FOSL2-mediated transcription of ISG20 induces M2 polarization of macrophages and enhances tumorigenic ability of glioblastoma cells.

BACKGROUND: Interferon stimulated exonuclease gene 20 (ISG20) has been reported to be correlated with macrophage infiltration in glioblastoma (GBM) in previous bioinformatics-based studies. This study explores the exact effect of ISG20 on macrophage polarization in GBM. METHODS: ISG20 expression in GBM tissues and cells was determined by RT-qPCR and/or immunohistochemistry. GBM cells were co-cultured with M0 macrophages (PMA-stimulated THP-1 cells) in vitro, followed by flow cytometry and ELISA to analyze the M2 polarization of macrophages. Fluorescence-contained GBM cells were intracranially injected into nude mice along with M0 macrophages to generate orthotopic xenograft tumor models. Upstream regulator of ISG20 was predicted using bioinformatics. Loss- or gain-of-function assays of Fos like 2 (FOSL2) and ISG20 were performed in GBM cells. DNA methylation level of FOSL2 was analyzed by bisulfite sequencing analysis. RESULTS: ISG20 was found highly expressed in GBM tissues and cells. ISG20 silencing in GBM cells decreased CD206 and CD163 levels in the co-cultured macrophages and reduced secretion of IL-10 and TGF-ß. It also enhanced survival of nude mice bearing xenograft tumors, blocked tumor growth, and suppressed M2 polarization of macrophages in vivo. FOSL2, highly expressed in GBM, bound to the ISG20 promoter to activate its transcription. FOSL2 silencing similarly blocked M2 polarization of macrophages, which was negated by ISG20 overexpression. The high FOSL2 expression in GBM was attributed to DNA hypomethylation. CONCLUSION: This study demonstrates that FOSL2 is highly expressed in GBM due to DNA hypomethylation. It activates transcription of ISG20, thus promoting M2 polarization of macrophages and GBM development.

Decreased levels of hydrogen sulfide in the hypothalamic paraventricular nucleus contribute to sympathetic hyperactivity induced by cerebral infarction.

Paroxysmal sympathetic hyperactivity (PSH) is a common clinical feature secondary to ischemic stroke (IS), but its mechanism is poorly understood. We aimed to investigate the role of H2S in the pathogenesis of PSH. IS patients were divided into malignant (MCI) and non-malignant cerebral infarction (NMCI) group. IS in rats was induced by the right middle cerebral artery occlusion (MCAO). H2S donor (NaHS) or inhibitor (aminooxy-acetic acid, AOAA) were microinjected into the hypothalamic paraventricular nucleus (PVN). Compared with the NMCI group, patients in the MCI group showed PSH, including tachycardia, hypertension, and more plasma norepinephrine (NE) that was positively correlated with levels of creatine kinase, glutamate transaminase, and creatinine respectively. The 1-year survival rate of patients with high plasma NE levels was lower. The hypothalamus of rats with MCAO showed increased activity, especially in the PVN region. The levels of H2S in PVN of the rats with MCAO were reduced, while the blood pressure and renal sympathetic discharge were increased, which could be ameliorated by NaHS and exacerbated by AOAA. NaHS completely reduced the disulfide bond of NMDAR1 in PC12 cells. The inhibition of NMDAR by MK-801 microinjected in PVN of rats with MCAO also could lower blood pressure and renal sympathetic discharge. In conclusion, PSH may be associated with disease progression and survival in patients with IS. Decreased levels of H2S in PVN were involved in regulating sympathetic efferent activity after cerebral infarction. Our results might provide a new strategy and target for the prevention and treatment of PSH.

Plasma Cytokine Expression and Immune Reconstitution in Early and Delayed Anti-HIV 96-Weeks Treatment: A Retrospective Study.

HIV is an immunodeficiency disease with emergence of inadequate corresponding reconstruction therapies. Pyroptosis of CD4+T cell is mainly caused by immune activation and inflammation that cannot be reduced by successful antiretroviral therapy (ART) alone. Coinfections because of CD4+T cell reconstitution failure can occur. Anti-inflammatory treatment determines the success of immune reconstitution. In our experiment, only a few cytokines could recover to normal level following a 2-year antiretroviral treatment in early ART initiation, which is consistent with current findings about adjuvant HIV anti-inflammatory therapy. Early infection is often accompanied by a more severe inflammatory response. Innate immunity cytokines like granulocyte macrophage-colony stimulating factor, IFN-γ induced protein 10 kDa, and tumor necrosis factor-α exhibited the most elevated levels among all kinds of inflammatory cytokines. The correlation analysis showed at least eight cytokines contributing to the changes of CD4/CD8 ratio.

A novel tumor immunotherapy-related signature for risk stratification, prognosis prediction, and immune status in hepatocellular carcinoma.

Immunotherapy as a strategy to deal with cancer is increasingly being used clinically, especially in hepatocellular carcinoma (HCC). We aim to create an immunotherapy-related signature that can play a role in predicting HCC patients' survival and therapeutic outcomes. Immunotherapy-related genes were discovered first. Clinical information and gene expression data were extracted from GSE140901. By a series of bioinformatics methods to analyze, overlapping genes were used to build an immunotherapy-related signature that could contribute to predict both the prognosis of people with hepatocellular carcinoma and responder to immune checkpoint blockade therapy of them in TCGA database. Differences of the two groups in immune cell subpopulations were then compared. Furthermore, A nomogram was constructed, based on the immunotherapy-related signature and clinicopathological features, and proved to be highly predictive. Finally, immunohistochemistry assays were performed in HCC tissue and normal tissue adjacent tumors to verify the differences of the four genes expression. As a result of this study, a prognostic protein profile associated with immunotherapy had been created, which could be applied to predict patients' response to immunotherapy and may provide a new perspective as clinicians focus on non-apoptotic treatment for patients with HCC.

Association between CD10 expression and phyllodes tumor: A retrospective case control study.

The present study aimed to explore the association between immunohistochemical markers and phyllodes tumor (PT). The retrospective case control study included biopsies from patients with PT who underwent surgical treatment, and patients with fibronenoma (FA), diagnosed in our hospital from October 2014 to May 2021. Differences in microscopic histopathological characteristics and expressions of common immunohistochemical markers (CD10, cluster of differentiation 117 marker, cluster of differentiation 34 marker, tumor protein P53, cell proliferation antigen) for different grades of PT and FA were analyzed. A total of 69 patients were enrolled, of them 34 with PT (12 with benign PT, 13 with borderline PT, and 9 with malignant PT) and 35 with FA. With the increase of tumor malignancy, significant enlargement trend was noted; for FA, most tumor boundaries were well-defined, the stromal distribution was homogeneous, the stromal cellularity was small. In contrast for PT, as the degree of malignancy increased, tumor boundary gradually became ill-defined and the stromal distribution was heterogeneous; stromal cellularity and stromal overgrowth had increased significantly (All P < .05). Multivariate analysis showed that among other markers only CD10 expression (OR = 0.67, 95%CI: -0.88, 2.22, P < .05) was independently associated with PT. The study showed that in addition to histological features, CD10 expression was independently associated with PT and has a potential to be used as a differentiation marker.

Dynamic Changes of Cytokine Profiles and Their Correlation With Tumor Recurrence Following Thermal Ablation in Hepatocellular Carcinoma.

The 5-year recurrence rate of thermal ablation for hepatocellular carcinoma (HCC) is high, and whether this treatment strategy induces systemic immune response remains elusive. This study aimed to investigate the effects of thermal ablation on HCC patients' cytokine profiles and to explore the correlation of cytokine profiles with tumor recurrence after ablation. A total of 22 HCC patients were included in this prospective study. The levels of 27 cytokines in the peripheral blood of HCC patients were measured before ablation (baseline), week 1, and week 4 after ablation using a Bio-Plex Pro Human Cytokine 27-plex Assay kit. Cytokines showed different dynamic changing trends after ablation treatment. It was found that the level of IL-6 was significantly elevated at week 1 and returned to the baseline level at week 4 after ablation. The level of IL-10 was slightly reduced at week 1 and significantly decreased at week 4. The levels of MCP-1, macrophage inflammatory protein-1ß (MIP-1ß), and TNF-α were similarly reduced at week 1 and increased at week 4. The levels of IL-17, platelet-derived growth factor-BB (PDGF-BB), and regulated upon activation, normal T cell expressed and secreted (RANTES) showed little to no change at week 1 while an observable increase at week 4. Patients with a high IL-10 level (2.99 pg/ml) at baseline and low levels of TNF-α (20.4 pg/ml), PDGF-BB (107.78 pg/ml), and RANTES (2303.94 pg/ml) at week 4 were at risk of tumor recurrence during 1-year follow-up. The results suggested that thermal ablation activated systemic immune responses by changing the levels of cytokines. The results also demonstrated that measurement of IL-10 at baseline, TNF-α, PDGF-BB, and RANTES at week 4 after ablation might predict the risk of tumor recurrence.

Multiplexed Photonic Crystal Fiber Gas-Sensing Network Based on Intracavity Absorption.

A highly sensitive hollow-core photonic crystal fiber (HC-PCF) gas-sensing network based on intracavity absorption is designed and experimentally verified. The capacity of the multichannel sensing network is expanded by time division multiplexing and wavelength division multiplexing technology. The voltage gradient method is employed in the wavelength scanning process of Fabry-Perot (F-P) filter to enhance the detection efficiency up to six times. The proposed sensing network has 16 sensing points. Experimental results show that the minimum detection limit (MDL) of this sensing system is 25.91 ppm and 26.85 ppm at the acetylene gas absorption peaks of 1530.371 nm and 1531.588 nm, respectively. As far as we know, it is the first time to obtain an intracavity sensing network via the application of an optical switch and DWDM at the same time. The sensing network can be used for high-capacity, low-concentration dangerous gas detection. It has great potential in environmental monitoring, industrial manufacturing, safety inspection and similar occasions.

Sodium Alginate Prevents Non-Alcoholic Fatty Liver Disease by Modulating the Gut-Liver Axis in High-Fat Diet-Fed Rats.

Previous studies have suggested that the sodium alginate (SA) is beneficial for the treatment of non-alcoholic fatty liver disease (NAFLD), while the potential mechanisms are largely unknown. The present study aimed to clarify the effects and potential mechanisms of SA in preventing NAFLD via the gut−liver axis. Thirty-two male Sprague−Dawley rats were randomly divided into four groups: normal control group (NC); high-fat diet group (HFD); HFD with 50 mg/kg/d sodium alginate group (LSA); HFD with 150 mg/kg/d sodium alginate group (HSA). After 16 weeks, the rats were scarified to collect blood and tissues. The results indicated that SA significantly reduced their body weight, hepatic steatosis, serum triglyceride (TG), alanine transaminase (ALT) and tumor necrosis factor α (TNF-α) levels and increased serum high-density lipoprotein-cholesterol (HDL-C) levels in comparison with HFD group (p < 0.05). The elevated mRNA and protein expression of genes related to the toll-like receptor 4 (TLR-4)/nuclear factor-kappa B (NF-κB)/nod-like receptor protein 3 (NLRP3) inflammatory signaling pathway in the liver of HFD-fed rats was notably suppressed by SA. In terms of the gut microbiota, the LSA group showed a significantly higher fecal abundance of Oscillospiraceae_UCG_005, Butyricicoccaceae_UCG_009 and Colidextribacter compared with the HFD group (p < 0.05). The rats in the HSA group had a higher abundance of unclassified_Lachnospiraceae, Colidextribacter and Oscillibacter compared with the HFD-associated gut community (p < 0.05). In addition, rats treated with SA showed a significant increase in fecal short chain fatty acids (SCFAs) levels and a decline in serum lipopolysaccharide (LPS) levels compared with the HFD group (p < 0.05). Moreover, the modulated bacteria and microbial metabolites were notably correlated with the amelioration of NAFLD-related indices and activation of the hepatic TLR4/NF-κB/NLRP3 pathway. In conclusion, SA prevented NAFLD and the potential mechanism was related to the modulation of the gut−liver axis.

Endoplasmic Reticulum Stress-Related Signature for Predicting Prognosis and Immune Features in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) with cancer cells under endoplasmic reticulum (ER) stress has a poor prognosis. This study is aimed at discovering credible biomarkers for predicting the prognosis of HCC based on ER stress-related genes (ERSRGs). We constructed a novel four-ERSRG prognostic risk model, including PON1, AGR2, SSR2, and TMCC1, through a series of bioinformatic approaches, which can accurately predict survival outcomes in HCC patients. Higher risk scores were linked to later grade, recurrence, advanced TNM stage, later T stage, and HBV infection. In addition, 20 fresh frozen tumors and normal tissues from HCC patients were collected and used to validate the genes expressed in the signature by qRT-PCR and immunohistochemical (IHC) assays. Moreover, we found the ER stress-related signature could reflect the infiltration levels of different immune cells in the tumor microenvironment (TME) and forecast the efficacy of immune checkpoint inhibitor (ICI) treatment. Finally, we created a nomogram incorporating this ER stress-related signature. In conclusion, our constructed four-gene risk model associated with ER stress can accurately predict survival outcomes in HCC patients, and the model's risk score is associated with the poor clinical classification.

A novel Cuproptosis-related LncRNA signature to predict prognosis in hepatocellular carcinoma.

Increased intracellular toxicity due to an imbalance in copper homeostasis caused by copper ion accumulation could regulate the rate of cancer cell growth and proliferation. The goal of this study was to create a novel Cuproptosis-related lncRNA signature that may be utilized to predict survival and immunotherapy in HCC patients. Cuproptosis-associated lncRNAs and differentially expressed lncRNAs between HCC tumor tissue and normal tissue were discovered first. By LASSO-Cox analysis, the overlapping lncRNAs were then utilized to build a Cuproptosis-associated lncRNA signature, which might be used to predict patient prognosis and responsiveness to immune checkpoint blockade (ICB) therapy. Differences in the infiltration of immune cell subpopulations between high and low-risk score subgroups were also analyzed. Moreover, a nomogram based on the Cuproptosis-associated lncRNA signature and clinical features was developed and demonstrated to have good predictive potential. Finally, qRT-PCR was performed in HerpG2 and MHCC-97H cell lines to explore whether these lncRNAs were indeed involved in the process of Cuproptosis. In summary, we created a prognostic lncRNA profile linked to Cuproptosis to forecast response to immunotherapy, which may provide a new potential non-apoptotic therapeutic perspective for HCC patients.

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Carbon dioxide (CO2), nitrous oxide (N2O), methane (CH4) and ammonia (NH3) emitted during the composting of livestock and poultry waste are important gaseous atmospheric pollutants. However, most previous studies on compost-related anthropogenic emissions of these gases were based on small reactor composting. Our understanding of their in situ emissions during industrial composting remains extremely limited. In order to explore the influence of gas produced by industrial composting on regional environment, we monitored CO2, CH4, N2O and NH3 emissions during industrial composting for 19 days and characterized the isotopic composition of emitted NH3. On average, the emission rates of CO2, CH4, N2O, and NH3 during the composting cycle were 86.8 g CO2-C·d-1·m-2, 9.8 g CH4-C·d-1·m-2, 3.7 mg N2O-N·d-1·m-2 and 736.6 mg NH3-N·d-1·m-2, respectively. The contribution of CH4 to daily global warming potential (GWP) was the highest (65%), followed by CO2, NH3(indirect), and N2O. Moreover, ammonia emitted from industrial compost had a mean δ15N value of -11.6‰±1.2‰ (range: -21.8‰--7.2‰). Overall, this study provided useful information for understanding greenhouse gas emission dynamics and characterizing atmospheric NH3 sources during composting process in livestock and poultry breeding areas.

Variations in dynamic tumor-associated antigen-specific T cell responses correlate with HCC recurrence after thermal ablation.

Background: Ablative therapy is a recommended treatment for hepatocellular carcinoma (HCC) not only for its effective eradication of tumors, but also for its induction of host immunity. However, the high 5-year recurrence rate after ablation underlines the poor understanding of the antitumor immunity response. Here, we investigated the effects of thermal ablation on antitumor immunity. Methods: We analyzed the dynamics of tumor-associated antigen (TAA)-specific immune responses and changes in peripheral blood mononuclear cell phenotype in patients with HCC before and after tumor ablation. We used the IFN-γ ELISPOT assay and immunophenotyping by flow cytometry to evaluate the effects of ablation on host immunity. The correlation between the T cell response and disease outcome was explored to uncover the efficacy of the immune response in inhibiting HCC recurrence. Results: Different TAA-specific T cell responses were identified among patients before and after ablation. One week after ablation, there was an improved immune state, with a switch from the dominance of an AFP-specific T cell response to that of a SMNMS-specific T cell response, which was correlated with better survival. Furthermore, an improvement in immune status was accompanied by a lower level of PD1+ and Tim3+ T cells in CD8+ T cells. Although this functional state was not durable, there was a higher degree of AFP-specific T cell responses at 4-weeks post-ablation. Furthermore, T cells presented a more exhausted phenotype at 4-weeks post-ablation than at the 1-week timepoint. Conclusions: Ablation elicits a transient antitumor immune response in patients with HCC by changing the profile of the T cell response and the expression of immune checkpoint molecules, which correlated with longer recurrence-free survival of patients with HCC.

A CpG Methylation Signature as a Potential Marker for Early Diagnosis of Hepatocellular Carcinoma From HBV-Related Liver Disease Using Multiplex Bisulfite Sequencing.

BACKGROUND: Aberrant methylation of CpG sites served as an epigenetic marker for building diagnostic, prognostic, and recurrence models for hepatocellular carcinoma (HCC). METHODS: Using Illumina 450K and EPIC Beadchip, we identified 34 CpG sites in peripheral blood mononuclear cell (PBMC) DNA that were differentially methylated in early HCC versus HBV-related liver diseases (HBVLD). We employed multiplex bisulfite sequencing (MBS) based on next-generation sequencing (NGS) to measure methylation of 34 CpG sites in PBMC DNA from 654 patients that were divided into a training set (n = 442) and a test set (n = 212). Using the training set, we selected and built a six-CpG-scorer (namely, cg14171514, cg07721852, cg05166871, cg18087306, cg05213896, and cg18772205), applying least absolute shrinkage and selection operator (LASSO) regression. We performed multivariable analyses of four candidate risk predictors (namely, six-CpG-scorer, age, sex, and AFP level), using 20 times imputation of missing data, non-linearly transformed, and backwards feature selection with logistic regression. The final model's regression coefficients were calculated according to "Rubin's Rules". The diagnostic accuracy of the model was internally validated with a 10,000 bootstrap validation dataset and then applied to the test set for validation. RESULTS: The area under the receiver operating characteristic curve (AUROC) of the model was 0.81 (95% CI, 0.77-0.85) and it showed good calibration and decision curve analysis. Using enhanced bootstrap validation, adjusted C-statistics and adjusted Brier score were 0.809 and 0.199, respectively. The model also showed an AUROC value of 0.84 (95% CI 0.79-0.88) of diagnosis for early HCC in the test set. CONCLUSIONS: Our model based on the six-CpG-scorer was a reliable diagnosis tool for early HCC from HBVLD. The usage of the MBS method can realize large-scale detection of CpG sites in clinical diagnosis of early HCC and benefit the majority of patients.

Distinct tumour antigen-specific T-cell immune response profiles at different hepatocellular carcinoma stages.

BACKGROUND: Cancer-testis antigens (CTAs) and tumour-associated antigens (TAAs) are frequently expressed in hepatocellular carcinoma (HCC); however, the role of tumour-antigen-specific T cell immunity in HCC progression is poorly defined. We characterized CTA- and TAA-specific T cell responses in different HCC stages and investigated their alterations during HCC progression. METHODS: Fifty-eight HCC patients, 15 liver cirrhosis patients, 15 chronic hepatitis B patients and 10 heathy controls were enrolled in total. IFN-γ ELSPOT using CTAs, including MAGE-A1, MAGE-A3, NY-ESO-1, and SSX2, and two TAAs, SALL4 and AFP, was performed to characterize the T-cell immune response in the enrolled individuals. The functional phenotype of T cells and the responsive T cell populations were analyzed using short-term T-cell culture. RESULTS: T cell responses against CTAs and TAAs were specific to HCC. In early-stage HCC patients, the SALL4-specific response was the strongest, followed by MAGE-A3, NY-ESO-1, MAGE-A1 and SSX2. One-year recurrence-free survival after transcatheter arterial chemoembolization plus radiofrequency ablation treatment suggested the protective role of CTA-specific responses. The four CTA- and SALL4-specific T cell responses decreased with the progression of HCC, while the AFP-specific T cell response increased. A higher proportion of CD4+ T cells specific to CTA/SALL4 was observed than AFP-specific T cell responses. CONCLUSIONS: The IFN-γ ELISPOT assay characterized distinct profiles of tumour-antigen-specific T cell responses in HCC patients. CTA- and SALL4-specific T cell responses may be important for controlling HCC in the early stage, whereas AFP-specific T cell responses might be a signature of malignant tumour status in the advanced stage. The application of immunotherapy at an early stage of HCC development should be considered.

GATA3 functions downstream of BRCA1 to suppress EMT in breast cancer.

Purpose: Functional loss of BRCA1 is associated with poorly differentiated and metastatic breast cancers that are enriched with cancer stem cells (CSCs). CSCs can be generated from carcinoma cells through an epithelial-mesenchymal transition (EMT) program. We and others have previously demonstrated that BRCA1 suppresses EMT and regulates the expression of multiple EMT-related transcription factors. However, the downstream mediators of BRCA1 function in EMT suppression remain elusive. Methods: Depletion of BRCA1 or GATA3 activates p18INK4C , a cell cycle inhibitor which inhibits mammary epithelial cell proliferation. We have therefore created genetically engineered mice with Brca1 or Gata3 loss in addition to deletion of p18INK4C , to rescue proliferative defects caused by deficiency of Brca1 or Gata3. By using these mutant mice along with human BRCA1 deficient as well as proficient breast cancer tissues and cells, we investigated and compared the role of Brca1 and Gata3 loss in the activation of EMT in breast cancers. Results: We discovered that BRCA1 and GATA3 expressions were positively correlated in human breast cancer. Depletion of BRCA1 stimulated methylation of GATA3 promoter thereby repressing GATA3 transcription. We developed Brca1 and Gata3 deficient mouse system. We found that Gata3 deficiency in mice induced poorly-differentiated mammary tumors with the activation of EMT and promoted tumor initiating and metastatic potential. Gata3 deficient mammary tumors phenocopied Brca1 deficient tumors in the induction of EMT under the same genetic background. Reconstitution of Gata3 in Brca1-deficient tumor cells activated mesenchymal-epithelial transition, suppressing tumor initiation and metastasis. Conclusions: Our finding, for the first time, demonstrates that GATA3 functions downstream of BRCA1 to suppress EMT in controlling mammary tumorigenesis and metastasis.

Health Conditions, Lifestyle Factors and Depression in Adults in Qingdao, China: A Cross-Sectional Study.

Background: Depression is a common mental illness. Previous studies suggested that health conditions and lifestyle factors were associated with depression. However, only few studies have explored the risk factors of depression in a large representative sample of the general population in the world. Methods: A population-based cross-sectional survey was conducted in the 2006 survey and 2009 survey in Qingdao, China. The participants with insufficient information were excluded: Zung score, body mass index (BMI), diabetes items, physical activity, smoking, or drinking. Finally, a total of 3,300 participants were included in this analysis. The category of depression was used in the Zung self-rating depression scale (ZSDS). The associations between different indicators of health conditions (diabetic status, BMI), lifestyle factors (physical activity, smoking, and alcohol consumption), and depression were assessed by the logistic regression model. Results: The mean Zung scores for all participants, male participants, and female participants were 29.73 ± 7.57, 28.89 ± 7.30, 30.30 ± 7.70, respectively. In all participants, those who were pre-diabetes status (OR: 1.53, 95% CI: 1.04-2.27), and irregular physical activity (OR: 0.39, 95% CI: 0.17-0.89) had an increased risk of depression. In man, the analysis showed an increased risk of depression those with pre-diabetes (OR: 2.49, 95% CI: 1.25-4.97), previously diagnosed diabetes (OR: 4.44, 95% CI: 1.58, 12.48), and in those irregular activities (OR: 0.07, 95% CI: 0.01-0.61). In women, those who were underweight (OR: 5.66, 95% CI: 1.04-30.71) had a greater risk of depression. Conclusions: These results suggested that health conditions and lifestyle factors were the potential risk factors for depression. Men with pre-diabetes, previously diagnosed diabetes, and irregular activity had an increased risk for depression; women with underweight status had a higher risk for depression.

Interferon-Induced Transmembrane Protein 3 Expression Upregulation Is Involved in Progression of Hepatocellular Carcinoma.

PURPOSE: Interferon-induced transmembrane protein 3 (IFITM3) is a key signaling molecule regulating cell growth in some tumors, but its function and mechanism in hepatocellular carcinoma (HCC) remain unknown. Our study investigated the relationship between the expression of IFITM3 and HCC development. Material and Methods. IFITM3 expression was identified via multiple gene expression databases and investigated in HCC tissue samples. Then, PLC/PRF/5 cells were transfected with lentivirus to knock down and overexpress the expression of IFITM3. IFITM3 expression, cell proliferation, and migration were detected by qRT-PCR, western blotting, QuantiGene Plex 2.0 assay, immunohistochemistry, CCK-8, and wound healing tests. RNA-seq technology identified the PI3K/AKT/mTOR pathway as an IFITM3-related signaling pathway for investigation. RESULTS: IFITM3 expression was higher in HCC tissues than in adjacent normal tissues, and the level of IFITM3 was higher in HCC tissues with low differentiation and metastatic potential than in those with high/medium differentiation and without metastatic potential. A higher RNA level of IFITM3 was found in samples with IFITM3 rs12252-CC genotype rather than the TT genotype. Knockdown of IFITM3 in PLC/PRF/5 cells inhibited cell proliferation and migration, blocked the expression of the PI3K/AKT/mTOR signaling pathway, and decreased the expression of vimentin. The results were opposite with the overexpression of IFITM3. CONCLUSION: Upregulation of IFITM3 plays a role in the development of HCC. Possibly through regulating HCC cell proliferation and migration, these effects are associated with the PI3K/AKT/mTOR signaling pathway. Upregulation of IFITM3 is also associated with the IFITM3 rs12252-CC genotype.

Neuroprotective effect of hydrogen sulfide against glutamate-induced oxidative stress is mediated via the p53/glutaminase 2 pathway after traumatic brain injury.

Several reports suggest that hydrogen sulfide (H2S) exerts multiple biological and physiological effects on the pathogenesis of traumatic brain injury (TBI). However, the exact molecular mechanism involved in this effect is not yet fully known. In this study, we found that H2S alleviated TBI-induced motor and spatial memory deficits, brain pathology, and brain edema. Moreover, sodium hydrosulfide (NaHS), an H2S donor, treatment markedly increased the expression of Bcl-2, while inhibited the expression of Bax and Cleaved caspase-3 in TBI-challenged rats. Tunnel staining also demonstrated these results. Treatment with NaHS significantly reduced the glutamate and glutaminase 2 (GLS-2) protein levels, and glutamate-mediated oxidative stress in TBI-challenged rats. Furthermore, we demonstrated that H2S treatment inhibited glutamate-mediated oxidative stress through the p53/GLS-2 pathway. Therefore, our results suggested that H2S protects brain injury induced by TBI through modulation of the glutamate-mediated oxidative stress in the p53/GLS-2 pathway-dependent manner.

Overexpression of lncRNA CASC2 inhibits the tumorigenesis of thyroid cancer via sponging miR-24-3p.

BACKGROUND: The incidence of thyroid cancer continues to rise all over the world. Thus, it is urgent to find a novel strategy for the treatment of thyroid cancer. Previous reports have confirmed that lncRNA CASC2 is involved in the pathogenesis of thyroid cancer. However, the mechanism by which CASC2 mediates the tumorigenesis of thyroid cancer remains unclear. METHODS: Gene and protein expressions in tissues or cells were detected by q-PCR and Western blot, respectively. Cell proliferation was tested by MTT assay. Flow cytometry was used to test cell apoptosis. Cell migration and invasion in thyroid cancer cells was detected by transwell assay. In addition, the correlation between CASC2 and miR-24-3p were investigated by Targetscan and dual-luciferase reporter assay. Finally, xenograft mice model was established to detect the effect of CASC2 on thyroid cancer in vivo. RESULTS: CASC2 was significantly downregulated in thyroid cancer. Overexpression of CASC2 inhibited the proliferation, migration, and invasion of thyroid cancer cells. In addition, upregulation of CASC2 could inhibit the tumorigenesis of TC via sponging miR-24-3p. Furthermore, overexpression of CASC2 significantly suppressed the growth of thyroid cancer in vivo. CONCLUSION: Overexpression of CCASC2 inhibits the tumorigenesis of thyroid cancer in vitro and in vivo. Thus, CASC2 may serve as a novel target for the treatment of thyroid cancer.

Genomic DNA methylation profiling indicates immune response following thermal ablation treatment for HBV-associated hepatocellular carcinoma.

Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) is the most common type of liver cancer in China. Thermal ablation is one of the main strategies for HCC treatment. However, few studies have investigated the properties of the immune response following thermal ablation thus far. In the present study, five subjects with HBV-associated HCC were recruited from The Beijing Youan Hospital. Peripheral blood mononuclear cells (PBMCs) were collected at three time points: Prior to thermal ablation (PR), 1-3 days post-ablation (P1) and 5-7 days post-ablation (P7). An Illumina 850K methylation microarray was employed to determine the DNA methylation profile of each sample. Data were analyzed using different methylation probes with the Bioconductor package in R. Following annotation of different methylation CG sites (CGs), the associated genes were subjected to an Ingenuity Pathway Analysis. A total of 3,000 significantly different CGs (adjusted P<0.05; |log(fold-change)|>0.5) were identified within the PR, P1 and P7 time points. Of these, 744 (24.8%) sites increased between the PR and P1 time points but gradually decreased at the P7 time point. The remaining 2,256 (75.2%) sites decreased between the PR and P1 time points gradually increased at the P7 time point. Following gene annotation of different CGs on the promoter, signaling pathways analysis demonstrated that 'p70S6K signaling', 'CXCR4 signaling', 'dendritic cell maturation', 'production of nitric oxide and reactive oxygen species in macrophages' pathways were activated at the P7 time point. The present study suggested that PBMC DNA methylation had changed soon after thermal ablation for subjects with HBV-associated HCC, and systemic immune responses were activated, particularly at the P7 time point.