ITGB4 upregulation is associated with progression of lower grade glioma.

Gliomas originating in the neuroepithelium account for about 80% of brain malignancies and are the most common cancer of the central nervous system. Clinical management of gliomas remains challenging despite significant advances in comprehensive therapies, including radiotherapy, chemotherapy, and surgery. The ITGB4 (Integrin subunit beta 4) gene encodes a receptor for laminins and its upregulation in tumor tissues is associated with poor prognosis. However, its role in glioma is not well understood. First, we performed a pan cancer analysis of ITGB4 expression in The Cancer Genome Atlas (TCGA) dataset. Survival analysis was done on Chinese Glioma Genome Atlas (CGGA) and TCGA. Immunohistochemistry was then used to validate the expression and role of ITGB4 in glioma. We finally analyzed the possible mechanism by immune infiltration and single-cell sequencing analysis. Here, we found that ITGB4 is upregulated in glioma and accurately predicts the prognosis of lower grade glioma (LGG). Univariate and multivariate Cox regression analyses showed that ITGB4 is a risk factor for LGG. Immunohistochemical analysis confirmed that ITGB4 accurately predicts LGG prognosis. Non-negative matrix factorization (NMF) cluster analysis showed that ITGB4 was closely related to immune related genes. Immune cell infiltration and single cell sequencing analyses indicated that ITGB4 may be closely related to the microenvironment of gliomas, especially tumor-associated fibroblasts. ITGB4 is a promising diagnostic and therapeutic factor in LGG patients.

Preliminary Results of Branch Level, Brachial Plexus Peripheral Nerve Stimulation on a Non-Human Primate.

Restoring functional hand control is a priority for those suffering from neurological impairments. Functional electrical stimulation (FES) is commonly applied to assist with rehabilitation. However, FES applied intramuscularly typically results in complex surgeries requiring many implants. This paper presents the preliminary findings from a feasibility study focused on evaluating the potential to access the upper extremity peripheral nerves through a single surgical approach (axillary approach). A single Japanese macaque (macaca fuscata) monkey was used to validate the feasibility of this study. Four of the five peripheral nerves which control the upper extremity were exposed, and had multi-contact epineural cuffs implanted: median, radial, ulnar and musculocutaneous. The axillary nerve was not accessible for epineural cuff placement with the current surgical approach used in this study. Electrical stimuli were used to produce movement contraction patterns of muscles relevant to the innervated peripheral nerves. In addition, to assist in quantifying the outcome, evoked potentials were simultaneously recorded from five extrinsic forearm flexors during median nerve stimulation. This feasibility study demonstrated that the axillary approach enables electrode placement to four of the five peripheral nerves required for upper extremity control through a single skin incision.Clinical relevance- This study demonstrated that the electrode placement to most of the peripheral nerves that control the arm and hand can be done by a single surgical approach: axillary approach.

Chronic subdural electrocorticography in nonhuman primates by an implantable wireless device for brain-machine interfaces.

Background: Subdural electrocorticography (ECoG) signals have been proposed as a stable, good-quality source for brain-machine interfaces (BMIs), with a higher spatial and temporal resolution than electroencephalography (EEG). However, long-term implantation may lead to chronic inflammatory reactions and connective tissue encapsulation, resulting in a decline in signal recording quality. However, no study has reported the effects of the surrounding tissue on signal recording and device functionality thus far. Methods: In this study, we implanted a wireless recording device with a customized 32-electrode-ECoG array subdurally in two nonhuman primates for 15 months. We evaluated the neural activities recorded from and wirelessly transmitted to the devices and the chronic tissue reactions around the electrodes. In addition, we measured the gain factor of the newly formed ventral fibrous tissue in vivo. Results: Time-frequency analyses of the acute and chronic phases showed similar signal features. The average root mean square voltage and power spectral density showed relatively stable signal quality after chronic implantation. Histological examination revealed thickening of the reactive tissue around the electrode array; however, no evident inflammation in the cortex. From gain factor analysis, we found that tissue proliferation under electrodes reduced the amplitude power of signals. Conclusion: This study suggests that subdural ECoG may provide chronic signal recordings for future clinical applications and neuroscience research. This study also highlights the need to reduce proliferation of reactive tissue ventral to the electrodes to enhance long-term stability.

Intracranial EEG Recordings of High-Frequency Activity From a Wireless Implantable BMI Device in Awake Nonhuman Primates.

OBJECTIVE: Wireless implantable brain machine interfaces (BMIs) are a promising tool to restore communication and motor functions for individuals with severe motor disability. Prior to clinical application, recording performance must be sufficiently confirmed by animal experiments. In this paper, we aimed to evaluate the performance of a novel BMI wireless device for recording brain activity in two nonhuman primates. METHOD: We customized a wireless device for implantable BMIs for clinical application. We used a battery instead of a wireless power charging system. Thirty-two electrodes were subdurally implanted over the left temporoparietal cortex. We evaluated the recording performance of the wireless device by auditory steady-state responses (ASSRs) and ketamine-induced responses. RESULT: The devices successfully recorded broadband oscillatory activities up to the high-frequency band from the temporal cortex in two awake macaque monkeys. Spectral analysis of raw signals demonstrated that the devices detected characteristic results of a 40-Hz ASSR and prominent high-frequency band activity induced by ketamine injection. CONCLUSION: We confirmed the functionality of the wireless device in recording and transmitting electrocorticography (ECoG) signals with both millisecond precision and recording stability. SIGNIFICANCE: These results provide confidence that this wireless device can be a translational tool for other fundamental neuroscientific studies in free-moving models.

DDOST Correlated with Malignancies and Immune Microenvironment in Gliomas.

Among the most common types of brain tumor, gliomas are the most aggressive and have the poorest prognosis. Dolichyl-diphosphooligosaccharide protein glycosyltransferase non-catalytic subunit (DDOST) encodes a component of the oligosaccharide transferase complex and is related to the N-glycosylation of proteins. The role of DDOST in gliomas, however, is not yet known. First, we performed a pan cancer analysis of DDOST in the TCGA cohort. The expression of DDOST was compared between glioma and normal brain tissues in the GEO and Chinese Glioma Genome Atlas (CGGA) databases. In order to explore the role of DDOST in glioma, we analyze the impact of DDOST on the prognosis of glioma patients, with the CGGA 325 dataset as a test set and the CGGA 693 dataset as a validation set. Immunohistochemistry was performed on tissue microarrays to examine whether DDOST has an impact on glioma patient survival. Next, using single-cell sequencing analysis, GSEA, immune infiltration analysis, and mutation analysis, we explored how DDOST affected the glioma tumor microenvironment. Finally, we evaluated the clinical significance of DDOST for glioma treatment by constructing nomograms and decision curve analysis (DCA) curves. We found that DDOST was overexpressed in patients with high grade, IDH wild type, 1p19q non-codel and MGMT un-methylated, which was associated with poor prognosis. Patients with high levels of DDOST, regardless of their clinical characteristics, had a worse prognosis. Immunohistochemical analysis confirmed the results of the above bioinformatics analysis. Mechanistic analysis revealed that DDOST was closely associated with the glioma microenvironment and negatively related to tumor-infiltrating B cells and CD4+ T cells and positively related to CAFs and tumor-associated macrophages. In conclusion, these findings suggested that DDOST mediated the immunosuppressive microenvironment of gliomas and could be an important biomarker in diagnosing and treating gliomas.

Electrocorticographic effects of acute ketamine on non-human primate brains.

Objective. Acute blockade of glutamate N-methyl-D-aspartate receptors by ketamine induces symptoms and electrophysiological changes similar to schizophrenia. Previous studies have shown that ketamine elicits aberrant gamma oscillations in several cortical areas and impairs coupling strength between the low-frequency phase and fast frequency amplitude, which plays an important role in integrating functional information.Approach. This study utilized a customized wireless electrocorticography (ECoG) recording device to collect subdural signals from the somatosensory and primary auditory cortices in two monkeys. Ketamine was administered at a dose of 3 mg kg-1(intramuscular) or 0.56 mg kg-1(intravenous) to elicit brain oscillation reactions. We analyzed the raw data using methods such as power spectral density, time-frequency spectra, and phase-amplitude coupling (PAC).Main results. Acute ketamine triggered broadband gamma and high gamma oscillation power and decreased lower frequencies. The effect was stronger in the primary auditory cortex than in the somatosensory area. The coupling strength between the low phase of theta and the faster amplitude of gamma/high gamma bands was increased by a lower dose (0.56 mg kg-1iv) and decreased with a higher dose (3 mg kg-1im) ketamine.Significance. Our results showed that lower and higher doses of ketamine elicited differential effects on theta-gamma PAC. These findings support the utility of ECoG models as a translational platform for pharmacodynamic research in future research.

Upregulated Expression of Cancer-Derived Immunoglobulin G Is Associated With Progression in Glioma.

OBJECTIVE: Gliomas are the most aggressive intracranial tumors accounting for the vast majority of brain tumors with very poor prognosis and overall survival (OS). Cancer-derived immunoglobulin G (cancer-IgG) has been found to be widely expressed in several malignancies such as breast cancer, colorectal cancer, and lung cancer. Cancer-IgG could promote tumorigenesis and progression. However, its role in glioma has not been revealed yet. METHODS: We mined open databases including the Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) to study the role of IGHG1, which encodes cancer-IgG in glioma. Examination of the differential expression of IGHG1 was carried out in the GEO and TCGA databases. Furthermore, its expression in different molecular subtypes was analyzed. Stratified analysis was performed with clinical features. Subsequently, immune infiltration analysis was conducted using single-sample gene set enrichment analysis (ssGSEA). GSEA was performed to reveal the mechanisms of IGHG1. Lastly, immunohistochemistry was processed to validate our findings. RESULTS: In this study, we found that the expression of IGHG1 was higher in glioma and molecular subtypes with poor prognosis. The overall survival of patients with a high expression of IGHG1 was worse in the stratified analysis. Immune infiltration analysis indicated that the expression level of IGHG1 was positively correlated with the stromal score, ESTIMATE score, and immune score and negatively correlated with tumor purity. Results from the GSEA and DAVID demonstrated that IGHG1 may function in phagosome, antigen processing and presentation, extracellular matrix structural constituent, antigen binding, and collagen-containing extracellular matrix. Finally, immunohistochemistry assay validated our findings that patients with a high expression of cancer-IgG had poor OS and disease-free survival (DFS). CONCLUSION: Cancer-IgG is a promising biomarker of diagnosis and treatment for patients with glioma.

DNMT family induces down-regulation of NDRG1 via DNA methylation and clinicopathological significance in gastric cancer.

BACKGROUND: Aberrant DNA methylation of tumor suppressor genes is a common event in the development and progression of gastric cancer (GC). Our previous study showed NDRG1, which could suppress cell invasion and migration, was frequently down-regulated by DNA methylation of its promoter in GC. PURPOSE AND METHODS: To analyze the relationship between the expression and DNA methylation of NDRG1 and DNA methyltransferase (DNMT) family. We performed a comprehensive comparison analysis using 407 patients including sequencing analysis data of GC from TCGA. RESULTS: NDRG1 was down-regulated in GC, and was negatively correlative to DNMT1 (r = -0.11, p = 0.03), DNMT3A (r = -0.10, p = 0.01), DNMT3B (r = -0.01, p = 0.88), respectively, whereas the DNA methylation of NDRG1 was positively correlative to DNMT family (DNMT1 r = 0.20, p < 0.01; DNMT3A r = 0.26, p < 0.001; DNMT3B r = 0.03, p = 0.57, respectively). NDRG1 expression was significantly inverse correlated with invasion depth (p = 0.023), but DNMT1 was significantly positive correlated with invasion depth (p = 0.049). DNMT3B was significantly correlated with the degree of tumor cell differentiation (p = 0.030). However, there was no association between the expression of DNMT3A and clinicopathological features. The KM plotter showed that NDRG1 (HR = 0.95, 95% CI [0.8-1.12], p = 0.53) and DNMT1 (HR = 1.04, 95% CI [0.88-1.23], p = 0.67) had no association with prognosis of GC patients, while, DNMT3A (p = 0.0064) and DNMT3B (p = 0.00025) displayed significantly association. But the overall survival of high expression of NDRG1 tended to be prolonged. CONCLUSION: These data suggest that down-regulation of NDRG1expression in GC may be due to its promoter DNA methylation via DNMT family. The demethylating agent maybe a potential target drug for GC patients.

A Prognostic DNA Damage Repair Genes Signature and Its Impact on Immune Cell Infiltration in Glioma.

OBJECTIVE: Glioma is the most frequent type of malignant cerebral tumors. DNA damage repair genes (DDRGs) play a crucial role in the development of cancer. In this study, we constructed a DDRGs signature and investigated the potential mechanisms involved in this disease. METHODS: RNA sequence data, microarray data, and corresponding clinical information of gliomas were downloaded from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO). Subsequently, we identified candidate genes by differential analysis and Cox regression analysis. The least absolute shrinkage and selection operator Cox regression model was utilized to construct a DDRGs signature using TCGA training dataset. According to this signature, patients with glioma were divided into low- and high-risk groups. The predictive ability of the signature was validated by prognostic analysis, receiver operating characteristic curves, principal component analysis, and stratification analysis in TCGA testing and CGGA verification datasets. CIBERSORT and single-sample gene set enrichment analysis (ssGSEA) were used to evaluate the immune microenvironment of glioma. Moreover, we conducted GSEA to determine the functions and pathways in the low- and high-risk groups. Finally, a nomogram was constructed by combining the signature and other clinical features. RESULTS: A total of 1,431 samples of glioma (592 from TCGA, 686 from the CGGA, and 153 from the GEO) and 23 samples of normal brain tissue from the GEO were analyzed in this study. There were 51 prognostic differentially expressed DDRGs. Additionally, five DDRGs (CDK4、HMGB2、WEE1、SMC3 and GADD45G) were selected to construct a DDRGs signature for glioma, stratifying patients into low- and high-risk groups. The survival analysis showed that the DDRGs signature could differentiate the outcome of the low- and high-risk groups, showing that high-risk gliomas were associated with shorter overall survival. The immune microenvironment analysis revealed that more immunosuppressive cells, such as tumor associated macrophages and regulatory T cells, were recruited in the high-risk group. GSEA also showed that high-risk glioma was correlated with the immune and extracellular matrix pathways. CONCLUSION: The five DDRGs signature and its impact on the infiltration of immunosuppressive cells could precisely predict the prognosis and provide guidance on the treatment of glioma.

Minimal Tissue Reaction after Chronic Subdural Electrode Implantation for Fully Implantable Brain-Machine Interfaces.

There is a growing interest in the use of electrocorticographic (ECoG) signals in brain-machine interfaces (BMIs). However, there is still a lack of studies involving the long-term evaluation of the tissue response related to electrode implantation. Here, we investigated biocompatibility, including chronic tissue response to subdural electrodes and a fully implantable wireless BMI device. We implanted a half-sized fully implantable device with subdural electrodes in six beagles for 6 months. Histological analysis of the surrounding tissues, including the dural membrane and cortices, was performed to evaluate the effects of chronic implantation. Our results showed no adverse events, including infectious signs, throughout the 6-month implantation period. Thick connective tissue proliferation was found in the surrounding tissues in the epidural space and subcutaneous space. Quantitative measures of subdural reactive tissues showed minimal encapsulation between the electrodes and the underlying cortex. Immunohistochemical evaluation showed no significant difference in the cell densities of neurons, astrocytes, and microglia between the implanted sites and contralateral sites. In conclusion, we established a beagle model to evaluate cortical implantable devices. We confirmed that a fully implantable wireless device and subdural electrodes could be stably maintained with sufficient biocompatibility in vivo.