Integrative analysis defines DDIT3 amplification as a correlative and essential factor for glioma malignancy.

Glioma, particularly glioblastoma multiforme (GBM), is a highly aggressive and lethal primary brain tumor with poor prognosis. Metabolic reprogramming and endoplasmic reticulum (ER) stress are two crucial factors contributing to glioma pathogenesis. However, the intricate coordination between these processes remains incompletely understood. Here, we conducted an integrative analysis to elucidate the nodal role of DNA Damage Inducible Transcript 3 (DDIT3) to couple metabolisms and stress responses in glioma. We demonstrated a positive association between DDIT3 amplification/enhanced expression with glioma malignancy, indicating its potential as a novel biomarker for prognosis and treatment stratification. Genomic and transcriptomic analyses further revealed the involvement of DDIT3 enhancement in glioma progression. Moreover, immune infiltration analysis showed that distinct DDIT3 expression groups had different immune microenvironment. Finally, in vitro validations confirmed the impact of DDIT3 on proliferation and migration of glioma cells. Our findings provide novel insights into the complex interplay between metabolic reprogramming and ER stress, and defines DDIT3 as a promising therapeutic target in glioma.

Disruption of neuronal RHEB signaling impairs oligodendrocyte differentiation and myelination through mTORC1-DLK1 axis.

How neuronal signaling affects brain myelination remains poorly understood. We show dysregulated neuronal RHEB-mTORC1-DLK1 axis impairs brain myelination. Neuronal Rheb cKO impairs oligodendrocyte differentiation/myelination, with activated neuronal expression of the imprinted gene Dlk1. Neuronal Dlk1 cKO ameliorates myelination deficit in neuronal Rheb cKO mice, indicating that activated neuronal Dlk1 expression contributes to impaired myelination caused by Rheb cKO. The effect of Rheb cKO on Dlk1 expression is mediated by mTORC1; neuronal mTor cKO and Raptor cKO and pharmacological inhibition of mTORC1 recapitulate elevated neuronal Dlk1 expression. We demonstrate that both a secreted form of DLK1 and a membrane-bound DLK1 inhibit the differentiation of cultured oligodendrocyte precursor cells into oligodendrocytes expressing myelin proteins. Finally, neuronal expression of Dlk1 in transgenic mice reduces the formation of mature oligodendrocytes and myelination. This study identifies Dlk1 as an inhibitor of oligodendrocyte myelination and a mechanism linking altered neuronal signaling with oligodendrocyte dysfunction.

Impact of redox-related genes on tumor microenvironment immune characteristics and prognosis of high-grade gliomas.

Introduction: High-grade glioma (HGG) defines a group of brain gliomas characterized by contrast enhancement, high tumor heterogeneity, and poor clinical outcome. Disturbed reduction-oxidation (redox) balance has been frequently associated with the development of tumor cells and their microenvironment (TME). Methods: To study the influence of redox balance on HGGs and their microenvironment, we collected mRNA-sequencing and clinical data of HGG patients from TCGA and CGGA databases and our own cohort. Redox-related genes (ROGs) were defined as genes in the MSigDB pathways with keyword "redox" that were differentially expressed between HGGs and normal brain samples. Unsupervised clustering analysis was used to discover ROG expression clusters. Over-representation analysis (ORA), gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were also employed to understand the biological implication of differentially expressed genes between HGG clusters. CIBERSORTx and ESTIMATE were used to profile the immune TME landscapes of tumors, and TIDE was used to evaluated the potential response to immune checkpoint inhibitors. Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression was used to construct HGG-ROG expression risk signature (GRORS). Results: Seventy-five ROGs were found and consensus clustering using the expression profile of ROGs divided the both IDH-mutant (IDHmut) and IDH-wildtype (IDHwt) HGGs into subclusters with different prognosis. Functional enrichment analysis revealed that the differential aggressiveness between redox subclusters in IDHmut HGGs were significantly associated with cell cycle regulation pathways, while IDHwt HGG redox subclusters showed differentially activated immune-related pathways. In silico TME analysis on immune landscapes in the TME showed that the more aggressive redox subclusters in both IDHmut and IDHwt HGGs may harbor a more diverse composition of tumor-infiltrating immune cells, expressed a higher level of immune checkpoints and were more likely to respond to immune checkpoint blockade. Next, we established a GRORS which showed AUCs of 0.787, 0.884, and 0.917 in predicting 1-3-year survival of HGG patients in the held-out validation datasets, and the C-index of a nomogram combining the GRORS and other prognostic information reached 0.835. Conclusion: Briefly, our results suggest that the expression pattern of ROGs was closely associated with the prognosis as well as the TME immune profile of HGGs, and may serve as a potential indicator for their response to immunotherapies.

Prognosis prediction and tumor immune microenvironment characterization based on tryptophan metabolism-related genes signature in brain glioma.

Glioma is the most common malignant tumor in the central nervous system with no significant therapeutic breakthrough in recent years. Most attempts to apply immunotherapy in glioma have failed. Tryptophan and its metabolism can regulate malignant features of cancers and reshape immune microenvironment of tumors. However, the role of tryptophan metabolism in glioma remains unclear. In current study, we explored the relationships between the expression pattern of tryptophan metabolism-related genes (TrMGs) and tumor characteristics, including prognosis and tumor microenvironment of gliomas through analyzing 1,523 patients' samples from multiple public databases and our own cohort. Based on expression of TrMGs, K-means clustering analysis stratified all glioma patients into two clusters with significantly different TrMG expression patterns, clinicopathological features and immune microenvironment. Furthermore, we constructed a tryptophan metabolism-related genes signature (TrMRS) based on seven essential TrMGs to classify the patients into TrMRS low- and high-risk groups and validated the prognostic value of the TrMRS in multiple cohorts. Higher TrMRS represented for potentially more active tryptophan catabolism, which could subsequently lead to less tryptophan in tumor. The TrMRS high-risk group presented with shorter overall survival, and further analysis confirmed TrMRS as an independent prognostic factor in gliomas. The nomograms uniting TrMRS with other prognostic factors manifested with satisfactory efficacy in predicting the prognosis of glioma patients. Additionally, analyses of tumor immune landscapes demonstrated that higher TrMRS was correlated with more immune cell infiltration and "hot" immunological phenotype. TrMRS was also demonstrated to be positively correlated with the expression of multiple immunotherapy targets, including PD1 and PD-L1. Finally, the TrMRS high-risk group manifested better predicted response to immune checkpoint inhibitors. In conclusion, our study illustrated the relationships between expression pattern of TrMGs and characteristics of gliomas, and presented a novel model based on TrMRS for prognosis prediction in glioma patients. The association between TrMRS and tumor immune microenvironment of gliomas indicated an important role of tryptophan and its metabolism in reshaping immune landscape and the potential ability to guide the application of immunotherapy for gliomas.

Purine metabolism-related gene expression signature predicts survival outcome and indicates immune microenvironment profile of gliomas.

Glioma is the most common malignant tumor in the central nervous system. The impact of metabolism on cancer development and the immune microenvironment landscape has recently gained broad attention. Purines are involved in multiple metabolic pathways. It has been proved that purine metabolism could regulate malignant biological behaviors and response to immune checkpoint inhibitors in multiple cancers. However, the relationship of purine metabolism with clinicopathological features and the immune landscape of glioma remains unclear. In this study, we explored the relationships between the expression of purine metabolism-related genes (PuMGs) and tumor features, including prognosis and microenvironment of glioma, based on analyses of 1,523 tumors from 4 public databases and our cohort. Consensus clustering based on 136 PuMGs classified the glioma patients into two clusters with significantly distinguished prognosis and immune microenvironment landscapes. Increased immune infiltration was associated with more aggressive gliomas. The prognostic Purine Metabolism-Related Genes Risk Signature (PuMRS), based on 11 critical PuMGs, stratified the patients into PuMRS low- and high-risk groups in the training set and was validated by validation sets from multiple cohorts. The high-risk group presented with significantly shorter overall survival, and further survival analysis demonstrated that the PuMRS was an independent prognostic factor in glioma. The nomogram combining PuMRS and other clinicopathological factors showed satisfactory accuracy in predicting glioma patients' prognosis. Furthermore, analyses of the tumor immune microenvironment suggested that higher PuMRS was correlated with increased immune cell infiltration and gene expression signatures of "hotË® tumors. Gliomas in the PuMRS high-risk group presented a higher expression level of multiple immune checkpoints, including PD-1 and PD-L1, and a better-predicted therapy response to immune checkpoint inhibitors. In conclusion, our study elucidated the relationship between the expression level of PuMGs and the aggressiveness of gliomas. Our study also endorsed the application of PuMRS to construct a new robust model for the prognosis evaluation of glioma patients. The correlations between the profiles of PuMGs expression and tumor immune microenvironment potentially provided guidance for immunotherapy in glioma.

Prognostic value of lactate metabolism-related gene expression signature in adult primary gliomas and its impact on the tumor immune microenvironment.

Glioma is one of the most malignant intracerebral tumors, whose treatment means was limited, and prognosis was unsatisfactory. Lactate metabolism patterns have been shown to be highly heterogenous among different tumors and produce diverse impact on the tumor microenvironment. To understand the characteristics and implications of lactate metabolism gene expression, we developed a lactate metabolism-related gene expression signature of gliomas based on RNA-sequencing data of a total of 965 patient samples from TCGA, CGGA, and our own glioma cohort. Sixty-three lactate metabolism-related genes (LMGs) were differentially expressed between glioma and normal brain tissue, and consensus clustering analysis identified two clusters distinct LMG expression patterns. The consensus clusters differed in prognosis, molecular characteristics and estimated immune microenvironment landscape involving immune checkpoint proteins, T cell dysfunction and exclusion, as well as tumor purity. Univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) Cox hazard regression was applied in determining of prognosis-related lactate metabolism genes (PRLMGs), on which prognostic lactate metabolism risk score (PLMRS) was constructed. The high PLMRS group was associated with significantly poorer patient outcome. A nomogram containing PLMRS and other independent prognostic variables was established with remarkable predictive performance on patient survival. Exploration on the somatic mutations and copy number variations of the high- and low-PLMRS groups demonstrated their distinct genetic background. Together, our results indicated that the expression signature of LMG was associated with the prognosis of glioma patients and influenced the activity of immune cells in the tumor microenvironment, which may serve as a potential biomarker for predicting response of gliomas to immunotherapy.

Prognostic value of cuproptosis-related genes signature and its impact on the reshaped immune microenvironment of glioma.

Glioma is the most prevalent malignancy in the central nervous system. The impact of ion-induced cell death on malignant tumors' development and immune microenvironment has attracted broad attention in recent years. Cuproptosis is a novel copper-dependent mechanism that could potentially regulate tumor cell death by targeting mitochondria respiration. However, the role of cuproptosis in gliomas remains unclear. In the present study, we investigated the relationships between the expression of cuproptosis-related genes (CRGs) and tumor characteristics, including prognosis and microenvironment of glioma, by analyzing multiple public databases and our cohort. Consensus clustering based on the expression of twelve CRGs stratified the glioma patients into three subgroups with significantly different prognosis and immune microenvironment landscapes. Reduced immune infiltration was associated with the less aggressive CRG cluster. A prognostic CRGs risk signature (CRGRS), based on eight critical CRGs, classified the patients into low- and high-risk groups in the training set and was endorsed by validation sets from multiple cohorts. The high-risk group manifested a shorter overall survival, and further survival analysis demonstrated that the CRGRS was an independent prognostic factor. The nomogram combining CRGRS and other clinicopathological factors exhibited good accuracy in predicting the prognosis of glioma patients. Moreover, analyses of tumor immune microenvironment indicated that higher CRGRS was correlated with increased immune cell infiltration but diminished immune function. Gliomas in the high-risk group exhibited higher expression of multiple immune checkpoints, including PD-1 and PD-L1, and a better predicted therapy response to immune checkpoint inhibitors. In conclusion, our study elucidated the connections between CRGs expression and the aggressiveness of gliomas, and the application of CRGRS derived a new robust model for prognosis evaluation of glioma patients. The correlations between the profiles of CRGs expression and immune tumor microenvironment illuminated prospects and potential indications of immunotherapy for glioma.

Extraventricular site indicates higher grade but better prognosis in adult supratentorial ependymomas: a 14-year single-center retrospective cohort.

Supratentorial extraventricular ependymoma (STEE) and supratentorial intraventricular ependymoma (STIE) are two subsets of supratentorial ependymoma (SE). These two subsets have similar gene features and only differ in original sites: STEE occurs in the brain parenchyma, and STIE is located in ventricles and surrounded by cerebral spinal fluid. The present study aims to depict the diversities of these two subsets and elucidate the potential effects of the anatomic site on the tumor with the same type, grade, and molecular features. Sixty-six consecutive adult SE patients from 2008 to 2021 were enrolled in our study. Clinical data, pathological features, and long-term outcomes were analyzed retrospectively. Results demonstrated that adult STEE presented with a higher proportion of WHO grade 3 (P = .028) and higher Ki-67 index (≥10%) (P = .019) compared to adult STIE. Survival analysis demonstrated that patients of grade 3 STEE exhibited a significantly longer overall survival (OS) than patients of grade 3 STIE (median OS, 24.4 months vs. 13.0 months; P = .004). Grade 2 (hazard ratio (HR) = 0.217; P < .001) and gross total resection (GTR) (HR = 0.156; P < .001) were identified as favorable prognostic factors for all adult SE. The STEE was also associated with a lesser hazard of death for patients of grade 3 on multivariate analysis (HR = 0.263; P = .047). These findings suggested that the extraventricular site was an indicator for higher grade and better prognosis in adult supratentorial ependymoma.

Animal models of male subfertility targeted on LanCL1-regulated spermatogenic redox homeostasis.

Oxidative stress in spermatozoa is a major contributor to male subfertility, which makes it an informed choice to generate animal models of male subfertility with targeted modifications of the antioxidant systems. However, the critical male germ cell-specific antioxidant mechanisms have not been well defined yet. Here we identify LanCL1 as a major male germ cell-specific antioxidant gene, reduced expression of which is related to human male infertility. Mice deficient in LanCL1 display spermatozoal oxidative damage and impaired male fertility. Histopathological studies reveal that LanCL1-mediated antioxidant response is required for mouse testicular homeostasis, from the initiation of spermatogenesis to the maintenance of viability and functionality of male germ cells. Conversely, a mouse model expressing LanCL1 transgene is protected against high-fat-diet/obesity-induced oxidative damage and subfertility. We further show that germ cell-expressed LanCL1, in response to spermatogenic reactive oxygen species, is regulated by transcription factor specific protein 1 (SP1) during spermatogenesis. This study demonstrates a critical role for the SP1-LanCL1 axis in regulating testicular homeostasis and male fertility mediated by redox balance, and provides evidence that LanCL1 genetically modified mice have attractive applications as animal models of male subfertility.

Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver.

Hepatosteatosis, characterized by excessive accumulation of lipids in the liver, is a major health issue in modern society. Understanding how altered hepatic lipid metabolism/homeostasis causes hepatosteatosis helps to develop therapeutic interventions. Previous studies identify mitochondrial dysfunction as a contributor to hepatosteatosis. But, the molecular mechanisms of mitochondrial dysfunction leading to altered lipid metabolism remain incompletely understood. Our previous work shows that Rheb, a Ras-like small GTPase, not only activates mTORC1 but also promotes mitochondrial ATP production through pyruvate dehydrogenase (PDH). In this study, we further demonstrate that Rheb controls hepatic triglyceride secretion and reduces diet-induced lipid accumulation in a mouse liver. Genetic deletion of Rheb causes rapid and spontaneous steatosis in the liver, which is unexpected from the role of mTORC1 that enhances lipid synthesis, whereas Rheb transgene remarkably reduces diet-induced hepatosteatosis. Results suggest that the hepatosteatosis in Rheb KO is an outcome of impaired lipid secretion, which is linked to mitochondrial ATP production of hepatocytes. Our findings highlight an under-appreciated role of Rheb in the regulation of hepatic lipid secretion through mitochondrial energy production, with therapeutic implication.

GATOR2 complex-mediated amino acid signaling regulates brain myelination.

Amino acids are essential for cell growth and metabolism. Amino acid and growth factor signaling pathways coordinately regulate the mechanistic target of rapamycin complex 1 (mTORC1) kinase in cell growth and organ development. While major components of amino acid signaling mechanisms have been identified, their biological functions in organ development are unclear. We aimed to understand the functions of the critically positioned amino acid signaling complex GAP activity towards Rags 2 (GATOR2) in brain development. GATOR2 mediates amino acid signaling to mTORC1 by directly linking the amino acid sensors for arginine and leucine to downstream signaling complexes. Now, we report a role of GATOR2 in oligodendrocyte myelination in postnatal brain development. We show that the disruption of GATOR2 complex by genetic deletion of meiosis regulator for oocyte development (Mios, encoding a component of GATOR2) selectively impairs the formation of myelinating oligodendrocytes, thus brain myelination, without apparent effects on the formation of neurons and astrocytes. The loss of Mios impairs cell cycle progression of oligodendrocyte precursor cells, leading to their reduced proliferation and differentiation. Mios deletion manifests a cell type-dependent effect on mTORC1 in the brain, with oligodendroglial mTORC1 selectively affected. However, the role of Mios/GATOR2 in oligodendrocyte formation and myelination involves mTORC1-independent function. This study suggests that GATOR2 coordinates amino acid and growth factor signaling to regulate oligodendrocyte myelination.

Elevated GIGYF2 expression suppresses tumor migration and enhances sensitivity to temozolomide in malignant glioma.

Glioma is a common type of malignant and aggressive tumor in the brain. Despite progress on mechanistic studies, current understanding of the initiation and progression of glioma remains incomplete. GIGYF2 is a critical regulator in neural development and degeneration, however, its contribution in glioma is not yet elucidated. In this study, using an integrative approach spanning bioinformatic analysis and functional approaches, we explored the potential contribution of GIGYF2 in glioma. Bioinformatic data from public database and our cohort showed that GIGYF2 expression was closely associated with low glioma malignancy and better patient survival. Elevation of GIGYF2 expression impaired cell migration and enhanced temozolomide sensitivity of human glioma cells. We further establish its molecular mechanism by demonstrating that GIGYF2 inhibits MMP-9 mediated cell migration pathway and pro-survival AKT/Bax/Caspase-3 signaling. Our work identifies the suppressive role of GIGYF2 in gliomas, and clarifies the relationship between GIGYF2 expression and glioma malignancy, which may provide a potential target for future interventions.

Rheb-regulated mitochondrial pyruvate metabolism of Schwann cells linked to axon stability.

The metabolic coupling of Schwann cells (SCs) and peripheral axons is poorly understood. Few molecules in SCs are known to regulate axon stability. Using SC-specific Rheb knockout mice, we demonstrate that Rheb-regulated mitochondrial pyruvate metabolism is critical for SC-mediated non-cell-autonomous regulation of peripheral axon stability. Rheb knockout suppresses pyruvate dehydrogenase (PDH) activity (independently of mTORC1) and shifts pyruvate metabolism toward lactate production in SCs. The increased lactate causes age-dependent peripheral axon degeneration, affecting peripheral nerve function. Lactate, as an energy substrate and a potential signaling molecule, enhanced neuronal mitochondrial metabolism and energy production of peripheral nerves. Albeit beneficial to injured peripheral axons in the short term, we show that persistently increased lactate metabolism of neurons enhances ROS production, eventually damaging mitochondria, neuroenergetics, and axon stability. This study highlights the complex roles of lactate metabolism to peripheral axons and the importance of lactate homeostasis in preserving peripheral nerves.

Rheb mediates neuronal-activity-induced mitochondrial energetics through mTORC1-independent PDH activation.

Neuronal activity increases energy consumption and requires balanced production to maintain neuronal function. How activity is coupled to energy production remains incompletely understood. Here, we report that Rheb regulates mitochondrial tricarboxylic acid cycle flux of acetyl-CoA by activating pyruvate dehydrogenase (PDH) to increase ATP production. Rheb is induced by synaptic activity and lactate and dynamically trafficked to the mitochondrial matrix through its interaction with Tom20. Mitochondria-localized Rheb protein is required for activity-induced PDH activation and ATP production. Cell-type-specific gain- and loss-of-function genetic models for Rheb reveal reciprocal changes in PDH phosphorylation/activity, acetyl-CoA, and ATP that are not evident with genetic or pharmacological manipulations of mTORC1. Mechanistically, Rheb physically associates with PDH phosphatase (PDP), enhancing its activity and association with the catalytic E1α-subunit of PDH to reduce PDH phosphorylation and increase its activity. Findings identify Rheb as a nodal point that balances neuronal activity and neuroenergetics via Rheb-PDH axis.

Inhibition of mitochondrial carrier homolog 2 (MTCH2) suppresses tumor invasion and enhances sensitivity to temozolomide in malignant glioma.

BACKGROUND: Malignant glioma exerts a metabolic shift from oxidative phosphorylation (OXPHOs) to aerobic glycolysis, with suppressed mitochondrial functions. This phenomenon offers a proliferation advantage to tumor cells and decrease mitochondria-dependent cell death. However, the underlying mechanism for mitochondrial dysfunction in glioma is not well elucidated. MTCH2 is a mitochondrial outer membrane protein that regulates mitochondrial metabolism and related cell death. This study aims to clarify the role of MTCH2 in glioma. METHODS: Bioinformatic analysis from TCGA and CGGA databases were used to investigate the association of MTCH2 with glioma malignancy and clinical significance. The expression of MTCH2 was verified from clinical specimens using real-time PCR and western blots in our cohorts. siRNA-mediated MTCH2 knockdown were used to assess the biological functions of MTCH2 in glioma progression, including cell invasion and temozolomide-induced cell death. Biochemical investigations of mitochondrial and cellular signaling alternations were performed to detect the mechanism by which MTCH2 regulates glioma malignancy. RESULTS: Bioinformatic data from public database and our cohort showed that MTCH2 expression was closely associated with glioma malignancy and poor patient survival. Silencing of MTCH2 expression impaired cell migration/invasion and enhanced temozolomide sensitivity of human glioma cells. Mechanistically, MTCH2 knockdown may increase mitochondrial OXPHOs and thus oxidative damage, decreased migration/invasion pathways, and repressed pro-survival AKT signaling. CONCLUSION: Our work establishes the relationship between MTCH2 expression and glioma malignancy, and provides a potential target for future interventions.

Circadian Rheb oscillation alters the dynamics of hepatic mTORC1 activity and mitochondrial morphology.

The morphological structure and metabolic activity of mitochondria are coordinately regulated by circadian mechanisms. However, the mechanistic interplay between circadian mechanisms and mitochondrial architecture remains poorly understood. Here, we demonstrate circadian rhythmicity of Rheb protein in liver, in line with that of Per2. Using genetic mouse models, we show that Rheb, a small GTPase that binds mTOR, is critical for circadian oscillation of mTORC1 activity in liver. Disruption of Rheb oscillation in hepatocytes by persistent expression of Rheb transgene interrupted mTORC1 oscillation. We further show that Rheb-regulated mTORC1 altered mitochondrial fission factor DRP1 in liver, leading to altered mitochondrial dynamics. Our results suggest that Rheb/mTORC1 regulated DRP1 oscillation involves ubiquitin-mediated proteolysis. This study identifies Rheb as a nodal point that couples circadian clock and mitochondrial architecture for optimal mitochondrial metabolism.

Decreased Risk in the Pancreatic Cancer With History of Hay Fever: A Meta-Analysis.

Background: An increasing incidence of pancreatic cancer has been observed worldwide over the last few decades. Previous reports suggested that hay fever, a common allergic disease, may function in pancreatic cancer. Data on hay fever as a risk or protective factor for pancreatic cancer was controversial in several case-control reports. So, we here did a meta-analysis on published studies to evaluate the association of hay fever and the risk of pancreatic cancer. Methods: A comprehensive literature search was performed through public databases. The association between hay fever and pancreatic cancer was evaluated by odds ratios (ORs) and 95% confidence intervals (CIs). The Cochran's Q test and I2 index were used to evaluate heterogeneity. Results: We included 8 population-based case-control studies involving 10,454 participants from 1986 to 2014. A history of hay fever was associated with a decreased risk of pancreatic cancer (OR, 0.57; 95% CI, 0.50-0.64, P < 0.00001) through fixed effect model. Conclusion: The result of our study suggested that hay fever may significantly decrease the risk of pancreatic cancer.

Engrailed 2 (EN2) acts as a glioma suppressor by inhibiting tumor proliferation/invasion and enhancing sensitivity to temozolomide.

BACKGROUND: Glioma is one of the most malignant brain tumors and accounts for the majority of brain cancer related death. Despite progress on mechanistic studies, current understandings of the initiation and progression of glioma are still incomplete. Previous studies demonstrate that Engrailed-2 (EN2), a homeobox-containing transcription factor, is associated with tumorigenesis in a range of cancers heterogeneously, however, the profiles of EN2 expression and its potential functions in gliomas remain unclear. METHODS: Real-time PCR was used to identify the expression of EN2 in glioma tissues. To study the biological function of EN2 in glioma, we compared the cell viability and proliferation profiles between EN2 overexpressed and control cells using cell counting kit-8 (CCK8) assay, EdU incorporation assay and colony formation assay. Flow cytometry and Hoechst staining assays were performed to investigate the role of EN2 on glioma cell death. Finally, wound healing and transwell assays were carried out to investigate the role of EN2 on glioma cell invasion. RESULTS: We identified that EN2 was downregulated in human gliomas compared with paired adjacent normal tissues and negatively associated with glioma malignancy. Elevated EN2 expression inhibits cell proliferation, enhances glioma sensitivity to temozolomide and inhibits migration/invasion of glioma cells. CONCLUSIONS: Our data identify a novel function of EN2 in glioma suppression and provide potential therapeutic targets for glioma therapy.

LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

Terahertz Spectroscopic Diagnosis of Myelin Deficit Brain in Mice and Rhesus Monkey with Chemometric Techniques.

While myelin deficit of the central nervous system leads to several severe diseases, the definitive diagnostic means are lacking. We proposed and performed terahertz time-domain spectroscopy (THz-TDS) combined with chemometric techniques to discriminate and evaluate the severity of myelin deficit in mouse and rhesus monkey brains. The THz refractive index and absorption coefficient of paraffin-embedded brain tissues from both normal and mutant dysmyelinating mice are shown. Principal component analysis of time-domain THz signal (PCA-tdTHz) and absorption-refractive index relation of THz spectrum identified myelin deficit without exogenous labeling or any pretreatment. Further, with the established PCA-tdTHz, we evaluated the severity of myelin deficit lesions in rhesus monkey brain induced by experimental autoimmune encephalomyelitis, which is the most-studied animal model of multiple sclerosis. The results well matched the pathological analysis, indicating that PCA-tdTHz is a quick, powerful, evolving tool for identification and evaluation myelin deficit in preclinical animals and potentially in para-clinical human biopsy.