A natural compound melatonin enhances the effects of Nimotuzumab via inhibiting EGFR in glioblastoma.

Sleep disorders are prevalent and debilitating symptoms in primary brain tumor patients, notably those receiving radiation therapy. Nevertheless, the relationship between sleep disorders, melatonin - a circadian rhythm regulatory hormone, and gliomas is underexplored. Melatonin exhibits various biological functions, one of them being anti-tumor activity. In the context of gliomas, often overexpressing EGFR, the humanized monoclonal antibody Nimotuzumab targets this marker. Our research discovered that variations in circadian rhythm significantly influence tumor growth in mice through impacting melatonin secretion. Harnessing proteogenomic, we identified that melatonin could inhibit the phosphorylation of EGFR and its downstream effectors, key elements in angiogenesis and tumor progression. Building on structural simulations, we propose that melatonin may amplify Nimotuzumab's anti-glioma efficacy by inhibiting EGFR TK dimerization. This proposition was validated in our in vitro and in vivo studies where melatonin synergistically augmented cytotoxicity and apoptosis in Nimotuzumab-treated glioma cells. Thus, melatonin shows promise as a beneficial addition to Nimotuzumab treatment in glioma patients.

Central nervous system complications in SARS-CoV-2-infected patients.

OBJECTIVE: To investigate the clinical manifestations, treatment and prognosis of COVID-19-associated central nervous system (CNS) complications. METHODS: In this single-centre observation study, we recruited patients with COVID-19-associated CNS complications at the neurology inpatient department of the Eighth Affiliated Hospital, Sun Yat-Sen University (Futian, Shenzhen) from Dec 2022 to Feb 2023. Patients were analysed for demographics, clinical manifestations, cerebrospinal fluid properties, electroencephalographic features, neuroimaging characteristics, and treatment outcome. All patients were followed-up at 1 and 2 months after discharge until Apr 2023. RESULTS: Of the 12 patients with COVID-19-associated CNS complications, the CNS symptoms occur between 0 days and 4 weeks after SARS-CoV-2 infection. The most common CNS symptoms were memory deficits (4/12, 33%), Unresponsiveness (4/12, 33%), mental and behavioural disorders (4/12, 33%). Seven of 12 cases can be categorized as probable SARS-CoV-2 encephalitis, and 5 cases can be described as brainstem encephalitis, acute disseminated encephalomyelitis, optic neuritis, multiple sclerosis or tremor probably associated with SARS-CoV-2 infection. Six patients received antiviral therapy, and 11 patients received glucocorticoid therapy, of which 3 patients received human immunoglobulin synchronously. Nine patients recovered well, two patients had residual neurological dysfunction, and one patient passed away from complications associated with tumor. CONCLUSION: In this observational study, we found that the inflammatory or immune-related complications were relatively common manifestations of COVID-19-associated CNS complications, including different phenotypes of encephalitis and CNS inflammatory demyelinating diseases. Most patients recovered well, but a few patients had significant neurological dysfunctions remaining.

Phytochemical-Mediated Glioma Targeted Treatment: Drug Resistance and Novel Delivery Systems.

Glioma, especially its most malignant type, Glioblastoma (GBM), is the most common and the most aggressive malignant tumour in the central nervous system. Currently, we have no specific therapies that can significantly improve its dismal prognosis. Recent studies have reported promising in vitro experimental results of several novel glioma-targeting drugs; these studies are encouraging to both researchers and patients. However, clinical trials have revealed that novel compounds that focus on a single, clear glioma genetic alteration may not achieve a satisfactory outcome or have side effects that are unbearable. Based on this consensus, phytochemicals that exhibit multiple bioactivities have recently attracted much attention. Traditional Chinese medicine and traditional Indian medicine (Ayurveda) have shown that phytocompounds inhibit glioma angiogenesis, cancer stem cells and tumour proliferation; these results suggest a novel drug therapeutic strategy. However, single phytocompounds or their direct usage may not reverse comprehensive malignancy due to poor histological penetrability or relatively unsatisfactory in vivo efficiency. Recent research that has employed temozolomide combination treatment and Nanoparticles (NPs) with phytocompounds has revealed a powerful dual-target therapy and a high blood-brain barrier penetrability, which is accompanied by low side effects and strong specific targeting. This review is focused on major phytocompounds that have contributed to glioma-targeting treatment in recent years and their role in drug resistance inhibition, as well as novel drug delivery systems for clinical strategies. Lastly, we summarize a possible research strategy for the future.

Proteomics identifies EGF-like domain multiple 7 as a potential therapeutic target for epidermal growth factor receptor-positive glioma.

BACKGROUND: Glioma, the most frequent primary tumor of the central nervous system, has poor prognosis. The epidermal growth factor receptor (EGFR) pathway and angiogenesis play important roles in glioma growth, invasion, and recurrence. The present study aimed to use proteomic methods to probe into the role of the EGF-EGFR-angiogenesis axis in the tumorigenesis of glioma and access the therapeutic efficacy of selumetinib on glioma. METHODS: Proteomic profiling was used to characterize 200 paired EGFR-positive and EGFR-negative glioma tissues of all pathological types. The quantitative mass spectrometry data were used for systematic analysis of the proteomic profiles of 10 EGFR-positive and 10 EGFR-negative glioma cases. Consensus-clustering analysis was used to screen target proteins. Immunofluorescence analysis, cell growth assay, and intracranial xenograft experiments were used to verify and test the therapeutic effect of selumetinib on glioma. RESULTS: Advanced proteomic screening demonstrated that the expression of EGF-like domain multiple 7 (EGFL7) was higher in EGFR-positive tumor tissues than in EGFR-negative tumor tissues. In addition, EGFL7 could act as an activator in vitro and in vivo to promote glioma cell proliferation. EGFL7 was associated strongly with EGFR and prognosis. EGFL7 knockdown effectively suppressed glioma cell proliferation. Selumetinib treatment showed tumor reduction effect in EGFR-positive glioblastoma xenograft mouse model. CONCLUSIONS: EGFL7 is a potential diagnostic biomarker and therapeutic target of glioma. Selumetinib could target the EGFR pathway and possibly improve the prognosis of EGFR-positive glioma.

Nomogram-Predicted Survival of Breast Cancer Brain Metastasis: a SEER-Based Population Study.

OBJECTIVE: The prognosis of patients with breast cancer brain metastasis (BCBM) was dismal and the prognoses varied according to different prognostic factors. In this study, we used the SEER (Surveillance Epidemiology and End Results) database to identify prognostic factors with the BCBMs. METHODS: We identified and built a robust prognostic model and developed reliable nomograms to estimate the individualized overall survival (OS) and breast cancer-specific survival (BCSS) of patients with BCBM. A total of 789 patients with newly diagnosed BCBM were identified from the SEER database and randomly divided into training (n = 554) and testing (n = 235) cohorts. The log-rank tests and the Cox proportional hazards model were applied to evaluate the prognostic effects of multiple clinicopathologic variables on the survival of training cohorts. Significant prognostic factors were combined to build the nomograms that were evaluated using the concordance index and calibration plots for internal and external validations. RESULTS: Two nomograms shared the common prognostic indicators including age, tumor subtype, chemotherapy, surgery, number of metastatic sites except the brain, and median household income. In the training cohort, the Harrell concordance index for the constructed nomogram to predict OS and BCSS was 0.668 and 0.676, respectively. The calibration plots were consistent between nomogram-predicted survival probability and actual survival probability. These results were reproducible when nomograms were applied to the testing cohort for external validation. CONCLUSIONS: Nomograms that predicted 6-month, 1-year, and 2-year OS and BCSS for patients with newly diagnosed BCBM with satisfactory performance were constructed to help physicians in evaluating the high risk of mortality in patients.

A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis.

H2AX safeguards genomic stability in a dose-dependent manner; however, mechanisms governing its proteostasis are poorly understood. Here, we identify a PRMT5-RNF168-SMURF2 cascade that regulates H2AX proteostasis. We show that PRMT5 sustains the expression of RNF168, an E3 ubiquitin ligase essential for DNA damage response (DDR). Suppression of PRMT5 occurs in methylthioadenosine phosphorylase (MTAP)-deficient glioblastoma cells and attenuates the expression of RNF168, leading to destabilization of H2AX by E3 ubiquitin ligase SMURF2. RNF168 and SMURF2 serve as a stabilizer and destabilizer of H2AX, respectively, via their dynamic interactions with H2AX. In supporting an important role of this signaling cascade in regulating H2AX, MTAP-deficient glioblastoma cells display higher levels of DNA damage spontaneously or in response to genotoxic agents. These findings reveal a regulatory mechanism of H2AX proteostasis and define a signaling cascade that is essential to DDR and that is disrupted by the loss of a metabolic enzyme in tumor cells.

Combined Therapy Sensitivity Index Based on a 13-Gene Signature Predicts Prognosis for IDH Wild-type and MGMT Promoter Unmethylated Glioblastoma Patients.

Glioblastoma (GBM) is one of the lethal tumors with poor prognosis. However, prognostic prediction approaches need to be further explored. Therefore, we developed an evaluation system that could be used for prognostic prediction of GBM patients. Published mRNA expression datasets from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Chinese Glioma Genome Atlas (CGGA) were analyzed. Quantitative Realtime-PCR of signature genes and molecular aberrations of 178 Xiangya GBM patients were used for confirmation. Gene set enrichment analysis (GSEA) was performed for functional annotation. As a result, we established a 13-gene signature which named Combined Therapy Sensitivity Index (CTSI). Based on a cutoff point, we divided patients into high-risk group and low-risk group. Based on Kaplan-Meier analysis and multivariate Cox regression analysis, we found that patients in the high-risk group had a shorter overall survival time than patients in the low-risk group (p<0.001 in TCGA and CGGA datasets, p=0.047 in GSE4271 dataset, p=0.008 in Xiangya GBM cohort, HR: 1.65-3.42). By comparing the status of IDH mutation, TERT promoter mutation (TERTp-mut) and MGMT promoter methylation, CTSI was predictable in IDH wild-type (IDH-wt)/MGMT promoter unmethylated (MGMTp-unmeth) patients (p=0.037 in IDH-wt/TERTp-mut/MGMTp-unmeth subgroup, HR: 1.98; p=0.032 in IDH-wt/TERTp-wt/MGMTp-unmeth subgroup, HR: 2.09). Based on GESA, the Gene Ontology (GO) gene sets were enriched differently between CTSI high-risk and low-risk groups. Our results showed CTSI risk score can predict the prognosis of IDH-wt/MGMTp-unmeth GBM patients. Based on CTSI, combined with the status of IDH mutation, TERT promoter mutation and MGMT promoter methylation, a stepwise prognosis evaluation system which can provide precise prognosis prediction for GBM patients was established.

Regular Music Exposure in Juvenile Rats Facilitates Conditioned Fear Extinction and Reduces Anxiety after Foot Shock in Adulthood.

Music exposure is known to play a positive role in learning and memory and can be a complementary treatment for anxiety and fear. However, whether juvenile music exposure affects adult behavior is not known. Two-week-old Sprague-Dawley rats were exposed to music for 2 hours daily or to background noise (controls) for a period of 3 weeks. At 60 days of age, rats were subjected to auditory fear conditioning, fear extinction training, and anxiety-like behavior assessments or to anterior cingulate cortex (ACC) brain-derived neurotrophic factor (BDNF) assays. We found that the music-exposed rats showed significantly less freezing behaviors during fear extinction training and spent more time in the open arm of the elevated plus maze after fear conditioning when compared with the control rats. Moreover, the BDNF levels in the ACC in the music group were significantly higher than those of the controls with the fear conditioning session. This result suggests that music exposure in juvenile rats decreases anxiety-like behaviors, facilitates fear extinction, and increases BDNF levels in the ACC in adulthood after a stressful event.

EGFL7 is an intercellular EGFR signal messenger that plays an oncogenic role in glioma.

Epidermal Growth Factor like domain 7 (EGFL7), also known as Vascular Endothelial-statin (VE-statin), is a secreted angiogenic factor. Recent data have demonstrated the potential oncogenic role and prognostic significance of EGFL7 in several human cancers. However, the clinical signature and further mechanisms of EGFL7's function in gliomagenesis are poorly understood. In the present study, we found that increased EGFL7 expression was associated with tumor grade. High expression of EGFL7 in EGFRvIII-positive glioblastoma multiforme (GBM) was determined to be a strong and independent risk factor for reduced life expectancy. EGFRvIII cells can secrete the EGFL7 protein to improve the activity of the ß-catenin/TCF4 Transcription complex in EGFRwt cells, thus promoting their own EGFL7 expression. Our research demonstrates that oncogenic activation of EGFRwt in GBM is likely maintained by a continuous EGFL7 autocrine flow line, and may be an attractive target for therapeutic intervention.

Sample Level Enrichment Analysis of KEGG Pathways Identifies Clinically Relevant Subtypes of Glioblastoma.

Background: Glioblastoma is the most lethal primary brain tumor in adults. Aberrant signal transduction pathways, associated with the progression of glioblastoma, have been identified recently and may offer a potential gene therapy strategy. Methods and Findings: We first used the sample level enrichment analysis to transfer gene expression profile of TCGA dataset into pathway enrichment z-score matrix. Then, we classified glioblastoma into five subtypes (Cluster A to Cluster E) by the consensus clustering and silhouette analysis. Principle component analysis showed the five subtype could be separated by first three principle components. Integrative omics data showed that mesenchymal subtype was rich in Cluster A, neural subtype was centered in Cluster D and proneural subtype was gathered in Cluster E, while Cluster E showed a high percentage of G-CIMP subtype. Additionally, according to analyze the overall survival and progression free survival of each subtype by Kaplan-Merie analysis and Cox hazard proportion model, we identified Cluster D and Cluster E received a better prognosis. Conclusions: We report a clinically relevant classification of glioblastoma based on sample level KEGG pathway enrichment profile and this novel classification system provided new insights into the heterogeneity of glioblastoma, and may be used as an important clinical tool to predict the prognosis.