Ganoderic acid A mitigates dopaminergic neuron ferroptosis via inhibiting NCOA4-mediated ferritinophagy in Parkinson's disease mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum, a renowned tonic traditional Chinese medicine, is widely recognized for the exceptional activity in soothing nerves and nourishing the brain. It has been extensively employed to alleviate various neurological disorders, notably Parkinson's disease (PD). AIM OF THE STUDY: To appraise the antiparkinsonian effect of GAA, the main bioactive constituent of G. lucidum, and clarify the molecular mechanism through the perspective of ferritinophagy-mediated dopaminergic neuron ferroptosis. MATERIALS AND METHODS: PD mouse and cell models were established using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+), respectively. Cell viability, behavioral tests and immunofluorescence analysis were performed to evaluate the neurotoxicity, motor dysfunction and dopaminergic loss, respectively. Biochemical assay kits were used to determine the levels of iron, lipid reactive oxygen species (ROS), malondialdehyde (MDA), total ROS and glutathione (GSH). Western blot and immunofluorescence were applied to detect the expressions of nuclear receptor co-activator 4 (NCOA4), ferritin heavy chain 1 (FTH1), p62 and LC3B. Additionally, NCOA4-overexpressing plasmid vector was constructed to verify the inhibitory effect of GAA on the neurotoxicity and ferroptosis-related parameters in PD models. RESULTS: GAA significantly mitigated MPP+/MPTP-induced neurotoxicity, motor dysfunction and dopaminergic neuron loss (p＜0.01 or p＜0.05). In contrast to MPP+/MPTP treatment, GAA treatment decreased the levels of iron, MDA, lipid and total ROS, while increasing the GSH level. GAA also reduced the levels of NCOA4 and LC3B, and enhanced the expressions of FTH1 and p62 in PD models (p＜0.01 or p＜0.05). However, the protective effect of GAA against the neurotoxicity, NCOA4-mediated ferritinophagy and ferroptosis in PD model was abolished by the overexpression of NCOA4 (p＜0.01). CONCLUSION: GAA exerted a protective effect on PD, and this effect was achieved by suppressing dopaminergic neuron ferroptosis through the inhibition of NCOA4-mediated ferritinophagy.

New roles of tumor-derived exosomes in tumor microenvironment.

Throughout tumorigenesis, the co-evolution of tumor cells and their surrounding microenvironment leads to the development of malignant phenotypes. Cellular communication within the tumor microenvironment (TME) plays a critical role in influencing various aspects of tumor progression, including invasion and metastasis. The release of exosomes, a type of extracellular vesicle, by most cell types in the body, is an essential mediator of intercellular communication. A growing body of research indicates that tumor-derived exosomes (TDEs) significantly expedite tumor progression through multiple mechanisms, inducing epithelial-mesenchymal transition and macrophage polarization, enhancing angiogenesis, and aiding in the immune evasion of tumor cells. Herein, we describe the formation and characteristics of the TME, and summarize the contents of TDEs and their diverse functions in modulating tumor development. Furthermore, we explore potential applications of TDEs in tumor diagnosis and treatment.

Butyrate as a promising therapeutic target in cancer: From pathogenesis to clinic (Review).

Cancer is one of the leading causes of mortality worldwide. The etiology of cancer has not been fully elucidated yet, and further enhancements are necessary to optimize therapeutic efficacy. Butyrate, a short­chain fatty acid, is generated through gut microbial fermentation of dietary fiber. Studies have unveiled the relevance of butyrate in malignant neoplasms, and a comprehensive understanding of its role in cancer is imperative for realizing its full potential in oncological treatment. Its full antineoplastic effects via the activation of G protein­coupled receptors and the inhibition of histone deacetylases have been also confirmed. However, the underlying mechanistic details remain unclear. The present study aimed to review the involvement of butyrate in carcinogenesis and its molecular mechanisms, with a particular emphasis on its association with the efficacy of tumor immunotherapy, as well as discussing relevant clinical studies on butyrate as a therapeutic target for neoplastic diseases to provide new insights into cancer treatment.

Immune checkpoint inhibitor-related pneumonitis: research advances in prediction and management.

The advent of immune-checkpoint inhibitors (ICIs) has revolutionized the treatment of malignant solid tumors in the last decade, producing lasting benefits in a subset of patients. However, unattended excessive immune responses may lead to immune-related adverse events (irAEs). IrAEs can manifest in different organs within the body, with pulmonary toxicity commonly referred to as immune checkpoint inhibitor-related pneumonitis (CIP). The CIP incidence remains high and is anticipated to rise further as the therapeutic indications for ICIs expand to encompass a wider range of malignancies. The diagnosis and treatment of CIP is difficult due to the large individual differences in its pathogenesis and severity, and severe CIP often leads to a poor prognosis for patients. This review summarizes the current state of clinical research on the incidence, risk factors, predictive biomarkers, diagnosis, and treatment for CIP, and we address future directions for the prevention and accurate prediction of CIP.

Gut microbiota and dietary intervention: affecting immunotherapy efficacy in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. In recent years, treatment with immune checkpoint inhibitors (ICIs) has gradually improved the survival rate of patients with NSCLC, especially those in the advanced stages. ICIs can block the tolerance pathways that are overexpressed by tumor cells and maintain the protective activity of immune system components against cancer cells. Emerging clinical evidence suggests that gut microbiota may modulate responses to ICIs treatment, possibly holding a key role in tumor immune surveillance and the efficacy of ICIs. Studies have also shown that diet can influence the abundance of gut microbiota in humans, therefore, dietary interventions and the adjustment of the gut microbiota is a novel and promising treatment strategy for adjunctive cancer therapy. This review comprehensively summarizes the effects of gut microbiota, antibiotics (ATBs), and dietary intervention on the efficacy of immunotherapy in NSCLC, with the aim of informing the development of novel strategies in NSCLC immunotherapy.

Rapid Discovery of Aß42 Fibril Disintegrators from Ganoderma lucidum via Ligand Fishing and Their Neuroprotective Effects on Alzheimer's Disease.

An amyloid-ß (Aß) fibril is a vital pathogenic factor of Alzheimer's disease (AD). Aß fibril disintegrators possess great potential to be developed into novel anti-AD agents. Here, a ligand fishing method was employed to rapidly discover Aß42 fibril disintegrators from Ganoderma lucidum using Aß42 fibril-immobilized magnetic beads, which led to the isolation of six Aß42 fibril disintegrators including ganodermanontriol, ganoderic acid DM, ganoderiol F, ganoderol B, ganodermenonol, and ergosterol. Neuroprotective evaluation in vitro exhibited that these Aß42 fibril disintegrators could significantly mitigate Aß42-induced neurotoxicity. Among these six disintegrators, ergosterol and ganoderic acid DM with stronger protecting activity were further selected to evaluate their neuroprotective effect on AD in vivo. Results showed that ergosterol and ganoderic acid DM could significantly alleviate Aß42-induced cognitive dysfunction and hippocampus neuron loss in vivo. Moreover, ergosterol and ganoderic acid DM could significantly inhibit Aß42-induced neuron apoptosis and Nrf2-mediated neuron oxidative stress in vitro and in vivo.

The multifaceted roles of common gut microbiota in immune checkpoint inhibitor-mediated colitis: From mechanism to clinical application.

With the arrival of the era of tumor immunotherapy, Immune Checkpoint Inhibitors have benefited countless tumor patients. However, the emergence of Immune-Related Adverse Events, especially Immune Checkpoint Inhibitor-Mediated Colitis (IMC), has become an important obstacle to immunotherapy. Therefore, it is very important to clarify the mechanism and influencing factors of IMC. The effect of gut microbiota on IMC is gradually becoming a research hotspot. Gut microbiota from different phyla can affect IMC by regulating innate and acquired immunity of tumor patients in various ways. In this review, we make a systematic and comprehensive introduction of the effect of gut microbiota on IMC. Through understanding the specific effects of gut microbiota on IMC, and then exploring the possibility of reducing IMC by regulating gut microbiota.

Protective Effects of Three Flavonoids from Dendrobium huoshanense Flowers on Alcohol-Induced Hepatocyte Injury via Activating Nrf2 and Inhibiting NF-κB Pathways.

Dendrobium huoshanense flowers have been widely used for liver protection in China. This work was aimed to discover the natural products with activity of mitigating alcoholic hepatocyte injury from Dendrobium huoshanense flowers via bioactivity-guided isolation, and to clarify the underlying mechanisms of these natural products. As a result, three flavonoids, 3'-O-methylquercetin-3-O-ß-D-galactopyranoside (1), 3'-O-methylquercetin-3-O-ß-D-glucopyranoside (2) and quercetin-3-O-ß-D-glucopyranoside (3), were firstly isolated from D. huoshanense flowers. Results exhibited that flavonoids 1-3 could enhance the cell viability, decrease the expression of ALT and AST, inhibit the cell apoptosis, alleviate the oxidative stress, and mitigate the inflammatory response of alcohol-induced L02 cells. Mechanism study exhibited that flavonoids 1-3 could increase the expression of Nrf2 as well as its downstream antioxidation genes of alcohol-induced L02 cells, while ML-385 (Nrf2 inhibitor) could abolish the inhibitory effects of 1-3 on alcohol-induced hepatocyte injury. Flavonoids 1-3 could also reduce the phosphorylation levels of IκBα and NF-κB p65 of alcohol-induced L02 cells, while SC75741 (NF-κB inhibitor) could not enhance the inhibitory effects of 1-3 on alcohol-induced L02 cells injury. The data above indicated that flavonoids 1-3 could inhibit alcohol-induced hepatocyte injury, which might be attributed to alleviating oxidative stress and mitigating inflammatory response by activating Nrf2 and inhibiting NF-κB pathways.

Tubular epithelial cell-to-macrophage communication forms a negative feedback loop via extracellular vesicle transfer to promote renal inflammation and apoptosis in diabetic nephropathy.

Background: Macrophage infiltration around lipotoxic tubular epithelial cells (TECs) is a hallmark of diabetic nephropathy (DN). However, how these two types of cells communicate remains obscure. We previously demonstrated that LRG1 was elevated in the process of kidney injury. Here, we demonstrated that macrophage-derived, LRG1-enriched extracellular vesicles (EVs) exacerbated DN. Methods: We induced an experimental T2DM mouse model with a HFD diet for four months. Renal primary epithelial cells and macrophage-derived EVs were isolated from T2D mice by differential ultracentrifugation. To investigate whether lipotoxic TEC-derived EV (EVe) activate macrophages, mouse bone marrow-derived macrophages (BMDMs) were incubated with EVe. To investigate whether activated macrophage-derived EVs (EVm) induce lipotoxic TEC apoptosis, EVm were cocultured with primary renal tubular epithelial cells. Subsequently, we evaluated the effect of LRG1 in EVe by investigating the apoptosis mechanism. Results: We demonstrated that incubation of primary TECs of DN or HK-2 mTECs with lysophosphatidyl choline (LPC) increased the release of EVe. Interestingly, TEC-derived EVe activated an inflammatory phenotype in macrophages and induced the release of macrophage-derived EVm. Furthermore, EVm could induce apoptosis in TECs injured by LPC. Importantly, we found that leucine-rich α-2-glycoprotein 1 (LRG1)-enriched EVe activated macrophages via a TGFßR1-dependent process and that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-enriched EVm induced apoptosis in injured TECs via a death receptor 5 (DR5)-dependent process. Conclusion: Our findings indicated a novel cell communication mechanism between tubular epithelial cells and macrophages in DN, which could be a potential therapeutic target.

The Role of Gut Microbiota in Lung Cancer: From Carcinogenesis to Immunotherapy.

The influence of microbiota on host health and disease has attracted adequate attention, and gut microbiota components and microbiota-derived metabolites affect host immune homeostasis locally and systematically. Some studies have found that gut dysbiosis, disturbance of the structure and function of the gut microbiome, disrupts pulmonary immune homeostasis, thus leading to increased disease susceptibility; the gut-lung axis is the primary cross-talk for this communication. Gut dysbiosis is involved in carcinogenesis and the progression of lung cancer through genotoxicity, systemic inflammation, and defective immunosurveillance. In addition, the gut microbiome harbors the potential to be a novel biomarker for predicting sensitivity and adverse reactions to immunotherapy in patients with lung cancer. Probiotics and fecal microbiota transplantation (FMT) can enhance the efficacy and depress the toxicity of immune checkpoint inhibitors by regulating the gut microbiota. Although current studies have found that gut microbiota closely participates in the development and immunotherapy of lung cancer, the mechanisms require further investigation. Therefore, this review aims to discuss the underlying mechanisms of gut microbiota influencing carcinogenesis and immunotherapy in lung cancer and to provide new strategies for governing gut microbiota to enhance the prevention and treatment of lung cancer.

Gene Expression Profiling of Tricarboxylic Acid Cycle and One Carbon Metabolism Related Genes for Prognostic Risk Signature of Colon Carcinoma.

Colorectal cancer (CRC) is one of the most prevalent malignant tumors worldwide. Colon adenocarcinoma (COAD) is the most common pathological type of CRC and several biomarkers related to survival have been confirmed. Yet, the predictive effect of a single gene biomarker is not enough. The tricarboxylic acid (TCA) cycle and carbon metabolism play an important role in tumors. Thus, we aimed to identify new gene signatures from the TCA cycle and carbon metabolism to better predict the survival of COAD. This study performed mRNA expression profiling in large COAD cohorts (n = 417) from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression and multivariate Cox regression analysis were performed, and receiver operating characteristic (ROC) curve was used to screen the variable combinations model which is most relevant to patient prognosis survival mostly. Univariable or multivariate analysis results showed that SUCLG2, SUCLG1, ACLY, SUCLG2P2, ATIC and ACO2 have associations with survival in COAD. Combined with clinical variables, we confirmed model 1 (AUC = 0.82505), most relevant to patient prognosis survival. Model 1 contains three genes: SUCLG2P2, SUCLG2 and ATIC, in which SUCLG2P2 and SUCLG2 were low-expressed in COAD, however, ATIC was highly expressed, and the expressions above are related to stages of CRC. Pearson analysis showed that SUCLG2P2, SUCLG2 and ATIC were correlated in normal COAD tissues, while only SUCLG2P2 and SUCLG2 were correlated in tumor tissues. Finally, we verified the expressions of these three genes in COAD samples. Our study revealed a possible connection between the TCA cycle and carbon metabolism and prognosis and showed a TCA cycle and carbon metabolism related gene signature which could better predict survival in COAD patients.

CD73 regulates hepatic stellate cells activation and proliferation through Wnt/ß-catenin signaling pathway.

Alcoholic liver fibrosis (ALF) is commonly associated with long-term alcohol consumption and the activation of hepatic stellate cells (HSCs). Inhibiting the activation and proliferation of HSCs is a critical step to alleviate liver fibrosis. Increasing evidence indicates that ecto-5'-nucleotidase (CD73) plays a vital role in liver disease as a critical component of extracellular adenosine pathway. However, the regulatory role of CD73 in ALF has not been elucidated. In this study, both ethanol plus CCl4-induced liver fibrosis mice model and acetaldehyde-activated HSC-T6 cell model were employed and the expression of CD73 was consistently elevated in vivo and in vitro. C57BL/6 J mice were intraperitoneally injected with CD73 inhibitor Adenosine 5'-(α, ß-methylene) diphosphate sodium salt (APCP) from 5th week to the 8th week in the development of ALF. The results showed APCP could inhibit the activation of HSCs, reduce fibrogenesis marker expression and thus alleviate ALF. Silencing of CD73 inhibited the activation of HSC-T6 cells and promoted apoptosis of activated HSC-T6 cells. What's more, the proliferation of HSC-T6 cells was inhibited, which was characterized by decreased cell viability and cycle arrest. Mechanistically, Wnt/ß-catenin pathway was activated in acetaldehyde-activated HSC-T6 cells and CD73 silencing or overexpression could regulate Wnt/ß-catenin signaling pathway. Collectively, our study unveils the role of CD73 in HSCs activation, and Wnt/ß-catenin signaling pathway might be involved in this progression.

Gender Differences of NLRP1 Inflammasome in Mouse Model of Alzheimer's Disease.

Background: There is a significant gender difference in the incidence and symptoms of Alzheimer's disease (AD), but its mechanisms are not completely understood. Recent studies showed that NLRP1 inflammasome was overexpressed in females under some pathological conditions such as nodular melanoma. Whether NLRP1 signals have a gender difference in AD has not been elucidated. This study was designed to investigate gender difference on the expressions of NLRP1 signals including NLRP1, Capase-1 and IL-1ß in the brains of APP/PS1+/- mice. Methods: Female and male APP/PS1+/- mice (30-weeks-old) were used in this study. Amyloid-ß (Aß) plaques were stained with Congo red dye and cell apoptosis was detected by TUNEL staining. Expressions of NLRP1, Capase-1 and IL-1ß were measured by immunofluorescent staining and Western blotting assay. Results: The numbers of Aß plaques in cortex and hippocampus and neuronal apoptosis in cortex were 4 and 2-folds in females than males, respectively (P < 0.001). The average size of Aß plaques in both cortex (females: 3527.11 ± 539.88 µm2 vs. males: 1920.44 ± 638.49 µm2) and hippocampus (females: 1931 ± 308.61 µm2 vs. males: 1038.55 ± 220.40 µm2) were also larger in females than males (P < 0.01). More interestingly, expressions of NLRP1, Caspase-1, and IL-1ß were markedly increased in the cortex of females as compared with males. Conclusions: These findings show that NLRP1 signals are higher in brains of female APP/PS1+/- mice than males, which may be related to the gender differences of AD.

Protein expression-based classification of gastric cancer by immunohistochemistry of tissue microarray.

Recently, the Cancer Genome Atlas and Asian Cancer Research Group propose two new classifications system of gastric cancer by using multi-platforms of molecular analyses. However, these highly complicated and cost technologies have not yet been translated into full clinical utility. In addition, the clinicians are expected to gain more guidance of treatment for different molecular subtypes. In this study, we developed a panel of gastric cancer patients in population from Southern China using commercially accessible TMA and immunohistochemical technology. A cohort of 259 GC patients was classified into 4 subtypes on the basis of expression of mismatch repair proteins (PMS2, MLH1, MSH2, and MSH6), E-cadherin and p21 protein. We observed that the subtypes presented distinct prognosis. dMMR-like subtype was associated with the best prognosis, and E-cadherin-a subtype was associated with the worst prognosis. Patients with p21-High and p21-Ligh subtypes had intermediate overall survival. In multivariate analysis, the dMMR-like subtype remained an independent prediction power for overall survival in the model. We described a molecular classification of gastric cancers using clinically applicable assay. The biological relevance of the four subtypes was illustrated by significant differences in prognosis. Our molecular classification provided an effective and inexpensive screening tool for improving prognostic models. Nevertheless, our study should be considered preliminary and carries a limited predictive value as a single-center retrospective study.

Identification of Key Gene and Pathways for the Prediction of Peritoneal Metastasis of Gastric Cancer by Co-expression Analysis.

Peritoneal metastasis is the most common pattern in advanced gastric cancer and can predict poor disease prognosis. Early detection of peritoneal tumor dissemination is restricted by small peritoneal deposits. Therefore, it is critical to identify a novel predictive marker and to explore the potential mechanism associated with this process. In the present study, one module that correlated with peritoneal metastasis was identified. Enrichment analysis indicated that the Focal adhesion and the PI3K-Akt signaling pathway were the most significant pathways. Following network and Molecular Complex Detection (MCODE) analysis, the hub-gene cluster that consisted of 19 genes was selected. Methionine sulfoxide reductase B3 (MSRB3) was identified as a seed gene. Survival analysis indicated that high expression levels of MSRB3 were independent predictors of peritoneal disease-free survival (pDFS) as determined by univariate (HR 8.559, 95% CI; 3.339-21.937; P<.001) and multivariate Cox analysis (HR 3.982, 95% CI; 1.509-10.509; P=.005). Furthermore, patients with high levels of MSRB3 exhibited a significantly lower Overall Survival (OS) (log-rank P = 0.007). The external validation was performed by the (The Cancer Genome Atlas (TCGA)) (log-rank P = 0.037) and Kaplan Meier-plotter (KMplotter) (log-rank P = 0.031) data. In vitro experiments confirmed that MSRB3 was a critical protein in regulating gastric cancer cell proliferation and migration. In conclusion, High expression levels of MSRB3 in GC can predict peritoneal metastasis and recurrence as well as poor prognosis. Furthermore, MSRB3 was involved in the regulation of the proliferation and migration of GC cells.

LPPR4 promotes peritoneal metastasis via Sp1/integrin α/FAK signaling in gastric cancer.

Gastric cancer (GC) is one of the most common malignancies which has high incidence and mortality worldwide. Peritoneal dissemination is the main route of metastasis in advanced GC. However, few reliable diagnostic or prognostic biomarkers are available for peritoneal metastasis of GC. This study aimed to investigate the effect of lipid phosphate phosphatase-related protein type 4 (LPPR4) on the prognosis of peritoneal metastasis in GC, so as to explore the underlying molecular mechanisms and clinical significance of the process. Differentially expressed genes (DEGs) between tumor tissues and adjacent normal tissues were identified. The prognostic values of the DEGs were tested in two independent cohorts (TCGA-STAD cohort and GSE62254 cohort). Eight DEGs including LPPR4 with prognostic value in GC peritoneal metastasis were identified. The expression of LPPR4 increased in peritoneal metastasis of GC tissues, and high LPPR4 expression was associated with poor overall survival in GC. Loss- and gain-of functional experiments were performed to reveal that LPPR4 could promote the migration, invasion and adhesion abilities of GC cells in vitro. Tumor peritoneal dissemination was investigated in a mouse model to reveal that LPPR4 could promote peritoneal metastasis of GC cells in vivo. According to the Kyoto Encyclopedia of Genes and Genomics (KEGG) and gene set enrichment analysis (GSEA), LPPR4 was found to be related to focal adhesion, cell adhesion molecules (CAMs) and ECM-receptor interaction pathways. LPPR4 knockdown significantly inhibited the expression of integrin α1, integrin α2, integrin α5, integrin α6, integrin α7, p-FAK, p-Akt, p-Src and MMP2. Moreover, this process was regulated by the Specificity Protein 1 (Sp1) transcription factor. Taken together, LPPR4 plays an essential role in promoting peritoneal metastasis of GC through Sp1/integrin α/FAK signaling, and acts as a novel biomarker of prognosis of GC peritoneal metastasis. The results suggest that LPPR4 may serve as a new therapeutic target for patients with GC peritoneal metastasis.

Identification of gene modules and hub genes in colon adenocarcinoma associated with pathological stage based on WGCNA analysis.

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality in the world, in which colon adenocarcinoma (COAD) is the most common histological subtype of CRC. In this study, our aim is to identify gene modules and representative candidate biomarkers for clinical prognosis of patients with COAD, and help to predict prognosis and reveal the mechanisms of cancer progression. Weighted gene co-expression network analysis (WGCNA) was performed to construct a co-expression network and identify gene modules correlated with TNM clinical staging of COAD patients. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed with the module gene. Protein-protein interaction (PPI) network and hub gene identification were explored with Cytoscape software. Finally, the hub gene mRNA level was validated in Oncomine database. Five gene modules, related with the pathological TNM stage, were constructed, and the gene module was enriched in cell proliferation, invasion and migration related GO terms and metabolic related KEGG pathways. A total of top 10 hub genes was identified, and in which six of the hub genes show a significant up-regulation in COAD as compared to normal tissue, including IVL, KRT16, KRT6C, KRT6A, KRT78 and SBSN. In conclusion, we identified five gene modules and six candidate biomarkers correlated with the TNM staging of COAD patients. These findings may help us to understand the tumor progression of COAD and provide prognostic biomarkers as well as therapeutic targets.

Comprehensive analysis of genes based on chr1p/19q co-deletion reveals a robust 4-gene prognostic signature for lower grade glioma.

Purpose: The chr1p/19q co-deletion is a favorable prognostic factor in patients with lower grade glioma. The aim of this study was to reveal key genes for prognosis and establish prognostic gene signatures based on genes encoded by chr1p/19q. Materials and methods: The data was downloaded from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA) and Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) between lower grade glioma tissue and normal brain were identified. The univariate COX regression, robust likelihood-base survival analysis (rbsurv) and multivariate COX regression analysis were used to establish the 4-gene-signature based on the DEGs. The receiver operating characteristic (ROC) curve and the Kaplan-Mere curve were used to verify the prediction accuracy of the signature. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were also performed to explore the reasons for good prognosis in patients with chr1p/19q deletion. Results: A total of 1346 DEGs were identified between lower grade glioma samples and normal brain samples in GSE16011, including 56 up-regulated mRNAs located on chr1p and 20 up-regulated mRNAs located on chr19q. We established a 4-gene-signature that was significantly associated with survival based on the 76 gene. The AUC of the 4-gene-signature for 5-year OS in TCGA and CGGA was 0.837 and 0.876, respectively, which was superior compared to other parameters such as chr1p/19q co-deletion, IDH mutant, WHO grade and histology type, especially in chr1p/19q non-co-deletion patients. GSEA and KEGG analysis suggested that the prolongation of chr1p/19q in patients could be associated with cell cycle and DNA mismatch repairing. Conclusions: We established a robust 4-gene-signature based on the chr1p/19q and we explored the potential function of these newly identified survival-associated genes by bioinformatics analysis. The 4-gene from the signature are promising molecular targets to be used in the future.

RNA sequencing and bioinformatics analysis of the long noncoding RNA-mRNA network in colorectal cancer.

Long noncoding RNA (lncRNA) plays an important regulatory role in tumorigenesis. This study aims to analyze the lncRNA-messenger RNA (mRNA) expression network and potential roles in colorectal cancer (CRC). The LncRNA expression profile was analyzed in CRC tissue by RNA sequencing and the functions of differentially expressed genes were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The lncRNA-mRNA network was predicted with bioinformatics. From the result, we identified 485 differential expression lncRNAs and 2383 mRNAs in CRC, GO, and KEGG analyses showed that the changes in lncRNAs were mainly associated with metabolism and transcription regulation that were different from mRNA function. Additionally, based on the predicted coexpression network, we identified that NONHSAT074176.2, downregulated in CRC tissue and cell lines, was a hub lncRNA in the development of CRC. Our results describe the lncRNA-mRNA network in detail and indicate that lncRNA NONHSAT074176.2 may be useful as a candidate diagnostic biomarker and may be a promising therapeutic target for CRC.

Therapeutic effects of STAT3 inhibition by nifuroxazide on murine acute graft graft-vs.-host disease: Old drug, new use.

Graft­vs.­host disease (GvHD) is a major and lethal complication of allogeneic bone marrow transplantation (allo­BMT). Although great development has been made, the treatment progress of this disorder is slow. Research has illustrated that STAT3 was critical for T cell alloactivation in GvHD. In the present study, the authors hypothesized that nifuroxazide, as the STAT3 inhibitor, treatment may attenuate the development of acute GvHD (aGvHD). The results demonstrated that nifuroxazide suppressed the development of aGvHD and significantly delayed aGvHD­induced lethality. Mice receiving nifuroxazide had mostly normal­appearing skin with minimal focal ulceration, mild edema and congestion in the liver, and a less­pronounced villus injury and less inflammatory infiltrate in the small intestine. Treatment with nifuroxazide inhibited the activation of STAT3, resulting in the regulation of the CD4+ T cells and CD4+CD25+ T cells and reduction of interferon­Î³ and tumor necrosis factor­α levels. In conclusion, nifuroxazide may be efficacious for post­transplant of GvHD, providing a potent drug for use as a prophylactic or as a second­line therapy for aGvHD in clinical trials.