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Kai Xiao,1 Shushan Zhao,2 Jian Yuan,1 Yimin Pan,1 Ya Song,2 Lanhua Tang3,4 1Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Department of Oncology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Lanhua TangDepartment of Oncology, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaEmail orchidtang@126.comObjectives: To identify the molecular subtypes of glioblastoma multiforme (GBM) related to M2 macrophage-based prognostic genes, then to preliminarily explore their biological functions and construct immunotherapy response gene models.Material and Methods: We used R language to analyze GBM microarray data, and other tools, including xCell and CIBERSORTx, to identify subtypes of GBM that related to M2 macrophages. The process started with the exploration of biological functions of the two subtypes by pathway analyses and GSEA, and continued with a combined procedure of constructing an M2 macrophage-related prognostic gene model and exploring the immune treatment response for GBM.Results: A high abundance of M2 macrophages in GBM was associated with poor prognosis. According to M2 macrophage-related prognostic genes, GBM was divided into two subtypes (cluster A and cluster B). The differential gene enrichment analysis of the two clusters showed that cluster A was less enriched in M2 macrophages and had immunopotential. The M2score, which was constructed based on M2 macrophage-related prognostic genes, was not only related to the survival and prognosis of patients with GBM, but also predictive of the effectiveness of immunotherapy in these patients. This result has been effectively verified in an external data set.Conclusion: GBM was successfully divided into two subtypes according to M2-macrophage-related prognostic genes. In GBM, a high M2score may indicate better clinical outcome and enhancement of the immunotherapy response.Keywords: glioblastoma, M2 macrophage, prognosis, immunotherapy, molecular subtypes

Imbalance in copper homeostasis can be lethal to the body. A recent study found that excess copper induces cell death in a way that has never been characterized before, which is dependent on mitochondrial stress and referred to as “cuproptosis.” The role of cuproptosis in tumors has not yet been elucidated. In this study, we revealed the complex and important roles of cuproptosis regulators and cuproptosis activity in tumors via a comprehensive analysis of multi-omics data from more than 10 000 samples of 33 tumor types. We found that the cyclin-dependent kinase inhibitor 2A is the most frequently altered cuproptosis regulator, and the cuproptosis regulator expression is dysregulated in various tumors. Additionally, we developed a cuproptosis activity score to reflect the overall cuproptosis level. Based on the expression levels of cuproptosis regulators, tumors can be divided into two clusters with different cuproptosis activities and survival outcomes. Importantly, cuproptosis activity was found to be associated with the prognosis of multiple tumors and multiple tumor-related pathways, including fatty acid metabolism and remodeling of the tumor microenvironment. Furthermore, cuproptosis extensively increased the sensitivity to multiple drugs and exhibited potential to predict the outcome of immunotherapy. We also comprehensively identified cuproptosis-related microRNAs, long non-coding RNAs, and transcription factors. In summary, this study reveals important molecular and clinical characteristics of cuproptosis regulators and cuproptosis activity in tumors, and suggests the use of cuproptosis as a promising tumor therapeutic approach. This study provides an important reference point for future cuproptosis-related research.

A Gram-positive, non-motile, non-spore-forming and short rod-shaped actinomycete strain, designated GA224T, was isolated from an electronic waste associated bioaerosols. The isolate is facultatively anaerobic, which is able to grow at 25–40 ℃ (optimum 37 ℃) and pH 6.5–8.5 (optimum 8.0). The diamino acid in the cell wall of strain GA224T is 2,4-diaminobutyric acid (DAB), while major menaquinone is MK-12. The polar lipid profile is composed of diphosphatidylglycerol, phosphatidylglycerol, unidentified phospholipids, unidentified glycolipids and unidentified lipid. The major cellular fatty acid is anteiso-C15:0 and iso-C16:0. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain GA224T fell within the genus Yonghaparkia, the highest 16S rRNA gene sequence similarity values (98.60%) being obtained with respect to Yonghaparkia alkaliphile KSL-113T. The draft genome of strain GA224T comprised 2,495,189 bp with a G+C content of 72.17 mol%. The average nucleotide identity and digital DNA-DNA hybridization values between strain GA224T and phylogenetically related Yonghaparkia species were lower than 95% and 70%, respectively. Based on the phenotypic, chemotaxonomic and genomic data, strain GA224T represents a novel species, for which the name Yonghaparkia aerolata sp. nov. is proposed, with GA224T as the type strain (= GDMCC 1.2165T = JCM 34462T).

Background Despite the development of new treatment protocols for glioblastoma (GBM), temozolomide (TMZ) resistance remains a primary hindrance. Previous studies, including our study, have shown that aberrant N6‐methyladenosine (m6A) modification is implicated in GBM pathobiology. However, the roles and precise mechanisms of m6A modification in the regulation of TMZ resistance in GBM remain unclear. Methods m6A individual‐nucleotide‐resolution cross‐linking and immunoprecipitation sequencing (miCLIP‐seq) was performed to identify m6A modification of transcripts in TMZ‐resistant and ‐sensitive tumors. To explore the role of METTL3 in TMZ resistance, TMZ‐resistant GBM cells were transfected with METTL3 shRNA or overexpression lentivirus and then assessed by cell viability, tumor sphere formation, and apoptosis assays. An intracranial GBM xenograft model was developed to verify the effect of METTL3 depletion during TMZ treatment in vivo. ATAC‐seq, ChIP‐qPCR, and dual‐luciferase reporter assays were carried out to verify the role of SOX4/EZH2 in the modulation of METTL3 expression upon TMZ treatment. Results We demonstrated that TMZ treatment upregulated the expression of the m6A methyltransferase METTL3, thereby increasing m6A modification of histone modification‐related gene transcripts. METTL3 is required to maintain the features of GBM stem cells. When combined with TMZ, METTL3 silencing suppressed orthotopic TMZ‐resistant xenograft growth in a cooperative manner. Mechanistically, TMZ induced a SOX4‐mediated increase in chromatin accessibility at the METTL3 locus by promoting H3K27ac levels and recruiting RNA polymerase II. Moreover, METTL3 depletion affected the deposition of m6A on histone modification‐related gene transcripts, such as EZH2, leading to nonsense‐mediated mRNA decay. We revealed an important role of EZH2 in the regulation of METTL3 expression, which was via an H3K27me3 modification‐independent manner. Conclusions Our findings uncover the fundamental mechanisms underlying the interplay of m6A RNA modification and histone modification in TMZ resistance and emphasize the therapeutic potential of targeting the SOX4/EZH2/METTL3 axis in the treatment of TMZ‐resistant GBM., 1. TMZ treatment causes an upregulation of METTL3 expression, thereby increasing m6A modification of histone modifiers. 2. TMZ induces SOX4‐mediated increase of chromatin accessibility at METTL3 locus. 3. METTL3 depletion affects the glioblastoma stem cell features via promoting nonsense‐mediated mRNA decay (NMD) of histone modifiers, such as EZH2. 4. EZH2‐SOX4 complex regulates METTL3 expression in an H3K27me3 independent manner.

Purpose: Gliomas are the most common primary malignant neoplasms of the central nervous system. Secreted phospholipases A2 (sPLA2s) are known to play an important role in various physiological processes, including bioactive lipid production, defense mechanisms, and cell signaling. However, their roles and clinical importance in gliomas remain unclear. Patients and methods: In this study, we analyzed the association between the expression of various sPLA2-encoding genes and the clinicopathology of gliomas, using the data of 1047 patients obtained from a public database. Immunohistochemical analysis of 82 glioma tissues was also carried out to assess the relationship between phospholipase A2 group V (PLA2G5) protein expression and the World Health Organization (WHO) glioma grades. Results: We found that high PLA2G5 gene expression was associated with unfavorable prognosis in both low-grade and high-grade gliomas. The immunohistochemistry of the 82 glioma tissues further confirmed that PLA2G5 protein expression was dependent on the WHO glioma grade. In addition, we found a correlation between PLA2G5 gene expression and both epithelial–mesenchymal transition and the isocitrate dehydrogenase 1 mutation status in these tumors. Conclusion: Our results indicate that PLA2G5 could be a potential biomarker for predicting poor prognosis in patients with gliomas.

Medulloblastoma (MB) is a highly heterogeneous and one of the most malignant pediatric brain tumors, comprising four subgroups: Sonic Hedgehog, Wingless, Group 3, and Group 4. Group 3 MB has the worst prognosis of all MBs. However, the molecular and cellular mechanisms driving the maintenance of malignancy are poorly understood. Here, we employed high-throughput single-cell and bulk RNA sequencing to identify novel molecular features of Group 3 MB, and found that a specific cell cluster displayed a highly malignant phenotype. Then, we identified the glutamate receptor metabotropic 8 (GRM8), and AP-1 complex subunit sigma-2 (AP1S2) genes as two critical markers of Group 3 MB, corresponding to its poor prognosis. Information on 33 clinical cases was further utilized for validation. Meanwhile, a global map of the molecular cascade downstream of the MYC oncogene in Group 3 MB was also delineated using single-cell RNA sequencing. Our data yields new insights into Group 3 MB molecular characteristics and provides novel therapeutic targets for this relentless disease.

Meningiomas are the most commonly diagnosed benign intracranial adult tumors. Subsets of meningiomas that present with extensive invasion into surrounding brain areas have high recurrence rates, resulting in difficulties for complete resection, substantially increased mortality of patients, and are therapeutically challenging for neurosurgeons. Exciting new data have provided insights into the understanding of the molecular machinery of invasion. Moreover, clinical trials for several novel approaches have been launched. Here, we will highlight the mechanisms which govern brain invasion and new promising therapeutic approaches for brain-invasive meningiomas, including pharmacological approaches targeting three major aspects of tumor cell invasion: extracellular matrix degradation, cell adhesion, and growth factors, as well as other innovative treatments such as immunotherapy, hormone therapy, Tumor Treating Fields, and biodegradable copolymers (wafers), impregnated chemotherapy. Those ongoing studies can offer more diversified possibilities of potential treatments for brain-invasive meningiomas, and help to increase the survival benefits for patients.

Glioblastoma (GBM) is a group of intracranial neoplasms with intra-tumoral heterogeneity. RNA N6-methyladenosine (m6A) methylation modification reportedly plays roles in immune response. The relationship between the m6A modification pattern and immune cell infiltration in GBM remains unknown. Utilizing expression data of GBM patients, we thoroughly explored the potential m6A modification pattern and m6A-related signatures based on 21 regulators. Thereafter, the m6A methylation modification-based prognostic assessment pipeline (MPAP) was constructed to quantitatively assess GBM patients’ clinical prognosis combining the Robustness and LASSO regression. Single-sample gene-set enrichment analysis (ssGSEA) was used to estimate the specific immune cell infiltration level. We identified two diverse clusters with diverse m6A modification characteristics. Based on differentially expressed genes (DEGs) within two clusters, m6A-related signatures were identified to establish the MPAP, which can be used to quantitatively forecast the prognosis of GBM patients. In addition, the relationship between 21 m6A regulators and specific immune cell infiltration was demonstrated in our study and the m6A regulator ELAVL1 was determined to play an important role in the anticancer response to PD-L1 therapy. Our findings indicated the relationship between m6A methylation modification patterns and tumor microenvironment immune cell infiltration, through which we could comprehensively understand resistance to multiple therapies in GBM, as well as accomplish precise risk stratification according to m6A-related signatures.

BackgroundManagement of tentorial notch meningiomas (TNM) remains a challenge for neurosurgeons. We demonstrate the clinical characteristics and surgical experiences of TNM based on our cases according to a proposed further classification.MethodsWe retrospectively analyzed clinical and follow-up data in a consecutive series of 53 TNM patients who underwent microsurgical operation from 2011 to 2019 in our institution. The operations were performed using various approaches. Clinical history, preoperative and postoperative neurofunction, imaging results, and surgical outcomes were collected for further classification of TNM.ResultsAll TNM cases were divided into anterior (T1), middle (T2), and posterior notch (T3). According to the direction of tumor extension and correlation with the neurovascular structures, detailed subtypes of anterior TNMs were identified as the central (T1a), posterior (T1b), and medial type (T1c). The middle TNMs were divided into the infratentorial (T2a), supratentorial (T2b), and supra-infratentorial type (T2c). The posterior TNMs were divided into superior (T3a), inferior (T3b), lateral (T3c), and straight sinus type (T3d) in reference to Bassiouni’s classification. Total removal of the tumor was achieved in 46 cases, with five cases of subtotal and two cases of partial removal without any recorded deaths in our series. In total, five subtotal resected cases underwent gamma-knife treatment and achieved stable disease. Postoperative aggravation or new onset cranial nerve dysfunction occurred in some individual cases, with incidences ranging from 3.77 to 15.10% and improved preoperative neurological deficits ranging from 0 to 100%.ConclusionFurther, TNM classification based on the intracranial location, extension direction, relationship with brainstem, and neurovascular structures guides preoperative evaluation, rational surgical approach selection, and surgical strategy formulation. Taking microsurgery as the main body, a satisfactory outcome of TNM treatment can be achieved for complicated tumors by combining stereotactic radiotherapy. This study demonstrates the surgical outcomes and complications in detail. Further classification might be helpful for treatment decisions in the future.

Glioma is the most common primary malignant tumour in the brain; temozolomide (TMZ) is the most prevalent chemotherapeutic drug currently used to combat this cancer. We reported previously that the long intergenic non‐protein coding RNA 470 (LINC00470) is a novel prognostic biomarker for glioma and promotes the tumour growth in an intracranial transplantation mouse model. However, the effects of LINC00470 on glioma cell proliferation, invasion and TMZ chemosensitivity, as well as its molecular mechanism, remain unclear. In this study, we found elevated expression levels of LINC00470 and MYC in glioma tissues and cells and decreased expression of microRNA‐134 (miR‐134). Functional studies have shown that LINC00470 promotes proliferation and invasion, and attenuates chemosensitivity of glioma cells, while miR‐134 exerts the opposite effect. In the rescue experiments, the tumorigenic effect of LINC00470 was offset by miR‐134. In the mechanism study, we found that LINC00470 was a competitive endogenous RNA (ceRNA) of miR‐134 and that miR‐134 can directly target MYC and negatively regulate its expression. Furthermore, MYC was positively correlated with ATP‐binding cassette subfamily C member 1 (ABCC1) expression in glioma cells and MYC up‐regulated ABCC1 expression. Further studies found that LINC00470 regulated MYC by sponging miR‐134 to regulate the expression of ABCC1. We concluded that LINC00470 promoted the expression of MYC and ABCC1 by suppressing miR‐134, thus promoting glioma cell proliferation and invasion, and attenuating TMZ chemosensitivity. Moreover, the LINC00470/miR‐134/MYC/ABCC1 axis constitutes a potential therapeutic target.

A Gram-positive, endospore-forming, rod-shaped bacterium with a single flagellum, and a motile strain, designated CX253, was isolated from bioaerosols. The isolate is facultatively anaerobic, is able to grow at 25–45 ℃ (optimum 37 ℃) and pH 6.5–10.0 (optimum 7.5), and can tolerate up to 5.0% NaCl (w/v) under aerobic conditions. The diagnostic diamino acid in the cell wall of strain CX253T is meso-diaminopimelic acid, while major isoprenoid quinone is menaquinone 6 (MK-6) along with a smaller amount of MK-7 (20%). The polar lipid profile is composed of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phospholipids and glycolipids. The major cellular fatty acid is iso-C15:0 and anteiso-C15:0. Phylogenetic analysis based on 16S rRNA gene and genome sequence grouped strain CX253T into the genus Bacillus. The strain was most closely related to Bacillus thermotolerans CCTCC AB 2012108 T by comparison of 16S rRNA gene sequence (97.2% similarity) and to Bacillus wudalianchiensis CCTCC AB 2015266 T by comparison of gyrB gene sequence (80.1% similarity). The draft genome of strain CX253T comprised 3,929,195 bp with a G + C content of 43.3 mol%. The average nucleotide identity and digital DNA–DNA hybridization values between strain CX253T and phylogenetically related Bacillus species were lower than 95% and 70%, respectively. Thus, the polyphasic evidence generated through phenotypic, chemotaxonomic and genomic methods confirmed that strain CX253T (= GDMCC 1.1608 T = KACC 21318 T) was a novel species of the genus Bacillus, for which the name Bacillus aerolatus sp. nov. is proposed.

The gut microbiome is crucial for the health of animals including human and is sensitive to environmental factors. Dechlorane Plus (DP) is a widely used polychlorinated flame retardant in commercial products for which general human population has been exposed to, but its effects on the gut microbiota are largely unknown. In this work, experiments were conducted to examine the effect of DP exposure on the intestinal microbiota by using Sprague-Dawley rats and a simulator of the human intestinal microbial ecosystem (SHIME). 16S rRNA gene high-throughput sequencing revealed that DP exposure in vivo reduced the relative abundance of the genera Prevotella, Quinella, and Ruminococcus, exposure in vitro decreased the relative abundance of Coriobacteriaceae, Parabacteroides, Bilophila, Sporolactobacillus, and Klebsiella. The phyla Synergistetes and Lentisphaerae were only detected in the descending colon. DP exposure also increased the concentrations of short-chain fatty acids (SCFAs) produced by the gut microbe both in vivo and in vitro, but SCFA metabolism was gradually inhibited as the increase of DP concentrations. These results indicated that DP exposure changed both the structure and metabolic function of the gut microbiota, suggesting more attention should be concentrated on the health effects of DP exposure, especially at higher doses.

A new ESIPT-based fluorescent probe, PHC2, for the detection of hypochlorous acid has been rationally designed and developed. Endowed by the specific reaction between hypochlorous acid and phenyl azo group, PHC2 features high degree of selectivity and sensitivity for HClO with a low detection limit (13.2 nM) under physiological conditions in neutral aqueous solution.

Malignancies arising in midline brain structures, including lymphomas, teratomas, germinomas, diffuse midline gliomas, and medulloblastomas typically respond to systemic therapies, and excessive surgical excision can result in serious complications, so that total surgical removal is not routinely performed. Identifying tumor specific biomarkers that can facilitate diagnosis at early stage and allow for dynamic surveillance of the tumor is of great clinical importance. However, existing standard methods for biopsy of these brain neoplasms are high risk, time consuming, and costly. Thus, less invasive and more rapid diagnosis tests are urgently needed to detect midline brain malignancies. Currently, tools for cerebrospinal biopsy of midline brain malignancies mainly include circulating tumor DNA, circulating tumor cells, and extracellular vesicles. Circulating tumor DNA achieved minimally invasive biopsy in several brain malignancies and has advantages in detecting tumor-specific mutations. In the field of tumor heterogeneity, circulating tumor cells better reflect the genome of tumors than surgical biopsy specimens. They can be applied for the diagnosis of leptomeningeal metastasis. Extracellular vesicles contain lots of genetic information about cancer cells, so they have potential in finding therapeutic targets and studying tumor invasion and metastasis.

Based on the classification and analysis of casing damage in the past years in S oilfield, the types of casing damage, the plane distribution, and the longitudinal distribution are studied. The main causes of casing damage in single well are analyzed. Propose the casing damage well management and measures to choose recommendations. The casing deformation wells in S oilfield are mainly deformed and mainly distributed on both sides of the fault in the plane. In the longitudinal direction, the leakage points are concentrated in the non-reservoir section, and the deformation faults are concentrated in the reservoir section. Well damage is mainly caused by abnormally high-pressure layer. During the development, the water injection plan should be adjusted in time and the oil well measures should be implemented in an effort to effectively reduce the annual number of casing damage. Discussed the influencing factors, discussed the forming mechanism of casing damage and proposed some suggestions to avoid or reduce casing damage in the same oilfield.

Stochastic processes are approximated by wavelet operators. For the stochastic process and the scale function satisfying some conditions, a new method is given to estimate the degree of approximation.

A nuisance parameter is introduced to the semimartingale regression model proposed by Aalen (1980), and we construct two estimators for this nuisance parameter based on the results of parametric estimation which were given by Mckeague (1986) using the method of sieves. The consistency of the estimators is also provided.