Systematic analysis of the necroptosis index in pan-cancer and classification in discriminating the prognosis and immunotherapy responses of 1716 glioma patients.

Necroptosis is a programmed form of necrotic cell death that serves as a host gatekeeper for defense against invasion by certain pathogens. Previous studies have uncovered the essential role of necroptosis in tumor progression and implied the potential for novel therapies targeting necroptosis. However, no comprehensive analysis of multi-omics data has been conducted to better understand the relationship between necroptosis and tumor. We developed the necroptosis index (NI) to uncover the effect of necroptosis in most cancers. NI not only correlated with clinical characteristics of multiple tumors, but also could influence drug sensitivity in glioma. Based on necroptosis-related differentially expressed genes, the consensus clustering was used to classify glioma patients into two NI subgroups. Then, we revealed NI subgroup I were more sensitive to immunotherapy, particularly anti-PD1 therapy. This new NI-based classification may have prospective predictive factors for prognosis and guide physicians in prioritizing immunotherapy for potential responders.

Integrative analysis to screen novel pyroptosis-related LncRNAs for predicting clinical outcome of glioma and validation in tumor tissue.

BACKGROUND: Pyroptosis, also known as inflammatory necrosis, is a programmed cell death that manifests itself as a continuous swelling of cells until the cell membrane breaks, leading to the liberation of cellular contents, which triggers an intense inflammatory response. Pyroptosis might be a panacea for a variety of cancers, which include immunotherapy and chemotherapy-insensitive tumors such as glioma. Several findings have observed that long non-coding RNAs (lncRNAs) modulate the bio-behavior of tumor cells by binding to RNA, DNA and protein. Nevertheless, there are few studies reporting the effect of lncRNAs in pyroptosis processes in glioma. METHODS: The principal goal of this study was to identify pyroptosis-related lncRNAs (PRLs) utilizing bioinformatic algorithm and to apply PCR techniques for validation in human glioma tissues. The second goal was to establish a prognostic model for predicting the overall survival patients with glioma. Predict algorithm was used to construct prognosis model with good diagnostic precision for potential clinical translation. RESULTS: Noticeably, molecular subtypes categorized by the PRLs were not distinct from any previously published subtypes of glioma. The immune and mutation landscapes were obviously different from previous subtypes of glioma. Analysis of the sensitivity (IC50) of patients to 30 chemotherapeutic agents identified 22 agents as potential therapeutic agents for patients with low riskscores. CONCLUSIONS: We established an exact prognostic model according to the expression profile of PRLs, which may facilitate the assessment of patient prognosis and treatment patterns and could be further applied to clinical.

Inhibition of hypoxia-inducible factor 1 by acriflavine renders glioblastoma sensitive for photodynamic therapy.

BACKGROUND: photodynamics therapy (PDT) induces tumor cell death through oxidative stress and is closely associated with the expression of hypoxia inducible factor-1a (HIF1a), which activates multiple downstream survival signaling pathways. Therefore, the purpose of this study was to investigate the expression levels of HIF1a proteins in PDT-treated GBM cells and to determine whether inhibition of HIF1a reduces survival signals to enhance the efficacy of PDT. RESULTS: PDT combined with Acriflavine (ACF, PA) decreased the expression of HIF1a and regulated the downstream expression of GLUT-1, GLUT-3, HK2 and other gluconeogenic pathway proteins. PA group significantly suppressed tumor growth to improve the efficacy of PDT. METHODS: We first performed the correlation of HIF1a, GLUT-1, GLUT-3, and HK2, and quantified the expression of HIF1a on tumor grades and IDH mutation classification by TCGA and CGGA databases. Then, we used immunohistochemistry method to detect four gene expression levels in human GBM tissues. Besides, we examined the effects of different treatments on the proliferation, migration and invasion ability of GBM cell lines by CCK8, wound healing and transwell assays. ACF, a HIF1a/HIF1ß dimerization inhibitor, was used to evaluate its adjuvant effect on the efficacy of PDT. CONCLUSION: HIF1a is activated in GBM cell lines and contributes to the survival of tumor cells after PDT in vitro and in vivo. PA group inhibited HIF1a expression and improved PDT efficacy in the treatment of recalcitrant GBM.

[Expression and clinical significance of ING4 and HIF-1 alpha in brain astrocytoma].

OBJECTIVE: To study the mRNA expression level of growth inhibition factor 4 (ING4) and hypoxia inducing factor 1 alpha (HIF-1 alpha), and their relationship with tumor malignant degree or the pathology classification in human brain astrocytoma. METHODS: The mRNA expression levels of ING4 and HIF-1 alpha were detected by RT-PCR method in 45 cases of grade I-IV human brain astrocytoma and 11 cases of control brain tissues from January 2009 to June 2010 in the Second Affiliated Hospital of Zhengzhou University, and their correlation was also analyzed. RESULTS: In the non-tumor brain tissue, the expression level of ING4 mRNA was 1.19 ± 0.22, while they were 0.91 ± 0.19, 0.74 ± 0.28, 0.54 ± 0.33 and 0.22 ± 0.19 in I-IV grade astrocytoma, respectively. Compared with the non-tumor control, the mRNA expression level of ING4 gene decreased significantly in the astrocytoma (P<0.05). And the expression of ING4 gradually reduced with the increase of the pathological classification of the astrocytoma.In the non-tumor brain tissue, the expression level of HIF-1 alpha mRNA was 0.26 ± 0.16, and they were 0.34 ± 0.19, 0.50 ± 0.23, 0.96 ± 0.15 and 1.04 ± 0.15 in I-IV grade astrocytoma, respectively.For HIF-1 alpha gene, the mRNA expression level increased significantly in the astrocytoma. Meanwhile, the expression gradually increased with the increase of the pathological classification of the astrocytoma (P<0.05). The mRNA expression showed a negative correlation between ING4 and HIF-1 alpha with the increase of the tumor malignant degree. CONCLUSION: The ING4 and HIF-1 alpha genes play a role in the tumorigenesis and development of human brain astrocytoma, and closely associate with the malignant degree of astrocytoma.

Trauma infant neurologic score predicts the outcome of traumatic brain injury in infants.

To investigate the clinical features of infancy traumatic brain injury (TBI) and the prognostic value of the Trauma Infant Neurologic Score (TINS), infants < 2 years of age with TBI who were admitted from 2000 to 2007 were retrospectively studied. Fifty-six patients with a mean age of 13.3 ± 6.5 months (range = 2-24) were identified. The clinical diagnoses, in terms of the severest injury, included scalp hematomas (n = 2), skull bone fractures (n = 3), epidural hematomas (n = 21), subdural hematomas (n = 14), cerebral contusion and laceration (n = 4), intracerebral hematomas (n = 7), traumatic subarachnoid hemorrhage (n = 2), diffuse axonal injury (n = 2) and diffuse brain swelling (n = 1). The most common clinical presentations were vomiting (66.1%), paleness (55.4%), irritability (37.3%), pupillary abnormalities (35.7%) and altered consciousness (32.1%). The mechanism of injury included falls (n = 41), vehicle accident (n = 9), abuse (n = 4) and unknown (n = 2). The TINS score ranged from 1 to 10 with a mean of 3.6 (SD = 2.4) in the whole patient cohort. The Children's Coma Scores (CCS) on admission were 13-15 (n = 31), 9-12 (n = 7) and 3-8 (n = 18). Thirty-nine of the infants were operated on and the other 17 infants were treated nonsurgically. Forty-eight patients (86%) were followed up for a period of 1-8 years (mean = 4.4) after discharge. In the followed-up patient cohort, the mean TINS score at admission was 3.8 ± 2.5. The total clinical outcome, according to the Glasgow Outcome Scale (GOS), was: 37 (77.1%) good recovery, 4 (8.3%) moderately disabled, 1 (2.1%) vegetative and 6 (12.5%) dead. For those who were operated on the outcome was: 25 (78.1%) good recovery, 4 (12.5%) moderately disabled and 3 (9.4%) dead, and for those who were not operated on: 12 (75.0%) good recovery, 1 (6.3%) vegetative and 3 (25.0%) dead. At two years of follow-up, the GOS included 34 (73.9%) good recovery, 3 (6.5%) moderately disabled, 2 (4.3%) severely disabled, 1 (2.2%) vegetative and 6 (13.0%) dead. Statistical tests revealed that the TINS scores were highly associated with the GOS. Higher TINS scores resulted in worse clinical outcome. The CCS scores were also to some degree associated with the GOS score. However, the CCS score on admission was not as discriminating as TINS, predicting only the best and worst outcome in our series. Our study showed that the clinical features of TBI in infants were different from those seen in adults regarding both the distribution of the pathology type and the clinical presenting symptoms. We found that the TINS scoring system is useful for predicting prognosis and outcome in infancy TBI and suggest that it could be routinely used in the infantile population.

[Molecular mechanism of LRIG1 cDNA-induced apoptosis in human glioma cell line H4].

BACKGROUND & OBJECTIVE: Leucine-rich repeats and immunoglobulin-like domains 1(LRIG1)is a kind of transmembrane glycoprotein,which is induced by epidermal growth factor (EGF),and develops inhibitory negative feedback by specific binding with epidermal growth factor receptor (EGFR). This research was to explore the molecular mechanism of LRIG1 inhibiting EGFR signal pathway. METHODS: Plasmid p3XFLAG-CMV9-LRIG1 was transfected into neuroglioma cell line H4. Changes of LRIG1 and EGFR expression at mRNA and protein levels were measured by RT-PCR and Western blot, respectively. Changes of cell proliferation and apoptosis were analyzed by MTT and flow cytometry methods. RESULTS: LRIG1 mRNA level in p3XFLAG-CMV9-LRIG1 transfected H4 cells (1.997+/-0.114) was significantly higher than that in control H4 cells (0.500+/-0.031),and p3XFLAG-CMV9 transfected group (0.357+/-0.035) (P< 0.001). LRIG1 protein level in p3XFLAG-CMV9-LRIG1 transfected H4 cells (1.790+/-0.119) was significantly higher than that in control H4 cells (0.717+/-0.038, P< 0.001), and p3XFLAG-CMV9 transfected H4 cells (0.930+/-0.076, P=0.001). EGFR mRNA level in p3XFLAG-CMV9-LRIG1 transfected H4 cells (0.463+/-0.033) was significantly lower than that in control H4 cells (1.157+/-0.067, P< 0.001), and p3XFLAG-CMV9 transfected H4 cells (0.933+/-0.058, P=0.002). EGFR protein level in p3XFLAG-CMV9-LRIG1 transfected H4 cells (0.703+/-0.067) was significantly lower than that in control H4 cells (1.280+/-0.078, P=0.003),and p3XFLAG-CMV9 transfected H4 cells (1.163+/-0.068,P=0.009). Apoptosis rate in LRIG1-transfected H4 cells (18.89%)was lower than that in control H4 cells (3.11%), and vector-transfected H4 cells (5.42%, P< 0.001). CONCLUSION: LRIG1 participates in construction of negative feedback loop of EGFR, which may inhibits growth of glioma cells.