The clinical, molecular, and therapeutic implications of time from primary diagnosis to brain metastasis in lung and breast cancer patients.

PURPOSE: Lung cancer (LC) and breast cancer (BC) are the most common causes of brain metastases (BMs). Time from primary diagnosis to BM (TPDBM) refers to the time interval between initial LC or BC diagnosis and development of BM. This research aims to identify clinical, molecular, and therapeutic risk factors associated with shorter TPDBM. METHODS: We retrospectively reviewed all diagnosed LC and BC patients with BM at Harbin Medical University Cancer Hospital from 2016 to 2020. A total of 570 patients with LC brain metastasis (LCBM) and 173 patients with breast cancer brain metastasis (BCBM) patients who met the inclusion criteria were enrolled for further analysis. BM free survival time curves were generated using Kaplan-Meier analyses. Univariate and multivariate Cox regression analyses were applied to identify risk factors associated with earlier development of BM in LC and BC, respectively. RESULTS: The median TPDBM was 5.3 months in LC and 44.4 months in BC. In multivariate analysis, clinical stage IV and M1 stage were independent risk factors for early development of LCBM. LC patients who received chemotherapy, targeted therapy, pulmonary radiotherapy, and pulmonary surgery had longer TPDBM. For BC patients, age ≥ 50 years, Ki67 ≥ 0.3, HER2 positive or triple-negative breast cancer subtype, advanced N stage, and no mastectomy were correlated with shorter TPDBM. CONCLUSIONS: This single-institutional study helps identify patients who have a high risk of developing BM early. For these patients, early detection and intervention could have clinical benefits.

Structural changes in eloquent cortex secondary to glioma in sensorimotor area.

This study aims to investigate the structural reorganization in the sensorimotor area of the brain in patients with gliomas, distinguishing between those with impaired and unimpaired strength. Using voxel-based morphometry (VBM) and region of interest (ROI) analysis, gray matter volumes (GMV) were compared in the contralesional primary motor gyrus, primary sensory gyrus, premotor area, bilateral supplementary motor area, and medial Brodmann area 8 (BA8). The results revealed that in patients with right hemisphere gliomas, the right medial BA8 volume was significantly larger in the impaired group than in the unimpaired group, with both groups exceeding the volume in 16 healthy controls (HCs). In patients with left hemisphere gliomas, the right supplementary motor area (SMA) was more pronounced in the impaired group compared to the unimpaired group, and both groups were greater than HCs. Additionally, the volumes of the right medial BA8 in both the impaired group were greater than HCs. Contralateral expansions in the gray matter of hand- and trunk-related cortices of the premotor area, precentral gyrus, and postcentral gyrus were observed compared to HCs. Furthermore, a negative correlation was found between hand Medical Research Council (MRC) score and volumes of the contralateral SMA and bilateral medial BA8. Notably, our findings reveal consistent results across both analytical approaches in identifying significant structural reorganizations within the sensorimotor cortex. These consistent findings underscore the adaptive neuroplastic responses to glioma presence, highlighting potential areas of interest for further neurosurgical planning and rehabilitation strategies.

Intraoperative radiotherapy in recurrent IDH-wildtype glioblastoma with gross total resection: A single-center retrospective study.

BACKGROUND: Isocitrate dehydrogenase-wildtype (IDHwt) glioblastoma (GBM) is one of the most aggressive primary brain tumors. The recurrence of GBM is almost inevitable. As an adjuvant option to surgery, intraoperative radiotherapy (IORT) is gaining increasing attention in the treatment of glioma. This study is aimed to evaluate the therapeutic efficacy of IORT on recurrent IDHwt GBM. METHODS: In total, 34 recurrent IDHwt GBM patients who received a second surgery were included in the analysis (17 in the surgery group and 17 in the surgery + IORT group). RESULTS: The progression-free survival and overall survival after the second surgery were defined as PFS2 and OS2, respectively. The median PFS2 was 7.3 months (95% CI: 6.3-10.5) and 10.6 months (95% CI: 9.3-14.6) for those patients who received surgery and surgery + IORT, respectively. Patients in the surgery + IORT group also had a longer OS2 (12.8 months, 95% CI: 11.4-17.2) than those in the surgery group (9.3 months, 95% CI: 8.9-12.9). The Kaplan-Meier survival curves, analyzed by log-rank test, revealed a statistically significant difference in PFS2 and OS2 between both groups, suggesting that IORT plays an active role in the observed benefits for PFS2 and OS2. The effects of IORT on PFS2 and OS2 were further confirmed by multivariate Cox hazards regression analysis. Two patients in the surgery group developed distant glioma metastases, and no radiation-related complications were observed in the IORT group. CONCLUSIONS: This study suggests that low-dose IORT may improve the prognosis of recurrent IDHwt GBM patients. Future prospective large-scale studies are needed to validate the efficacy and safety of IORT.

Analysis of Factors Influencing the Duration of Early Enteral Nutrition Support in Patients Diagnosed with Acute Pancreatitis.

Objective: This study aimed to assess the current status of early enteral nutrition (EN) support among patients diagnosed with acute pancreatitis (AP) and analyze the factors influencing its duration. The findings aimed to provide guidance for the development of tailored EN support protocols for pancreatitis patients. Methods: A convenience sampling method was employed, and 51 patients diagnosed with acute pancreatitis (AP) were enrolled from the Gastroenterology Department of Zhoushan Hospital between May 2020 and June 2021. Data analysis included the categorization of patients based on their early enteral nutrition (EN) support duration, followed by thorough statistical analysis, including logistic regression, to identify the factors impacting EN duration. Results: The mean duration of early EN support among AP patients was (93.57 ± 43.29) hours. A mere 13.73% of patients initiated EN within 48 hours of admission. Upon categorizing patients by the median duration of EN support, multiple logistic regression analysis revealed several significant risk factors influencing the duration of EN in AP patients, including patient age, underlying medical conditions, severity of pancreatitis, nutritional status, and blood lipase levels (P < .05). Conclusion: The study highlights the significant influence of disease severity and patients' functional status on the duration of early EN support in AP cases. It emphasizes the importance of a comprehensive patient assessment by medical professionals to determine the optimal timing for initiating EN support.

The involvement of brain regions associated with lower KPS and shorter survival time predicts a poor prognosis in glioma.

Background: Isocitrate dehydrogenase-wildtype glioblastoma (IDH-wildtype GBM) and IDH-mutant astrocytoma have distinct biological behaviors and clinical outcomes. The location of brain tumors is closely associated not only with clinical symptoms and prognosis but also with key molecular alterations such as IDH. Therefore, we hypothesize that the key brain regions influencing the prognosis of glioblastoma and astrocytoma are likely to differ. This study aims to (1) identify specific regions that are associated with the Karnofsky Performance Scale (KPS) or overall survival (OS) in IDH-wildtype GBM and IDH-mutant astrocytoma and (2) test whether the involvement of these regions could act as a prognostic indicator. Methods: A total of 111 patients with IDH-wildtype GBM and 78 patients with IDH-mutant astrocytoma from the Cancer Imaging Archive database were included in the study. Voxel-based lesion-symptom mapping (VLSM) was used to identify key brain areas for lower KPS and shorter OS. Next, we analyzed the structural and cognitive dysfunction associated with these regions. The survival analysis was carried out using Kaplan-Meier survival curves. Another 72 GBM patients and 48 astrocytoma patients from Harbin Medical University Cancer Hospital were used as a validation cohort. Results: Tumors located in the insular cortex, parahippocampal gyrus, and middle and superior temporal gyrus of the left hemisphere tended to lead to lower KPS and shorter OS in IDH-wildtype GBM. The regions that were significantly correlated with lower KPS in IDH-mutant astrocytoma included the subcallosal cortex and cingulate gyrus. These regions were associated with diverse structural and cognitive impairments. The involvement of these regions was an independent predictor for shorter survival in both GBM and astrocytoma. Conclusion: This study identified the specific regions that were significantly associated with OS or KPS in glioma. The results may help neurosurgeons evaluate patient survival before surgery and understand the pathogenic mechanisms of glioma in depth.

Identification of a cellular senescence-related-lncRNA (SRlncRNA) signature to predict the overall survival of glioma patients and the tumor immune microenvironment.

Background: Gliomas are brain tumors that arise from glial cells, and they are the most common primary intracranial tumors with a poor prognosis. Cellular senescence plays a critical role in cancer, especially in glioma. In this study, we constructed a senescence-related lncRNA (SRlncRNA) signature to assess the prognosis of glioma. Methods: The Cancer Genome Atlas was used to collect SRlncRNA transcriptome profiles and clinical data about glioma. Patients were randomized to training, testing, and whole cohorts. LASSO and Cox regression analyses were employed to construct the SRlncRNA signature, and Kaplan-Meier (K-M) analysis was performed to determine each cohort's survival. Receiver operating characteristic (ROC) curves were applied to verify the accuracy of this signature. Gene set enrichment analysis was used to visualize functional enrichment (GSEA). The CIBERSORT algorithm, ESTIMATE and TIMER databases were utilized to evaluate the differences in the infiltration of 22 types of immune cells and their association with the signature. RT-qPCR and IHC were used to identify the consistency of the signature in tumor tissue. Results: An SRlncRNA signature consisting of six long non-coding RNAs (lncRNAs) was constructed, and patients were divided into high-risk and low-risk groups by the median of their riskscore. The KM analysis showed that the high-risk group had worse overall survival, and the ROC curve confirmed that the riskscore had more accurate predictive power. A multivariate Cox analysis and its scatter plot with clinical characteristics confirmed the riskscore as an independent risk factor for overall survival. GSEA showed that the GO and KEGG pathways were mainly enriched in the immune response to tumor cells, p53 signaling pathway, mTOR signaling pathway, and Wnt signaling pathway. Further validation also yielded significant differences in the risk signature in terms of immune cell infiltration, which may be closely related to prognostic differences, and qRT-PCR and IHC confirmed the consistency of the expression differences in the major lncRNAs with those in the prediction model. Conclusion Our findings indicated that the SRlncRNA signature might be used as a predictive biomarker and that there is a link between it and immune infiltration. This discovery is consistent with the present categorization system and may open new avenues for research and personalized therapy.

Association of cortical and subcortical microstructure with disease severity: impact on cognitive decline and language impairments in frontotemporal lobar degeneration.

BACKGROUND: Cortical and subcortical microstructural modifications are critical to understanding the pathogenic changes in frontotemporal lobar degeneration (FTLD) subtypes. In this study, we investigated cortical and subcortical microstructure underlying cognitive and language impairments across behavioral variant of frontotemporal dementia (bvFTD), semantic variant of primary progressive aphasia (svPPA), and nonfluent variant of primary progressive aphasia (nfvPPA) subtypes. METHODS: The current study characterized 170 individuals with 3 T MRI structural and diffusion-weighted imaging sequences as portion of the Frontotemporal Lobar Degeneration Neuroimaging Initiative study: 41 bvFTD, 35 nfvPPA, 34 svPPA, and 60 age-matched cognitively unimpaired controls. To determine the severity of the disease, clinical dementia rating plus national Alzheimer's coordinating center behavior and language domains sum of boxes scores were used; other clinical measures, including the Boston naming test and verbal fluency test, were also evaluated. We computed surface-based cortical thickness and cortical and subcortical microstructural metrics using tract-based spatial statistics and explored their relationships with clinical and cognitive assessments. RESULTS: Compared with controls, those with FTLD showed substantial cortical mean diffusivity alterations extending outside the regions with cortical thinning. Tract-based spatial statistics revealed that anomalies in subcortical white matter diffusion were widely distributed across the frontotemporal and parietal areas. Patients with bvFTD, nfvPPA, and svPPA exhibited distinct patterns of cortical and subcortical microstructural abnormalities, which appeared to correlate with disease severity, and separate dimensions of language functions. CONCLUSIONS: Our findings imply that cortical and subcortical microstructures may serve as sensitive biomarkers for the investigation of neurodegeneration-associated microstructural alterations in FTLD subtypes. Flowchart of the study design (see materials and methods for detailed description).

New insights into glioma frequency maps: From genetic and transcriptomic correlate to survival prediction.

Increasing evidence indicates that glioma topographic location is linked to the cellular origin, molecular alterations and genetic profile. This research aims to (a) reveal the underlying mechanisms of tumor location predilection in glioblastoma multiforme (GBM) and lower-grade glioma (LGG) and (b) leverage glioma location features to predict prognosis. MRI images from 396 GBM and 190 LGG (115 astrocytoma and 75 oligodendroglioma) patients were standardized to construct frequency maps and analyzed by voxel-based lesion-symptom mapping. We then investigated the spatial correlation between glioma distribution with gene expression in healthy brains. We also evaluated transcriptomic differences in tumor tissue from predilection and nonpredilection sites. Furthermore, we quantitively characterized tumor anatomical localization and explored whether it was significantly related to overall survival. Finally, we employed a support vector machine to build a survival prediction model for GBM patients. GBMs exhibited a distinct location predilection from LGGs. GBMs were nearer to the subventricular zone and more likely to be localized to regions enriched with synaptic signaling, whereas astrocytoma and oligodendroglioma tended to occur in areas associated with the immune response. Synapse, neurotransmitters and calcium ion channel-related genes were all activated in GBM tissues coming from predilection regions. Furthermore, we characterized tumor location features in terms of a series of tumor-to-predilection distance metrics, which were able to predict GBM 1-year survival status with an accuracy of 0.71. These findings provide new perspectives on our understanding of tumor anatomic localization. The spatial features of glioma are of great value in individual therapy and prognosis prediction.

Corrigendum: Developing an immune-related signature for predicting survival rate and the response to immune checkpoint inhibitors in patients with glioma.

[This corrects the article DOI: 10.3389/fgene.2022.899125.].

Developing an Immune-Related Signature for Predicting Survival Rate and the Response to Immune Checkpoint Inhibitors in Patients With Glioma.

Background: Glioma is one of the most aggressive cancer types affecting the central nerve system, with poor overall survival (OS) rates. The present study aimed to construct a novel immune-related signature to predict prognosis and the efficiency of immunotherapy in patients with glioma. Methods: The mRNA expression data and other clinical information of patients with glioblastoma multiforme (GBM) and low grade glioma (LGG) were obtained from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. The immune-related genes were obtained from the Immunology Database and Analysis Portal database. Subsequently, an immune-related signature was created following the results obtained from the Least Absolute Shrinkage and Selection Operator regression model. To validate the predictability of the signature, Kaplan-Meier survival curves and time-dependent receiver operating characteristic curves were created. Moreover, both univariate and multivariate analyses were carried out using the OS between this signature and other clinicopathologic factors, and a nomogram was constructed. In addition, the association between signature, immune cell infiltration, tumor mutation burden and immunophenoscore were determined. Results: Results of the present study using 118 GBM and LGG samples uncovered 15 immune-related genes that were also differently expressed in glioma samples. These were subsequently used to construct the immune-related signature. This signature exhibits the ability to predict prognosis, the infiltration of immune cells in the tumor microenvironment and the response of patients with glioma to immunotherapy. Conclusion: Results of the present study demonstrated that the aforementioned novel immune-related signature may accurately predict prognosis and the response of patients with glioma to immunotherapy.

Circular RNA circHECTD1 facilitates glioma progression by regulating the miR-296-3p/SLC10A7 axis.

Glioma is the most common type of primary brain tumor. Treatment options for recurrent gliomas include surgery, chemotherapy, and radiation therapy, but the clinical outcome is usually limited. In recent years, circular RNAs have been found to play a vital role in several human cancers. Gene Expression Omnibus database was utilized to verify the differentially expressed circRNAs. Then we detected that the expression of circular RNA circHECTD1 was significantly increased. The expression and function of circHECDT1 has not yet been reported in glioma. Then we confirmed that the level of circHECTD1 was significantly increased both in glioma tissues and cell lines, which is negatively correlated with the overall survival of patients. Knockdown of circHECTD1 inhibited proliferation and invasion in vitro, and also reduced the growth of tumor and prolonged the prognosis in vivo. Knockdown of circHECTD1 significantly elevated the miR-296-3p expression in LN229 and T98G cells. Luciferase reports and RNA immunoprecipitation data indicated that miR-296-3p was a direct target of circHECTD1 and that the miR-296-3p expression negatively regulated SLC10A7. Rescue experiments showed that the overexpression of SLC10A7 could impede the effects of circHECTD1 silencing on the proliferation and invasion of glioma cells. In this study, we identified that circHECTD1 regulates SLC10A7 by interacting with miR-296-3p in glioma cells. In conclusion, this study investigated a novel biomarker panel consisting of the circHECTD1/miR-296-3p/SLC10A7 axis, which is critical for glioma tumorigenesis and invasiveness and may represent a novel therapeutic target for intervening in glioma progression.

Impact of Electroacupuncture Stimulation on Postoperative Constipation for Patients Undergoing Brain Tumor Surgery.

BACKGROUND: Constipation is frequently encountered in patients undergoing brain tumor resection. Constipation has negative effects on daily living, well-being, and individuals' quality of life. We examined the impact of acupuncture and electroacupuncture (EA) stimulation on postoperative constipation for patients undergoing brain tumor resection. METHODS: Patients undergoing brain tumor resection (n = 150) were randomly divided into a nontreatment group, an acupuncture group, and an EA group. Rome III Diagnostic Criteria, Cleveland Clinic Constipation Score, symptom assessment, Patient Assessment of Constipation Quality of Life questionnaire, Self-Rating Anxiety Scale, and a Self-Rating Depression Scale were collected. RESULTS: Acupuncture and EA were effective in relieving postoperative constipation. Electroacupuncture decreased constipation and improved quality of life scores. CONCLUSION: Acupuncture and EA are novel adjuvant therapies to treat constipation.

HOXB9 enhances the ability of lung cancer cells to penetrate the blood-brain barrier.

Even after multimodal therapy, the prognosis is dismal for patients with brain metastases from non-small cell lung cancer (NSCLC). Although the blood-brain barrier (BBB) limits tumor cell penetration into the brain parenchyma, some nevertheless colonize brain tissue through mechanisms that are not fully clear. Here we show that homeobox B9 (HOXB9), which is commonly overexpressed in NSCLC, promotes epithelial-to-mesenchymal transition (EMT) and tumor migration and invasion. Animal experiments showed that HOXB9 expression correlates positively with the brain metastatic potential of human NSCLC cells, while brain metastatic cells derived through in vivo selection showed greater HOXB9 expression than their cells of origin. Comparable results were obtained after immunohistochemical analysis of clinical primary NSCLC and matched brain metastasis samples obtained after surgery. Using an in vitro BBB model, knockdown and overexpression experiments showed that HOXB9-dependent expression of MMP9 in NSCLC cells leads to reduced expression of junctional proteins in cultured human vascular endothelial cells and enhanced transmigration of tumor cells. These data indicate that HOXB9 enables NSCLC cells to break away from the primary tumor by inducing EMT, and promotes brain metastasis by driving MMP9 production and degradation of intercellular adhesion proteins in endothelial cells comprising the BBB.

Long non-coding RNA linc00645 promotes TGF-ß-induced epithelial-mesenchymal transition by regulating miR-205-3p-ZEB1 axis in glioma.

Accumulating evidence indicates long noncoding RNAs (lncRNA) play a vital role in tumor progression. However, the role of linc00645-induced accelerated malignant behavior in glioblastoma (GBM) remains unknown. In the present study, linc00645 expression was significantly upregulated in GBM tissues and cell lines. High level of linc00645 was associated with poor overall survival in GBM patients. Knockdown of linc00645 suppressed the proliferation, stemness, migration, invasion, and reversed transforming growth factor (TGF)-ß-induced motility of glioma cell lines. Furthermore, linc00645 directly interacted with miR-205-3p and upregulated of miR-205-3p impeded efficiently the increase of ZEB1 induced by linc00645 overexpression. Moreover, knockdown of linc00645 significantly suppressed the progression of glioma cells in vivo. miR-205-3p was a target of linc00645 and linc00645 modulates TGF-ß-induced glioma cell migration and invasion via miR-205-3p. Taken together, our findings identified the linc00645/miR-205-3p/ZEB1 signaling axis as a key player in EMT of glioma cells triggered by TGF-ß. These data elucidated that linc00645 plays an oncogenic role in glioma and it may serve as a prognostic biomarker and a potential therapeutic target for the treatment of glioma in humans.

Modulating lncRNA SNHG15/CDK6/miR-627 circuit by palbociclib, overcomes temozolomide resistance and reduces M2-polarization of glioma associated microglia in glioblastoma multiforme.

BACKGROUND: Accumulating evidence demonstrates the oncogenic roles of lncRNA (long non-coding RNA) molecules in a wide variety of cancer types including glioma. Equally important, However, tumorigenic functions of lncRNA in glioma remain largely unclear. A recent study suggested lncRNA SNHG15 played a role for regulating angiogenesis in glioma but its role in the tumor microenvironment (TME) was not investigated. METHODS: First, we showed that SNHG15 was upregulated in GBM cells and associated with a poor prognosis for the patients of GBM using public databases. Next, we collected temozolomide sensitive (TMZ-S) and resistant (TMZ-R) clinical samples and demonstrated that co-culturing TMZ-R cells with HMC3 (microglial) cells promoted M2-polarization of HMC3 and the secretion of pro-GBM cytokines TGF-ß and IL-6. RESULTS: Comparative qPCR analysis of TMZ-S and TMZ-R cells showed that a significantly higher level of SNHG15, coincidental with a higher level of Sox2, ß-catenin, EGFR, and CDK6 in TMZ-R cells. Subsequently, using bioinformatics tool, a potential mechanistic route for SNHG15 to promote GBM tumorigenesis was by inhibiting tumor suppressor, miR-627-5p which leads to activation of CDK6. Gene-silencing technique was employed to demonstrate that suppression of SNHG15 indeed led to the suppression of GBM tumorigenesis, accompanied by an increase miR-627-5p and decreased its two oncogenic targets, CDK6 and SOX-2. In addition, SNHG15-silenced TMZ-R cells became significantly sensitive towards TMZ treatment and less capable of promoting M2-phenotype in the HMC3 microglial cells. We then evaluated the potential anti-GBM activity of CDK6 inhibitor, palbociclib, using TMZ-R PDX mouse models. Palbociclib treatment significantly reduced tumorigenesis in TMZ-R/HMC3 bearing mice and SNHG15 and CDK6 expression was significantly reduced while miR-627-5p level was increased. Additionally, palbociclib treatment appeared to overcome TMZ resistance as well as reduced M2 markers in HMC3 cells. CONCLUSION: Together, we provided evidence supporting the usage of CDK6 inhibitor for TMZ-resistant GBM cases. Further investigation is warranted for the consideration of clinical trials.

P68 RNA helicase promotes invasion of glioma cells through negatively regulating DUSP5.

Gliomas are the most common central nervous system tumors. They show malignant characteristics indicating rapid proliferation and a high invasive capacity and are associated with a poor prognosis. In our previous study, p68 was overexpressed in glioma cells and correlated with both the degree of glioma differentiation and poor overall survival. Downregulating p68 significantly suppressed proliferation in glioma cells. Moreover, we found that the p68 gene promoted glioma cell growth by activating the nuclear factor-κB signaling pathway by a downstream molecular mechanism that remains incompletely understood. In this study, we found that dual specificity phosphatase 5 (DUSP5) is a downstream target of p68, using microarray analysis, and that p68 negatively regulates DUSP5. Upregulating DUSP5 in stably expressing cell lines (U87 and LN-229) suppressed proliferation, invasion, and migration in glioma cells in vitro, consistent with the downregulation of p68. Furthermore, upregulating DUSP5 inhibited ERK phosphorylation, whereas downregulating DUSP5 rescued the level of ERK phosphorylation, indicating that DUSP5 might negatively regulate ERK signaling. Additionally, we show that DUSP5 levels were lower in high-grade glioma than in low-grade glioma. These results suggest that the p68-induced negative regulation of DUSP5 promoted invasion by glioma cells and mediated the activation of the ERK signaling pathway.

miR-186-5p Promotes Apoptosis by Targeting IGF-1 in SH-SY5Y OGD/R Model.

In recent years, accumulating evidence has revealed that microRNAs play critical roles in ischemia stroke. This study was designed to investigate the expression level and effects of microRNA (miR)-186-5p on ischemia stroke, and its underlying molecular mechanism. Firstly, we demonstrated that miR-186-5p were significantly up-regulated and induced apoptosis in oxygen and glucose deprivation/reperfusion (OGD/R) model. Moreover, we found that miR-186-5p reduced the expression of insulin-like growth factor (IGF)-1, an essential factor for the development of the nervous system. Meanwhile, miR-186-5p inhibitor enhanced cell viability and IGF-1 expression. Furthermore, IGF-1 was confirmed as a direct target gene of miR-186-5p by luciferase activity assay. In addition, miR-186-5p was upregulated in ischemia stroke patients' serum compared with healthy donors. These data demonstrated that miR-186-5p was an adverse factor by inducing neuron apoptosis and suppressing IGF-1 in ischemia stroke model, and suggested that miR-186-5p may be a diagnostic marker and potential therapeutic target for ischemia stroke patients.

CD70, a novel target of CAR T-cell therapy for gliomas.

Background: Cancer immunotherapy represents a promising treatment approach for malignant gliomas but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified cluster of differentiation (CD)70 as a novel immunosuppressive ligand and glioma target. Methods: Normal tissues derived from 52 different organs and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression. The association between CD70 and patients' overall survival and its impact on T-cell death was also evaluated. Human and mouse CD70-specific chimeric antigen receptors (CARs) were tested respectively against human primary GBMs and murine glioma lines. The antitumor efficacies of these CARs were also examined in orthotopic xenograft and syngeneic models. Results: CD70 was not detected in peripheral and brain normal tissues but was constitutively overexpressed by isocitrate dehydrogenase (IDH) wild-type primary LGGs and GBMs in the mesenchymal subgroup and recurrent tumors. CD70 was also associated with poor survival in these subgroups, which may link to its direct involvement in glioma chemokine productions and selective induction of CD8+ T-cell death. To explore the potential for therapeutic targeting of this newly identified immunosuppressive axis in GBM tumors, we demonstrate that both human and mouse CD70-specific CAR T cells recognize primary CD70+ GBM tumors in vitro and mediate the regression of established GBM in xenograft and syngeneic models without illicit effect. Conclusion: These studies identify a previously uncharacterized and ubiquitously expressed immunosuppressive ligand CD70 in GBMs that also holds potential for serving as a novel CAR target for cancer immunotherapy in gliomas.