Dendritic cell therapy for neurospoagioma: Immunomodulation mediated by tumor vaccine.

Neurospagioma, arising from different glial cells such as astrocytes, oligodendrocytes, and ependymal cells, stands as the prevalent intracranial tumor within the central nervous system. Among its variants, glioblastoma (GBM) represents the most aggressive form, characterized by a notably high occurrence rate and a discouragingly low survival prognosis. The formidable challenge posed by glioblastoma underscores its critical importance as a life-threatening ailment. Currently, clinical approaches often involve surgical excision along with a combination of radiotherapy and chemotherapy. However, these treatments frequently result in a notable recurrence rate, accompanied by substantial adverse effects that significantly compromise the overall prognosis. Hence, there is a crucial need to investigate novel and dependable treatment strategies. Dendritic cells (DCs), being specialized antigen-presenting cells (APCs), hold a significant position in both innate and adaptive immune responses. Presently, DC vaccines have gained widespread application in the treatment of various tumors, including neurospoagioma. In this review, we summarize the immunomodulatory effects and related mechanisms of DC vaccines in neurospoagioma as well as the progress of clinical trials to propose possible challenges of DC vaccines and new development directions.

Histone lactylation-derived LINC01127 promotes the self-renewal of glioblastoma stem cells via the cis-regulating the MAP4K4 to activate JNK pathway.

Gliomas are the most prevalent and aggressive brain tumors, exhibiting high proliferation, abnormal glycolysis, and poor prognosis. LncRNAs act as regulatory molecules and play crucial roles in the malignant behaviors of GBM cells, including cell self-renewal. However, the regulatory mechanisms involved are largely unknown. In this study, we performed bioinformatics analysis to explore NF-κB pathway-related lncRNAs. ECAR and qRT-PCR were used to measure the relationship between glycolytic activity and lncRNA expression. Assays such as RIP-PCR and ChIP-PCR were employed to reveal the regulatory mechanisms of the lncRNA. Neurosphere formation and limiting dilution assays were performed to evaluate the self-renewal capacity of GBM cells. In our study, we identified an NF-κB pathway-related lncRNA named LINC01127 in GBM, which was found to be associated with poor progression of GBM. Functionally, the NF-κB pathway promoted warburg effect, which, in turn, induced the lactylation of H3 histone and increased the expression of LINC01127. Consequently, this enhancement of LINC01127 expression led to the promotion of self-renewal in GBM cells. Furthermore, LINC01127 regulated MAP4K4 expression in cis by directly guiding POLR2A to the MAP4K4 promoter regions, thereby leading to JNK pathway activation, and ultimately modulating the self-renewal of GBM cells. Moreover, the activated JNK pathway promoted the phosphorylation of IκBα. Overall, targeting LINC01127-mediated axis impeded orthotopic tumor growth in GBM xenografts. Taken together these results revealed that warburg effect-induced histone lactylation drives NF-κB-related LINC01127 expression, thereby promoting the self-renewal of GBM cells through the MAP4K4/JNK/NF-κB axis, and providing substantial evidence that LINC01127 might provide a novel therapeutic strategy for GBM patients.

HK3 stimulates immune cell infiltration to promote glioma deterioration.

BACKGROUND: Glioma is the most common and lethal type of brain tumor, and it is characterized by unfavorable prognosis and high recurrence rates. The reprogramming of energy metabolism and an immunosuppressive tumor microenvironment (TME) are two hallmarks of tumors. Complex and dynamic interactions between neoplastic cells and the surrounding microenvironment can generate an immunosuppressive TME, which can accelerate the malignant progression of glioma. Therefore, it is crucial to explore associations between energy metabolism and the immunosuppressive TME and to identify new biomarkers for glioma prognosis. METHODS: In our work, we analyzed the co-expression relationship between glycolytic genes and immune checkpoints based on the transcriptomic data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) and found the correlation between HK3 expression and glioma tumor immune status. To investigate the biological role of HK3 in glioma, we performed bioinformatics analysis and established a mouse glioblastoma (GBM) xenograft model. RESULTS: Our study showed that HK3 significantly stimulated immune cell infiltration into the glioma TME. Tissue samples with higher HK3 expressive level showed increasing levels of immune cells infiltration, including M2 macrophages, neutrophils, and various subtypes of activated memory CD4+ T cells. Furthermore, HK3 expression was significantly increasing along with the elevated tumor grade, had a higher level in the mesenchymal subtype compared with those in other subtypes of GBM and could independently predict poor outcomes of GBM patients. CONCLUSION: The present work mainly concentrated on the biological role of HK3 in glioma and offered a novel insight of HK3 regulating the activation of immune cells in the glioma microenvironment. These findings could provide a new theoretical evidence for understanding the metabolic molecular within the glioma microenvironment and identifying new therapeutic targets.

Using integrated analysis from multicentre studies to identify RNA methylation-related lncRNA risk stratification systems for glioma.

BACKGROUND: N6-methyladenosine (m6A), 5-methylcytosine (m5C) and N1-methyladenosine (m1A) are the main RNA methylation modifications involved in the progression of cancer. However, it is still unclear whether RNA methylation-related long noncoding RNAs (lncRNAs) affect the prognosis of glioma. METHODS: We summarized 32 m6A/m5C/m1A-related genes and downloaded RNA-seq data and clinical information from The Cancer Genome Atlas (TCGA) database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to identify differentially expressed (DE-) RNA methylation-related lncRNAs in order to construct a prognostic signature of glioma and in order to determine their correlation with immune function, immune therapy and drug sensitivity. In vitro and in vivo assays were performed to elucidate the effects of RNA methylation-related lncRNAs on glioma. RESULTS: A total of ten RNA methylation-related lncRNAs were used to construct a survival and prognosis signature, which had good independent prediction ability for patients. It was found that the high-risk group had worse overall survival (OS) than the low-risk group in all cohorts. In addition, the risk group informed the immune function, immunotherapy response and drug sensitivity of patients with glioma in different subgroups. Knockdown of RP11-98I9.4 and RP11-752G15.8 induced a more invasive phenotype, accelerated cell growth and apparent resistance to temozolomide (TMZ) both in vitro and in vivo. We observed significantly elevated global RNA m5C and m6A levels in glioma cells. CONCLUSION: Our study determined the prognostic implication of RNA methylation-related lncRNAs in gliomas, established an RNA methylation-related lncRNA prognostic model, and elucidated that RP11-98I9.4 and RP11-752G15.8 could suppress glioma proliferation, migration and TMZ resistance. In the future, these RNA methylation-related lncRNAs may become a new choice for immunotherapy of glioma.

Safety and Efficacy of Anlotinib Hydrochloride Plus Temozolomide in Patients with Recurrent Glioblastoma.

PURPOSE: Glioblastoma (GBM) is a highly vascularized tumor with few treatment options after disease recurrence. Here, we report the efficacy and safety of anlotinib hydrochloride plus temozolomide in patients with recurrent GBM. PATIENTS AND METHODS: Patients with first definite postsurgical progression of histologically confirmed GBM preceded by standard radiotherapy and temozolomide chemotherapy were eligible for inclusion. All patients received temozolomide (150-200 mg/m2, orally, every day (QD) d1-5/4 wk) and anlotinib (10 mg, orally, QD, d1-14/3 wk) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by the Response Assessment in Neuro-Oncology (RANO) criteria. RESULTS: Twenty-one patients were enrolled between May 2020 and July 2021, with a median age of 55 (range 27-68) years old. According to the Response Assessment in Neuro-Oncology (RANO) criteria, tumor response occurred in 17 patients, of which 9 patients had a complete response, and the objective response rate was 81.0% [95% confidence interval (CI), 62.6-99.3]. The disease control rate was 95.2% (95% CI, 76.2-99.9), with three additional patients achieving a stable disease without tumor progression. The median PFS was 7.3 months (95% CI, 4.9-9.7), and the 6-month PFS rate was 61.9% (95% CI, 39.3-84.6). The median overall survival was 16.9 months (95% CI, 7.8-26.0). The most common adverse events were leukocytopenia (66.7%), thrombocytopenia (38.1%), and hypertriglyceridemia (38.1%). Five patients had nine grade 3 adverse events, with a 23.8% incidence rate. Two patients discontinued therapy due to ischemic stroke (grade 3) and wound dehiscence (grade 1), respectively. No grade 4 or treatment-related deaths occurred in this study. CONCLUSIONS: Anlotinib combined with temozolomide is efficacious and tolerated in patients with recurrent GBM.

Development and validation of a pyroptosis-related genes signature for risk stratification in gliomas.

Background: Glioma is a highly heterogeneous disease, causing the prognostic prediction a challenge. Pyroptosis, a programmed cell death mediated by gasdermin (GSDM), is characterized by cell swelling and the release of inflammatory factors. Pyroptosis occurs in several types of tumor cells, including gliomas. However, the value of pyroptosis-related genes (PRGs) in the prognosis of glioma remains to be further clarified. Methods: In this study, mRNA expression profiles and clinical data of glioma patients were acquired from TCGA and CGGA databases, and one hundred and eighteen PRGs were obtained from the Molecular Signatures Database and GeneCards. Then, consensus clustering analysis was performed to cluster glioma patients. The least absolute shrinkage and selection operator (LASSO) Cox regression model was used to establish a polygenic signature. Functional verification of the pyroptosis-related gene GSDMD was achieved by gene knockdown and western blotting. Moreover, the immune infiltration status between two different risk groups were analyzed through the "gsva" R package. Results: Our results demonstrated that the majority of PRGs (82.2%) were differentially expressed between lower-grade gliomas (LGG) and glioblastoma (GBM) in the TCGA cohort. In univariate Cox regression analysis, eighty-three PRGs were shown to be associated with overall survival (OS). A five-gene signature was constructed to divide patients into two risk groups. Compared with patients in the low-risk group, patients in the high-risk group had obviously shorter OS (p < 0.001). Also, we found that the high-risk group showed a higher infiltrating score of immune cells and immune-related functions. Risk score was an independent predictor of OS (HR > 1, p < 0.001). Furthermore, knockdown of GSDMD decreased the expression of IL-1ß and cleaved caspase-1. Conclusion: Our study constructed a new PRGs signature, which can be used to predict the prognosis of glioma patients. Targeting pyroptosis might serve as a potential therapeutic strategy for glioma.

Dexamethasone and compliance affect TTFields efficacy to glioblastoma patients: a systematic review and meta-analysis.

TTFields is a novel treating modality of glioblastoma (GBM) which can significantly prolong the overall survival (OS) of newly diagnosed or recurrent glioblastoma. Some researchers have revealed that a variety of factors can affect the efficacy of TTFields. So, we review the available literature about the influencing factors on efficacy of TTFields and then choose two experimentally supported factors: the dose of dexamethasone and compliance of TTFields to perform a meta-analysis. The PubMed, Embase, and the Cochrane Library are searched. Five articles are identified between 2014 and 2017. Three articles are about the compliance of TTFields. Two articles are about the dose of dexamethasone. The Newcastle-Ottawa Quality Assessment Scale (NOS) is used as an assessment tool to evaluate the methodological quality of all included trials. The scale's range varies from 0 to 9 stars. According to the Cochrane Handbook for Systematic Reviews of Interventions, articles are graded in six items to evaluate the risk of bias. Two reviewers rate the studies independently and the final decision is reached by consensus.Our data shows that the median OS is conspicuously longer in the TTFields group in which the dose of dexamethasone is ≤ 4.1 mg, WMD = 9.23 [95% CI 5.69-12.78]; P < 0.05). And the patients whose compliance of TTFields treatment ≥ 75% (≥ 18 h per day) have a significant lower overall survival risk than the patients whose compliance of TTFields treatment < 75% (HR = 0.57 [95% CI 0.46-0.70]; P < 0.00001).TTFields is a safe and efficient novel treatment modality. The dose of dexamethasone ≤ 4.1 mg of TTFields treatment and the compliance of TTFields treatment ≥ 75%, ≥ 18 h per day are beneficial to the prognosis of the glioblastoma patients.

Prevention of chronic diabetic complications in type 1 diabetes by co-transplantation of umbilical cord mesenchymal stromal cells and autologous bone marrow: a pilot randomized controlled open-label clinical study with 8-year follow-up.

BACKGROUND AIMS: To explore the long-term safety and benefit of umbilical cord mesenchymal stromal cell (MSCs) plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D). METHODS: In the primary completion of this trial (ClinicalTrials.gov identifier: NCT01374854), the authors randomized patients (n = 21 per group) to either SCT or standard care (control) and previously reported effects on insulin secretion. The authors report about the incidence of chronic diabetes complications (primary endpoint) after 8 years of follow-up. The authors also report on secondary endpoints, safety, islet function and metabolic control. RESULTS: Data were obtained from 14 of 21 patients in the SCT group and 15 of 21 patients in the control group who completed follow-up. At 8 years, the incidence of peripheral neuropathy was 7.1% (one of 14) in the SCT group versus 46.7% (seven of 15) in the control group (P = 0.017). The incidence of diabetic nephropathy was 7.1% (one of 14) in the SCT group versus 40.0% (six of 15) in the control group (P = 0.039). The incidence of retinopathy was 7.1% (one of 14) in the SCT group versus 33.3% (five of 15) in the control group (P = 0.081). Two patients (two of 14, 14.3%) in the SCT group and 11 patients (11 of 15, 73.3%) in the control group developed at least one complication (P = 0.001). One and six patients in the SCT group and control group, respectively, had at least two complications (P = 0.039). No malignancies were reported in the treated group. CONCLUSIONS: Co-transplantation of umbilical cord MSCs and aBM-MNCs in patients with established T1D was associated with reduced incidence of chronic diabetes complications.

DREAM: a database of experimentally supported protein-coding RNAs and drug associations in human cancer.

The Drug Response Gene Expression Associated Map, also referred as "DREAM" ( http://bio-big-data.cn:8080/DREAM ), is a manually curated database of experimentally supported protein-coding RNAs and drugs associations in human cancers. The current version of the DREAM documents 3048 entries about scientific literatures supported drug sensitivity or drug intervention related protein-coding RNAs from PubMed database and 195 high-throughput microarray data about drug sensitivity or drug intervention related protein-coding RNAs data from GEO database. Each entry in DREAM database contains detailed information on protein-coding RNA, drug, cancer, and other information including title, PubMed ID, journal, publish time. The DREAM database also provides some data visualization and online analysis services such as volcano plot, GO/KEGG enrichment function analysis, and novel drug discovery analysis. We hope the DREAM database should serve as a valuable resource for clinical practice and basic research, which could help researchers better understand the effects of protein-coding RNAs on drug response in human cancers.

Glioblastoma Cell-Derived lncRNA-Containing Exosomes Induce Microglia to Produce Complement C5, Promoting Chemotherapy Resistance.

Glioblastoma (GBM), the most common malignant primary brain cancer in adults, nearly always becomes resistant to current treatments, including the chemotherapeutic temozolomide (TMZ). The long noncoding RNA (lncRNA) TMZ-associated lncRNA in GBM recurrence (lnc-TALC) promotes GBM resistance to TMZ. Exosomes can release biochemical cargo into the tumor microenvironment (TME) or transfer their contents, including lncRNAs, to other cells as a form of intercellular communication. In this study, we found that lnc-TALC could be incorporated into exosomes and transmitted to tumor-associated macrophages (TAM) and could promote M2 polarization of the microglia. This M2 polarization correlated with secretion of the complement components C5/C5a, which occurred downstream of lnc-TALC binding to ENO1 to promote the phosphorylation of p38 MAPK. In addition, C5 promoted the repair of TMZ-induced DNA damage, leading to chemotherapy resistance, and C5a-targeted immunotherapy showed improved efficacy that limited lnc-TALC-mediated TMZ resistance. Our results reveal that exosome-transmitted lnc-TALC could remodel the GBM microenvironment and reduce tumor sensitivity to TMZ chemotherapy, indicating that the lnc-TALC-mediated cross-talk between GBM cells and microglia could attenuate chemotherapy efficacy and pointing to potential combination therapy strategies to overcome TMZ resistance in GBM.See related Spotlight by Zhao and Xie, p. 1372.

Roles of Long Noncoding RNAs in Conferring Glioma Progression and Treatment.

Accompanying the development of biomedicine, our knowledge of glioma, one of the most common primary intracranial carcinomas, is becoming more comprehensive. Unfortunately, patients with glioblastoma (GBM) still have a dismal prognosis and a high relapse rate, even with standard combination therapy, namely, surgical resection, postoperative radiotherapy and chemotherapy. The absence of validated biomarkers is responsible for the majority of these poor outcomes, and reliable therapeutic targets are indispensable for improving the prognosis of patients suffering from gliomas. Identification of both precise diagnostic and accurate prognostic markers and promising therapeutic targets has therefore attracted considerable attention from researchers. Encouragingly, accumulating evidence has demonstrated that long noncoding RNAs (lncRNAs) play important roles in the pathogenesis and oncogenesis of various categories of human tumors, including gliomas. Nevertheless, the underlying mechanisms by which lncRNAs regulate diverse biological behaviors of glioma cells, such as proliferation, invasion and migration, remain poorly understood. Consequently, this review builds on previous studies to further summarize the progress in the field of lncRNA regulation of gliomas over recent years and addresses the potential of lncRNAs as diagnostic and prognostic markers and therapeutic targets.

A Voxel-Based Radiographic Analysis Reveals the Biological Character of Proneural-Mesenchymal Transition in Glioblastoma.

Introduction: Proneural and mesenchymal subtypes are the most distinct demarcated categories in classification scheme, and there is often a shift from proneural type to mesenchymal subtype in the progression of glioblastoma (GBM). The molecular characters are determined by specific genomic methods, however, the application of radiography in clinical practice remains to be further studied. Here, we studied the topography features of GBM in proneural subtype, and further demonstrated the survival characteristics and proneural-mesenchymal transition (PMT) progression of samples by combining with the imaging variables. Methods: Data were acquired from The Cancer Imaging Archive (TCIA, http://cancerimagingarchive.net). The radiography image, clinical variables and transcriptome subtype from 223 samples were used in this study. Proneural and mesenchymal subtype on GBM topography based on overlay and Voxel-based lesion-symptom mapping (VLSM) analysis were revealed. Besides, we carried out the comparison of survival analysis and PMT progression in and outside the VLSM-determined area. Results: The overlay of total GBM and separated image of proneural and mesenchymal subtype revealed a correlation of the two subtypes. By VLSM analysis, proneural subtype was confirmed to be related to left inferior temporal medulla, and no significant voxel was found for mesenchymal subtype. The subsequent comparison between samples in and outside the VLSM-determined area showed difference in overall survival (OS) time, tumor purity, epithelial-mesenchymal transition (EMT) score and clinical variables. Conclusions: PMT progression was determined by radiography approach. GBM samples in the VLSM-determined area tended to harbor the signature of proneural subtype. This study provides a valuable VLSM-determined area related to the predilection site, prognosis and PMT progression by the association between GBM topography and molecular characters.

Applications of brain organoids in neurodevelopment and neurological diseases.

A brain organoid is a self-organizing three-dimensional tissue derived from human embryonic stem cells or pluripotent stem cells and is able to simulate the architecture and functionality of the human brain. Brain organoid generation methods are abundant and continue to improve, and now, an in vivo vascularized brain organoid has been encouragingly reported. The combination of brain organoids with immune-staining and single-cell sequencing technology facilitates our understanding of brain organoids, including the structural organization and the diversity of cell types. Recent publications have reported that brain organoids can mimic the dynamic spatiotemporal process of early brain development, model various human brain disorders, and serve as an effective preclinical platform to test and guide personalized treatment. In this review, we introduce the current state of brain organoid differentiation strategies, summarize current progress and applications in the medical domain, and discuss the challenges and prospects of this promising technology.

DNA Damage Repair in Brain Tumor Immunotherapy.

With the gradual understanding of tumor development, many tumor therapies have been invented and applied in clinical work, and immunotherapy has been widely concerned as an emerging hot topic in the last decade. It is worth noting that immunotherapy is nowadays applied under too harsh conditions, and many tumors are defined as "cold tumors" that are not sensitive to immunotherapy, and brain tumors are typical of them. However, there is much evidence that suggests a link between DNA damage repair mechanisms and immunotherapy. This may be a breakthrough for the application of immunotherapy in brain tumors. Therefore, in this review, first, we will describe the common pathways of DNA damage repair. Second, we will focus on immunotherapy and analyze the mechanisms of DNA damage repair involved in the immune process. Third, we will review biomarkers that have been or may be used to evaluate immunotherapy for brain tumors, such as TAMs, RPA, and other molecules that may provide a precursor assessment for the rational implementation of immunotherapy for brain tumors. Finally, we will discuss the rational combination of immunotherapy with other therapeutic approaches that have an impact on the DNA damage repair process in order to open new pathways for the application of immunotherapy in brain tumors, to maximize the effect of immunotherapy on DNA damage repair mechanisms, and to provide ideas and guidance for immunotherapy in brain tumors.

Mutant IDH1 Enhances Temozolomide Sensitivity via Regulation of the ATM/CHK2 Pathway in Glioma.

PURPOSE: Isocitrate dehydrogenase 1 (IDH1) mutations are the most common genetic abnormalities in low-grade gliomas and secondary glioblastomas. Glioma patients with these mutations had better clinical outcomes. However, the effect of IDH1 mutation on drug sensitivity is still under debate. MATERIALS AND METHODS: IDH1-R132H mutant cells were established by lentivirus. IDH1-R132H protein expression was confirmed by western blot. The expression of ataxia telangiectasia mutated (ATM) signaling pathway and apoptosis-related proteins were detected by immunofluorescence and western blot. Temozolomide (TMZ) induced cell apoptosis was detected by flow cytometry. Tumor cell proliferation was detected by Cell Counting Kit-8. In vivo nude mice were used to confirm the in vitro roles of IDH1 mutation. RESULTS: We established glioma cell lines that expressed IDH1-R132H mutation stably. We found that TMZ inhibited glioma cells proliferation more significantly in IDH1 mutant cells compared to wild type. The IC50 of TMZ in IDH1-R132H mutant group was less than half that of wild-type group (p < 0.01). TMZ significantly induced more DNA damage (quantification of γH2AX expression in IDH1 mutation vs. wild type, p < 0.05) and apoptosis (quantification of AnnexinV+propidium iodide-cells in IDH1 mutation versus wild type, p < 0.01) in IDH1 mutant gliomas compared to wild-type gliomas. The ATM-associated DNA repair signal was impaired in IDH1 mutant cells. Inhibiting the ATM/checkpoint kinase 2DNA repair pathway further sensitized IDH1 mutant glioma cells to chemotherapy. We found that IDH1 mutation significantly inhibited tumor growth in vivo (the tumor size was analyzed statistically, p < 0.05). Moreover, we confirmed that gliomas with IDH1 mutation were more sensitive to TMZ in vivo compared to wild type significantly and the results were consistent with the in vitro experiment. CONCLUSION: These results provide evidence that combination of TMZ and ATM inhibitor enhances the antitumor effect in IDH1 mutant gliomas.

Tumor Cell-Derived TGFß1 Attenuates Antitumor Immune Activity of T Cells via Regulation of PD-1 mRNA.

Dysfunction in T-cell antitumor activity contributes to the tumorigenesis, progression, and poor outcome of clear cell renal cell carcinoma (ccRCC), with this dysfunction resulting from high expression of programmed cell death-1 (PD-1) in T cells. However, the molecular mechanisms maintaining high PD-1 expression in T cells have not been fully investigated in ccRCC. Here, we describe a mechanism underlying the regulation of PD-1 at the mRNA level and demonstrated its impact on T-cell dysfunction. Transcriptomic analysis identified a correlation between TGFß1 and PD-1 mRNA levels in ccRCC samples. The mechanism underlying the regulation of PD-1 mRNA was then investigated in vitro and in vivo using syngeneic tumor models. We also observed that TGFß1 had prognostic significance in patients with ccRCC, and its expression was associated with PD-1 mRNA expression. CcRCC-derived TGFß1 activated P38 and induced the phosphorylation of Ser10 on H3, which recruited p65 to increase SRSF3 and SRSF5 expression in T cells. As a result, the half-life of PD-1 mRNA in T cells was prolonged. SRSF3 coordinated with NXF1 to induce PD-1 mRNA extranuclear transport in T cells. We then demonstrated that TGFß1 could induce SRSF3 expression to restrict the antitumor activity of T cells, which influenced immunotherapy outcomes in ccRCC mouse models. Our findings highlight that tumor-derived TGFß1 mediates immune evasion and has potential as a prognostic biomarker and therapeutic target in ccRCC.See related Spotlight on p. 1464.

Erythrocyte-rich thrombi related to serum iron contribute to single stent retrieval and favorable clinical outcomes in acute ischemic stroke by endovascular treatment.

BACKGROUND: Erythrocyte-rich thrombi seem to be associated with favorable clinical outcomes of patients with AIS by endovascular treatment (EVT), as observed from previous studies. However, only few studies show whether erythrocyte-rich thrombi can be associated with favorable clinical outcomes by EVT and which factor can be related to erythrocyte-rich thrombi. This retrospective study aimed to evaluate the relationship between erythrocyte-rich thrombi and favorable clinical outcomes and further explored factors associated with erythrocyte-rich thrombi. METHODS: This study was carried out retrospectively from March 2016 to April 2019 on patients who suffered acute ischemic stroke and were treated by EVT at this stroke center. The laboratory test and clinical data were assessed for the relationship between erythrocyte-rich thrombi and favorable clinical outcomes and factors associated with erythrocyte-rich thrombi. All thrombi were divided into erythrocyte-rich thrombi group and fibrin-rich thrombi group based on the proportion of area of the predominant composition which was more than 50% in retrieved thrombi. RESULTS: This retrospective study enrolled 84 patients, including 32 patients in the erythrocyte-rich thrombi group and 52 patients in the fibrin-rich thrombi group. It showed single stent retrieval (p = 0.017, adjusted OR: 4.061, 95% CI: 1.281-12.872) and favorable clinical outcomes (p < 0.001, adjusted OR: 14.648, 95% CI: 4.637-46.270) were both significantly associated with erythrocyte-rich thrombi. A significant difference in the factor associated with erythrocyte-rich thrombi was serum iron, which correlated positively with erythrocyte fraction in thrombi (p < 0.001, r: 0.452). CONCLUSIONS: Erythrocyte-rich thrombi could contribute to single stent retrieval and favorable clinical outcomes by EVT, and serum iron might be the factor associated with erythrocyte-rich thrombi.

Neutrophil extracellular traps mediate the crosstalk between glioma progression and the tumor microenvironment via the HMGB1/RAGE/IL-8 axis.

Objective: Neutrophil extracellular traps (NETs) produced by tumor-infiltrating neutrophils (TINs) are associated with poor prognosis in patients with several types of cancer. However, the mechanisms underlying the involvement of NETs in glioma progression remain largely unknown. This study aimed to elucidate the roles of NETs in biological processes that drive the crosstalk between glioma progression and the tumor microenvironment. Methods: Neutrophil infiltration and NETs formation were investigated in glioma tissue through immunohistochemistry, and their relationships with clinicopathological features and outcomes were statistically evaluated. The effects of NETs on glioma cell progression were studied in a co-culture system. In vivo and in vitro experiments validated the reactive oxygen species activity and cytokine production of TINs, as well as the ERK signaling pathway activation and the metastasis of gliomas. Results: Neutrophil infiltration and NETs formation were induced in high-grade glioma compared with low-grade glioma. NETs induced by TINs were determined to be an oncogenic marker of high-grade gliomas and to be involved in cell proliferation and invasion. NETs overproduction promoted glioma cell proliferation, migration, and invasion. Furthermore, HMGB1 was found to bind to RAGE and activate the NF-κB signaling pathway in vitro. In addition, NETs stimulated the NF-κB signaling pathway, thus promoting IL-8 secretion in glioblastoma. Subsequently, IL-8 recruited neutrophils which in turn mediated NETs formation via the PI3K/AKT/ROS axis in TINs. Conclusions: Our results suggest that NETs produced by TINs mediate the crosstalk between glioma progression and the tumor microenvironment by regulating the HMGB1/RAGE/IL-8 axis. Targeting NETs formation or IL-8 secretion may be an effective approach to inhibit glioma progression.

ATRX/EZH2 complex epigenetically regulates FADD/PARP1 axis, contributing to TMZ resistance in glioma.

Rationale: Glioma is the most common primary malignant brain tumor in adults. Chemoresistance of temozolomide (TMZ), the first-line chemotherapeutic agent, is a major issue in the management of patients with glioma. Alterations of alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene constitute one of the most prevalent genetic abnormalities in gliomas. Therefore, elucidation of the role of ATRX contributing to TMZ resistance in glioma is urgently needed. Methods: We performed the bioinformatics analysis of gene expression, and DNA methylation profiling, as well as RNA and ChIP-seq data sets. CRISPR-Cas9 gene editing system was used to achieve the ATRX knockout in TMZ resistant cells. In vitro and in vivo experiments were carried out to investigate the role of ATRX contributing to TMZ resistance in glioma. Results: We found that ATRX expression was upregulated via DNA demethylation mediated by STAT5b/TET2 complex and strengthened DNA damage repair by stabilizing PARP1 protein in TMZ resistant cells. ATRX elicited PARP1 stabilization by the down-regulating of FADD expression via the H3K27me3 enrichment, which was dependent on ATRX/EZH2 complex in TMZ resistant cells. Magnetic resonance imaging (MRI) revealed that the PARP inhibitor together with TMZ inhibited glioma growth in ATRX wild type TMZ resistant intracranial xenograft models. Conclusions: The present study further illustrated the novel mechanism of the ATRX/PARP1 axis contributing to TMZ resistance. Our results provided substantial new evidence that PARP inhibitor might be a potential adjuvant agent in overcoming ATRX mediated TMZ resistance in glioma.

NoncoRNA: a database of experimentally supported non-coding RNAs and drug targets in cancer.

NoncoRNA (http://www.ncdtcdb.cn:8080/NoncoRNA/) is a manually curated database of experimentally supported non-coding RNAs (ncRNAs) and drug target associations that aim to potentially provide a high-quality data resource for exploring drug sensitivity/resistance-related ncRNAs in various human cancers. ncRNA are RNA molecular that do not encode proteins, but are involved in gene regulation and cellular functions in variety of human diseases, including neurodegenerative diseases and cancers. Here, we developed NoncoRNA which contained 8233 entries between 5568 ncRNAs and 154 drugs in 134 cancers. Each entry in the NoncoRNA contains detailed information on the ncRNAs, drugs, and cancers, the ncRNA expression pattern and experimental detection techniques, drug response and other targets, literature references, and other information. NoncoRNA offers a user-friendly, open access web interface to easily browse, search, and download data. NoncoRNA also provides a submission page for researchers to submit newly validated ncRNA-drug-cancer associations. NoncoRNA might serve as an immeasurable resource for understanding the roles of ncRNAs in cancer therapy.