Abstract Aims Glioma is characterized by an immunosuppressed environment and a poor prognosis. The accumulation of Amyloid β (A β ) leads to an active environment during the early stages of Alzheimer's disease (AD). A β is also present in glioma tissues; however, the biological and translational implications of A β in glioma are elusive. Methods Immunohistochemical (IHC) staining, Kaplan–Meier (KM) survival analysis and Cox regression analysis on a cohort of 79 patients from our institution were performed to investigate the association between A β and the malignancy of glioma. Subsequently, the potential of oligomer‐A β 42 (OA β 42) to inhibit glioma growth was investigated in vivo and in vitro . Immunofluorescence staining and phagocytosis assays were performed to evaluate the activation of microglia. Finally, RNA‐seq was utilized to identify the predominant signaling involved in this process and in vitro studies were performed to validate them. Results A positive correlation between A β and a favorable prognosis was observed in glioma. Furthermore, OA β 42 suppressed glioma growth by enhancing the phagocytic activity of microglia. Insulin‐like growth factor 1 (IGF‐1) secreted by OA β 42‐activated microglia was essential in the engulfment process. Conclusion Our study proved an anti‐glioma effect of A β , and microglia could serve as a cellular target for treating glioma with OA β 42.
Background: Brain tumor initiating cells (BTICs) play a key role in the progression and relapse of the dreadful glioblastoma. Targeting the TLX involved self-renewal mechanism of BITCs may enable us to develop novel therapeutic strategy for glioblastoma.Methods: The function of NR2E (TLX) and its interacting protein-LSD1 in BTICs were characterized by gene knockdown combined with tumor sphere formation assay, cell-growth assay, co-immunoprecipitation and chromatin immunoprecipitation assays. NR2E interacting peptide of LSD1 was identified and confirmed by Amide Hydrogen/Deuterium Exchange and Mass Spectrometry (HDX-MS) and in vitro functional assay with LSD1 fragment deletion mutants. The in vivo function of the peptide was further examined with patient-derived glioblastoma initiating cell xenograft mouse model.Findings: NR2E1 recruits LSD1 to remove the active epigenetic marker H3K4me3 at Pten promoter and repress its expression, thereby promoting BTIC proliferation. LSD1 peptide (L197-211) that locates at the LSD1 SWIRM domain is critical for the interaction between NR2E1 and LSD1. Overexpression of this peptide inhibits BTIC proliferation and brain tumor growth.Interpretation: Our studies show that NR2E1 partners with LSD1 to promote the self-renewal of BTICs. Interference of NR2E1 and LSD1 interaction by peptide L197-211 may be explored as a novel therapeutic strategy for malignant brain tumors.Funding Information: This work was supported by funds from National Natural Science Foundation of China (NSFC) (Grant No. 81773156 to PY and Grant No. 8187232 to YM) and the support of the Ministry of Education of Singapore Academic Research Fund to the Singapore researchers to KS.Declaration of Interests: The authors declare that no competing interest exists.Ethics Approval Statement: The animal experiments were performed under the approval from Animal Experimentation Ethics Committee (AEEC) in the Sixth Affiliated Hospital of Sun Yatsen University.
Abstract BACKGROUND Glioma is one of the leading causes of brain tumors, but few etiologic factors of primary gliomas were identified. Previous observational research has shown an association between viral infection and glioma risk. Here, we sought to use Mendelian Randomization (MR) analysis to explore the direction and magnitude of the causal relationship between viral infections and glioma. METHODS We conducted a two-sample bi-directional MR analysis using Genome-Wide Association Study (GWAS) data. Summary statistics data of glioma were collected from the most extensive meta-analysis GWAS involving 12,488 cases and 18,169 controls. Single Nucleotide Polymorphisms (SNPs) associated with the exposures were used as instrumental variables to estimate the causal relationship between glioma and twelve types of viral infections from corresponding GWAS data. In addition, sensitivity analyses were performed. RESULTS After correcting for multiple tests and sensitivity analysis, we detected that genetically predicted VZV infection significantly decreased the risk of lower-grade glioma (LGG) development (OR=0.85, 95% CI: 0.76-0.96, P=0.0066, FDR=0.0396). No causal effects of the other eleven viral infections on glioma and reverse causality were detected. CONCLUSIONS Our research is one of this field's first and most significant studies. We showed robust evidence supporting that genetically predicted VZV infection reduces the risk of LGG. The findings from our research are a big step forward in understanding the etiology of glioma.
Background: Medulloblastoma (MB) is one of the most malignant neuroepithelial tumors in the central nervous system. This study aimed to establish an effective prognostic nomogram and risk grouping system for predicting overall survival (OS) of patients with MB. Materials and Methods: The nomogram was constructed based on data from the database of Surveillance, Epidemiology, and End Results (SEER). This database consisted of 2,824 patients with medulloblastoma and was used as the training cohort. The data of another additional 161 patients treated at the Sun Yat-sen University Cancer Center (SYSUCC) were used as the external validation cohort. Cox regression analysis was used to select independent prognostic factors. Concordance index (C-index) and calibration curve were used to predict the prognostic effect of the nomogram for overall survival. Results: In the training cohort, Cox regression analyses showed that the prognostic factors included histopathology, surgery, radiotherapy, chemotherapy, tumor size, dissemination, and age at diagnosis. The internal and external validated C-indexes were 0.681 and 0.644, respectively. Calibration curves showed that the nomogram was able to predict 1-, 3-, and 5-year OS for patients with MB precisely. Using the training cohort, a risk grouping system was built, which could perfectly classify patients into four risk nomogroups with a 5-year survival rate of 83.9%, 76.5%, 64.5%, and 46.8%, respectively. Conclusion: We built and validated a nomogram and risk grouping system that can provide individual prediction of OS and distinguish MB patients from different risk groups. This nomogram and risk grouping system could help clinicians making better treatment plan and prognostic assessment.
The present study explored the predictive value of systemic inflammatory indexes in diagnosing grade III gliomas of oligodendroglial origin.A retrospective study of 154 patients with grade III gliomas was conducted. Systemic inflammatory indexes, including neutrophil-to-lymphocyte ratio (NLR), albumin-to-gamma-glutamyl transferase ratio (AGR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, prognostic nutritional index, and fibrinogen-to-albumin ratio, were reviewed. The resulting predictive model was externally validated using a demographic-matched cohort of 49 grade III glioma patients.In the training set, gliomas of oligodendroglial origin tended to have a lower NLR (P=0.018) and a higher AGR (P=0.036) than those with tumors of astrocytic origin. Moreover, both NLR and AGR had predictive value for oligodendroglial tumors, when compared with astrocytic tumors. The best diagnostic value was obtained using NLR + AGR (AUC =64.9%, 95% CI: 55.5-74.3%, P=0.005). In the validation set, NLR + AGR satisfactorily predicted the presence of oligodendroglial tumors (AUC =66.5%, 95% CI: 50.6-82.4%, P<0.05) and co-deletion of 1p/19q (AUC =73.7%, 95% CI: 59.2-88.1%, P=0.005). Multivariate analysis further demonstrated NLR + AGR as an independent predictor for overall survival.Pretreatment NLR and AGR aid in prognosis and diagnosing grade III oligodendroglial gliomas.
Objective: To observe side-reaction and preliminary efficacy of local adoptive immunotherapy with cytokine-induced killer cells and to develop an aggressive treatment way to improve the prognosis of malignant gliomas. Methods: The tumor was resected totally or sub-totally under the neurosurgical microscope,when radiotherapy and chemotherapy have been finished for at least 6 weeks,if the patients were eligible, the CIK cells combined with 0.5 million IU interleukin-2 (IL-2) were infused via the ommaya reservoir-catheter system placed into the surgical resection cavity during operation. CIK cells were generated ex vivo by incubating peripheral blood mononuclear cells of the patient 7–10 days ago, and the number of CIK cells was 4 x 108,with the total volume is less than 4 ml, then, IL-2 alone was given via the ommaya reservoir on day 3 and 5 to complete one cycle of the therapy. This 7-day cycle was repeated at the next week. Each two-cycle constituted one full course of therapy. The treatment consisted of two 1-week cycles of therapy over 8–12 weeks period. Side-reaction were observed, such as headache,fever,and so on. Besides side-reaction, The efficacy was assessed by MRI scans retreated at 2- or 3-month interval and the survival of the patient summarized according to the follow-up also. Results: From September 2002 to May 2004, six malignant glioma patients were treated with local CIK cells therapy for ten courses, all the patients were followed up from 7 to 24 months by the end of March 2005. The Side-reaction included fever in two cases, headache in three cases and transient aphasia in one case and limb weakness in one patients, they were all controlled and the patient could tolerate. For the six patients in our study, with two out of 6 patients were still alive by the end of May 2016, survival time without recurrence was 13 and 12 years and the Karnofsky Permanence Scale were 100 and 70, respectively. Of the four patients with tumor recurrence, disease-free survival time was twenty months without other treatment after immunotherapy in one case, the rest three patients died. The efficacy was assessed: CR was in two cases;PR and ST were each in one case and PR in two cases. CONCLUSION: CIK cells can be administered intracavitary into CNS to treat primary malignant gliomas,the side-reaction was well tolerated; According to the eligibility criteria strictly, local cytokine-induced killer cell therapy for malignant gliomas appears to be safe and effective, it should be considered an option for patients with high-grade gliomas refractive to standard therapeutic approaches.
Abstract Background Lung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A deep understanding of molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs. Methods Here, we performed integrated analyses of genomic, transcriptomic, proteomic, metabolomic, and single-cell RNA sequencing data which were derived from a total number of 154 patients with paired and unpaired primary lung cancer and LC-BrM, spanning four published and two newly generated patient cohorts on both bulk and single cell levels. Results We uncovered that LC-BrMs exhibited a significantly greater intra-tumor heterogeneity. We also observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TTN , TP53 , MUC16 , LRP1B , RYR2 , and EGFR . In addition, the genome-wide landscape of somatic copy number alterations was similar between primary lung cancers and LC-BrM lesions. Nevertheless, several regions of focal amplification were significantly enriched in LC-BrMs, including 5p15.33 and 20q13.33. Intriguingly, integrated analyses of transcriptomic, proteomic, and metabolomic data revealed mitochondrial-specific metabolism was activated but tumor immune microenvironment was suppressed in LC-BrMs. Subsequently, we validated our results by conducting real-time quantitative reverse transcription PCR experiments, immunohistochemistry, and multiplexed immunofluorescence staining of patients’ paired tumor specimens. Therapeutically, targeting oxidative phosphorylation with gamitrinib in patient-derived organoids of LC-BrMs induced apoptosis and inhibited cell proliferation. The combination of gamitrinib plus anti-PD-1 immunotherapy significantly improved survival of mice bearing LC-BrMs. Patients with a higher expression of mitochondrial metabolism genes but a lower expression of immune genes in their LC-BrM lesions tended to have a worse survival outcome. Conclusions In conclusion, our findings not only provide comprehensive and integrated perspectives of molecular underpinnings of LC-BrMs but also contribute to the development of a potential, rationale-based combinatorial therapeutic strategy with the goal of translating it into clinical trials for patients with LC-BrMs.
Abstract Context Precision medicine for pituitary neuroendocrine tumors (PitNETs) is limited by the lack of reliable research models. Objective To generate patient-derived organoids (PDOs), which could serve as a platform for personalized drug screening for PitNET patients. Design From July 2019 to May 2022, a total of 32 human PitNET specimens were collected for the establishment of organoids with an optimized culture protocol. Setting This study was conducted at Sun Yat-Sen University Cancer Center. Patients PitNET patients who were pathologically confirmed were enrolled in this study. Interventions Histological staining and whole-exome sequencing were utilized to confirm the pathologic and genomic features of PDOs. A drug response assay on PDOs was also performed. Main Outcome Measures PDOs retained key genetic and morphological features of their parental tumors. Results PDOs were successfully established from various types of PitNET samples with an overall success rate of 87.5%. Clinical nonfunctioning PitNETs-derived organoids (22/23, 95.7%) showed a higher likelihood of successful generation compared to those from functioning PitNETs (6/9, 66.7%). Preservation of cellular structure, subtype-specific neuroendocrine profiles, mutational features, and tumor microenvironment heterogeneity from parental tumors was observed. A distinctive response profile in drug tests was observed among the organoids from patients with different subtypes of PitNETs. With the validation of key characteristics from parental tumors in histological, genomic, and microenvironment heterogeneity consistency assays, we demonstrated the predictive value of the PDOs in testing individual drugs. Conclusion The established PDOs, retaining typical features of parental tumors, indicate a translational significance in innovating personalized treatment for refractory PitNETs.
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