 0.81-0.91), respectively. The positive likelihood ratio and negative likelihood ratio were 5.4 (95% CI 3.8-7.5) and 0.31 (95% CI 0.26-0.37), respectively. The diagnostic odds ratio was 17 (95% CI 12-26). The area under the curve of the summary receiver-operating characteristic curve was 0.86 (95% CI 0.83-0.89). Race, assay method, type of cancer, sample size, and publication date might be sources of heterogeneity in our meta-analysis. Subgroup analyses showed that the sensitivity in Caucasians was higher than that in Asians (0.81, 95% CI 0.71-0.91; and 0.71, 95% CI 0.66-0.77, respectively), but the specificity in Asians was better than that in Caucasians (0.87, 95% CI 0.81-0.92; and 0.85, 95% CI 0.73-0.97, respectively). The chemiluminescent microparticle immunoassay had the highest sensitivity, with 0.79 (95% CI 0.73-0.97), and the enzyme-linked immunosorbent assay had the highest specificity, with 0.87 (95% CI 0.79-0.94). HE4 had high diagnostic efficacy when screening for small cell lung cancer with the highest specificity (0.90, 95% CI 0.77-1.00). CONCLUSIONS: HE4 is a relatively promising and effective biomarker for the diagnosis of lung cancer. Furthermore, given the limitations of our study, additional large-scale and well-designed studies are needed in the future.

Sensitivity of non-small cell lung cancer to erlotinib is regulated by the Notch/miR-223/FBXW7 pathway.

Recent evidence supports a role for microRNA-223 (miR-223) in modulating tumor cell sensitivity to chemotherapeutic drugs; however, its role in cellular resistance to the effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) used in treatment of non-small cell lung cancer (NSCLC) remains to be elucidated. The levels of miR-223 in parental cell line (HCC827) and erlotinib resistant HCC827 cell line (HCC827/ER) were detected by qRT-PCR. HCC827/ER cells were treated with MK-2206 to block the Akt signaling pathway or RO4929097 to block the Notch signaling pathway, and then transfected with an miR-223 inhibitor or interference expression plasmid of F-Box/WD repeat-containing protein 7 (FBXW7) or insulin-like growth factor 1 receptor (IGF1R). HCC827 cells were transfected with miR-223 mimics. Next, CCK-8, colony formation, and flow cytometric apoptosis assays were used to assess cell resistance to erlotinib. When compared with its expression in HCC827 cells, miR-223 expression was significantly up-regulated in HCC827/ER cells. Blocking either the Akt or Notch signaling pathway and reducing miR-223 expression resulted in decreased resistance in HCC827/ER cells. Conversely, increasing miR-223 expression induced cell resistance to erlotinib in HCC827 cells. miR-223 enhanced resistance to erlotinib by down-regulating FBXW7 expression. Reducing FBXW7 expression lowered resistance to erlotinib in HCC827/ER cells, while interference with expression of IGF1R produced no significant effect. This study demonstrated that NSCLC cells can up-regulate their levels of miR-223 expression via the Akt and Notch signaling pathways. miR-223 may serve as an important regulator of erlotinib sensitivity in NSCLC cells by targeting FBXW7.

Celastrol attenuates angiotensin II mediated human umbilical vein endothelial cells damage through activation of Nrf2/ERK1/2/Nox2 signal pathway.

Angiotensin II (Ang II), as a crucial factor of endothelial dysfunction, participates in endothelial oxidative damage and inflammation, which is present in all cardiovascular disease (CVD). Celastrol, extracted from Trypterygiun wilfordii Hook F. ("Thunder of God Vine"), is a natural compound with antioxidant and anti-inflammatory activities. In this study, the protective effects of celastrol on human umbilical vein endothelial cell (HUVEC) injury induced by Ang II were observed and its mechanisms were elucidated. Compared with the control group, Ang II significantly increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, enhanced reactive oxygen species levels and proinflammatory cytokines, decreased antioxidant enzyme activities, and suppressed cellular viability and promoted cell apoptosis. It accomplished this via inhibition of the nuclear factor erythroid 2-related factor 2 (Nrf2), increasing the expression levels of Nox2 and AngII type 1 receptor (AT1 receptor), and inducing the phosphorylation of extracellular signal regulated kinase (ERK1/2). In contrast, celastrol effectively suppressed reactive oxygen species generation, improved endothelial cell activity, and ameliorated Ang II-mediated HUVEC injury through activation of Nrf2, inhibition of Nox2/AT1 receptor expression, and upregulated phosphorylation of ERK1/2. After treatment with brusatol, a specific inhibitor of Nrf2, the protective effects of celastrol on Ang II-induced damage in HUVECs were remarkably alleviated. Taken together, celastrol-induced activation of Nrf2 and inhibition of NADPH oxidase activity were critical for the inhibition of Ang II-mediated endothelial dysfunction, and demonstrated the potential application of celastrol in CVD therapy.

The ROS derived mitochondrial respirstion not from NADPH oxidase plays key role in Celastrol against angiotensin II-mediated HepG2 cell proliferation.

Angiotensin II (AngII) is an important factor that promotes the proliferation of cancer cells, whereas celastrol exhibits a significant antitumor activity in various cancer models. Whether celastrol can effectively suppress AngII mediated cell proliferation remains unknown. In this study, we studied the effect of celastrol on AngII-induced HepG2 cell proliferation and evaluated its underlying mechanism. The results revealed that AngII was able to significantly promote HepG2 cell proliferation via up-regulating AngII type 1 (AT1) receptor expression, improving mitochondrial respiratory function, enhancing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, increasing the levels of reactive oxygen species (ROS) and pro-inflammatory cytokines. The excess ROS from mitochondrial dysfunction is able to cause the apoptosis of tumor cells via activating caspase3 signal pathway. In addition, the reaction between NO and ROS results in the formation of peroxynitrite (ONOO-), and then promoting cell damage. celastrol dramatically enhanced ROS generation, thereby causing cell apoptosis through inhibiting mitochodrial respiratory function and boosting the expression levels of AngII type 2 (AT2) receptor without influencing NADPH oxidase activity. PD123319 as a special inhibitor of AT2R was able to effectively decreased the levels of inflammatory cytokines and endothelial nitric oxide synthase (eNOS) activity, but only partially attenuate the effect of celastrol on AnII mediated HepG2 cell proliferation. Thus, celastrol has the potential for use in liver cancer therapy. ROS derived from mitochondrial is an important factor for celastrol to suppress HepG2 cell proliferation.