Coixendide efficacy in combination with temozolomide in glioblastoma and transcriptome analysis of the mechanism.

The purpose of this study was to explore the role of coixendide (Coix) combine with temozolomide (TMZ) in the treatment of Glioblastoma (GBM) and explore its possible mechanism. CCK-8 was used to determine the inhibitory rate of Coix group, TMZ group and drug combination group on GBM cells, and the combination index (CI) was calculated to determine whether they had synergistic effect. Then RNA was extracted from each group, transcriptome sequencing was performed, and differentially expressed genes (DEGs) were identified. The possible mechanism was analyzed by GO enrichment analysis and KEGG enrichment analysis. The CI of Coix and TMZ indicating a synergistic effect when TMZ concentration is 0.1 mg/ml and Coix concentration is 2 mg/ml. Transcriptome sequencing analysis showed that interferon (IFN) related genes were down-regulated by Coix and up-regulated by TMZ and combined drugs, however, the up-regulation induced by combined drugs was less than that of TMZ. Besides IFN related genes, cholesterol metabolism pathway were also been regulated. Coix and TMZ have synergistic effects in the treatment of GBM at certain doses. RNA-Seq results suggested that the abnormal on genetic materials caused by DNA damage induced by TMZ treatment can be sensed by IFN related genes and activates antiviral IFN signaling, causing the activation of repairing mechanism and drug resistance. Coix inhibits IFN related genes, thereby inhibits drug resistance of TMZ. In addition, the activation of ferroptosis and the regulation of DEGs in cholesterol metabolism pathway were also contributed to the synergistic effects of Coix and TMZ.

Dissecting the Immunological Profiles in NSD3-Amplified LUSC through Integrative Multi-Scale Analyses.

The histone H3 lysine 36 (H3K36) methyltransferase NSD3, a neighboring gene of FGFR1, has been identified as a critical genetic driver of lung squamous cell carcinoma (LUSC). However, the molecular characteristics, especially the immunological roles of NSD3 in driving carcinogenesis, are poorly understood. In this study, we systematically integrated multi-omics data (e.g., genome, transcriptome, proteome, and TMA array) to dissect the immunological profiles in NSD3-amplified LUSC. Next, pharmaco-transcriptomic correlation analysis was implemented to identify the molecular underpinnings and therapeutic vulnerabilities in LUSC. We revealed that NSD3-amplified LUSC presents a non-inflamed tumor immune microenvironment (TIME) state in multiple independent LUSC patient cohorts. Predictably, elevated NSD3 expression was correlated with a worse immunotherapy outcome. Further molecular characterizations revealed that the high activity of unfolded protein response (UPR) signaling might be a pivotal mediator for the non-immunogenic phenotype of NSD3-amplified LUSC. Concordantly, we showed that NSD3-amplified LUSCs exhibited a more sensitive phenotype to compounds targeting UPR branches than the wild-type group. In brief, our multi-level analyses point to a previously unappreciated immunological role for NSD3 and provide therapeutic rationales for NSD3-amplified squamous lung cancer.

Hepatic blood flow regulation but not oxygen extraction capability is impaired in prolonged experimental abdominal sepsis.

Impaired oxygen utilization has been proposed to play a significant role in sepsis-induced liver dysfunction, but its magnitude and temporal course during prolonged resuscitation is controversial. The aim of this study is to evaluate the capability of the liver to increase oxygen extraction in sepsis during repeated acute portal vein blood flow reduction. Twenty anesthetized and mechanically ventilated pigs with hepatic hemodynamic monitoring were randomized to fecal peritonitis or controls (n = 10, each). After 8-h untreated sepsis, the animals were resuscitated for three days. The ability to increase hepatic O2 extraction was evaluated by repeated, acute decreases in hepatic oxygen delivery (Do2) via reduction of portal flow. Blood samples for liver function and liver biopsies were obtained repeatedly. Although liver function tests, ATP content, and Do2 remained unaltered, there were signs of liver injury in blood samples and overt liver cell necrosis in biopsies. With acute portal vein occlusion, hepatic Do2 decreased more in septic animals compared with controls [max. decrease: 1.66 ± 0.68 mL/min/kg in sepsis vs. 1.19 ± 0.42 mL/min/kg in controls; portal venous flow (Qpv) reduction-sepsis interaction: P = 0.028]. Hepatic arterial buffer response (HABR) was impaired but recovered after 3-day resuscitation, whereas hepatic oxygen extraction increased similarly during the procedures in both groups (max. increase: 0.27 ± 0.13 in sepsis vs. 0.18 ± 0.09 in controls; all P > 0.05). Our data indicate maintained capacity of the liver to acutely increase O2 extraction, whereas blood flow regulation is transiently impaired with the potential to contribute to liver injury in sepsis.NEW & NOTEWORTHY The capacity to acutely increase hepatic O2 extraction with portal flow reduction is maintained in sepsis with accompanying liver injury, but hepatic blood flow regulation is impaired.

Cisplatin-resistant A549 non-small cell lung cancer cells can be identified by increased mitochondrial mass and are sensitive to pemetrexed treatment.

BACKGROUND: Cisplatin plus pemetrexed combination therapy is considered the standard treatment for patients with advanced, non-squamous, non-small-cell lung cancer (NSCLC). However, advanced NSCLC has a 5-year survival rate of below 10%, which is mainly due to therapy resistance. We previously showed that the NSCLC cell line A549 harbors different subpopulations including a mesenchymal-like subpopulation characterized by increased chemo- and radiotherapy resistance. Recently, therapy resistance in hematological and solid tumors has been associated with increased mitochondrial activity. Thus, the aim of this study was to investigate the role of the mitochondrial activity in NSCLC chemotherapy resistance. METHODS: Based on MitoTracker staining, subpopulations characterized by the highest 10% (Mito-High) or lowest 10% (Mito-Low) mitochondrial mass content were sorted by FACS (Fluorescence-Activated Cell Sorting) from paraclonal cultures of the NSCLC A549 cell line . Mitochondrial DNA copy numbers were quantified by real-time PCR whereas basal cellular respiration was measured by high-resolution respirometry. Cisplatin and pemetrexed response were quantified by proliferation and colony formation assay. RESULTS: Pemetrexed treatment of parental A549 cells increased mitochondrial mass over time. FACS-sorted paraclonal Mito-High cells featured increased mitochondrial mass and mitochondrial DNA copy number compared to the Mito-Low cells. Paraclonal Mito-High cells featured an increased proliferation rate and were significantly more resistant to cisplatin treatment than Mito-Low cells. Interestingly, cisplatin-resistant, paraclonal Mito-High cells were significantly more sensitive to pemetrexed treatment than Mito-Low cells. We provide a working model explaining the molecular mechanism underlying the increased cisplatin- and decreased pemetrexed resistance of a distinct subpopulation characterized by high mitochondrial mass. CONCLUSIONS: This study revealed that cisplatin resistant A549 lung cancer cells can be identified by their increased levels of mitochondrial mass. However, Mito-High cells feature an increased sensitivity to pemetrexed treatment. Thus, pemetrexed and cisplatin target reciprocal lung cancer subpopulations, which could explain the increased efficacy of the combination therapy in the clinical setting.

Overexpression of ecotropic viral integration site-1 is a prognostic factor of lung squamous cell cancer.

AIM: To explore the expression and clinical significance of ecotropic viral integration site-1 (EVI1) of lung squamous cell cancer (SCC). METHODS: The expression of EVI1 in SCC was detected by immunohistochemistry and the validation cohort was divided into EVI1 high-expression group and low-expression group according to the cutoff of immunohistochemical score. The correlations between EVI1 expression and the clinicopathological factors were analyzed by χ2 test. The relation between EVI1 expression and overall survival rate was evaluated by univariate analysis with Kaplan-Meier method. The independent prognostic factor was identified by multivariate analysis with Cox regression model. RESULTS: In this study, the EVI1 high-expression percentage was 32.32% (53/164). EVI1 high expression was significantly associated with a poorer overall 5-year survival rate of SCC (P=0.021). Moreover, EVI1 high expression was identified as an independent prognostic factor of SCC, predicting the unfavorable prognosis (P=0.013). CONCLUSION: High expression of EVI1 was significantly associated with a poorer prognosis and it was identified as an independent prognostic factor of SCC.

Soluble Glycoprotein 130 and Heat Shock Protein 27 as Novel Candidate Biomarkers of Chronic Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Despite their importance, the current clinical biomarkers of chronic heart failure have limitations. In this study, soluble glycoprotein 130 (sgp130), heat shock protein 27 (hsp27), dipeptidyl peptidase IV (dpp4) and cathepsin S (CTSS) were tested for their potential as novel biomarkers for diagnosing chronic heart failure (CHF) with preserved ejection fraction. METHODS: We compared the circulating levels of sgp130, hsp27, dpp4, and cathepsin S in patients with CHF with preserved ejection fraction (n=50) and in controls (n=50), determined how well these candidate biomarkers distinguish patients with CHF from controls, and assessed whether these candidates are superior to N-terminal pro brain natriuretic peptide (NT-pro-BNP) as diagnostic tools. RESULTS: After adjusting for clinical covariates, patients with CHF showed significantly higher mean concentrations of sgp130 (317.38pg/ml vs. 215.90 pg/ml), hsp27 (2601.02 pg/ml vs. 923.61 pg/ml) and NT-pro-BNP (982.35 pg/ml vs. 331.99 pg/ml), but not dpp4 (6930.9 4pg/ml vs. 7081.37 pg/ml) or CTSS (1050.46 pg/ml vs. 984.96 pg/ml), than did controls. In the receiver operating characteristic curve analysis, hsp27 showed the most notable difference between CHF patients and controls, with the largest area under the curve (AUC) (0.920); the AUC values for sgp130 and NT-pro-BNP were 0.877 and 0.882, respectively. CONCLUSIONS: Soluble glycoprotein 130 and hsp27 are novel candidate biomarkers for diagnosing CHF with preserved ejection fraction and thus warrant further investigation; neither dpp4 nor CTSS showed promise as biomarkers of CHF.